CA2822769A1 - Tamper resistant solid oral dosage forms - Google Patents
Tamper resistant solid oral dosage forms Download PDFInfo
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- CA2822769A1 CA2822769A1 CA2822769A CA2822769A CA2822769A1 CA 2822769 A1 CA2822769 A1 CA 2822769A1 CA 2822769 A CA2822769 A CA 2822769A CA 2822769 A CA2822769 A CA 2822769A CA 2822769 A1 CA2822769 A1 CA 2822769A1
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- 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
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
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- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- 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
-
- 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
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- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
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- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
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- 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
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- 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
- A61K9/5089—Processes
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- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
Abstract
Disclosed in certain embodiments is a solid oral dosage form comprising: (a) an inert tamper resistant core; and (b) a coating surrounding the core, the coating comprising an active agent.
Description
TAMPER RESISTANT SOLID ORAL DOSAGE FORMS
FIELD OF THE INVENTION
[0001] The present invention relates to the field of solid oral pharmaceutical dosage forms that are resistant to tampering such as splitting, crushing, shearing, grinding or chewing.
BACKGROUND
FIELD OF THE INVENTION
[0001] The present invention relates to the field of solid oral pharmaceutical dosage forms that are resistant to tampering such as splitting, crushing, shearing, grinding or chewing.
BACKGROUND
[0002] Solid oral pharmaceutical dosage forms, most often in the form of tablets, are a common mode of delivering active agents for the treatment or prevention of diseases and conditions. For a variety of reasons, patients who are prescribed these dosage forms sometimes attempt to split or divide the formulation into multiple units.
These reasons include cost containment, as the price of a specified amount of a dosage form in a given strength is often less than double the price (or the same price) as compared to the same amount of dosage forms in half the strength. This provides the incentive for a patient to split their dose under their own initiative, or under the direction of their health care provider. There have also been proposals for mandatory tablet splitting by various state Medicaid programs.
These reasons include cost containment, as the price of a specified amount of a dosage form in a given strength is often less than double the price (or the same price) as compared to the same amount of dosage forms in half the strength. This provides the incentive for a patient to split their dose under their own initiative, or under the direction of their health care provider. There have also been proposals for mandatory tablet splitting by various state Medicaid programs.
[0003] Tablet splitting can be problematic if the patient has cognitive impairment that limits the ability of the patient to understand and remember instructions for tablet splitting; or arthritis or other impairment of manual dexterity; or Parkinson's disease or other tremors; or visual impairment.
[0004] Another problem with tablet splitting is overdosing or underdosing as it is often difficult to split tablets with a degree of certainty as to the dose contained in each fragment. This can be a particular issue with respect to active agents with a narrow therapeutic window (e.g., warfarin, levothyroxine and digoxin), where a slight variation in dosing can lead to sub-therapeutic or toxic plasma levels.
[0005] Further, the splitting of certain controlled release dosage forms (e.g., opioids, theophylline, calcium channel blockers) compromises the integrity of the dosage form, resulting in the immediate release of an amount of active agent intended for release over an extended period of time. This can also result in toxic plasma levels.
[0006] A study of 11 commonly split tablets showed that 8 of the 11 tablets, when split, failed to produce half-tablets that met the content uniformity test for tablets from the United States Pharmacopeia, which requires a discrepancy that falls within 85% and 115% of the intended dosage. Notably, scoring of the tablet did not predict whether the tablet would pass or fail this test. See, Teng et al. Lack of medication dose uniformity in commonly split tablets. J Am Pharm Assoc. 2002;42:195-9.
[0007] Splitting or crushing of dosage forms of drugs susceptible to abuse (e.g., opioid analgesics) is also a common method of abusers to obtain an amount of active agent for illicit use. For example, immediate release opioid formulations can be split or crushed in order to provide the active agent available for parenteral or nasal abuse.
[0008] Controlled release opioid formulations can also be split or crushed in order to make the active agent available therein (intended for release over an extended period) available for immediate parenteral, nasal or oral administration.
[0009] There is a need in the art for both immediate and controlled release solid oral dosage forms that are resistant to tampering (e.g., splitting or crushing) which minimize the problems associated therewith.
[0010] All references disclosed herein are incorporated by reference in their entireties for all purposes.
SUMMARY OF THE INVENTION
SUMMARY OF THE INVENTION
[0011] It is an object of certain embodiments of the present invention to provide a solid oral dosage form comprising an active agent (e.g., an opioid analgesic), which is resistant to tampering (e.g., splitting, crushing, shearing, grinding, chewing or a combination thereof).
[0012] It is an object of certain embodiments of the present invention to provide a solid oral dosage form comprising an active agent, which is subject to less overdosing caused by splitting the dosage form into uneven doses.
