EP3062778A1 - Formes pharmaceutiques en granulés anti-abus à libération immédiate - Google Patents

Formes pharmaceutiques en granulés anti-abus à libération immédiate

Info

Publication number
EP3062778A1
EP3062778A1 EP14858628.2A EP14858628A EP3062778A1 EP 3062778 A1 EP3062778 A1 EP 3062778A1 EP 14858628 A EP14858628 A EP 14858628A EP 3062778 A1 EP3062778 A1 EP 3062778A1
Authority
EP
European Patent Office
Prior art keywords
dosage form
core
cellulose
immediate release
granules
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP14858628.2A
Other languages
German (de)
English (en)
Other versions
EP3062778A4 (fr
Inventor
Dinesh K. Haswani
Derek V. Moe
Victoria A. O'neill
Manuel A. Vega Zepeda
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Clexio Bioscience Ltd
Original Assignee
Cima Labs Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US2014/047014 external-priority patent/WO2015065547A1/fr
Application filed by Cima Labs Inc filed Critical Cima Labs Inc
Publication of EP3062778A1 publication Critical patent/EP3062778A1/fr
Publication of EP3062778A4 publication Critical patent/EP3062778A4/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61K9/48—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
    • 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
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

  • the present invention relates to the field of oral dosage forms that contain abuse- deterrent features, in particular including immediate release dosage forms that contain a drug that is commonly susceptible to abuse.
  • Pharmaceutical products including both prescription and over-the-counter pharmaceutical products, while useful for improving health of a person in need, are also susceptible to intentional and unintentional abuse and overdosing.
  • Examples of commonly abused active pharmaceutical ingredients include psychoactive drugs, anxiolytics, sedative hypnotics, stimulants, depressants, and analgesics such as narcotic analgesics, among others.
  • a complete list of specific drug compounds that are commonly abused would be lengthy; a short listing of some classes of drugs commonly abused includes opioids and morphine derivatives, barbiturates, amphetamines, ketamine, and other drugs that can cause psychological or physical dependence.
  • Some common techniques for intentionally abusing a drug begin with an abuser obtaining a solid dosage form such as an orally administered tablet or capsule, and crushing the solid dosage form into a powder.
  • the powder may be administered by an abuser by nasal insufflation (i.e., "snorting") to introduce the drug to the abuser's bloodstream intranasally.
  • the crushed dosage form may be combined with a solvent that is capable of dissolving the drug (active pharmaceutical ingredient, or "API”), and the solvent with the dissolved drug may be injected directly into an abuser's bloodstream.
  • an abuser might simply ingest multiple units (e.g., tablets) of the dosage form together, e.g., simultaneously. Each one of the multiple dosage form units -immediately releases an amount of drug to produce a short-term concentration spike of the drug in the user's bloodstream and a desired "high" in the user.
  • multiple units e.g., tablets
  • Each one of the multiple dosage form units -immediately releases an amount of drug to produce a short-term concentration spike of the drug in the user's bloodstream and a desired "high" in the user.
  • the pharmaceutical industry has identified various mechanisms of adapting drug compositions and oral dosage forms that can be useful to discourage abuse of oral dosage forms.
  • Pharmaceutical companies have studied dosage forms that contain a nasal irritant or an effervescent agent, which can cause irritation or pain in a nasal passage if the dosage form is crushed and then snorted, thus discouraging abuse by nasal insufflation.
  • Another possible abuse deterrent may be addition of an emetic agent which can deter abuse by causing emesis on ingestion of multiple doses.
  • Another abuse deterrent involves adding an antagonist of an API to a dosage form that will substantially block the effect of the drug.
  • the dosage form can be designed to release the API as desired in an immediate release dosage form, and can also include one or a combination of feature that will prevent or deter abuse of the API.
  • the abuse deterrent features described herein can be included singly or in any combination in an immediate release dosage form.
  • a dosage form as described can include a gelling polymer to prevent or compromise abuse practices wherein the dosage form is crushed and then combined with a small amount of a solvent to produce a liquid composition that contains a concentrated amount of API and that can be delivered to an abuser using a syringe.
  • the gelling polymer can be any polymer useful to achieve this functionality, and can be placed in the dosage form at any location to allow the gelling polymer to perform as described and still allow immediate release of the API.
  • a gelling polymer can be included in a core of a coated of core-shell particle or in a matrix of a dosage form that suspends the core-shell particles.
  • the core may contain any amount of gelling polymer, such as from 0 to 100 percent gelling polymer based on a total weight of the core.
  • the core in a core-shell particle may comprise a filler, e.g., up to 100 percent filler, such as a sugar sphere or microcrystalline cellulose sphere (up to 100 percent microcrystalline cellulose spheres such as those available under the trade name Celphere®).
  • a filler e.g., up to 100 percent filler, such as a sugar sphere or microcrystalline cellulose sphere (up to 100 percent microcrystalline cellulose spheres such as those available under the trade name Celphere®).
  • Another type of abuse deterrent feature can be a wax that alone or with other ingredients, e.g., the gelling polymer, is effective in compromising abuse practices wherein a dosage form is crushed and combined with a solvent to produce a liquid composition that can be abused by nasal insufflation or delivered to an abuser using a syringe.
  • the wax can additionally inhibit or prevent an abuser from grinding the dosage form into a powder because upon grinding the wax will smear as opposed to fracturing or powdering.
  • wax can be included in a dosage form at any location that allows the wax to function as an abuse deterrent feature while not interfering with an immediate release profile of the API.
  • a wax can be included in a core of a coated particle.
  • a core may contain any amount of wax, such as from 0 to 100 percent wax based on a total weight of the core, such as up to 50, 75, or 80 weight percent wax based on a total weight of the core.
  • Still another type of abuse deterrent feature can be a filler or binder that alone or in combination with other ingredients can compromise abuse practices wherein a dosage form is being crushed and combined with a small amount of a solvent to produce a liquid composition that can be delivered to an abuser using a syringe.
  • the filler or binder can inhibit or prevent an abuser from grinding the dosage form into a powder because upon grinding, the polymeric filler or binder will smear as opposed to fracturing or powdering.
  • the filler or binder can be included in a dosage form in any manner and location that allows the filler or binder to function as an abuse deterrent feature while not interfering with an immediate release profile of the API.
  • a filler or binder can be included in a core of a coated particle.
  • a core may contain any amount of polymeric filler or binder such as from 0 to 100 percent filler or binder on a total weight of the core, or up to 50, 75, or 80 weight percent filler or binder based on a total weight of the core.
  • Yet another type of abuse deterrent feature can be a film layer that surrounds or covers API in a dosage form and that is optionally resistant to being dissolved by one or more of the solvents commonly used by abusers to dissolve an API for injection, including water and C 1 -C 4 alcohols such as ethanol, methanol, and mixtures thereof.
  • the film layer may be prepared from any film material that is disposed as a continuous layer on a coated particle at a location to enclose and surround the API.
  • Examples of film layers can optionally and preferably provide properties of a solvent-resistant film, which is a film that is slow or difficult to dissolve in a limited or small volume of one the solvents commonly used by abusers to dissolve API of a dosage form.
  • an abuser may grind the dosage form and combine the ground dosage form with a solvent (as described) in an attempt to produce a solution that contains the concentrated API and the solvent, and that may be efficiently injected or snorted.
  • a solvent as described
  • a solvent-resistant film layer that surrounds API of a dosage form can prevent an abuser from easily accessing and so manipulating the API.
  • an immediate release dosage form can include these features in a coated particle, such as a core-shell particle.
  • An exemplary core-shell particle can include a core and one or more layers surrounding the core.
  • the API may be included in the core, or in one or more layers surrounding the core, or in both the core and one or more layers surrounding the core.
  • the dosage form may additionally contain core-shell particles that do not include the API in either the core, or in any layer surrounding the core.
  • the core can include any one or more of: a gelling polymer, wax, binder, or filler, alone or in combination. Alternately, the core may comprise a microcrystalline cellulose or sugar sphere.
  • a film layer may surround and enclose the core, or an API-containing layer that is disposed around the core.
  • the film layer may preferably be a solvent-resistant film in the form of a continuous coating that covers the core, which contains API, or that covers an API-containing layer or coating disposed around the core, or that covers a core that has no API-containing layer or coating disposed around the core and contains no API.
  • a coated particle as described herein can be useful in a dosage form that includes one or more optional abuse deterrent features, and a matrix such as a compressed matrix that is formed to allow for immediate release of the API present in the coated particles.
  • An exemplary matrix composition may comprise additional gelling polymer, disintegrant, or both additional gelling polymer and disintegrant.
  • additional gelling polymer as used above means an amount of gelling polymer that is in addition to an amount of gelling polymer present in the coated particles.
  • the additional gelling polymer may be the same or different in nature, chemistry, molecular weight, etc., as compared to the gelling polymer that is included in the coated particles.
  • a disintegrant as a component of the matrix may be useful to facilitate release of the API of the dosage form, e.g., API present in the coated particles.
  • the active pharmaceutical ingredient included in the dosage form, especially in the coated particle surrounded by a film layer can be any active pharmaceutical ingredient desired to be administered orally, and may in particular be a type of active pharmaceutical ingredient that is commonly susceptible to abuse.
  • active pharmaceutical ingredients that are considered to be commonly susceptible to abuse include psychoactive drugs, tranquilizers, sedative hypnotics, anxiolytics, stimulants, depressants, and narcotic analgesics, among others.
  • Certain more specific classes of drugs commonly abused includes opioids, barbiturates, benzodiazepines, amphetamines, as well as many other drugs that are known to cause psychological or physical dependence.
  • Dosage forms of the present description can be useful as immediate release dosage forms, and may also include abuse deterrent features as described.
  • the abuse deterrent features can discourage or prevent abuse by nasal insufflation, by injection, and can also be effective to prevent or significantly limit the success of abuse by the common methods (especially with immediate release oral dosage forms) of orally taking multiple dosage form units together.
  • the final mode of abuse (sometimes referred to herein as "multi- tablet dosing") is often particularly difficult to deter, especially in immediate release oral dosage forms, making these described dosage forms particularly useful as abuse-deterrant oral immediate release dosage forms.
  • Embodiments of the described dosage forms can be effective in the absence of other types of abuse deterrent features such as nasal irritants, emetic agents, bittering agents, and effervescent agents, to inhibit nasal insufflation or other forms of abuse, or the inclusion of drug antagonists of the subject drug.
  • abuse deterrent features such as nasal irritants, emetic agents, bittering agents, and effervescent agents
  • the invention relates to an immediate release dosage form that includes core-shell particles.
  • the core-shell particles include: an inner core containing a gelling polymer; at least one layer surrounding the core, the at least one layer including a film layer surrounding the core; and an active pharmaceutical ingredient.
  • the active pharmaceutical ingredient is also surrounded by the film layer that surrounds the core.
  • the invention in another aspect, relates to an immediate release dosage form that includes core-shell particles.
  • the core-shell particles include a core and an active pharmaceutical layer surrounding the core.
  • the active pharmaceutical layer contains an active pharmaceutical ingredient.
  • the core contains less than 5 weight percent of a total amount of the active pharmaceutical ingredient in the core-shell particles.
  • the invention in yet another aspect relates to an immediate release dosage form that contains core-shell particles.
  • the core-shell particles include: a core and an active pharmaceutical ingredient.
  • the dosage form further includes a matrix.
  • the matrix includes disintegrant and an additional amount of gelling polymer.
  • the invention in still another aspect, relates to an immediate release dosage form that includes two types of core-shell particles.
  • One type of core-shell particles includes a core and an active pharmaceutical layer surrounding the core as discussed above.
  • the core of these particles optionally contains less than 5 weight percent of the total amount of the API in that core-shell particle, and in some instances contains less than 1 weight percent of the total amount of the API in that core-shell particle, or even contains no significant amount of the API.
  • the other type of core shell particles comprise the core, but do not contain an active pharmaceutical layer surrounding the core.
  • FIGS 1A, IB, and 1C illustrate embodiments of core-shell particles as described, in cross section.
  • Figures 2A and 2B illustrate embodiments of core-shell particles as described, in cross section.
  • Figure 3 is a perspective view of an embodiment of a dosage form as described.
  • Figure 4 shows a plot of Multiple Tablet oral Abuse Resistance (Supratherapeutic Dosing) - Dissolution of Hydrocodone Bitartrate in 0.1N HC1 media as a function of time.
  • Figure 5 shows a plot of multiple tablet oral abuse resistance (supratherapeutic dosing) - dissolution of acetaminophen in 0.1N HC1 media as a function of time.
  • Figure 6 shows a plot of multiple tablet oral abuse resistance (supratherapeutic dosing) - dissolution of hydrocodone bitartrate in 0.1N HC1 media as a function of time.
  • Figure 7 shows a plot of multiple tablet oral abuse resistance (supratherapeutic dosing) - dissolution of acetaminophen in 0. IN HC1 media as a function of time
  • Figure 8 shows a plot of multiple tablet oral abuse resistance (supratherapeutic dosing) - dissolution of hydrocodone bitartrate in 0. IN HC1 media as a function of time.
  • Figure 9 shows a plot of multiple tablet oral abuse resistance (supratherapeutic dosing) - dissolution of acetaminophen in 0.1N HC1 media as a function of time.
  • Figure 10 shows a plot of multiple tablet oral abuse resistance (supratherapeutic dosing) - dissolution of oxycodone hydrochloride from oxycodone hydrochloride /aceta- minophen tablets (5/325 mg/tablet and 7.5/325 mg/ tablet of oxycodone hydrochloride/ acetaminophen) in 0. IN HC1 media as a function of time.
  • Figure 11 shows a plot of multiple tablet oral abuse resistance (supratherapeutic dosing) - dissolution of acetaminophen from oxycodone hydrochloride/acetaminophen tablets (5/325 mg/tablet and 7.5/325 mg/ tablet of oxycodone hydrochloride/ acetamino- phen) in 0.1N HC1 media as a function of time.
  • Figure 12 shows a plot of multiple tablet oral abuse resistance (supratherapeutic dosing) - dissolution of hydrocodone bitartrate from hydrocodone bitartrate /acetaminophen tablets (5/325 mg/tablet and 7.5/325 mg/ tablet of hydrocodone bitartrate/acetamino- phen) in 0.1N HC1 media as a function of time.
  • Figure 13 shows a plot of multiple tablet oral abuse resistance (supratherapeutic dosing) - dissolution of acetaminophen from hydrocodone bitartrate /acetaminophen tablets (5/325 mg/tablet and 7.5/325 mg/ tablet of hydrocodone bitartrate/acetaminophen) in 0.1N HC1 media as a function of time.
  • Figure 14 shows a plot of multiple tablet oral abuse resistance (supratherapeutic dosing) - dissolution of hydrocodone bitartrate from hydrocodone bitartrate /acetaminophen tablets (10/325 mg/ tablet of hydrocodone bitartrate/acetaminophen, tested both as intact tablets and crushed tablets) in 0. IN HC1 media as a function of time.
  • Figure 15 shows a plot of multiple tablet oral abuse resistance (supratherapeutic dosing) - dissolution of acetaminophen from hydrocodone bitartrate /acetaminophen tablets (10/325 mg/ tablet of hydrocodone bitartrate/acetaminophen, tested both as intact tablets and crushed tablets) in 0. IN HC1 media as a function of time.
  • the present description relates to immediate release dosage forms that include one or more abuse deterrent features for reducing the potential for a) parenteral abuse, b) abuse by nasal insufflation ("snorting"), and c) abuse by simultaneous oral ingestion of multiple oral dosage form units (tablets or capsules) of a drug.
  • abuse deterrent features are achieved by preparing the dosage form to include certain structural features and certain ingredients that have now been determined to effectively prevent an abuser from realizing the intended biological effect of the drug abuse by using certain presently-common methods used to abuse the API.
  • a dosage form prepared to contain one or more of the described abuse deterrent features, as a deterrent to abuse of one or more API that is commonly susceptible to abuse, can still be constructed to provide immediate release of the one or more API upon normal therapeutic use by oral ingestion.
  • expressions such as “abuse deterrent” and “preventing” or “deterring” or “inhibiting” practices and processes associated with the abuse and overdose of drugs relate to features of the claimed formulations that provide significant physical and chemical impediments to these practices and processes.
  • the objective in such deterrence includes both making abuse practices significantly more difficult to carry out, and making any product resulting from an attempt to carry out such abuse practices on the claimed formulations significantly less desirable, less profitable, and less abusable to the potential abuser.
  • immediate release refers to a dosage form that upon oral ingestion by a human releases substantially all of a contained active pharmaceutical ingredient into a gastrointestinal tract for biological uptake in a short time.
  • immediate release refers to a dosage form that upon oral ingestion by a human releases substantially all of a contained active pharmaceutical ingredient into a gastrointestinal tract for biological uptake in a short time.
  • in vitro methods of measuring a release profile of a dosage form, for the purpose of determining whether a dosage form exhibits an immediate release or extended release dissolution profile are known in the pharmaceutical arts.
  • examples of immediate release dosage forms as described herein can be measured to be capable of releasing substantially all of a total amount of at least one type of active pharmaceutical ingredient (e.g., an API commonly susceptible to abuse) contained in the dosage form (e.g., at least 75, 80, or 90 weight percent of the total amount of the API in a dosage form) into a solution (e.g., acidic aqueous solution) of a suitable pH within 240 minutes, e.g., in less than 180 minutes, less than 90 minutes, or less than 60, 30, 15, or 5 minutes.
  • active pharmaceutical ingredient e.g., an API commonly susceptible to abuse
  • a solution e.g., acidic aqueous solution
  • a release profile of a dosage form of the present description may be measured by a method that exposes the dosage form to a volume of up to 900 milliliters (e.g., 300 milliliters, or 900 milliliters, based on various test methods) of hydrochloric acid (0.01 to 0.1N) (e.g., aqueous hydrochloric acid) at a pH of from 1 to 2, and at a temperature of 37 degrees Celsius.
  • hydrochloric acid (0.01 to 0.1N
  • aqueous hydrochloric acid e.g., aqueous hydrochloric acid
  • the dosage forms described herein demonstrate not less than 90% of API released in 60 minutes when administered at therapeutic doses, wherein the release profiles may be evaluated by dissolution in 300 mL of 0.1N HC1 media using USP II apparatus at 50 RPM paddle speed and 37°C.
  • a release profile of a dosage form of the present description may alternatively be measured by a method that exposes the dosage form to a volume of up to 900 milliliters (e.g., 300 milliliters, or 900 milliliters, based on various test methods) of hydrochloric acid (0.01 to 0.1N) (e.g., aqueous hydrochloric acid) at a pH of about 4.5 (representative of the pH conditions of a fed stomach), and at a temperature of 37 degrees Celsius.
  • hydrochloric acid e.01 to 0.1N
  • aqueous hydrochloric acid e.g., aqueous hydrochloric acid
  • extended release can be defined as not more than 95% release of the API at 60 minutes, wherein the release profiles may be evaluated, for example, by dissolution in 300 mL of 0. IN HC1 media using USP II apparatus at 50 RPM paddle speed and 37°C.
  • the dosage forms described herein demonstrate:
  • a "supratherapeutic dose” will be understood to correspond to administration of five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, or twelve or more individual dose units, e.g., tablets, simultaneously. It will also be understood that administering multiple individual dose units simultaneously would reasonably include administering those multiple doses sequentially over a short time interval, e.g., over an interval of less than 60 minutes, less than 30 minutes, less than 15 minutes, less than 5 minutes or less than one minute.
  • Dosage forms as described can be formulated to provide an immediate release profile of an API, and can also be prepared to include effective or advantageous abuse deterrent features that are effective to deter abuse of the same API (e.g., one that is commonly susceptible to abuse) that exhibits the immediate release profile.
  • effective or advantageous abuse deterrent features that are effective to deter abuse of the same API (e.g., one that is commonly susceptible to abuse) that exhibits the immediate release profile.
  • the combination of immediate release of an API with broad abuse resistance of the same API for multiple abuse modalities including multi-tablet dosing, as described herein, is not believed to be previously known.
  • dosage forms as described herein can provide an immediate release profile of an API, and can at the same time include abuse deterrent features that provide general abuse deterrence or abuse resistance of the same API.