[0013] It is an object of certain embodiments of the present invention to provide a solid oral dosage form comprising an active agent, which is subject to less underdosing caused by splitting the dosage form into uneven doses.
[0014] It is an object of certain embodiments of the present invention to provide a solid oral dosage form comprising an active agent susceptible to abuse (e.g., an opioid analgesic), which is subject to less parenteral abuse than other dosage forms.
[0015] It is an object of certain embodiments of the present invention to provide a solid oral dosage form comprising an active agent susceptible to abuse, which is subject to less intranasal abuse than other dosage forms.
[0016] It is an object of certain embodiments of the present invention to provide a solid oral dosage form comprising an active agent susceptible to abuse, which is subject to less oral abuse than other dosage forms.
[0017] It is an object of certain embodiments of the present invention to provide a solid oral dosage form comprising an active agent susceptible to abuse, which is subject to less diversion than other dosage forms.
[0018] It is a further object of certain embodiments of the present invention to provide a method of treating pain in human patients with a solid oral dosage form comprising an opioid analgesic while reducing the abuse potential of the dosage form.
[0019] It is a further object of certain embodiments of the present invention to treat a disease or condition (e.g., pain) by administering a solid oral dosage form as disclosed herein to a patient in need thereof
[0020] It is a further object of certain embodiments of the present invention to provide a method of manufacturing an oral dosage form of an active agent (e.g., an opioid analgesic) as disclosed herein.
[0021] It is a further object of certain embodiments of the present invention to provide a use of a medicament in the manufacture of a dosage form as disclosed herein that is resistant to tampering (e.g., splitting, crushing, shearing, grinding, chewing or a combination thereof).
[0022] It is a further object of certain embodiments of the present invention to provide a use of a medicament (e.g., an opioid analgesic) in the manufacture of a dosage form as disclosed herein for the treatment of a disease state (e.g., pain).
[0023] These objects and others are accomplished by the present invention, which in certain embodiments is directed to a solid oral dosage form comprising (a) an inert tamper resistant core; and (b) a coating surrounding the core, the coating comprising an active agent.
[0024] In certain embodiments, the present invention is directed to a method of preparing a solid oral dosage form comprising: surrounding an inert tamper resistant core with a coating comprising an active agent.
[0025] In certain embodiments, the present invention is directed to a method of preparing a solid oral dosage form comprising: (a) preparing an inert tamper resistant core; and (b) surrounding the core with a coating comprising an active agent.
[0026] In certain embodiments, the present invention is directed to a method of treating a subject or patient for a disease or condition comprising administering to a subject or patient in need thereof a solid oral dosage form as disclosed herein. The methods of treating a disease or condition include single or repeated dosing over a time interval.
[0027] In certain embodiments, the present invention is directed to a method of providing preventative treatment to a subject or patient comprising administering to a subject or patient in need thereof a solid oral dosage form as disclosed herein. The preventative methods include single or repeated dosing over a time interval.
[0028] In certain embodiments, the present invention is directed to a method of treating pain comprising administering to a patient in need thereof, a solid oral dosage form comprising an opioid analgesic as disclosed herein.
[0029] In certain embodiments, the present invention is directed to a method of reducing the incidence of overdosing, comprising dispensing a solid oral dosage form as disclosed herein.
[0030] In certain embodiments, the present invention is directed to a method of reducing the incidence of underdosing, comprising dispensing a solid oral dosage form as disclosed herein.
[0031] In certain embodiments, the present invention is directed to a method of reducing the abuse potential of an active agent susceptible to abuse comprising dispensing a solid oral dosage form as disclosed herein.
[0032] In certain embodiments, the present invention is directed to method of reducing the incidence of overdosing, comprising preparing a solid oral dosage form as disclosed herein.
[0033] In certain embodiments, the present invention is directed to method of reducing the incidence of underdosing, comprising preparing a solid oral dosage form as disclosed herein.
[0034] In certain embodiments, the present invention is directed to a method of reducing the abuse potential of an active agent susceptible to abuse comprising preparing a solid oral dosage form as disclosed herein.
[0035] In certain embodiments, the present invention is directed to a use of a drug in the preparation of a tamper resistant solid oral dosage form for treating or preventing a disease, the dosage form comprising: (a) an inert tamper resistant core;
and (b) a coating surrounding the core, the coating comprising an active agent.
and (b) a coating surrounding the core, the coating comprising an active agent.
[0036] In certain embodiments, the present invention is directed to a use of a drug susceptible to abuse in the preparation of a tamper resistant solid oral dosage form, the dosage form comprising: (a) an inert tamper resistant core; and (b) a coating surrounding the core, the coating comprising an active agent.
[0037] The term "inert" with respect to an inert core means that an active agent is not included in the core. This does not include a minimal amount of active agent that may migrate into the core from the coating during the manufacturing process or during storage. The term "inert" also does not exclude aversive agents such as opioid antagonists in the core of the present invention.