  • the dosage forms can also be more specifically characterized as resistant to certain common methods of abuse, such as 1) abuse by injection (e.g., by steps that include grinding a dosage form and dissolving API of the dosage form), 2) abuse by nasal insufflation (e.g., also by grinding and optionally dissolving API of a dosage form), and 3) abuse by multi-tablet dosing by oral consumption, meaning simultaneous oral ingestion of multiple or excessive quantities of orally administered dosage forms such as tablets or capsules.
  • the third mode of abuse, multi-tablet dosing is particularly common with immediate release dosage forms and is particularly difficult to defend against by design of a dosage form structure or by formulation. Accordingly, that the presently-described dosage forms can be effective to prevent or deter abuse (or even accidental overdose) by the mode of multi-tablet dosing can be a particularly useful feature of the dosage forms described herein.
  • in vitro testing of exemplary dosage forms as described herein indicates that exemplary dosage forms provide deterrence against abuse by multi-tablet dosing. More specifically, in vitro testing of exemplary dosage forms was performed by conducting dissolution testing of one or more dosage forms (tablets) in 300 milliliters of 0.1N HCL maintained at 37 degrees Celsius using a 50 RPM paddle speed. See, Example 26 (a) and Figures 4 and 5 herein. As shown at Figures 4, 5, 6, 7, 8 and 9, the amount (percentage per tablet) of API (opioid) or APAP (acetaminophen) released in the media is reduced with an increase in the number of tablets.
  • API opioid
  • APAP acetaminophen
  • in vitro testing indicates that exemplary dosage forms provide deterrence against abuse by multi-tablet dosing, even if the dosage form is crushed prior to administration/testing.
  • in vitro testing was performed by conducting dissolution testing of multiple (twelve) crushed tablets according to the same protocol as described above for testing intact tablets (i.e., in 300 or 900 milliliters of 0.1N HC1 maintained at 37 degrees Celsius using a 50 RPM paddle speed). See, Example 93 and Figures 14-15 herein. As shown in Figures 14-15, the percentage of the API (the opioid and APAP) that was released in the media was reduced with an increase in the number of crushed tablets.
  • Example 94 which provided the data shown in Figures 14-15 were prepared as per Example 93.
  • dosage forms as described herein provide a method of preventing a short-term concentration spike of the drug in the bloodstream of a patient who is prescribed the drug, or in the bloodstream of an abuser who consumes the drug for recreational purposes, in the event that a patient or the abuser intentionally or
  • dosage forms as described herein provide a method whereby a drug overdose may be prevented in the event that a patient intentionally or unintentionally consumes a supratherapeutic dose of the drug.
  • serpratherapeutic is meant a dose that exceeds what would normally be prescribed for therapy, for example a dose in excess of four, five, six, seven, eight, nine, ten, eleven or twelve individual dose units ⁇ e.g., tablets, capsules, etc.).
  • a dosage form as described can include one or more gelling polymers.
  • a gelling polymer can act as an abuse deterrent feature by compromising abuse practices wherein an active pharmaceutical ingredient of a dosage form is being dissolved in a small volume of solvent or being accessible or easily isolatable if combined with solvent with the gelling polymer also present.
  • a gelling polymer can also deter or prevent abuse of an API in a dosage form by increasing the viscosity of a combination of the ground dosage form with solvent (especially a "small volume" of solvent) to a viscosity that is sufficiently high to prevent the combination or the API from being taken up by and injected using a syringe.
  • a preferred gelling polymer contained in a ground dosage form when exposed to a limited volume (or "small volume") of solvent such as a Ci_ 4 alcohol (e.g., ethanol or methanol) or water, can form a non-injectable mass ranging from an insoluble mass, to a gel, to a viscous slurry, each of which exhibits a viscosity that substantially prevents either uptake by or injection from a needle of a hypodermic syringe.
  • solvent such as a Ci_ 4 alcohol (e.g., ethanol or methanol) or water
  • Suitable gelling polymers include one or a combination of polymers that, as part of a dosage form, upon contact of the dosage form with a small volume of solvent, will absorb the solvent and swell to form a viscous or semi-viscous substance that significantly reduces or minimizes the amount of free solvent that can contain an amount of a solubilized API and that can be drawn into a syringe.
  • the gelled polymer can also reduce the overall amount of drug extractable with the solvent by entrapping the drug in a gel matrix.
  • the gelling polymer can be present in the dosage form at a location and in an amount that together allow the gelling polymer to produce a viscous gel in the event of an abuser grinding the dosage form and combining the crushed dosage form with a solvent.
  • the gelling polymer, as present in the dosage form will preferably not interfere with desired dissolution of the dosage form, the desired release (immediate release) of API from the dosage form, or the uptake of the API by a patient ingesting the intact immediate release dosage form for an intended therapeutic purpose.
  • An exemplary location for the gelling polymer is in a coated particle that also includes active
  • a pharmaceutical ingredient such as in a core or in a layer coated to surround the core; wherein an amount of active pharmaceutical ingredient is contained in either the core, or a layer coated to surround the core, or is contained in both.
  • Another exemplary location is within a matrix used to form a compressed tablet, a capsule (e.g., a compressed capsule), a caplet, or another type of dosage form that contains a coated particle that contains active pharmaceutical ingredient.
  • Gelling polymer may also be present, in the core, or in a layer surrounding the core, of a coated particle that does not include an active pharmaceutical ingredient.
  • the gelling polymer can be present in a dosage form at any desired amount and at any portion of, or location in a dosage form structure.
  • the amount of gelling polymer can be any useful amount, meaning an amount that can produce an abuse-deterrent viscous mixture or gel if the dosage form is crushed, ground, powdered, etc., and mixed with solvent.
  • a useful amount of total gelling polymer in a dosage form may be in a range from 0.5 to 90 weight percent gelling polymer based on a total weight of the dosage form, e.g., from 0.7 to 20, or 2 to 15 weight percent gelling polymer based on total weight of the dosage form.
  • total gelling polymer can be present in one or more locations of the dosage form, to achieve the specified total amount, such as in a portion at a coated particle (e.g., core), a matrix (e.g., compressed matrix) structure that supports and contains the coated particles, or in both the coated particles and the matrix.
  • a coated particle e.g., core
  • a matrix e.g., compressed matrix
  • a core (uncoated) of a core-shell particle can contain any useful amount of gelling polymer, such as from 0 up to and including 100 percent gelling polymer in a core of a core-shell particle, e.g., from 10 to 95 weight percent gelling polymer based on a total weight of the core, such as from 40 to 85 or 50 to 75 weight percent gelling polymer based on total weight core.
  • an amount of gelling polymer present in a core of a core shell polymer may be, e.g., in a range from 0.5 to 15 weight percent gelling polymer (present in the core) per total weight of the dosage form, such as from 1 to 10 weight percent gelling polymer (present in the core) per total weight dosage form.
  • An amount of gelling polymer present in a matrix of a dosage form may be any desired amount, such as an amount in a range from 0.5 to 15 weight percent gelling polymer (as excipient in a matrix) based on a total weight of the dosage form, such as from 1 to 10 weight percent gelling polymer (present as excipient in a matrix) based on total weight dosage form.
  • a useful gelling polymer can be any polymeric material that exhibits the ability to retain a significant fraction of adsorbed solvent in its molecular structure, e.g., the solvent being a solvent otherwise useful by an abuser to extract API from a dosage form or a crushed or powdered dosage form, the solvent for example being water or a Ci to C 4 alcohol such as ethanol or methanol, etc.
  • examples of gelling polymers include materials that can swell or expand to a very high degree when placed in contact with such a solvent. The swelling or expansion may cause the gelling polymer to experience from a two- to one-thousand-fold volume increase from a dry state.
  • gelling polymers include swellable polymers sometimes referred to as osmopolymers or hydrogels.
  • the gelling polymer may be non-cross-linked, lightly crosslinked, or highly crosslinked.
  • the crosslinking may involve covalent or ionic bonds with the polymer possessing the ability to swell in the presence of a solvent, and when cross-linked will not dissolve in the solvent.
  • a gelling polymer upon dissolution or dispersion in an aqueous solution or dispersion (e.g., water) at a concentration of 2% w/w (based on the dry material), creates a solution/dispersion with a viscosity of from about 100 to about 200,000 mPa-s (e.g., 4,000 to 175,000 mPa-s, and 4,000 to 50,000 mPa-s) as measured at 20 degrees Celsius (+/- 0.2 degree Celsius) using the analysis method described in the USP 33 monograph for hypromellose (incorporated herein by reference).
  • an aqueous solution or dispersion e.g., water
  • a concentration of 2% w/w based on the dry material
  • suitable gelling polymers include pharmaceutically acceptable polymers that undergo an increase in viscosity upon contact with a solvent, as described.
  • Various examples of polymers are known to be useful in this manner, generally including natural and synthetic starches (i.e., modified or pregelatinized modified starch), natural and synthetic celluloses, acrylates, and polyalkylene oxides.
  • natural starches include natural starches include corn starch, potato starch, rice starch, tapioca starch and wheat starch, hydroxypropyl starch such as hydroxypropyl corn starch, hydroxypropyl pea starch and hydropropyl potato starch (derivative of natural starch) .
  • Examples of synthetic starches include acetylated distarch adipate, waxy maize basis, acid-treated maize starch, acid-treated waxy maize starch, distarch phosphate, waxy maize basis, oxidized waxy maize starch, and sodium octenyl succinate starch.
  • Examples of celluloses include carboxymethylcellulose calcium, carboxymethylcellulose sodium, ethycellulose, methylcellulose, cellulose ethers such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxyethylmethyl cellulose, hydroxypropyl methyl cellulose, carboxymethylcellulose sodium, and low substituted hydroxypropyl cellulose.
  • Examples of acrylates include Eudragit RS, RL, NE, NM.
  • polyalkylene oxides examples include polyethylene oxide such as POLYOX N10, N80, N60K, WSR-1105 LEO, or WSR-301 LEO, or WSR-303 LEO.
  • Suitable gelling polymers include polyethylene oxide, polyvinyl alcohol, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethylmethylcellulose, sodium carboxymethylcellulose,
  • hydroxyethylcellulose polyacrylic acid and polyvinyl carboxy polymers such as those commercially available under the trade name Carbopol®, and other high molecular weight polymers capable of attaining a viscosity level effective to prevent uptake in a syringe, if combined with a small volume of solvent as described.
  • Suitable gelling polymers can include, if of sufficiently high molecular weight: ethylcellulose, cellulose acetate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate and cellulose triacetate, cellulose ether, cellulose ester, cellulose ester ether, cellulose; acrylic resins comprising copolymers synthesized from acrylic and methacrylic acid esters, for example acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl
  • methacrylates cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
  • Exemplary gelling polymers can include natural polymers such as those derived from a plant or animal, as well as polymers prepared synthetically. Examples include polyhydroalkylcellulose having a molecular weight greater than 50,000; poly(hydroxy- alkylmethacrylate) having a molecular weight of from 5,000 to 5,000,000; polyvinylpyrrolidone) having a molecular weight of from 100,000 to 3,000,000; anionic and cationic hydrogels; poly(electrolyte) complexes; poly( vinyl alcohol) having a low acetate residual; a swellable mixture of agar and carboxymethyl cellulose; a swellable
  • composition comprising methyl cellulose mixed with a sparingly cross-linked agar; a polyether having a molecular weight of from 10,000 to 6,000,000; water-swellable copolymer produced by a dispersion of finely divided copolymer of maleic anhydride with styrene, ethylene, propylene, or isobutylene; water swellable polymer of N-vinyl lactams; and the like.
  • polymers useful as a gelling polymer include pectin having a molecular weight ranging from 30,000 to 300,000; polysaccharides such as agar, acacia, karaya, tragacanth, algins and guar; polyacrylamides; water-swellable indene maleic anhydride polymers; Good-rite® polyacrylic acid having a molecular weight of 80,000 to 200,000; Polyox® polyethylene oxide polymers having a molecular weight of 100,000 to
  • a gelling polymer may be, or may include, hydroxypropyl methyl cellulose (e.g., Hypromellose or HPMC), and hydroxy methyl cellulose, methyl cellulose, hydroxyethylmethyl cellulose, and sodium carboxymethyl cellulose.
  • HPMC Hypromellose
  • HPMC hydroxypropyl methyl cellulose
  • HPMC Hypromellose
  • HPMC hydroxypropyl methyl cellulose
  • HPMC hydroxypropyl methyl cellulose
  • suitable, commercially available hydroxypropyl methylcellulose polymers include HPMC K100M, Methocel K100LV and Methocel K4M.
  • a specific class of gelling polymer is the class of carbomer polymers, which are polymers derived from acrylic acid (e.g., acrylic acid homopolymers) and crosslinked with polyalcohol allyl ethers, e.g., crosslinked with polyalkenyl ethers of pentaerythritol or sucrose.
  • Carbomer polymers are hydrophilic and are not substantially soluble in water. Rather, these polymers swell when dispersed in water forming a colloidal, mucilage-like dispersion.
  • Carboxyl groups provided by acrylic acid residues of the polymer backbone are responsible for certain behavior of the polymers. Particles of this polymer can be viewed as a network structure of polymer chains interconnected by crosslinks.
  • the structure can swell in water by up to one thousand times of an original (dry) volume (and ten times an original diameter of polymer particles) to form a gel when exposed to a pH environment above 4-6.
  • the pKa of these polymers can be 6 ⁇ 0.5.
  • carboxylate groups pendant from the polymer backbone can ionize at a pH above 6, producing a repulsion between the negatively-charged particles, which adds to the swelling of the polymer if exposed to solvent at this pH range.
  • a dosage form as described herein can preferably include a pH adjuster in an amount and location within the dosage form to raise the pH of a carbomer polymer to at least 6, to substantially neutralize the carboxylate groups.
  • a suitable amount of a pH adjuster may be from about 1 to about 10 miUimoles, or from about 5 to about 9 miUimoles, or from about 6 to about 8 miUimoles, or from about 7 to about 7.5 miUimoles of the pH adjuster per gram of the carbomer polymer that is present in the dosage form.
  • the pH adjuster is present in a dosage form according to the invention in an amount that is from about 1 to about 5 percent by weight, or from about 2 to about 4 percent by weight, or about 3 to 4 percent by weight based on the total weight of the dosage form.
  • Carbomer polymers are often referred to in the art using alternative terminology such as, for example, carbomer homopolymer, acrylic acid polymers, carbomera,
  • Carbopol carboxy polymethylene, carboxyvinyl polymer, Pemulen, polyacrylic acid, and poly(acrylic acid)
  • the USP-NF lists three umbrella monographs i.e. for "carbomer copolymer,” for “carbomer homopolymer,” and for “carbomer interpolymer.”
  • carbopol (carbomer) polymers that may be useful as a gelling polymer can have an average equivalent weight of 76 per carboxyl group.
  • suitable commercially available carbomers include Carbopol® 934, 934P NF, Carbopol® 974P NF and Carbopol® 97 IP NF, Carbopol® 940, and Carbopol® 941, Carbopol® 71G, commercially available from Lubrizol. Examples of such polymers are described in U.S. Pat. Nos. 2,798,053 and 2,909,462, the entireties of which are incorporated herein by reference.
  • a gelling polymer e.g., Carbopol®
  • a gelling polymer can have a molecular weight and viscosity-increasing performance that will reduce or substantially inhibit an ability of an abuser to extract API from a combination of dosage form and a small volume of solvent, as described, while also being capable of being processed into a compressed dosage form.
  • a gelling polymer can also be characterized by viscosity of a solution prepared from the gelling polymer.
  • Product information for commercially available Carbopol® polymers reports that viscosities of different Carbopol® polymers are as follows:
  • xanthan gum polymers which includes natural polymers useful as hydrocolloids, and derived from fermentation of a carbohydrate.
  • a molecular weight of a Xanthan gum may be approximately 1,000,000.
  • Xanthan gum has been shown to provide particularly useful extraction resistance in a dosage form as described, and therefore may be preferred in dosage forms as described, especially if present in an amount of at least 2 or 3 weight percent based on a total weight of a dosage form.
  • the dosage form may optionally include another abuse deterrent in the form of a wax, such as a wax/fat material as described in Applicant's co-pending United States patent application 2008/0311205, the entirety of which is incorporated herein by reference.
  • the wax can be a solid wax material that is present in the dosage form at a location that inhibits an abuser from crushing, grinding, or otherwise forming the dosage form into a ground powder that might be abused by a nasal insufflation mode, or from which active pharmaceutical agent can be easily accessed and removed such as by dissolution or extraction using a solvent.
  • the wax may be present in the dosage form at a location and in an amount to also not interfere with desired uptake of the active pharmaceutical ingredient by a patient upon oral ingestion, in an immediate release dosage form.
  • An exemplary location is at a core of a core-shell particle, especially a core that also contains gelling polymer and that either may or may not contain active pharmaceutical ingredient.
  • Wax located at a core of a particle e.g., a core-shell particle
  • the dosage form may also include core shell particles that do not contain an API.
  • Wax that is located at a core of such a particle e.g., a core-shell particle
  • the API e.g., API present in API-containing core shell particles that are also present in the dosage form
  • the active ingredient is inhibited or prevented from becoming thereafter dissolved in a solvent such as water, or otherwise efficiently accessed by an abuser.
  • a core (uncoated) of a core-shell particle can contain any useful amount of wax, up to and including 100 percent wax, e.g., from 0.1 to 85 weight percent wax based on a total weight of the core, such as from 15 to 60 or 25 to 50 weight percent wax based on total weight core. More generally, a useful amount of wax in a dosage form (e.g., with the wax located in the coated particle, e.g., in the core) may be in a range from 0.05 to 15 weight percent wax based on total weight of a dosage form, e.g., from 0.1 to 10 or from 2 to 5 weight percent wax based on total weight of the dosage form.
  • the wax may be a wax (e.g., fat) material that is generally hydrophobic and that may be either solid or liquid at room temperature, preferably solid at room temperature (25 degrees Celsius).
  • Generally useful fats include those hydrophobic materials that are fatty acid-based compounds generally having a hydrophilic/lipophilic balance (HLB) of 6 or less, more preferably 4 or less, and most preferably 2 or less.
  • HLB hydrophilic/lipophilic balance
  • a fat can have any melting temperature, with preferred fats being solid at room temperature and having a melting point that is at least 30 degrees Celsius, e.g., at least 40 degrees Celsius, e.g., at least 50 degrees Celsius.
  • Useful fats include fatty acids and fatty esters that may be substituted or unsubstituted, saturated or unsaturated, and that have a chain length of at least 10, 12, or 14 carbons.
  • the esters may include a fatty acid group bound to any of an alcohol, glycol, or glycerol.
  • glycercols for example, mono-, di-, and tri-fatty substituted glycerols can be useful as well as mixtures thereof.
  • Suitable wax ingredients include fatty acid esters, glycerol fatty acid esters, fatty glyceride derivatives, waxes, and fatty alcohols such as, for example, glycerol behenate (a.k.a. glyceryl behenate, glycerin behenate, glycerol docosanoate) (e.g., COMPRITOL®), glycerol palmitostearate (PRECIROL®), glycerol monostearate, stearoyl macroglycerides (GELUCIRE® 50/13).
  • glycerol behenate a.k.a. glyceryl behenate, glycerin behenate, glycerol docosanoate
  • COMPRITOL® glycerol palmitostearate
  • PRECIROL® glycerol monostearate
  • stearoyl macroglycerides glycerol monostearate
  • waxes more generally include insect and animal waxes, vegetable waxes, mineral waxes, petroleum waxes, and synthetic waxes; particularly examples include beeswax, carnauba wax, condelilla wax, montan wax, ouricury wax, rice-bran wax, jojoba wax, microcrystalline wax, cetyl ester wax, cetyl alcohol, anionic emulsifying wax, nonionic emulsifying wax and paraffin wax.
  • the dosage form may optionally include another abuse deterrent in the form of a filler or binder material provided in a manner to compromising abuse practices wherein an abuser crushes, grinds, or otherwise forms the dosage form into a ground powder that might be abused by a nasal insufflation mode, or from which active pharmaceutical agent can be easily accessed and removed such as by dissolution or extraction using a solvent.
  • another abuse deterrent in the form of a filler or binder material provided in a manner to compromising abuse practices wherein an abuser crushes, grinds, or otherwise forms the dosage form into a ground powder that might be abused by a nasal insufflation mode, or from which active pharmaceutical agent can be easily accessed and removed such as by dissolution or extraction using a solvent.
  • the binder or filler may be present in the dosage form at a location and in an amount to also not interfere with desired uptake of the active pharmaceutical ingredient by a patient upon oral ingestion, in an immediate release dosage form.
  • An exemplary location is at a core of a core-shell particle.
  • Suitable filler or binder located at a core of a particle e.g., a core-shell particle
  • that also includes active pharmaceutical ingredient e.g., at a layer covering the core, or within the core
  • the dosage form may also include core shell particles that do not contain an API.
  • Filler or Binder that is located at a core of such a particle e.g., a core-shell particle