[00381 The term "sustained release" is defined for purposes of the present invention as the release of the drug at such a rate that blood (e.g., plasma) concentrations are maintained within the therapeutic range but below toxic concentrations over a period of time of at least about 12 hours or longer, or at least 24 hours or longer.
Preferably, a controlled release dosage form can provide once daily or twice daily dosing.
[0039] The term "controlled-release" encompasses "sustained release", "extended release", "delayed release" or any other modified (i.e., non-immediate) release.
[0040] The term "polyethylene oxide" is defined for purposes of the present invention as a composition of polyethylene oxide having a molecular weight of at least 25,000, based on rheological measurements, and preferably having a molecular weight of at least 100,000. Compositions with lower molecular weight are usually referred to as polyethylene glycols.
[0041] For purposes of the present invention, the term "opioid analgesic"
means one or more compounds selected from base opioid agonists, mixed opioid agonist-antagonists, partial opioid agonists, pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates and solvates thereof and mixtures thereof.
[0042] The term "patient" means a subject who has presented a clinical manifestation of a particular symptom or symptoms suggesting the need for treatment, who is treated preventatively or prophylactically for a condition, or who has been diagnosed with a condition to be treated.
[0043] The term "subject" is inclusive of the definition of the term "patient"
and does not exclude individuals who are entirely normal in all respects or with respect to a particular condition.
[0044] As used herein, the term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
[0045] As used herein, resistance to splitting, crushing, shearing, grinding and/or chewing results from a dosage form (or any portion thereof) having a preferable breaking strength of at least 400 Newtons.
[0046] The term "chiral center" refers to a carbon atom to which four different groups are attached.
[0047] The term "enantiomer" or "enantiomeric" refers to a molecule that is nonsuperimposable on its mirror image and hence optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction.
[0048] The term "racemic" refers to a mixture of enantiomers.
[0049] The term "resolution" refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.
BRIEF DESCRIPTION OF THE DRAWINGS
[0050] FIG. 1 is a graphical representation of a single coated core embodiment of the present invention.
[0051] FIG. 2 is a graphical representation of a multiparticulate embodiment of the present invention.
[0052] FIG. 3 is a graphical representation of a unitary core of the present invention.
[0053] FIG. 4 is a graphical representation of a core of the present invention having an inner component and an outer component.
DETAILED DESCRIPTION
[0054] In some instances, for particular medications, tablet splitting is condoned or even encouraged by physicians as a means of reducing the high cost of prescription drugs. Widespread use of tablet splitting, however, without consideration of the patient and the particular dosage form can have detrimental effect.
[0055] Potential detrimental effects include (i) an increased amount of drug released over a short period of time associated with splitting certain controlled release dosage forms (e.g., controlled release opioids); (ii) an upset stomach or foul taste in a patient's mouth with splitting dosage forms of foul tasting or gastro-irritative agents (e.g., ciprofloxacin, aspirin); (iii) unusable fragments with the attempted splitting of friable dosage forms such as sublingual nitroglycerin;
and (iv) uneven dosing with more drug in one half than in the other, which is a particular problem with drugs tablet which require a narrow therapeutic window for each individual patient (e.g., levothyroxine, warfarin and digoxin).
[0056] Splitting and crushing is also a methodology utilized by drug abusers in order to liberate active agent from a dosage form for illicit use (e.g., parenteral, nasal or oral abuse). This is a problem with both immediate release and controlled release dosage forms containing drugs susceptible to abuse (e.g., opioid analgesics or stimulants).
[0057] The present invention thus provides a solid oral dosage form that is resistant to tampering (e.g., splitting, crushing, shearing, grinding, chewing or a combination thereof) that might otherwise be carried out in order to liberate the active agent contained therein, thus reducing the likelihood of these associated detrimental effects.
[0058] Referring to Fig. 1, the dosage forms of the present invention may comprise an inert (i.e., without an active agent) tamper resistant core (10); and a coating surrounding the core (11), the coating comprising an active agent (12).
[0059] The dosage form can be a single coated core (e.g., in tablet form) which coating contains the entire intended dose as depicted in Fig. 1 or can be in the form of multiparticulates as depicted in Fig. 2, with a plurality of tamper resistant coated cores (20). The tamper resistant coated cores have an active agent coating surrounding each core, with the active agent divided among the plurality of coated cores. The multiparticulates can be contained in an optional pharmaceutically acceptable capsule (21).
[0060] As depicted in Figure 3, the inert tamper resistant core can be unitary (30) with a sufficient hardness in order to be tamper resistant or as depicted in Fig. 4, can have an inner component (40) which is tamper or non-tamper resistant, that is coated with a tamper resistant outer component (41) of a suitable hardness.
[0061] The coating on the inert tamper resistant cores can have a suitable amount of active agent to provide a therapeutic effect. Depending on the active agent, the amount can be, e.g., from about 0.1 mg to about 1 gram, about 1 mg to about mg, or about 10 mg to about 100 mg. Typically, the weight of the coating when applied to the inert cores is about 1% to about 25% of the total weight of the dosage form although this can be higher or lower depending on the load of active agent required for a therapeutic effect.
[0062] The tamper resistant cores of the present invention are of a sufficient hardness to present difficulty in splitting, crushing, shearing, grinding or chewing the final dosage form in an attempt to fragment the dosage form. Preferably, the tamper resistant core has a breaking strength of at least about 400Newtons, at least about 500 Newtons, at least about 600 Newtons, at least about 700 Newtons, at least about 800 Newtons or at least about 1 KiloNewton.
[0063] The present invention further provides a pharmaceutical package comprising a single or plurality of solid oral dosage forms, e.g., tablets, of the present invention. The package can be, e.g., a blister pack, bottle, tube, bags, vial, box, container or any other suitable packaging material. The container can hold an amount of dosage forms such as 1 to 5000, 1 to 1000, 1 to 500, 1 to 120, 1 to 100, 1 to 90, 1 to 60, 1 to 50, 1 to 30, 1 to 28, 1 to 21, 1 to 14, 1 to 7 or 1 to 5.
Specific amounts of dosage forms included in packaging materials include 1 (single dose), 7 (e.g., once daily dosing for one week), 14 (e.g., twice daily dosing for one week), 21 (e.g., three times daily dosing for 1 week), 28 (e.g., four times daily dosing for 1 week), 30 (e.g., once daily dosing for one month), 60 (e.g., twice daily dosing for one month), 90 (e.g., three times daily dosing for 1 month), 100 (typically a 1-3 month supply) or 120 (e.g., four times daily dosing for 1 month).
IMMEDIATE RELEASE DOSAGE FORMS
[0064] The solid oral dosage forms of the present invention can be in the form of an inert tamper resistant core coated with an immediate release coating of the active agent. Immediate release dosage forms of drugs susceptible to abuse are sometimes split or crushed in order for the drug to be readily available for parenteral or nasal abuse. Thus, the present invention may discourage the illicit use of immediate release formulations by inhibiting the ability to effectively split or crush the dosage form. The immediate release tamper resistant dosage forms of the present invention also discourage the splitting of dosage forms that can result in an overdose or underdose of the active agent contained therein.
[0065] The immediate release coating can be applied by various methodologies such as spray coating, dipping, powder layering or compression coating. In embodiments wherein the active agent does not provide the necessary bulk to process the immediate release coating, various excipients can be utilized in order to facilitate processing.
[0066] In spray coated dosage forms, the active agent is typically dissolved in solution and sprayed onto the inert cores of the present invention in either single or multiparticulate form. The process may include spraying of very finely atomized droplets of solution onto the inert cores in a stream of hot process air or other suitable gas. By having the drug in solution rather than suspension, improved uniformity of the coating can be achieved. The solution can be an aqueous or organic solvent and include various binders such as polyvinylpyrrolidone, natural and synthetic gums including gum arabic, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, methylcellulose, pullulan, dextrin, starch, polyvinyl alcohol among others.
[0067] In powder layering, inert tamper resistant cores of the present invention may be spray coated with a binder to provide tackiness. The active agent in powder form is then sprayed onto the binder coated inert cores. The spraying powder comprising the active agent may also include additional excipients, including glidants, diluents, stabilizers, coloring agents, and additional binders. Suitable glidants include, e.g., colloidal silicon dioxide and/or talc. Suitable diluents include, e.g., polysaccharides, monosaccharides, corn starch, and the like.
[0068] In compression coating, the active agent is combined with suitable excipients (e.g., glidants, diluents) and compression coated onto the inert tamper resistant cores of the present invention. In certain embodiments, a Manesty Dry-Cota press (e.g., Model 900) can be utilized. This apparatus consists of two side by side interconnected tablet presses where the inert core is made on one press and then mechanically transferred to the next press for compression coating. Each press has an independent powder feed mechanism so that the inert core blend is loaded on one machine, and the coating blend is loaded on the other machine. Mechanical transfer arms rotate between the machines to remove cores from the core press and transfer them to the coating press. Other presses which may be used to prepare the dosage forms of the present invention include Elizabeth Hata HT-AP44-MSU-C; Killian RLUD; and Fette PT 4090, each of which has a dual feed system for coating blend and pre-made cores.