  • the API e.g., API present in API- containing core shell particles that are also present in the dosage form
  • the active pharmaceutical ingredient is inhibited or prevented from becoming thereafter dissolved in a solvent such as water or otherwise efficiently accessed by an abuser.
  • filler or binder When present within a core or particle of a dosage form, e.g., at a core of a core- shell particle, filler or binder may be present in any useful amount, such as from 0 up to and including 100 percent filler or binder (singly or in combination) in a core of a core- shell particle, e.g., from 10 to 95 weight percent filler or binder (singly or in combination) based on total weight of the core, such as from 40 to 85 or 50 to 75 weight percent based on total weight core.
  • cores that contain high levels of filler include spherical particles that contain 100 percent sugar, and spherical particles that contain 100 percent microcrystalline cellulose.
  • Inert spherical filler products such as these, having useful particle sizes, are commercially available under the trade name Celphere®, and under the trade name Suglets® (sugar spheres, also containing starch), including as follows:
  • CELPHERE SCP-100 (Particle size ( ⁇ ) 75-212); CELPHERE SCP-102 (Particle size ( ⁇ ) 106-212); CELPHERE SCP-203 (Particle size ( ⁇ ) 150-300); CELPHERE SCP- 305 (Particle size ( ⁇ ) 300-500); CELPHERE SCP-507 (Particle size ( ⁇ ) 500-710); CELPHERE SCP-708 (Particle size ( ⁇ ) 710-850).
  • the particle sizes of these can be considered to be useful for any core as described herein, prepared of any single filler, gelling polymer, binder, any combination thereof, or any single or combination of materials combined with API.
  • a film layer or coating as part of a core-shell particle that is located over and surrounds an API.
  • the film layer may also be present as a layer or coating on core shell particles which do not contain an API or an API layer.
  • the film layer can be any film layer capable of being applied as a film layer to core-shell particles, to surround API, or to core-shell particles that do not contain an API or an API layer.
  • the film layer may be prepared from, and will include any pharmaceutically acceptable film forming polymer material, such as one or more of a binder (e.g. as described herein, such as hydroxypropyl cellulose, poly(methyl methacrylates), ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyl methyl cellulose, polyvinyl alcohol, and the like), a solvent-resistant layer, and a pH-sensitive layer (also sometimes referred to as a reverse enteric material or layer), e.g., Eudragit® E 100.
  • the film layer may include any one of these materials alone (e.g., a film layer may include 100 percent of a single one of these types of materials), or a film layer may include a combination of two or more of these types of materials.
  • a solvent-resistant layer is a film layer that retards or prevent release of a drug in a solvent (e.g., one or more of water, ethanol, and methanol) while still allowing the drug to release normally in a gastrointestinal tract when ingested as an immediate release oral dosage form.
  • a solvent e.g., one or more of water, ethanol, and methanol
  • This type of abuse deterrent feature e.g., solvent-resistant film
  • the solvent-resistant film can dissolve in a human gastrointestinal tract with sufficient rapidity to allow for an immediate release profile.
  • this type of solvent-resistant film covers and encloses API of a core-shell particle and acts as a film barrier or retardant to prevent or retard access to the API by use of solvent.
  • a solvent-resistant film is one that does not readily or immediately dissolve in a small volume of a solvent of the type often used by an abuser to dissolve an API, such as any one of water or a C 1 -C 4 alcohol such as ethanol or methanol.
  • a "small volume” refers to an amount of such a solvent that can contain an amount of dissolved API that is sufficiently concentrated to be useful to an abuser to realize the intended biological effect of the drug abuse, and that is also capable of being administered for abuse of the API, e.g., a volume that can contain an amount (concentration) of API that is effective to achieve a desired "high” if administered by injection or nasal insufflation, the volume also being sufficiently small to allow the volume to be administered by injection or nasal insufflation.
  • an API in the dosage form must be capable of being accessed and dissolved at sufficient concentration by an abuser without undue complication, into a "small volume" of solvent, which is a volume that can be administered by injection or by nasal insufflation.
  • a "small volume” of solvent means 50 milliliters or less, or 20 milliliters or less, or 10 milliliters or less, or 5 milliliters or less (volumes which could be injected or used for nasal insufflation).
  • a solvent-resistant film layer can be a film placed on a core-shell particle that is difficult to dissolve in a "small volume" of water or a C 1 -C 4 alcohol such as ethanol or methanol, e.g., that does not immediately dissolve in one or more of water or any one of a C 1 -C 4 alcohol such as methanol or ethanol.
  • the solvent-resistant film thereby retards or prevents an abuser from accessing an API portion of a core-shell particle if the core-shell particle is placed in one of these solvents.
  • the solvent-resistant film need not be completely or substantially insoluble in any one of these solvents, or in all of the solvents, and it must be capable of allowing the API to be accessed with sufficient rapidity, in a gastrointestinal tract, for the dosage form to be useful as an immediate release dosage form.
  • a particular example of a solvent-resistant film is a film that exhibits solubility properties that depend on the pH of a solvent.
  • An example of a solvent-resistant film may be a film that is substantially or completely insoluble at a pH that is greater than a pH condition of a human stomach, and that is sufficiently soluble at a pH condition of a stomach (and gastrointestinal tract) to allow the film to dissolve and release API with sufficient rapidity that the dosage form can be useful as an immediate release oral dosage form.
  • a pH-sensitive layer is a type of solvent-resistant film, and can be disposed in a dosage form to surround an active pharmaceutical ingredient and inhibit or prevent access to and dissolution of the active pharmaceutical ingredient in a solvent outside of a stomach (e.g., at a neutral pH environment), while still allowing the active pharmaceutical ingredient to be efficiently released from an immediate release dosage form at a lower pH environment of a user's stomach.
  • This type of abuse deterrent feature can prevent or significantly impede an abuser's access to an active pharmaceutical agent of a dosage form (e.g., at the core of a core-shell particle or in a layer disposed on the core, or in both the core and the layer disposed on the core) by use of a solvent that is outside of a stomach and that does not have a relatively acidic pH, such as water or a C1-C4 alcohol such as ethanol, methanol, etc., or a mixture thereof, having a pH that is higher than a pH found in a human stomach, for example a pH greater than 4; greater than 5; or greater than 5.5; or greater than 6.
  • a pH-sensitive layer may be useful as a solvent-resistant film, placed in a dosage form as a layer of a core-shell particle to surround, cover, or enclose a portion of the core- shell particle that contains active pharmaceutical ingredient.
  • an active pharmaceutical ingredient may be located as desired at a core or at a layer outside of an uncoated or coated core; a solvent-resistant film in the form of a pH- sensitive layer may be disposed as a separate layer surrounding or covering the portion of the core-shell particle that contains the active pharmaceutical ingredient.
  • the pH-sensitive layer may be in direct contact with (adjacent to) a core or a layer that includes active pharmaceutical ingredient; alternately a core-shell particle may include one or more intermediate layers between a pH-sensitive layer and a core or layer that includes active pharmaceutical ingredient.
  • a pH-sensitive layer may be included in the dosage form as a layer of a core-shell particle that does not contain either an API layer or any API.
  • a useful pH-sensitive layer may include a polymer or other material that can be placed as a layer of a particle as described herein, such as to cover a more inner layer or core that contains active pharmaceutical ingredient, to form a pH-sensitive film
  • the pH-sensitive film can be solubilized by exposure to a liquid that exhibits a pH that may be present in a stomach of a user of the dosage form, such as a pH below 6 or below 5.5.
  • a pH below 6 or below 5.5 a pH below 6 or below 5.5.
  • the pH-sensitive layer can contain polymer that is not easily or substantially soluble at a pH that is higher than a pH found in a human stomach, e.g., a pH greater than 6; by being insoluble at a pH greater than 6, the pH-sensitive polymer will not dissolve in many solvents easily available and commonly used by an abuser to extract a water-soluble drug from a dosage form such as water, ethanol, methanol, etc.
  • pH-sensitive polymer useful in a pH-sensitive layer include the class of reverse enteric polymers that contain cationic-functional groups and that exhibit pH- dependent solubility as described herein.
  • examples include polymers that contain basic functional groups such as amino groups, and that exhibit solubility at pH conditions found in a (human) stomach but not at relatively higher pH conditions, e.g., not above a pH of 4, 5, or 5.5, or not above a pH of 6.
  • pH-sensitive polymers include copolymers of dimethyl aminoethyl methacrylates, and neutral methacrylic acid esters; e.g., dimethyl aminoethyl methacrylate, butyl methacrylates, and methyl methacrylates, such as at a ratio of 2: 1 : 1.
  • Examples of such polymers are commercially available under the trade name Eudragit® E-100, Eudragit® E PO, Eudragit® E 12,5, and similar amino-functional pH-sensitive polymers.
  • a preferred pH-sensitive polymer is the polymer Eudragit El 00, but any polymer that is sufficiently hydrophilic at a low pH and hydrophobic at a higher pH to exhibit pH-dependent solubility as described, may also be effective if otherwise acceptable for use in a pharmaceutical dosage form, for example as a non-toxic ingredient of an oral dosage form.
  • Reverse enteric compositions are also described in EP 1694724 Bl, titled "pH Sensitive Polymer and Process for Preparation Thereof.”
  • a solvent-resistant film layer When present as a coating of a particle that contains active pharmaceutical ingredient, a solvent-resistant film layer may be present at any amount useful as an abuse deterrent feature, such as in a range from 0.1 to 90 weight percent of a total weight of a core-shell particle, e.g., from 3 to 50 or 4 to 40 weight percent solvent-resistant polymer per total weight core-shell particle. More generally, a useful amount solvent-resistant film layer or polymer in a dosage form may be in a range from 1 to 50 weight percent solvent- resistant film layer or polymer based on a total weight of a dosage form, e.g., from 2 to 30 or from 3 to 15 weight percent solvent-resistant polymer based on total weight dosage form. Similarly, when present as a coating of a particle that does not contain an API, a solvent-resistant film layer may be present at any amount useful as an abuse deterrent feature, for example in the same numerical ranges as are disclosed above for coating particles that contain API.
  • a dosage form as presently described can also preferably include a disintegrant, which functions to cause the dosage form to expand and break up during use, e.g., at conditions of a human stomach, to allow active pharmaceutical ingredient of the dosage form to be released in a manner to achieve an immediate release profile.
  • Disintegrants are known ingredients of pharmaceutical dosage forms, with various examples being known and commercially available.
  • disintegrants examples include compositions of or containing sodium starch glycolate, starch (e.g., maize starch, potato starch, rice starch, tapioca starch, wheat starch, corn starch and pregelatinized starch), croscarmellose sodium, crospovidone (crosslinked polyvinyl N-pyrrolidone or PVP) (polyplasdone XL- 10), sodium starch glycolate (EXPLOTAB® or PRIMOJEL®), any combination of two or more of the foregoing, and other pharmaceutically acceptable materials formed into particles having a particle size, density, etc., to allow processing of the disintegrant into a useful immediate release dosage form.
  • starch e.g., maize starch, potato starch, rice starch, tapioca starch, wheat starch, corn starch and pregelatinized starch
  • croscarmellose sodium crospovidone (crosslinked polyvinyl N-pyrrolidone or PVP) (polyplasdon
  • the disintegrant can be present in an immediate release dosage form at any location that allows the disintegrant to function as desired, to expand within the intact dosage form, upon ingestion, to cause the ingested dosage form to break apart and allow for desired immediate release of active pharmaceutical ingredient from the dosage form, in a stomach.
  • One useful location for a disintegrant can be as a component of an excipient used to contain core-shell particles that contain active pharmaceutical ingredient, as described herein, in a dosage form such as a compressed tablet or capsule.
  • disintegrant When included as an excipient of a dosage form, disintegrant may be present in an amount useful to achieve immediate release of an API of a dosage form.
  • useful amounts of disintegrant in an immediate release dosage form as described herein may be in a range from 0.5 to 50 weight percent disintegrant based on a total weight of the dosage form, e.g., from 1 to 30 weight percent disintegrant based on total weight of the dosage form.
  • the amount of disintegrant in a matrix of a dosage form can be consistent with these amounts, e.g., disintegrant can be included in a matrix (e.g., total of a dosage form that is other than the coated particles or API) of a dosage form in an amount in a range from 0.5 to 50 weight percent disintegrant based on a total weight of the matrix, e.g., from 1 to 30 weight percent disintegrant based on total weight matrix.
  • a dosage form as described can also include any of various known and
  • excipients that may be useful to achieve desired processing and performance properties of an immediate release dosage form.
  • excipients include fillers, binders, lubricants, glidants, coloring agents, pH-adjusters, etc., and can be included in core-shell particles or in a matrix (e.g., compressed matrix) of a tablet or capsule.
  • a matrix e.g., compressed matrix
  • a pH-adjuster can be included in an immediate release dosage form as described, for example at a location to affect pH at a specific location of the dosage form that is only a portion of a total dosage form.
  • a pH-adjuster in the form of a base may be included at a location of a gelling polymer that contains acid functionalities, to neutralize the acid functionalities.
  • the amount of pH-adjuster included at the location of the gelling polymer can be an amount effective to neutralize the acid functionalities of the gelling polymer at that location.
  • a component of a dosage form as described that includes an acid- functional gelling polymer such as a carbopol may include a base in an amount and location to neutralize the acid functionalities of that polymer.
  • the pH-adjuster can be located at a location effective to cause such neutralization, e.g., at the location of the dosage form that contains the acid-functional gelling polymer, for example at a core of a core-shell particle or as part of an excipient that includes acid-functional gelling polymer and that functions to bind particles together as a dosage form.
  • fillers examples include lactose, starch, dextrose, sucrose, fructose, maltose, mannitol, sorbitol, kaolin, microcrystalline cellulose, powdered cellulose, calcium sulfate, calcium phosphate, dicalcium phosphate, lactitol or any combination of the foregoing.
  • a filler will have a molecular weight that does not result in a substantial viscosity increase or formation of a gel as described herein for a gelling polymer, if combined with a solvent such as water.
  • a filler may be present in any portion of a dosage form as described, including a core-shell particle; the filler may be present in a core, in a layer containing an active pharmaceutical ingredient that is disposed on the core, in a solvent resistant film, in the matrix, or in two or more of these portions of the dosage form.
  • the filler may be present at any one or more of these portions of a dosage form in an amount to provide desired processing or functional properties of a portion of the dosage form and of the entire dosage form.
  • the amount of total filler in a dosage form can also be as desired to provide desired functionality, including an immediate release profile, for example in an amount in a range from 0 to 80 weight percent filler based upon the total weight of the dosage form, e.g. from 5 to 50 percent filler based on total weight dosage form.
  • binders examples include polymeric material such as alginic acid, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, starch, pregelatinized starch, polyvinyl alcohol, polyethylene oxide, polyvinylpyrrolidone, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose and any combination of two or more of these.
  • polymeric material such as alginic acid, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, starch, pregelatinized starch, polyvinyl alcohol, polyethylene oxide, polyvinylpyrrolidone, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose and any combination of two or more of these.
  • a binder may be a water soluble material; as compared to non-binder ingredients such as a gelling polymer, a binder is of a molecular weight that does not result in formation of a gel or a highly viscous composition upon combining with a small volume of water.
  • a binder can exhibit a relatively low molecular weight as compared to a gelling polymer, and a relatively lower viscosity (e.g., when measured in a 2% aqueous solution).
  • Polymer useful as a binder may typically have a molecular weight of less than 50,000, e.g., less than 30,000, or less than 10,000.
  • a binder may be present in any portion of a dosage form as described, including a core or a film or coating of a core-shell particle, or as part of an excipient to contain or bind core-shells particles in a dosage form.
  • Filler may be included in a core of a core-shell particle in combination with active pharmaceutical ingredient, gelling polymer or both; as part of an active pharmaceutical layer located over a core or another layer of a core-shell particle; as part of a solvent-resistant film; or within an excipient useful to bind particles into a dosage form.
  • a binder may be present at any one or more of these portions of an immediate release dosage form as described, in an amount to provide desired processing or functional properties in each portion of the dosage form and of the overall dosage form.
  • the amount of total binder in a dosage form can also be as desired to provide desired functionality, including immediate release functionality, for example in an amount in a range from 0.1 to 10 weight percent binder based on a total weight of a dosage form, e.g., from 0.5 to 7 weight percent binder based on total weight dosage form.
  • lubricants include inorganic materials such as talc (a hydrated magnesium silicate; polymers, such as, PEG 4000; fatty acids, such as stearic acid; fatty acid esters, such as glyceride esters (e.g., glyceryl monostearate, glyceryl tribehenate, and glyceryl dibehenate); sugar esters (e.g., sorbitan monostearate and sucrose monopalmitate); glyceryl dibehenate (Compritol® 888 ATO); and metal salts of fatty acids (e.g., magnesium stearate, calcium stearate, and zinc stearate).
  • talc a hydrated magnesium silicate
  • polymers such as, PEG 4000
  • fatty acids such as stearic acid
  • fatty acid esters such as glyceride esters (e.g., glyceryl monostearate, glyceryl tribehenate, and gly
  • Lubricant may be included in an immediate release dosage form as described, in any useful amount, such as an amount in a range from 0.1 to 10 weight percent lubricant based on a total weight of a dosage form, e.g., from 0.5 to 7 weight percent lubricant based on total weight dosage form.
  • glidants examples include colloidal silicon dioxide, untreated fumed silica (e.g., as available under the trade name Cab-O-Sil®), and crystalline or fused quartz. Glidant may be included in an immediate release dosage form as described, in any useful amount.
  • coloring agents include FD&C-type dyes and lakes, fruit and vegetable extracts, titanium dioxide, iron oxides and mixtures thereof.
  • a coloring agent may be incorporated into a dosage form by blending the coloring agent any other ingredient. Alternately, coloring agent may be applied to an outer surface of a dosage form.
  • APIs that can be particularly useful can be those types of active pharmaceutical ingredients that can be subject to abuse, addiction, overdosing, or two or more of these; such APIs can be located in the dosage form at a location to cause the API to be subject to abuse deterrent features of the core-shell particle, e.g., at a core or inner layer of a core-shell particle.
  • Drugs commonly susceptible to abuse include sedative-hypnotics, stimulants (e.g., central nervous system ((CNS) stimulants), anxiolytics, antipsychotics, dissociative anesthetics, and narcotic analgesics including but not limited to drugs that can cause psychological or physical dependence on the drug.
  • stimulants e.g., central nervous system ((CNS) stimulants
  • anxiolytics e.g., central nervous system ((CNS) stimulants
  • anxiolytics e.g., antipsychotics
  • dissociative anesthetics e.g., narcotic analgesics
  • narcotic analgesics including but not limited to drugs that can cause psychological or physical dependence on the drug.
  • therapeutically acceptable drug salt drug derivative, drug analog, drug homologue, or polymorph of an active pharmaceutical ingredient.
  • Sedative hypnotics include, for example, barbiturates, for example phenobarbital, methobarbital, amobarbital, pentobarbital, and secobarbital and pharmaceutically acceptable salts thereof; benzodiazepines, for example diazepam, chlorodiazepoxide, lorazepam, triazolam, temazepam, alprazolam and flurazepam and pharmaceutically acceptable salts thereof; phenothiazines, such as for example, alimemazine,
  • chlorpromazine thioridazine, and pharmaceutically acceptable salts thereof, and sleep medications, such as for example, Zolpidem, zaleplon, and eszopiclone and
  • Anxiolytics include, for example,
  • CNS Stimulants include, for example, amphetamines, such as for example, dextroamphetamine, levoamphetamine (benzadrine), methamphetamine (methadrine), pseudoephedrine, and Adderall (amphetamine mixed salts) and pharmaceutically acceptable salts thereof, and non-amphetamine psychostimulants such as methylphenidate, modafmil and armodafmil and pharmaceutically acceptable salts thereof.
  • amphetamines such as for example, dextroamphetamine, levoamphetamine (benzadrine), methamphetamine (methadrine), pseudoephedrine, and Adderall (amphetamine mixed salts) and pharmaceutically acceptable salts thereof
  • non-amphetamine psychostimulants such as methylphenidate, modafmil and armodafmil and pharmaceutically acceptable salts thereof.
  • Narcotic analgesics include opioids such as, for example, buprenorphine, butorphanol, codeine, dihydrocodeine, dihydromorphine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, methadone, fentanyl, meperidine, tramadol, propoxyphene, and