[0069] In any of the above immediate release coating embodiments, a film coat (e.g., for taste, protective or cosmetic purposes) can be overcoated on the immediate release layer and/or utilized as an undercoat between the inert core and the active agent layer. An example of such a coating is Opadry .
CONTROLLED RELEASE DOSAGE FORMS
[0070] The solid oral dosage forms of the present invention can be in the form of an inert tamper resistant core coated with a controlled release coating of the active agent. Splitting controlled release dosage forms is subject to the same issues as immediate release dosage forms (e.g., parenteral and nasal abuse, non-uniform fragments). In addition, controlled release dosage forms are subject to oral abuse when an amount of drug intended for an extended period of time is liberated for immediate illicit use by splitting or crushing. Thus, the dosage forms of the present invention discourage the illicit use of controlled release formulations.
Further, if a patient administers a half tablet of many controlled release dosage forms (without illicit intent), often the integrity of the dosage form is compromised and a toxic amount of active agent can be released. The controlled release tamper resistant dosage forms of the present invention also discourage the splitting of dosage forms that can result in an overdose or underdose of the active agent contained therein.
[0071] In certain embodiments, an immediate release coating of the active agent is applied to the inert tamper resistant cores of the present invention (e.g., as disclosed above) followed by an application of a controlled release coating over the active layer. In other embodiments, the active agent can be included (i.e., dispersed) in controlled release excipients in the coating without a separate active agent layer and controlled release layer. The controlled release coating can be applied by various methodologies (e.g., spray coating and compression coating as discussed above) with the inclusion of excipient(s) to provide the desired release rate.
[0072] A non-limiting list of suitable controlled release materials which may be selected for inclusion in the controlled release layer according to the present invention includes hydrophilic and hydrophobic materials such as sustained release polymers, gums, acrylic resins, protein-derived materials, waxes, shellacs, and solid or semi-solid oils such as hydrogenated castor oil and hydrogenated vegetable oil.
More specifically, the controlled release materials can be, e.g., alkylcelluloses such as ethylcellulose, acrylic and methacrylic acid polymers and copolymers, and cellulose ethers, such as hydroxyalkylcelluloses (e.g., hydroxypropylmethylcellulose) and carboxyalkylcelluloses. Waxes include, e.g., natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures of the same (e.g., beeswax, carnauba wax, stearic acid and stearyl alcohol). Certain embodiments utilize mixtures of two or more of the foregoing controlled release materials in the matrix of the core. However, any pharmaceutically acceptable hydrophobic or hydrophilic controlled release material which is capable of imparting controlled release of the active agent may be used in accordance with the present invention. The controlled release coating may also contain suitable quantities of additional excipients, e.g., lubricants, binders, granulating aids, diluents, colorants, flavorants and glidants, all of which are conventional in the pharmaceutical art.
[0073] In any of the controlled release coating embodiments, a film coat (e.g., for taste, protective or cosmetic purposes) can be overcoated on the controlled release layer and/or utilized as an undercoat between the inert core and the active agent layer.
OTHER TAMPER RESISTANT EMBODIMENTS
[0074] In other embodiments, the inert tamper resistant dosage forms that are resistant to splitting, crushing, etc., can further include additional agents that are aversive to oral, parenteral and/or nasal abuse of the dosage form.
[0075] In certain embodiments of the present invention, the dosage form comprises a bittering agent in the inert core, in the coating, or in both the inert core and the coating, to discourage an abuser from tampering with the dosage form (e.g., by chewing, splitting or crushing) and thereafter inhaling or swallowing the tampered dosage form due to the resultant unpleasant taste. Various bittering agents can be employed including, for example and without limitation, natural, artificial and synthetic flavor oils and flavoring aromatics and/or oils, oleoresins and extracts derived from plants, leaves, flowers, fruits, etc., and combinations thereof.
Nonlimiting representative flavor oils include spearmint oil, peppermint oil, eucalyptus oil, oil of nutmeg, allspice, mace, oil of bitter almonds, menthol and the like. Useful bittering agents can be artificial, natural and synthetic fruit flavors such as citrus oils including lemon, orange, lime, grapefruit, and fruit essences and the like. Additional bittering agents include sucrose derivatives (e.g., sucrose octaacetate), chlorosucrose derivatives, quinine sulphate, and the like. The preferred bittering agent for use in the present invention is Denatonium Benzoate NF-Anhydrous, sold under the name Bitrex . (Macfarlan Smith Limited, Edinburgh, UK).