  • Antipsychotic agents can include, for example, phenothiazines as listed above, butyrophenones, such as, for example, droperidol and haloperidol, dibenzoxazepines such as loxapine, and atypical antipsychotic agents such as aripiprazole, clozapine, olanzapine, quetiapine, risperidone ziprasidone, paliperidone and remoxipride.
  • muscle relaxants such as for example cyclobenzaprine and pharmaceutically acceptable salts thereof
  • cannabinols e.g., A ⁇ cannabidiol. A 2 -cannabidiol, A 3 -cannabidiol, ⁇ 3 ' 7 - cannabidiol, A 4 -cannabidiol, A 5 -cannabidiol, and A 6 -cannabidiol
  • cannabinoids such as dronabinol, delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), nabilone, dexanabinol, ajulemic acid, cannabinor, rimonabant and taranabant, and pharmaceutically acceptable salts thereof
  • dissociative anesthetic agents such as ketamine and
  • the amount of active pharmaceutical ingredient included in an immediate release dosage form can be any useful amount, as is known and as may be found in relevant literature such as Goodman & Gillman's, The Pharmacological Basis of Therapeutics, 9th ed. pages 219-222, 361-396, 521-535 1996.
  • typical therapeutic amounts of oxycodone range 5 mg, 10 mg, or up to 400 mg, for the hydrochloride salt.
  • the active pharmaceutical ingredient can be present in such dosage form in an amount normally prescribed, typically 0.5 to 25 percent on a dry weight basis, based on the total weight of the dosage form.
  • narcotic analgesics such as opioids in a single unit dosage form, such as at a level from about 1 to about 500 mg, or from about 1 to about 250 mg, or from about 1 to about 100 mg; for example, 2.5, 5, 7.5, 10, 15, 20, or 30, milligram (mg) per dosage form unit.
  • a dosage form contains any appropriate amount of an API to provide a therapeutic effect.
  • the present invention is also directed to methods of treatment, comprising orally administering an effective amount of the herein described immediate release abuse deterrent dosage form.
  • Also provided herein is a method for treating sleep disorders in a subject in need thereof by administering an effective amount of the herein described immediate release abuse deterrent dosage form containing an API that is a sedative hypnotic drug such as a barbiturate.
  • Also provided herein is a method for treating psychoses in a subject in need thereof by administering an effective amount of the herein described immediate release abuse deterrent dosage form containing an API that is an antipsychotic drug such as quetiapine.
  • an "effective amount" of when used in connection with composition described herein is an amount sufficient to produce a therapeutic result in a subject in need thereof.
  • a therapeutic result can include, but is not limited to treating or preventing pain, sleep disorders, anxiety or psychotic symptomology by a subject.
  • a dosage form as described can optionally include one or more additional APIs of a type that is not commonly susceptible to abuse.
  • additional APIs may be any suitable or desired API, such as those in the class of non-steroidal analgesic drugs.
  • non-steroidal analgesic drugs refers to drugs that include those commonly referred to as non-steroidal anti-inflammatory drugs, or "NSAIDS,” and acetaminophen, which is non-steroidal, but does not act via an inflammation mechanism. Accordingly, the term “non-steroidal analgesic drugs” would include acetaminophen, and also include NSAIDS such as aspirin, ibuprofen, and naproxen.
  • the dosage form also exhibits immediate release properties with respect to these not-commonly- subject-to-abuse APIs.
  • these APIs can be present in the dosage form at any useful level, typically 0.5 to 25, e.g., 1 to 10 weight percent of the API on a dry weight basis, based on a total weight of the dosage form, e.g., at a level of or between 5, 25, 50, 75, 100, 125, 150, 175, 200, 300, 325, 500, 750 or up to or exceeding 1000 milligram (mg) per dosage form unit.
  • a dosage form contains an appropriate amount of an API to provide a therapeutic effect.
  • An immediate release dosage form as described can include one or more of the described abuse deterrent features, alone or in combination; e.g., one or more of: gelling polymer as part of a core-shell particle (e.g., at a core of the core-shell particle); wax as part of a core-shell particle (e.g., at a core of the core-shell particle); binder or filler as part of a core-shell particle (e.g., at a core of the core-shell particle); a film layer that may optionally be a solvent-resistant film (e.g., pH-sensitive film) as part of a core-shell layer; or gelling polymer as a component of an excipient or binder used to hold core-shell particles together as part of in an immediate release dosage form.
  • gelling polymer as part of a core-shell particle (e.g., at a core of the core-shell particle); wax as part of a core-shell particle (e.g., at a core of the core-shell particle
  • Certain embodiments of the described dosage forms can specifically exclude other types of abuse deterrents.
  • some dosage forms include nasal irritant to discourage or prevent abuse by nasal insufflation.
  • the nasal irritant can be a mucous membrane irritant or nasal passageway irritant that, if inhaled through a nasal passageway when contained in a ground or powdered dosage form, can induce pain or irritation of the abuser's nasal passageway tissue.
  • surfactants such as sodium lauryl sulfate, poloxamer, sorbitan monoesters, and glyceryl monooleates.
  • dosage forms of the present description do not require, and can specifically exclude, nasal irritant agents such as those described above.
  • dosage forms can include an emetic agent, to cause vomiting.
  • Certain particular embodiments of dosage forms of the present description do not require and can specifically exclude an emetic agent.
  • some dosage forms include an effervescent agent that acts as a deterrent to abuse by nasal insufflation.
  • the effervescent includes an acidic component and a basic component that release a gas such as oxygen or carbon dioxide when combined in the presence of an aqueous media, such as upon nasal insufflation.
  • the acid source may be, for example, citric acid, tartaric acid, malic acid, maleic acid, lactic acid, glycolic acid, ascorbic acid, fumaric acid, adipic acid, succinic acid, salts thereof, and combinations thereof.
  • the base may be, for example, a carbonate or bicarbonate. Dosage forms of the present description do not require, and can specifically exclude, an effervescent agent in the form of an acid and a base that can combine to a gas such as oxygen or carbon dioxide.
  • Still other dosage forms include a biologically active chemical compound that functions as an antagonist to an active pharmaceutical ingredient.
  • An antagonist may prevent the potential abuse of a dosage form in a manner, including the method of consuming multiple or several or more dosage form units at once.
  • Antagonist agents are compounds that block or negate the effect of an active pharmaceutical ingredient, and are available and known for various classes of drugs including opioids and other
  • antagonist agents for opioids include compounds such as naltrexone, naloxone, nalmefene, cyclazacine, levallorphan.
  • antagonist agents and methods for preparing antagonist agents for incorporation into a dosage form are provided in U.S. Patent Nos. 7,682,633 and 7,658,939, which are incorporated herein by reference.
  • an immediate release dosage form that includes an opioid and that includes one or more abuse deterrent feature as described herein (e.g., a gelling polymer, wax, solvent-resistant film, or a combination thereof), can be formulated to not contain and to specifically exclude an antagonist of an API that is also included in the dosage form, e.g., an opioid antagonist in a dosage form containing an opioid.
  • an opioid antagonist in a dosage form containing an opioid.
  • a dosage form can include particles 10A that contain API.
  • the particle e.g., coated particle or "core-shell” particle
  • the particle can include a core 12a (or “uncoated core"), which may be coated with one or more layers, films or coatings, e.g., 14a, 16a, or any additional layer or coating that is coated over, underneath, or intermediate to these.
  • the layer designated 16a may be an API containing layer
  • the layer designated as 14a may be a solvent resistant, e.g., a pH sensitive film layer.
  • Particle 10A can contain one or more of the ingredients described herein, such as any one or more of API (especially an API that is susceptible to abuse), a gelling polymer, optional wax, optional solvent-resistant layer, as well as one or more additional layer or layers under, over, or intermediate to these layers or between either layer and the core.
  • API especially an API that is susceptible to abuse
  • a gelling polymer such as silicone wax, optional solvent-resistant layer, as well as one or more additional layer or layers under, over, or intermediate to these layers or between either layer and the core.
  • Each layer can be present in size or amount (e.g., thickness) that will result in a useful immediate release dosage form having one or more of the presently described abuse deterrent features.
  • a core or layer of particle 10a can be filler, binder, other excipient, or solvent (not more than a residual amount, if any) such as water or ethanol for use in preparing the coated particle, and that is substantially removed after formation of the core, coating, or coated particle.
  • the core 10A can include any amount of the different ingredients of: a gelling polymer (e.g. from 0 to 100 percent of a core), filler as described herein such as sugar (mannitol) or microcrystalline cellulose (e.g., from 0 to 100 percent of a core), binder (e.g., from 0 to 100 percent of a core), and wax (e.g., from 0 to 100 percent of a core).
  • core-shell particles 10a are believed to be new and inventive, certain method steps useful to prepare these novel coated particles may be known. Available methods include certain methods and processing steps known to be useful for preparing particles and coated particles in the pharmaceutical arts.
  • a core-shell particle 10a can be prepared by an initial step of mixing ingredients of core 12a with a solvent such as water or ethanol and forming the mixture into a spherical core particle by known methods. The particle may be dried and separated by size, and then one or more coating in the form of a continuous film or layer can be applied to the core, optionally successively to produce multiple layers surrounding the core.
  • General processing to produce a multi-layer coated particle can include a series of steps such as compounding, mixing, granulation, wet milling, coating (by any method such as fluidized bed coating, spray coating, etc.), and one or more drying steps such as by use of a fluidized bed or other drying method.
  • coated or uncoated particles can be sorted or separated based on size to produce a composition or a collection of particles having a desired size range and distribution.
  • the coated granulate compositions according to the invention may be prepared by a process comprising:
  • step (ii) layering the granules formed in step (i) with a solution or suspension
  • step (iii) coating the layered granules formed in step (ii) with a solution or suspension comprising a film forming polymer material to form a coated layered granulate.
  • the process above may further comprise steps of milling and drying the granulate formed in step (i).
  • the steps of the process above would be modified as follows:
  • step (iii) coating the layered sphere formed in step (ii) with a solution or suspension comprising a film forming polymer material to form a coated layered sphere.
  • Compressed tablets according to the invention may be prepared by a process comprising:
  • a second API e.g., acetaminophen
  • a gelling polymer e.g., polymethyl methacrylate
  • a disintegrant e.g., polymethyl methacrylate
  • at least one additional excipient selected from a filler, a colorant, and a pH adjusting agent, to form a first mixture and then blending the first mixture for a suitable time;
  • step (ii) adding a lubricant to the blended mixture formed in step (i) to form a
  • step (iii) compressing the blended mixture formed in step (ii) to form compressed tablets.
  • a suitable time for the blending in step (i) may be, for example, from about 5 to about 90 minutes, or from about 10 to about 60 minutes, or from about 20 to about 40 minutes, or about 30 minutes.
  • a suitable time for the blending in step (ii) may be, for example, from about 1 to about 30 minutes, or from about 5 to about 20 minutes, or about 10 minutes.
  • an immediate release dosage form as described can include a core-shell particle 10A that includes a core 12A that contains only a minor amount of API or that contains an insubstantial amount of API.
  • Core 12A may contain less than 5 weight percent, e.g., less than 1 or less than 0.5 weight percent active pharmaceutical ingredient based on a total weight of the core of the core- shell particle.
  • core 12A may contain less than 5 weight percent of a total amount of pharmaceutical ingredient in a core-shell polymer, e.g., less than 5, less than 1, or less than 0.5 weight percent active pharmaceutical ingredient based on total weight of API in the core-shell particle.
  • a major portion of API can be contained outside of core 12A, e.g., in an API layer 16a, which can contain at least 50, at least 75, or at least 90, or at least 95 weight percent of a total amount of the API in a core- shell polymer.
  • Core 12A can include binder, gelling polymer (e.g., HPMC), wax, or filler, optionally alone or in combination, each in an amount to allow the materials of the core to function as one or more abuse deterrent features as described herein. See the examples included herewith for examples of useful amounts and ranges of amounts of these ingredients.
  • gelling polymer e.g., HPMC
  • wax e.g., wax
  • filler optionally alone or in combination, each in an amount to allow the materials of the core to function as one or more abuse deterrent features as described herein. See the examples included herewith for examples of useful amounts and ranges of amounts of these ingredients.
  • core 12A contains gelling polymer, wax, binder, or filler, or any combination of these, and no API (meaning not more than an insignificant amount, such as less than 0.5 or less than 0.1 weight percent based on the weight of core 12A).
  • core 12A, not containing API can be coated with a coating layer that contains API, e.g., an active pharmaceutical layer or API layer 16A.
  • core-shell particle 10A includes core 12A, which does not contain any API, and API layer 16A, which contains an amount of API, such as a total amount of API (e.g., API commonly susceptible to abuse) to be contained in a dosage form prepared from particles 10A.
  • API layer 16A can contain one or more ingredients as described herein useful to form API layer 16A as a layer over an outer surface of core 12 A.
  • API in API layer 16A can be a type of API that is commonly susceptible to abuse, such as an opioid, and can account for all of or most of (e.g., at least 70, at least 80, at least 90, or at least 95 percent) the total amount of that type of API in the core-shell particles and in the dosage form; in this embodiment the core can contain less than 10, less than 5, or less than 1 percent of the total amount of API in the core-shell particles, and less than 10, 5, or 1 percent of the total amount of API in the dosage form.)
  • Useful non-API ingredients in an API layer can include a binder along with the API.
  • the API and binder can be carried in a solvent (e.g., water, ethanol, or both) and coated and dried to form a preferably continuous film layer on an outer surface of core 12A, i.e., API layer 16A. See the examples included herewith for examples of useful amounts and ranges of amounts of these ingredients.
  • a solvent e.g., water, ethanol, or both
  • a core-shell particle 10A can also optionally include a film layer, e.g., a solvent- resistant layer (e.g., a pH-sensitive layer) 14A as described herein.
  • a film layer e.g., a solvent- resistant layer (e.g., a pH-sensitive layer) 14A as described herein.
  • a dosage form as described can include a core- shell particle 10B that includes a core 12B that does contain a useful amount of API, such as an amount of API useful in an immediate release dosage form having one or more abuse deterrent features as described herein, prepared to include particles 10B. See figures 2A and 2B.
  • core 12B of particle 10B can contain a gelling polymer, optional wax, optional binder or filler, and an amount of API.
  • core 12B contains gelling polymer, optional wax, optional binder, and API.
  • core 12B, containing API can optionally be coated with solvent-resistant layer (e.g., a pH-sensitive layer) 14B as described herein for use in an immediate release dosage form.
  • solvent-resistant layer e.g., a pH-sensitive layer
  • Core 12B may also optionally be coated with a coating layer that contains API, e.g., an active pharmaceutical layer or API layer prior to application of the solvent-resistant layer.
  • API containing core-shell particles as described herein may contain API of a type that is susceptible to abuse:
  • a dosage form as described can include a core- shell particle 10B, as depicted in Figure 2B, that that does not contain an API layer, and does not contain any API.
  • a particle 10B, containing no API may include core 12B containing gelling polymer, optional wax, and optional binder, which core 12B may optionally be coated with solvent-resistant layer (e.g., a pH-sensitive layer) 14B as described herein for use in an immediate release dosage form.
  • solvent-resistant layer e.g., a pH-sensitive layer
  • a coated particle 10a or 10b that includes API, and optionally, a coated particle 10B that does not include API can be included in any of a variety of dosage forms, examples including a compressed tablet or compressed capsule, a suppository, capsule, caplet, pill, gel, soft gelatin capsule, etc.
  • a dosage form 12 can be prepared as a compressed tablet or compressed capsule.
  • Tablet or capsule 12 can contain core-shell particles 10 (e.g., 10A or 10B) distributed within a matrix 20, compressed to form the compressed tablet or capsule 12.
  • Core-shell particles 10A or 10B can be as described herein, generally or specifically, and can contain an amount of API suited to provide a desired dosage upon ingestion of tablet or capsule 12; e.g., matrix 20 does not include any substantial amount of API.
  • Matrix 20 can include ingredients useful in combination with the core-shell particles 10A, 10B, to produce an immediate release dosage form.
  • useful excipients of an immediate release dosage form can include ingredients that allow the dosage form to break up or disintegrate upon ingestion and facilitate exposure to fluid in a stomach, such as a useful amount of disintegrant.
  • examples of such excipients for such a dosage form can also include one or more ingredients that act as an abuse deterrent feature, such as a gelling polymer as described herein.
  • Other excipients can be useful for processing to form a compressed dosage form, and also may allow the compressed dosage form to function as an immediate release dosage form, with one or more abuse deterrent features.
  • the following non-limiting examples show various dosage forms as described herein.
  • the described and exemplified dosage forms can be made from methods that include granulating, coating, and compressing steps as follows.
  • ethyl cellulose Hydroalcoholic solution of ethylcellulose is added. Alternatively the granulation can be produced through top spraying the hydroalcoholic solution in a fluid bed granulator.
  • a portion of the ethyl cellulose for example from about 10 to about 50% by weight, or from about 10 to about 40% by weight, or from about 15 to about 30 % by weight, is dry mixed with the Glyceryl behenate and hypromellose K100M prior to adding the hydroalcoholic solution containing the balance of the ethyl cellulose. 1. (alternative when API is included in the core) Glyceryl behenate and
  • hypromellose K100M and API are dry mixed in a high shear granulator.
  • Hydroalcoholic solution of ethylcellulose is added.
  • the granulation can be produced through top spraying the hydroalcoholic solution in a fluid bed granulator.
  • a portion of the ethyl cellulose for example from about 10 to about 50% by weight, or from about 10 to about 40%> by weight, or from about 15 to about 30 % by weight, is dry mixed with the Glyceryl behenate and hypromellose K100M prior to adding the hydroalcoholic solution containing the balance of the ethyl cellulose.
  • the granules are then wet milled using a size reduction mill (Granumill) and then dried using a fluid bed, and optionally screened.
  • a size reduction mill Granumill
  • the polymer granules are then layered using Wurster fluid bed layering process with API (or alternatively, granulated using high shear granulation or top spray fluid bed granulation process).
  • Step 3 (alternative when the coated granule will not contain API)
  • the layering step is omitted and the coating of Step 4 below is applied to the granulate prepared in Step 1.
  • Step 4 The layered granules of Step 3 (or alternatively, when the coated granule will not contain API, the granules prepared in Step l)are then coated using a fluid bed coater equipped with a Wurster insert (bottom spray assembly) with ethanolic suspension of Eudragit El 00 copolymer and magnesium stearate. Coated particles are then screened and blended.
  • acetaminophen tablets manufactured using the coated intermediate is as follows:
  • API-containing coated granules APAP, crospovidone, Carbopol 71G, sodium bicarbonate, mannitol, optionally coated granules containing no API, and optionally a desired colorant, are then added to the blender and mixed.
  • Magnesium stearate (and optionally colorant) is then added to the blender and mixed. The blend is compressed into tablets using a rotary tablet press.
  • Granules were manufactured in a high shear granulator, where hypromellose and glyceryl behenate were dry mixed for 3 minutes. Then, a 10% hydroalcoholic solution of ethylcellulose N10 was slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition was continued until the entire amount of ethylcellulose was added. The granules were then wet milled using a size reduction mill (Granumill) and were subsequently loaded into fluid bed for drying.
  • a size reduction mill Granules were then wet milled using a size reduction mill (Granumill) and were subsequently loaded into fluid bed for drying.
  • the prepared granules were then layered in a bottom spray fluid bed coater with a 12% aqueous solution of hydrocodone bitartrate and HPMC 2910.
  • hydrocodone bitartrate layered granules were then coated in a bottom spray fluid bed coater with 25 % alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate. The resulting coated granules were subsequently used for further blending and compression process.
  • coated granules were prepared according to Example 1 above and mixed with paracetamol and other excipients (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into hydrocodone/acetaminophen tablets.
  • paracetamol and other excipients carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose
  • Example 3 Hydrocodone Bitartrate/ Acetaminophen
  • Table 5 Hydrocodone/acetaminophen Granule Formulation
  • Coated granules were prepared according to the procedure described in Example 1. The prepared coated granules were then mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into hydrocodone/acetaminophen tablets.
  • excipients carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose
  • Example 4 Hydrocodone Bitartrate/ Acetaminophen
  • Table 8 Hydrocodone/acetaminophen granule composition
  • Coated granules were prepared according to the procedure described in Example 1. The prepared coated granules were then mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into hydrocodone/acetaminophen tablets.
  • Table 10 Hydrocodone/acetaminophen tablet composition
  • Example 5 Hydrocodone Bitartrate/ Acetaminophen Table 1 1 1 : Hydrocodone/acetaminophen granule composition
  • Coated granules were prepared according to the procedure described in Example 1. The prepared coated granules were then mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, red iron oxide, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into hydrocodone/acetaminophen tablets.
  • excipients carbopol, crospovidone, sodium bicarbonate, mannitol, red iron oxide, microcrystalline cellulose
  • Example 6 Oxycodone hydrochloride (single API) (Celphere core) Table 14: Oxycodone granule composition
  • Microcrystalline cellulose particles were layered in a bottom spray fluid bed coater with a 12% aqueous solution of oxycodone hydrochloride and HPMC 2910.
  • the oxycodone hydrochloride layered particles were then coated in a bottom spray fluid bed coater with 25 % alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate. The resulting coated particles were subsequently used for further blending and compression process.
  • the coated particles were mixed with other excipients (crospovidone and lactose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into oxycodone tablets.
  • Table 16 Oxycodone hydrochloride tablet composition
  • Example 7 Hydrocodone Bitartrate/ Acetaminophen (sugar sphere core)
  • Table 17 Hydrocodone bitartrate granule composition
  • Sugar sphere particles were layered in a bottom spray fluid bed coater with an aqueous solution of hydrocodone bitartrate and HPMC 2910.
  • hydrocodone bitartrate layered particles were then coated in a bottom spray fluid bed coater with 25 % alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate. The resulting coated particles were subsequently used for further blending and compression process.
  • Table 18 Hydrocodone bitartrate tablet composition
  • coated spheres were mixed with acetaminophen and other excipients
  • Example 8 Hydrocodone Bitartrate/ Acetaminophen (Celphere core) Table 20: Hydrocodone bitartrate granule composition
  • Coated spheres were prepared as in Example 7, and mixed with acetaminophen and other excipients (mannitol, microcrystalline cellulose, xanthan gum and crospovidone) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into hydrocodone tablets.
  • acetaminophen and other excipients mannitol, microcrystalline cellulose, xanthan gum and crospovidone
  • Coated spheres were prepared as in Example 7, and mixed with acetaminophen and other excipients (mannitol, microcrystalline cellulose, carbopol, sodium bicarbonate and crospovidone) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into tablets.
  • acetaminophen and other excipients mannitol, microcrystalline cellulose, carbopol, sodium bicarbonate and crospovidone
  • Granules were prepared and coated as described in Example 1. The coated granules were then mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into oxycodone/acetaminophen tablets.
  • excipients carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose
  • Example 11 Oxycodone Hydrochloride / Acetaminophen Table 29: Oxycodone hydrochloride granule composition
  • Granules were prepared and coated as described in Example 1. The coated granules were then mixed with acetaminophen and other excipients (xanthan gum, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into oxycodone/ acetaminophen tablets.
  • excipients xanthan gum, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose
  • Granules were prepared and coated as described in Example 1. The coated granules were then mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into oxycodone/acetaminophen tablets.
  • excipients carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose
  • Granules were prepared and coated as described in Example 1. The coated granules were then mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into hydrocodone /acetaminophen tablets.
  • excipients carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose
  • Granules were prepared and coated as described in Example 1. The coated granules were then mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into hydrocodone /acetaminophen tablets.
  • excipients carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose
  • Example 15 Hydrocodone Bitartrate/ Acetaminophen Table 41 : Hydrocodone bitartrate granule composition
  • Granules were prepared and coated as described in Example 1. The coated granules were then mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into hydrocodone /acetaminophen tablets.
  • excipients carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose
  • Example 16 Hydrocodone Bitartrate/ Acetaminophen Table 44: Hydrocodone bitartrate granule composition
  • Granules were prepared and coated as described in Example 1. The coated granules were then mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into hydrocodone /acetaminophen tablets.
  • excipients carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose
  • Granules were prepared and coated as described in Example 1. The coated granules were then mixed with Paracetamol and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose and coloring agents) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into hydrocodone /acetaminophen tablets.
  • Table 48 Hydrocodone bitartrate granule composition
  • Granules are prepared and coated as described in Example 1. The coated granules are then mixed with the other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes.
  • Granules are prepared and coated as described in Example 1. The coated granules are then mixed with the other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes.
  • Magnesium stearate (non-bovine) is then added to lubricate the blend and the mixture is blended for an additional 5 minutes prior to compressing into phenobarbital tablets.
  • Granules are prepared and coated as described in Example 1. The coated granules are then mixed with the other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes.
  • Magnesium stearate (non-bovine) is then added to lubricate the blend and the mixture is blended for an additional 5 minutes prior to compressing into Diazepam tablets.
  • Granules are prepared and coated as described in Example 1. The coated granules are then mixed with the other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes.
  • Coated granules were prepared according to the Example 1 above.
  • the prepared coated granules were then mixed with Paracetamol and other excipients (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose, colorants such as FD and C blue, red iron oxide or yellow iron oxide are premixed and blended in a bin blender for 30 minutes.
  • Magnesium stearate was then added to lubricate the blend and the resulting mixture was blended for an additional 5 minutes prior to compressing into hydrocodone/ acetaminophen tablets .
  • Table 57 Hydrocodone / APAP Tablet compositions
  • the dosage form (intact and crushed) prepared according to Example 3 above (10/325mg hydrocodone bitartrate/ Acetaminophen tablet) was taken up in a small volume of water and extracted to simulate the amount of hydrocodone that was available to abusers via intravenous (IV) route.
  • the resultant mixture was assessed for ability to draw the mixture through a filter material into a syringe for IV injection.
  • Various needle sizes and extraction volumes were evaluated. Filtrates were assayed by HPLC for content of hydrocodone bitartrate.
  • Table 58 Amount of hydrocodone extracted from two lots of 10/325mg hydrocodone bitartrate/ Acetaminophen tablets at 100° C and Room Temperature (RT)
  • Example 25 Simulated nasal fluid extraction study of Formulations according to
  • the dosage form prepared according to Example 3 above (10/325mg hydrocodone bitartrate/ Acetaminophen tablets) was crushed using a pestle and mortar and placed in 10 mL of simulated nasal fluid at 37 °C, with gentle agitation to simulate the amount of hydrocodone bitartrate available for abuse by nasal insufflation. Aliquots were removed at 10 and 30 minutes for analysis of hydrocodone bitartrate by HPLC. The amount of hydrocodone bitartrate extracted from crushed tablets for simulated nasal insufflation is provided in the table below.
  • This method is for the determination of hydrocodone bitartrate released from simulated nasal fluid extractions of hydrocodone bitartrate extended-release tablets.
  • Solvent A (0.1% HFBA in H 2 0): Combine 1 mL of HFBA and 1 L of HPLC grade water, and mix well. Solvent A is stable for 14 days. Proportionate volumes may be prepared.
  • Mobile Phase 70:30 Solvent A:MeOH: Combine 700 mL of Solvent A and 300 mL of MeOH, and mix well. Prepared solutions are stable for 1 month. Proportionate volumes may be prepared.
  • the HPLC pump may be used to mix the mobile phase.
  • Diluent/Medium (0.1 N HCl): Combine 25 mL of 12 N HCl and 3 L of DI water, and mix well. 0. IN HCl is stable for 4 weeks. Proportionate volumes may be prepared.
  • Injector Flush (50:50 MeOH:H 2 0): Combine 500 mL of MeOH and 500 mL of HPLC grade water, and mix well. 50:50 MeOH:H 2 0 is stable for 1 month. Proportionate volumes may be prepared.
  • Proportionate volumes may be prepared.
  • Working Standard Solution Pipette 15 mL of each stock standard solution into separate 50-mL volumetric flasks. Dilute to volume with 0.1 N HCl diluent, and mix well. These working standard solutions are approximately 90 micrograms/mL (as anhydrous hydrocodone bitartrate) and are stable for 43 days under ambient laboratory conditions (unprotected from light). Proportionate volumes may be prepared.
  • the dosage form prepared according to Example 3 and 5 above was evaluated for multiple tablet oral abuse resistance by stirring the selected number of tablets in 300 mL of 0. IN HC1. Dissolution was performed using USP Apparatus II at 50 rpm and 37 °C. One to twelve tablets were added to the vessel simultaneously and aliquots were removed after 5, 10, 15, 30, 60, 120, 240 and 360 minutes of agitation and analyzed for hydrocodone bitartrate ( Figure 4) and APAP ( Figure 5) by HPLC. The results were plotted against time and appear in Figures 4 and 5.
  • the dosage form prepared according to Example 17 above was evaluated for multiple tablet oral abuse resistance by stirring the selected number of tablets in 300 mL of 0. IN HC1. Dissolution was performed using USP Apparatus II at 50 rpm and 37 °C. One to twelve tablets were added to the vessel simultaneously and aliquots were removed after 5, 10, 15, 30, 60, 120, 240 and 360 minutes of agitation and analyzed for hydrocodone bitartrate ( Figure 6) and APAP ( Figure 7) by HPLC. The results were plotted against time and appear in Figures 6 and 7.
  • the dosage form prepared according to Example 17 above was evaluated for multiple tablet oral abuse resistance by stirring the selected number of tablets in 300 mL of 0. IN HC1. Dissolution was performed using USP Apparatus II at 50 rpm and 37 °C. One to twelve tablets were added to the vessel simultaneously and aliquots were removed after 5, 10, 15, 30, 60, 120, 240 and 360 minutes of agitation and analyzed for hydrocodone bitartrate and APAP by HPLC. The results were plotted against time and appear in Figure 8 (hydrocodone bitartrate) and Figure 9 (APAP).
  • Example 27 Coated esketamine granules
  • Coated esketamine granules are prepared as per the process described in Example 1 with slight variation from Example 1 in components as illustrated below.
  • Table 60 Esketamine hydrochloride granule compositions
  • coated granules prepared per Example 27 above are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol,
  • microcrystalline cellulose microcrystalline cellulose
  • V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and the resulting mixture was blended for additional 5 minutes prior to compressing into tablets.
  • Example 29 Coated esketamine granules
  • Coated esketamine granules are prepared as per the process described in Example 1 with slight variation from Example 1 in components as illustrated in the Table below.
  • Coated granules prepared per Example 29 above are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate is added to lubricate the blend and the resulting mixture was blended for additional 5 minutes prior to compressing into tablets.
  • Example 31 Coated esketamine granules
  • Esketamine granules are manufactured using a process similar to that described in Example 1 above with some modification to the process.
  • the active ingredient instead of being layered on the granules resides in the core where it is granulated with other excipients as per the Table below, and is subsequently coated with Eudragit E-100.
  • Granules are manufactured in a high shear granulator where hypromellose, Esketamine hydrochloride and glyceryl behenate are dry mixed for 3 minutes. Then a 10%
  • hydroalcoholic solution of ethylcellulose is slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition is continued until the entire amount of ethylcellulose is added. The granules are then wet milled using a size reduction mill (Granumill) and subsequently loaded into fluid bed for drying.
  • a size reduction mill Granumill
  • Esketamine hydrochloride granules are then coated in a bottom spray fluid bed coater with 25 % alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate (2: 1). The coated granules are subsequently used in blending and compression process.
  • Table 64 Esketamine hydrochloride granule composition
  • Coated granules prepared per Example 31 above are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate is added to lubricate the blend and the resulting mixture was blended for additional 5 minutes prior to compressing into tablets.
  • Example 33 Coated esketamine granules
  • Esketamine granules are manufactured using a process similar to that described in Example 1 and Example 32 above with some modification to the process.
  • the active ingredient is granulated with other excipients per the table below, and is subsequently coated with Eudragit E- 100.
  • Granules containing Esketamine hydrochloride are manufactured in a high shear granulator where hypromellose, esketamine hydrochloride and glyceryl behenate are dry mixed for 3 minutes. Then a 10% hydroalcoholic solution of ethylcellulose is slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition is continued until the entire amount of ethylcellulose is added. The granules are then wet milled using a size reduction mill (Granumill) and then loaded into fluid bed for drying.
  • a size reduction mill Granules containing Esketamine hydrochloride
  • the granules are then coated in a bottom spray fluid bed coater with 25 % alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate (2:1). The resulting coated granules are subsequently used for blending and compression process.
  • coated granules prepared per Example 33 above are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Example 35 Coated Zolpidem granules
  • Coated Zolpidem tartrate granules are prepared as per the process described in Example 1 as per the composition illustrated in the Table below.
  • Table 68 Zolpidem tartrate granule compositions
  • Coated Zolpidem granules are prepared as per the process described in Example 35 above.
  • the coated granules are mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Quetiapine granules are manufactured using a process similar to that described in Example 1 above with some modification to the process.
  • the Quetiapine fumarate instead of being layered on the granules, resides in the core where it granulated along with other excipients per Table 70 (Granulation) and is subsequently coated with Eudragit E- 100 and magnesium stearate.
  • Granules are manufactured in a high shear granulator where hypromellose, Quetiapine fumarate, a portion of the Lutrol, sodium lauryl sulphate and glyceryl behenate are dry mixed for 3 minutes. Then a 10% hydroalcoholic solution of ethylcellulose is slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition is continued until the entire amount of ethylcellulose is added. The granules are then wet milled using a size reduction mill (Granumill) and then loaded into fluid bed for drying.
  • a size reduction mill Granules are then wet milled using a size reduction mill (Granumill) and then loaded into fluid bed for drying.
  • quetiapine fumarate granule composition The quetiapine fumarate granules are then coated in a bottom spray fluid bed coater with alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate. The resulting coated granules are then used in blending and compression process.
  • Table 70 Quetiapine fumarate coated granule composition
  • coated granules prepared per Example 37 above are subsequently mixed with other components (carbomer, crospovidone, remaining portion of Lutrol, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Example 39 Coated Quetiapine granules
  • Quetiapine granules are manufactured using a process similar to that described in Example 1 and with some modification to the process.
  • the Quetiapine fumarate instead of being layered on the granules, resides in the core where it is granulated along with other excipients per Table 72 and is subsequently coated with Eudragit E-100.
  • Granules are manufactured in a high shear granulator where hypromellose, Quetiapine fumarate, sodium lauryl sulphate, portion of Lutrol and glyceryl behenate are dry mixed for 3 minutes. Then a 10% hydroalcoholic solution of ethylcellulose is slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition is continued until the entire amount of ethylcellulose is added. The granules are then wet milled using a size reduction mill (Granumill) and then loaded into fluid bed for drying.
  • a size reduction mill Granules are then wet milled using a size reduction mill (Granumill) and then loaded into fluid bed for drying.
  • Quetiapine Fumarate granules are then coated in a bottom spray fluid bed coater with alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate. The resultant coated granules are subsequently used for blending and compression process.
  • Table 72 Quetiapine fumarate granule compositions
  • coated granules prepared as per Example 39 above are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose, and remaining portion of Lutrol) and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Example 41 Coated Hydromorphone granules
  • Coated hydromorphone granules are prepared as per the process described in Example 1 with slight variation from Example 1 in components as illustrated below.
  • Coated hydromorphone granules are prepared as per the process described in Example 1 and Example 41 above.
  • the coated granules are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Coated methamphetamme granules are prepared according to the process described in Example 1.
  • Coated methamphetamine granules are prepared as per the process described in Example 1 and Example 43 above.
  • the coated granules are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Coated oxymorphone granules are prepared as per the process described Example 1.
  • Coated oxymorphone granules are prepared as per the process described in
  • Example 1 and Example 45 above The coated granules are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes. Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • other components carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose
  • Coated oxycodone granules are prepared as per the process described in Example 1.
  • Coated oxycodone granules are prepared as per the process described in Example 1 and Example 47 above.
  • the coated granules are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Coated morphine granules are prepared as per the process described in Example 1.
  • Coated morphine granules are prepared as per the process described in Example 1 and Example 49 above.
  • the coated granules are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Example 51 Coated mixed amphetamine salts granules
  • Coated granules containing mixed amphetamine salts are prepared as per the process described in Example 1.
  • Table 84 Mixed amphetamine salt granule formulation
  • Coated granules containing mixed amphetamine salts are prepared as per the process described in Example 1 and Example 51 above.
  • the coated granules are subsequently mixed with other components such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Example 53 Codeine phosphate granules
  • Coated granules containing Codeine phosphate are prepared as per the process described in Example 1 with some modifications to the composition as described below.
  • Table 86 Codeine phosphate granule formulation
  • Coated granules containing codeine phosphate are prepared as per the process described in Example 1 and Example 53 above.
  • the coated granules are subsequently mixed with other active ingredient (paracetamol), and other components (carbomer, crospovidone, sodium bicarbonate, mannitol, colorant, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • active ingredient paracetamol
  • other components carbomer, crospovidone, sodium bicarbonate, mannitol, colorant, microcrystalline cellulose
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Table 87 Codeine phosphate/ APAP tablet formulation
  • Coated granules containing methylphenidate hydrochloride are prepared as per the process described in Example 1.
  • Coated granules containing methylphenidate hydrochloride are prepared as per the process described in Example 1 and Example 55 above.
  • the coated granules are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Example 57 Oxycodone hydrochloride granules
  • Coated granules containing oxycodone hydrochloride were prepared and coated as per the process described in Example 1.
  • Granules were manufactured in a high shear granulator where Hypromellose and glyceryl behenate were dry mixed for 3 minutes. Then a 10% hydroalcoholic solution of ethylcellulose N10 was slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition was continued until the entire amount of ethylcellulose was added. The granules were then wet milled using a size reduction mill (Granumill) and were subsequently loaded into fluid bed for drying. The prepared granules were then layered in a bottom spray fluid bed coater with a 12% aqueous solution of oxycodone hydrochloride and HPMC 2910 (2: 1).
  • the oxycodone hydrochloride layered granules were then coated in a bottom spray fluid bed coater with 25 % alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate (2: 1). The resulting coated granules were subsequently used for further blending and compression process.
  • Example 58 Oxycodone / acetaminophen tablets
  • coated granules prepared according to the example 57 above were mixed with another active agent, Paracetamol, and other excipients (carbomer, crospovidone, sodium bicarbonate, mannitol, FD&C blue, micro crystalline cellulose), and blended in a V- blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and blended for additional 5 minutes prior to compressing into oxycodone/ APAP tablets.
  • Table 91 Oxycodone hydrochloride tablet formulation
  • Example 59 Oxycodone / acetaminophen tablets
  • coated granules prepared according to the example 57 above were mixed with another active agent, Paracetamol, and other excipients ( carbomer, crospovidone, sodium bicarbonate, mannitol, FD&C blue, microcrystalline cellulose), and blended in a V- blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and blended for additional 5 minutes prior to compressing into oxycodone/ APAP tablets.