[0076] In certain embodiments of the present invention, the dosage form comprises an irritant in the inert core, in the coating, or in both the inert core and the coating, to discourage an abuser from tampering with the dosage form (e.g., by chewing, splitting or crushing) and thereafter inhaling or swallowing the tampered dosage form due to the resultant burning or irritating effect to the abuser upon inhalation, injection, and/or swallowing of the tampered dosage form. Various irritants can be employed including, for example and without limitation capsaicin, a capsaicin analog with similar type properties as capsaicin, and the like. Some capsaicin analogues or derivatives include for example and without limitation, resiniferatoxin, tinyatoxin, heptanoylisobutylamide, heptanoyl guaiacylamide, other isobutylamides or guaiacylamides, dihydrocapsaicin, homovanillyl octylester, nonanoyl vanillylamide, or other compounds of the class known as vanilloids.
[0077] In other embodiments, a gelling agent can be included in the inert core, in the coating, or in both the inert core and the coating, such that when the dosage form is tampered with, the gelling agent preferably imparts a gel-like quality to the tampered dosage form in the presence of a liquid (e.g., an extracting solvent or within the mucosa) to hinder the ability to inject or inhale the active agent.
Various gelling agents can be employed including, for example and without limitation, sugars or sugar derived alcohols, such as mannitol, sorbitol, and the like, starch and starch derivatives, cellulose derivatives, such as microcrystalline cellulose, sodium caboxymethyl cellulose, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose, attapulgites, bentonites, dextrins, alginates, carrageenan, gum tragacanth, gum acacia, guar gum, xanthan gum, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, the carbomers and carbopols, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, surfactants, mixed surfactant/wetting agent systems, emulsifiers, other polymeric materials, and mixtures thereof.
[0078] In other embodiments, opioid antagonists can be used in the present invention to discourage illicit use. The antagonist can be naltrexone, naloxone, nalmefene, nalide, nalmexone, nalorphine, nalorphine dinicotinate, cyclazocine, levallorphan, pharmaceutically acceptable salts thereof, and mixtures thereof.
The antagonist can be in the coating, the inert core, or in both the inert core and the coating. The antagonist (as well as the other aversive agents) can be releasable or sequestered, such that the agent is only releasable if the dosage form is tampered with. Sequestered dosage forms can be formulated in accordance with U.S.
Patent No. 6,696,088.
INERT TAMPER RESISTANT CORES
[0079] Non-limiting examples of suitable inert core materials include polymers such as polyalkylene oxides (e.g., polymethylene oxides, polyethylene oxides, polypropylene oxides) polyethylenes, polypropylenes, polyvinyl chlorides, polycarbonates, polystyrenes, polyacrylates, polycaprolactone, polymethacrylates copolymers thereof, and mixtures thereof.
[0080] A suitable inert core material can be processed to produce a tamper resistant core by heating the material (i.e., curing) to its melting (softening) point and then cooling the material. The heating may be monitored by a temperature measurement in the interior of a formed core using a temperature sensor. In other embodiments, the core can be subject to ultrasonic forces. Compressive force may optionally be applied, continuously or discontinuously, to form the core. The method of producing a tamper resistant core according to the invention may be accelerated by rapidly cooling formed cores after the application of heat. This may proceed, for example by conveying the formed cores through a cooling chamber or by placing them into a cooling medium, such as for example into a liquid gas. See, U.S. Patent Publication No. 2007/0003616.
[0081] In an aspect of the invention, a core is formed having a breaking strength of at least 400 Newtons. In another aspect of the invention, a core is formed having a breaking strength of at least 500 Newtons, at least 600 Newtons, at least 700 Newtons, at least 800 Newtons or at least 1 KiloNewton.
[0082] Cores of such breaking strength can be prepared by adapting the technologies described in the art to the presently disclosed invention. Non-limiting examples of such technologies are described in the following published US
patent applications: US 2005/0236741 and US 2008/0317854, which describe abuse-proof dosage forms that incorporate a binder having a breaking strength of 500 Newtons, and exposing the dosage forms to ultrasound and force; US 2006/0002859 and US
2008/0312264, which describe abuse-proof dosage forms having a breaking strength of 500 Newtons, produced by melt extrusion with a planetary-gear extruder; US
2006/0188447, US 2008/0311049, US 2009/0005408 and US 2007/0003616, which describe abuse-proof dosage having a polymer with a breaking strength of at least 500 Newtons; US 2006/0193782 and US 2008/0247959 which describe abuse-proof dosage forms having a polymer with a breaking strength of at least 500 Newtons and thermoformed without extrusion; US 2006/0193914, US 2008/0311187, and US
2010/0151028 which describe crush resistant dosage forms having a resistance to crushing of at least 400 Newtons and release of active agent that is at least partially delayed.
[0083] In order to achieve a core breaking strength according to the invention, the core can comprise at least one natural or synthetic wax with the specified breaking strength. Waxes with a softening point of at least 60 C are preferably used, for example, carnauba wax and beeswax. The wax can be used together with one or more suitable core polymers.