  • Table 92 Oxycodone / acetaminophen tablet formulations
  • Armodafmil granules are manufactured using a process similar to that described in Example 1 and with some modification to the process.
  • Armodafmil instead of being layered on the granules, resides in the core where it is granulated along with other excipients as per Table 93, and is subsequently coated with Eudragit E- 100.
  • Granules are manufactured in a high shear granulator where hypromellose, Armodafmil, povidone and glyceryl behenate are dry mixed for 3 minutes. Then a 10% hydroalcoholic solution of ethylcellulose is slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition is continued until the entire amount of ethylcellulose is added. The granules are then wet milled using a size reduction mill (Granumill) and subsequently loaded into fluid bed for drying.
  • a size reduction mill Granules are then wet milled using a size reduction mill (Granumill) and subsequently loaded into fluid bed for drying.
  • Armodafmil granules are then coated in a bottom spray fluid bed coater with alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate. The resultant coated granules are subsequently used for blending and compression process.
  • Table 93 Armodafinil granule formulations
  • coated granules prepared as per Example 60 above are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Phenobarbital granules are manufactured using a process similar to that described in Example 1 and with some modification to the process.
  • Phenobarbital instead of being layered on the granules, resides in the core where it is granulated along with other excipients per the Table below, and is subsequently coated with Eudragit E-100.
  • Granules are manufactured in a high shear granulator where hypromellose, phenobarbital, povidone and glyceryl behenate are dry mixed for 3 minutes. Then a 10% hydroalcoholic solution of ethylcellulose is slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition is continued until the entire amount of ethylcellulose is added. The granules are then wet milled using a size reduction mill (Granumill) and subsequently loaded into fluid bed for drying.
  • a size reduction mill Granules are then wet milled using a size reduction mill (Granumill) and subsequently loaded into fluid bed for drying.
  • Phenobarbital granule formulations are then coated in a bottom spray fluid bed coater with alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate. The resultant coated granules are subsequently used for blending and compression process.
  • Table 95 Phenobarbital granule formulations
  • coated granules prepared as per Example 62 above are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Coated diazepam granules are prepared as per the process described in Example 1 with slight variation from Example 1 in components as illustrated in the Table below.
  • Example 65 Diazepam tablets
  • Coated diazepam granules are prepared as per the process described in Example 1 and Example 64 above.
  • the coated granules are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Example 66 Hydrocodone bitartrate granules
  • Coated granules containing hydrocodone bitartrate are prepared as per the process described in Example 1.
  • Coated granules containing hydrocodone bitartrate are prepared as per the process described in Example 1 and Example 66 above.
  • the coated granules are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Granules were manufactured in a high shear granulator, where hypromellose, glyceryl behenate, and a portion (67%) of the ethylcellulose were dry mixed for 3 minutes. Then, a hydroalcoholic ( ⁇ 28 parts of water and ⁇ 72 parts of alcohol) solution of ethylcellulose (10% wt/wt) was slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition was continued until the entire amount of ethylcellulose was added. The granules were then wet milled using a size reduction mill (Granumill) and were subsequently loaded into fluid bed for drying.
  • a size reduction mill Granumill
  • the prepared granules were then layered in a bottom spray fluid bed coater with a
  • the oxycodone bitartrate layered granules were then coated in a bottom spray fluid bed coater with 25 % alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate.
  • the resulting coated granules were subsequently blended for homogeneity and used for further blending and compression process.
  • Coated granules were prepared according to the Example 68 above, and mixed with Paracetamol (manufactured using acetaminophen and gelatin) and other excipients (as listed in Table 104 below), and blended for approximately 270 revolutions.
  • Example 70 Coated Oxycodone Granules, 5%
  • Granules were prepared, layered with API and subsequently coated. These coated particles were then blended with other components and compressed into tablets.
  • Granules were manufactured in a high shear granulator, where hypromellose, a portion of ethyl cellulose and glyceryl behenate were dry mixed for 3 minutes. Then a 10% w/w hydroalcoholic ( ⁇ 28 parts of water and ⁇ 72 parts of ethanol) solution of ethyl cellulose 10 cP was slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition was continued until the entire amount of ethyl cellulose was added. The granules were then wet milled using a size reduction mill (Granumill) and were subsequently loaded into fluid bed for drying.
  • a size reduction mill Granumill
  • the prepared granules were then layered in a bottom spray fluid bed coater with a 12%) w/w aqueous solution of oxycodone hydrochloride and HPMC 2910 E3.
  • the oxycodone hydrochloride layered granules were then coated in a bottom spray fluid bed coater with 25 % alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate. The resulting coated granules were subsequently blended for homogeneity and used for further blending and compression process.
  • Example 71 Coated polymer granules
  • Granules were manufactured in a high shear granulator, where hypromellose, a portion of ethyl cellulose and glyceryl behenate were dry mixed for 3 minutes. Then a 10% w/w hydroalcoholic ( ⁇ 28 parts of water and ⁇ 72 parts of ethanol) solution of ethyl cellulose 10 cP was slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition was continued until the entire amount of ethyl cellulose was added. The granules were then wet milled using a size reduction mill (Granumill) and were subsequently loaded into fluid bed for drying.
  • a size reduction mill Granumill
  • Example 72 A and Example 72B are Example 72A and Example 72B:
  • the oxycodone hydrochloride coated granules were prepared according to the Example 70 and mixed with coated polymer granules prepared according to Example 71.
  • Another active agent i.e. Paracetamol (manufactured using acetaminophen and gelatin) and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol and microcrystalline cellulose were added and blended for approximately 270 revolutions.
  • Magnesium stearate was then added to lubricate the blend and blended for additional 45 revolutions prior to compressing into oxycodone/acetaminophen tablets.
  • Example 73 In vitro Analysis of multiple tablet oral abuse resistance
  • Example 72A and Example 72B The dosage form prepared according to Example 72A and Example 72B was evaluated for in vitro multiple tablet oral abuse resistance by stirring the selected number of tablets in 300 mL of 0.1N HCl. Dissolution was performed using USP apparatus II at 50 RPM and 37 °C. One to twelve tablets were added to the vessel simultaneously and aliquots were removed periodically and analyzed for oxycodone hydrochloride (Figure 10) and Acetaminophen (APAP) [Figure 11] by HPLC. The results were plotted against time and appear in Figure 10 and Figure 11.
  • oxycodone hydrochloride Figure 10
  • APAP Acetaminophen
  • Granules were manufactured in a high shear granulator, where hypromellose, a portion of ethyl cellulose and glyceryl behenate were dry mixed for 3 minutes. Then a 10% w/w hydroalcoholic ( ⁇ 28 parts of water and ⁇ 72 parts of ethanol) solution of ethyl cellulose 10 cP was slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition was continued until the entire amount of ethyl cellulose was added. The granules were then wet milled using a size reduction mill (Granumill) and were subsequently loaded into fluid bed for drying.
  • a size reduction mill Granumill
  • Example 75 Hydrocodone bitartrate Coated Granules, 5%
  • the granules prepared according to Example 74 were then layered in a bottom spray fluid bed coater with a 12% w/w aqueous solution of hydrocodone bitartate and HPMC 2910 E3.
  • the hydrocodone bitartrate layered granules were then coated in a bottom spray fluid bed coater with 25 % alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate.
  • hydrocodone bitartrate coated granules were prepared according to the Example 75 above and mixed with polymer granules prepared according to Example 74.
  • Another active agent i.e. Paracetamol (manufactured using acetaminophen and gelatin) and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose were added and blended for approximately 270 revolutions.
  • Magnesium stearate was then added to lubricate the blend and blended for additional 45 revolutions prior to compressing into hydrocodone/acetaminophen tablets.
  • Example 77 A and Example 77B Hydrocodone bitartrate tablets
  • hydrocodone bitartrate coated granules 5% were prepared according to the Example 75 above and mixed with coated polymer granules prepared according to Example 71.
  • Another active agent i.e. Paracetamol (manufactured using acetaminophen and gelatin) and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose were added to the blender and blended for approximately 270 revolutions.
  • Magnesium stearate was then added to lubricate the blend and blended for additional 45 revolutions prior to compressing into hydrocodone/ acetaminophen tablets.
  • Example 78 In vitro Analysis of multiple tablet oral abuse resistance
  • Example 76 and Example 77A and Example 77B were evaluated for in vitro multiple tablet oral abuse resistance by stirring the selected number of tablets in 300 mL of 0.1N HCl. Dissolution was performed using USP apparatus II at 50 RPM and 37 °C. One to twelve tablets were added to the vessel simultaneously and aliquots were removed periodically and analyzed for hydrocodone bitartrate (Figure 12) and APAP (Figure 13) by HPLC. The results were plotted against time and appear in Figure 12 and Figure 13.
  • Example 79 Coated Oxycodone Granules, 5%
  • Granules are prepared and subsequently coated. These coated particles are then blended with other components and compressed into tablets.
  • Granules are manufactured in a high shear granulator, where oxycodone hydrochloride, hypromellose, a portion of ethyl cellulose and glyceryl behenate is dry mixed for 3 minutes. Then a hydroalcoholic solution of ethyl cellulose 10 cP is slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition is continued until the entire amount of ethyl cellulose is added. The granules are then wet milled using a size reduction mill (Granumill) and subsequently loaded into fluid bed for drying. The oxycodone hydrochloride granules are then coated in a bottom spray fluid bed coater with 25 % alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate.
  • Example 80 Oxycodone/acetaminophen tablets
  • the oxycodone hydrochloride coated granules, 5% are prepared according to the Example 79 above and mixed with another active agent i.e. Paracetamol (manufactured using acetaminophen and gelatin) and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystallme cellulose and blended for approximately 270 revolutions. Magnesium stearate is then added to lubricate the blend and blended for additional 45 revolutions prior to compressing into oxycodone/acetaminophen tablets.
  • another active agent i.e. Paracetamol (manufactured using acetaminophen and gelatin) and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystallme cellulose and blended for approximately 270 revolutions.
  • Magnesium stearate is then added to lubricate the blend and blended for additional 45 revolutions
  • Oxycodone hydrochloride granules are prepared and subsequently coated. These coated particles are then blended with other components and compressed into tablets. Table 119: Granules Formulation
  • Granules are manufactured in a high shear granulator, where oxycodone hydrochloride, hypromellose, a portion of ethyl cellulose and glyceryl behenate is dry mixed for 3 minutes. Then a hydroalcoholic solution of ethyl cellulose 10 cP is slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition is continued until the entire amount of ethyl cellulose is added. The granules are then wet milled using a size reduction mill (Granumill) and subsequently loaded into fluid bed for drying. The oxycodone hydrochloride granules are then coated in a bottom spray fluid bed coater with 25 % alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate.
  • Example 82 Oxycodone/acetaminophen tablets
  • the oxycodone hydrochloride coated granules, 2.5% are prepared according to the Example 81 above and mixed with another active agent i.e. Paracetamol (manufactured using acetaminophen and gelatin) and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystallme cellulose and blended for approximately 270 revolutions. Magnesium stearate is then added to lubricate the blend and blended for additional 45 revolutions prior to compressing into oxycodone/acetaminophen tablets.
  • another active agent i.e. Paracetamol (manufactured using acetaminophen and gelatin) and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystallme cellulose and blended for approximately 270 revolutions.
  • Magnesium stearate is then added to lubricate the blend and blended for additional 45 revolutions
  • Oxycodone hydrochloride granules are prepared and subsequently coated. These coated particles are then blended with other components and compressed into tablets.
  • Granules are manufactured in a high shear granulator, where oxycodone hydro- chloride, hypromellose, a portion of ethyl cellulose and glyceryl behenate is dry mixed for 3 minutes. Then a hydroalcoholic solution of ethyl cellulose 10 cP is slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition is continued until the entire amount of ethyl cellulose is added. The granules are then wet milled using a size reduction mill (Granumill) and subsequently loaded into fluid bed for drying. The oxycodone hydrochloride granules are then coated in a bottom spray fluid bed coater with 25 % alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate.
  • Example 84 Oxycodone/acetaminophen tablets
  • the oxycodone hydrochloride coated granules, 3.75% are prepared according to the Example 83 above and mixed with another active agent i.e. Paracetamol
  • Oxycodone hydrochloride granules are prepared and subsequently coated. These coated particles are then blended with other components and compressed into tablets. Table 125: Granules Formulation
  • Granules are manufactured in a high shear granulator, where oxycodone hydrochloride, hypromellose, a portion of ethylcellulose and glyceryl behenate is dry mixed for 3 minutes. Then a hydroalcoholic solution of ethyl cellulose 10 cP is slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition is continued until the entire amount of ethyl cellulose is added. The granules are then wet milled using a size reduction mill (Granumill) and subsequently loaded into fluid bed for drying. The oxycodone hydrochloride granules are then coated in a bottom spray fluid bed coater with 25 % alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate.
  • the oxycodone hydrochloride coated granules, 4% are prepared according to Example 85 above and mixed with another active agent i.e. Paracetamol (manufactured using acetaminophen and gelatin) and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystallme cellulose and blended for approximately 270 revolutions. Magnesium stearate is then added to lubricate the blend and blended for additional 45 revolutions prior to compressing into oxycodone/acetaminophen tablets.
  • another active agent i.e. Paracetamol (manufactured using acetaminophen and gelatin) and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystallme cellulose and blended for approximately 270 revolutions.
  • Magnesium stearate is then added to lubricate the blend and blended for additional 45 revolutions prior to
  • Oxycodone granules are prepared, and subsequently coated. These coated particles are then blended with other components and compressed into tablets.
  • Granules are manufactured in a high shear granulator, where oxycodone hydrochloride, hypromellose, a portion of ethyl cellulose and glyceryl behenate is dry mixed for 3 minutes. Then a hydroalcoholic solution of ethyl cellulose 10 cP is slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition is continued until the entire amount of ethyl cellulose is added. The granules are then wet milled using a size reduction mill (Granumill) and subsequently loaded into fluid bed for drying. The oxycodone hydrochloride granules are then coated in a bottom spray fluid bed coater with 25 % alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate.
  • the oxycodone hydrochloride coated granules (3%) are prepared according to Example 87 above and mixed with another active agent i.e. Paracetamol (manufactured using acetaminophen and gelatin) and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose and blended for approximately 270 revolutions. Magnesium stearate is then added to lubricate the blend and blended for additional 45 revolutions prior to compressing into oxycodone/acetaminophen tablets.
  • another active agent i.e. Paracetamol (manufactured using acetaminophen and gelatin) and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose and blended for approximately 270 revolutions.
  • Magnesium stearate is then added to lubricate the blend and blended for additional 45 revolutions prior to compressing into oxyco
  • Oxycodone granules are prepared and subsequently coated. These coated particles are then blended with other components and compressed into tablets.
  • Granules are manufactured in a high shear granulator, where oxycodone hydrochloride, hypromellose, a portion of ethyl cellulose and glyceryl behenate is dry mixed for 3 minutes. Then a hydroalcoholic solution of ethyl cellulose 10 cP is slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition is continued until the entire amount of ethyl cellulose is added. The granules are then wet milled using a size reduction mill (Granumill) and subsequently loaded into fluid bed for drying. The oxycodone hydrochloride granules are then coated in a bottom spray fluid bed coater with 25 % alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate.
  • Example 90 Oxycodone/acetaminophen tablets
  • the oxycodone hydrochloride coated granules, 3.5% are prepared according to the Example 89 above and mixed with another active agent i.e. Paracetamol (manufactured using acetaminophen and gelatin) and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystallme cellulose and blended for approximately 270 revolutions. Magnesium stearate is then added to lubricate the blend and blended for additional 45 revolutions prior to compressing into oxycodone/acetaminophen tablets.
  • another active agent i.e. Paracetamol (manufactured using acetaminophen and gelatin) and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystallme cellulose and blended for approximately 270 revolutions.
  • Magnesium stearate is then added to lubricate the blend and blended for additional 45 revolutions
  • Oxycodone hydrochloride granules are prepared and subsequently coated. These coated particles are then blended with other components and compressed into tablets.
  • Granules are manufactured in a high shear granulator, where oxycodone hydrochloride, hypromellose, a portion of ethyl cellulose and glyceryl behenate is dry mixed for 3 minutes. Then a hydroalcoholic solution of ethyl cellulose 10 cP is slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition is continued until the entire amount of ethyl cellulose is added. The granules are then wet milled using a size reduction mill (Granumill) and subsequently loaded into fluid bed for drying. The oxycodone hydrochloride granules are then coated in a bottom spray fluid bed coater with 25 % alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate.
  • the oxycodone hydrochloride coated granules, 5.25% are prepared according to the Example 91 above and mixed with another active agent i.e. Paracetamol
  • hydrocodone bitartrate coated granules were prepared according to the Example 75 and mixed with another active agent i.e. Paracetamol (manufactured using acetaminophen and gelatin) along with other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose (blended for approximately 270 revolutions). Magnesium stearate was then added to lubricate the blend and blended for additional 45 revolutions prior to compressing into hydrocodone/acetaminophen tablets.
  • Paracetamol manufactured using acetaminophen and gelatin
  • other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose (blended for approximately 270 revolutions).
  • Magnesium stearate was then added to lubricate the blend and blended for additional 45 revolutions prior to compressing into hydrocodone/acetaminophen tablets.
  • Example 94 In vitro Analysis of multiple tablet oral abuse resistance - Crushed and Intact Tablets
  • the dosage form (crushed or intact) prepared according to Example 93 was evaluated for in vitro multiple tablet oral abuse resistance by conducting dissolution experiments in 300 mL or 900 mL of 0.1N HCl. Dissolution was performed using USP apparatus II at 50 RPM and 37 °C. Twelve tablets (crushed or intact) were added to the vessel simultaneously or sequentially and aliquots were removed periodically and were analyzed for hydrocodone bitartrate and APAP by HPLC. Crushing of the tablets was carried out using a morter and pestle (twelve strokes). The results were plotted against time and appear in Figure 14 and Figure 15.
  • Coated granules prepared per Example 31 are subsequently mixed with coated polymer granules prepared according to Example 71 , and other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended for 270 revolutions. Magnesium stearate is added to lubricate the blend and the resulting mixture was blended for additional 45 revolutions prior to compressing into tablets.
  • Table 138 Tablet Formulation
  • Coated granules prepared per Example 31 are subsequently mixed with polymer granules prepared according to Example 74, and other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended for 270 revolutions.
  • Magnesium stearate is added to lubricate the blend and the resulting mixture was blended for additional 45 revolutions prior to compressing into tablets.
  • coated granules prepared per Example 27 are subsequently mixed with coated polymer granules prepared according to Example 71 and other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystallme cellulose) and blended for 270 revolutions.
  • coated polymer granules prepared according to Example 71 and other components carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystallme cellulose
  • Magnesium stearate is added to lubricate the blend and the resulting mixture was blended for additional 45 revolutions prior to compressing into tablets.
  • coated granules prepared per Example 27 above are subsequently mixed with polymer granules prepared according to Example 74 and other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystallme cellulose) and blended for 270 revolutions.
  • Magnesium stearate is added to lubricate the blend and the resulting mixture was blended for additional 45 revolutions prior to compressing into tablets.