[0084] A tamper resistant core according to the invention can also be formed by coating a conventional core with a tamper resistant material such as cellulose acetate, such that the core is thereby rendered tamper resistant. The tamper resistant material may be coated onto a core using coating methods described above. The active agent coating (immediate or controlled release) can then be coated onto the tamper resistant coating of the inert core.
[0085] Splitting a dosage form can be more difficult when it has an asymmetrical shape. Splitting may also be more difficult if the dosage form has a shape that is roundish or spherical as compared to flattish, oval or longish.
[0086] Shaping of the tablet may be performed by applying force, e.g., a force of greater than or equal to 0.5 KiloNewton, preferably of 1 to 100 KiloNewton.
The force is preferably exerted with the assistance of a press, preferably a tablet press, with shaping rollers or shaping belts equipped with rollers. The formulation mixture may also be extruded with the assistance of an extruder to yield a strand which is singulated into formed articles having the desired size.
[0087] A suitable method for determining the breaking strength of a tablet core is published in the European Pharmacopoeia 1997, page 143, 144, method no. 2.9.8.
[0088] In other embodiments, the inert core material can include a natural or synthetic abrasive material such as metal oxides (e.g., alumina, ceria, silica, and zirconia), carbides (e.g., calcium carbide, silicon carbide (carborundum), tungsten carbide and cementite), nitrides (e.g., titanium nitride, aluminum nitride and gallium nitride) and co-formed products or combinations thereof. The abrasive material is preferably durable enough to inhibit splitting, crushing, shearing, grinding, or chewing of the dosage form, while also not presenting a safety/toxicity issue to the patient.
ACTIVE AGENTS
[0089] A solid oral dosage form of the present invention may include any drug, or combination of drugs, that can be incorporated into a coating for application directly over an inert tamper resistant core. The present invention is particularly suited to drugs that should not be administered in split or divided solid dosage forms.
Accordingly, the present invention is particularly suited to drugs such as, for example, antibiotics, opioids, hormones, anti-psychotic agents, stimulants, anti-hypertensive agents, and sedatives. More specific, non-limiting examples include controlled release verapamil, extended-release oxycodone, extended release morphine, coated aspirin, niroglycerin, digoxin, levothyroxine and warfarin.
[0090] The inert tamper resistant cores can be used to produce solid oral dosage forms according to the present invention that make drug abuse more difficult.
A drug abuser will find it more difficult to simply split or crush a solid oral dosage form according to the present invention to produce a powder suitable for nasal or intravenous administration. Accordingly, the instant invention is particularly suited to prepare oral dosage forms of commonly abused drugs such as, for example, opioids, tranquilizers, CNS depressants, CNS stimulants, anti-anxiolytics (e.g., benzodiazepines), sedatives, hypnotics, stimulants (including amphetamine, dextroamphetamine, dinoprostone, methylphenidate, modafinil, pemoline and appetite suppressants such as phenylpropanolamine), and cannabinoids, among others.
[0091] Opioids useful in the present invention include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts, stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof. Preferably, the opioid is selected from the group consisting of codeine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, tramadol, pharmaceutically acceptable salts, stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof.
[0092] In other embodiments, the active agent can be selected from barbiturates such as phenobarbital, secobarbital, pentobarbital, butabarbital, talbutal, aprobarbital, mephobarbital, butalbital, pharmaceutically acceptable salts thereof, and the like;
benzodiazepines such as diazepam, chlordiazepoxide, alprazolam, triazolam, estazolam, clonazepam, flunitrazepam, pharmaceutically acceptable salts thereof, and the like; stimulants such as gamma-hydroxybutyrate, dextroamphetamine, methylphenidate, sibutramine, methylenedioxyrnethamphetamine, pharmaceutically acceptable salts thereof, and the like; other agents such as marinol, meprobamate and carisoprodol; and all pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof.
[0093] In other embodiments, the active agent can be an anti-psychotic agent such as amisulpride, aripiprazole bifemelane, bromperidol, clozapine, chlorpromazine, haloperidol, iloperidone loperidone, olanzapine, quetiapine, fluphenazine, furnarate, risperidone, thiothixene, thioridazine, sulpride, ziprasidone, and all pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof.
[0094] In other embodiments, the active agent can be an anti-hypertensive agent such as beta adrenergic blockers (e.g., propranolol, metoprolol and timolol), calcium channel blockers (L-type and T-type; e.g., diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET
receptor antagonists (e.g., sitaxsentan, atrsentan, and compounds disclosed in U.S.
Pat. Nos. 5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compounds disclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat), nitrates and pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof.