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Emergency Medicine (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des formes pharmaceutiques orales à libération immédiate qui possèdent des propriétés anti-abus. Plus précisément, les formes pharmaceutiques selon l'invention dissuadent de tout abus par l'ingestion de multiples doses individuelles. En outre, les formes pharmaceutiques selon l'invention protègent contre toute overdose cas d'ingestion accidentelle ou intentionnelle de multiples doses individuelles.
EP14858628.2A 2013-10-31 2014-10-29 Formes pharmaceutiques en granulés anti-abus à libération immédiate Withdrawn EP3062778A4 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US201361898207P 2013-10-31 2013-10-31
PCT/US2014/047014 WO2015065547A1 (fr) 2013-10-31 2014-07-17 Formes pharmaceutiques en granulés anti-abus à libération immédiate
US14/333,986 US20150118300A1 (en) 2013-10-31 2014-07-17 Immediate Release Abuse-Deterrent Granulated Dosage Forms
US14/477,354 US20150118301A1 (en) 2013-10-31 2014-09-04 Immediate Release Abuse-Deterrent Granulated Dosage Forms
PCT/US2014/054061 WO2015065586A1 (fr) 2013-10-31 2014-09-04 Formes pharmaceutiques en granulés anti-abus à libération immédiate
US14/484,793 US20150118295A1 (en) 2013-10-31 2014-09-12 Immediate Release Abuse-Deterrent Granulated Dosage Forms
PCT/US2014/062887 WO2015066172A1 (fr) 2013-10-31 2014-10-29 Formes pharmaceutiques en granulés anti-abus à libération immédiate

Publications (2)

Publication Number Publication Date
EP3062778A1 true EP3062778A1 (fr) 2016-09-07
EP3062778A4 EP3062778A4 (fr) 2017-07-19

Family

ID=53005066

Family Applications (1)

Application Number Title Priority Date Filing Date
EP14858628.2A Withdrawn EP3062778A4 (fr) 2013-10-31 2014-10-29 Formes pharmaceutiques en granulés anti-abus à libération immédiate

Country Status (5)

Country Link
EP (1) EP3062778A4 (fr)
CA (1) CA2900858C (fr)
EA (1) EA032013B1 (fr)
IL (1) IL245125B (fr)
WO (1) WO2015066172A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150118300A1 (en) 2013-10-31 2015-04-30 Cima Labs Inc. Immediate Release Abuse-Deterrent Granulated Dosage Forms
JP6696994B2 (ja) 2014-12-08 2020-05-20 クレシオ・バイオサイエンシズ・リミテッド 即放性乱用抑止性顆粒剤形
WO2018044895A1 (fr) * 2016-08-29 2018-03-08 Cima Labs Inc. Formes posologiques à libération immédiate permettant la dissuasion des abus et présentant une résistance à l'alcool
KR20210028159A (ko) 2018-06-27 2021-03-11 클렉시오 바이오사이언시스 리미티드 주요 우울 장애를 치료하는 방법
KR20210074275A (ko) 2018-10-05 2021-06-21 클렉시오 바이오사이언시스 리미티드 주요 우울 장애를 치료하기 위한 에스케타민의 복용 요법
US20220062200A1 (en) 2019-05-07 2022-03-03 Clexio Biosciences Ltd. Abuse-deterrent dosage forms containing esketamine
EP3965733A4 (fr) 2019-05-07 2023-01-11 Clexio Biosciences Ltd. Formes posologiques dissuasives d'abus contenant de l'eskétamine
EP4084786A1 (fr) 2019-12-30 2022-11-09 Clexio Biosciences Ltd. Régime posologique à base d'eskétamine pour le traitement d'un trouble dépressif majeur

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9401894D0 (en) * 1994-02-01 1994-03-30 Rhone Poulenc Rorer Ltd New compositions of matter
ES2284643T3 (es) * 2000-04-20 2007-11-16 Novartis Ag Composicion de revestimiento enmascarante del sabor.
CN1525851A (zh) * 2001-05-11 2004-09-01 ������ҩ�����޹�˾ 抗滥用阿片样物质控释剂型
US9125833B2 (en) * 2005-11-02 2015-09-08 Relmada Therapeutics, Inc. Multimodal abuse resistant and extended release opioid formulations
US20090022798A1 (en) * 2007-07-20 2009-01-22 Abbott Gmbh & Co. Kg Formulations of nonopioid and confined opioid analgesics
BRPI0815387B8 (pt) * 2007-08-13 2021-05-25 Abuse Deterrent Pharmaceutical Llc composição farmacêutica, método para fazer uma composição farmacêutica e uso da composição farmacêutica
WO2010044842A1 (fr) * 2008-10-16 2010-04-22 University Of Tennessee Research Foundation Formes pharmaceutiques orales inviolables contenant un agent embolisant
EP2635258A1 (fr) * 2010-11-04 2013-09-11 AbbVie Inc. Formulations de médicaments
JP6199321B2 (ja) * 2012-03-02 2017-09-20 ローズ ファーマシューティカルズ エル．ピー． 不正使用抵抗性の即時放出製剤

Also Published As

Publication number Publication date
EP3062778A4 (fr) 2017-07-19
IL245125B (en) 2021-06-30
CA2900858C (fr) 2017-05-02
WO2015066172A1 (fr) 2015-05-07
EA032013B1 (ru) 2019-03-29
CA2900858A1 (fr) 2015-05-07
EA201690874A1 (ru) 2016-08-31
IL245125A0 (en) 2016-06-30

Similar Documents

Publication Publication Date Title
US11844796B2 (en) Immediate release abuse-deterrent granulated dosage forms
US11534409B2 (en) Immediate release abuse-deterrent granulated dosage forms
AU2014342412A1 (en) Immediate release abuse-deterrent granulated dosage forms
CA2900858C (fr) Formes pharmaceutiques en granules anti-abus a liberation immediate
US11324707B2 (en) Abuse-deterrent dosage forms containing esketamine
US20170157052A1 (en) Immediate release dosage forms that deter abuse by oral ingestion of multiple dosage units
BR112016009748B1 (pt) Formas de dosagem oral de liberação imediata dissuasora de uso abusivo e usos da mesma

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20160525

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

A4 Supplementary search report drawn up and despatched

Effective date: 20170621

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 9/20 20060101AFI20170614BHEP

Ipc: A61P 25/04 20060101ALI20170614BHEP

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20181008

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: CLEXIO BIOSCIENCES LTD.

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Effective date: 20220117