[0095] In further embodiments, other therapeutically active agents may be used in accordance with the present invention. Examples of such therapeutically active agents include antihistamines (e.g., dimenhydrinate, diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate), non-steroidal anti-inflammatory agents (e.g., naproxen, diclofenac, indomethacin, ibuprofen, sulindac, Cox-2 inhibitors), acetaminophen, anti-emetics (e.g., metoclopramide, methylnaltrexone), anti-epileptics (e.g., phenyloin, meprobmate and nitrazepam), anti-tussive agents and expectorants, anti-asthmatics (e.g. theophylline), antacids, anti-spasmodics (e.g. atropine, scopolamine), antidiabetics (e.g., insulin), bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline, penicillins, cephalosporins, erythromycins), hormones (e.g., estrogens and progestins), anti-hemorrhoidals, psychotropics, anti-diarrheals, mucolytics, decongestants (e.g.
pseudoephedrine), laxatives, vitamins, and pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof.
[0096] Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like;
organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts such as arginate, asparaginate, glutamate and the like; metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; and organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like.
[0097] The tamper resistant dosage forms can be used to treat any disease or condition requiring pharmacological therapy. Such disease states include without limitation, pain and anti-psychotic disorders.
[0098] Pain syndromes include but are not limited to acute or chronic pain that is either nociceptive (for example somatic or visceral) or non-nociceptive (for example neuropathic or sympathetic) in origin. In some embodiments, the pain is nociceptive pain including, but not limited to, surgical pain, inflammatory pain such as that associated with inflammatory bowel syndrome or rheumatoid arthritis, pain associated with cancer, and pain associated with osteoarthritis. In some embodiments, the pain is non-nociceptive pain including, but not limited to, neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia, focal peripheral nerve injury, anesthesia clolorosa, central pain (for example, post-stroke pain, pain due to spinal cord injury or pain associated with multiple sclerosis), and peripheral neuropathy (for example, diabetic neuropathy, inherited neuropathy or other acquired neuropathies).
[0099] Psychotic disorder include but are not limited to psychotic depression, postpartum depression, affective disorder, schizoaffective disorder, schizophreniform disorder, schizophrenia, delusional disorder, brief psychotic disorder, shared psychotic disorder, borderline personality disorder, manic-depressive disorder, obsessive-compulsive disorder, Huntington's Disease, Tourette's syndrome and tic disorder.
[00100] The following examples are set forth to assist in understanding the invention and should not be construed as specifically limiting the invention described and claimed herein. Such variations of the invention, including the substitution of all equivalents now known or later developed, which would be within the purview of those skilled in the art, and changes in formulation or minor changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein.
1001011 This application claims priority from U.S. Provisional Application Serial No. 61/426,903, filed December 23, 2010, the disclosure of which is hereby incorporated by reference.
Examples The following examples are provided to illustrate, but not to limit, the present invention.
Prophetic Example 1 A tablet may be constructed using the following materials and processes:
Core Polyethylene oxide 149 mg Magnesium stearate 1 mg Total 150 mg Coating Active pharmaceutical ingredient (API) 5 mg HPMC 10 mg Overcoat HPMC 10 mg Manufacturing process I. Blend the polyethylene oxide with the magnesium stearate.
11. Compress into round 7mm tablet cores using a rotary tablet press to achieve a target weight of 150mg.
111. Cure the cores in a conventional tablet coater by heating to an exhaust temperature of 72C for 15 minutes.
IV. Allow the tablets to cool while continuously rotating the tablet bed.
Add a dusting of magnesium stearate, if necessary, to prevent the cores agglomerating.
V. Disperse the active ingredient and HPMC for the active coating in water to a solids content of 10-15%.
VI. Apply the active ingredient-containing coating to the tablet cores using the tablet coater to a target weight gain of 15mg/tablet.
VII. Disperse the HPMC (for the overcoat) in water to a solids content of 15%.
VIII. Apply the overcoat to the active ingredient-coated cores in the tablet coater to achieve a target weight gain of 10mg/tablet.
Prophetic Example 2 I. An inert tablet was prepared using 200 mg of high molecular weight polyethylene oxide (PEO 303 ¨ MW 7,000,000), as set forth below.
II. To prepare the core, a single station Manesty Type F 3 tablet press is equipped with 7.94 mm, round, standard concave plain tooling. A powdered aliquot of the PEO, was weighed out to target weight of 200 mg, charged into the die, and compressed to form the inert.
III. Several compression inert tablets prepared as above are placed onto a tray, which are placed in a Hotpack model 435304 oven targeting 72 C for 30 minutes to cure.
IV. Thereafter, 20 mg of hydrocodone bitartrate are spray coated onto the inert core in a hydroxypropylmethycellulose solution.
[001001 The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.
[00381 The term "sustained release" is defined for purposes of the present invention as the release of the drug at such a rate that blood (e.g., plasma) concentrations are maintained within the therapeutic range but below toxic concentrations over a period of time of at least about 12 hours or longer, or at least 24 hours or longer.
Preferably, a controlled release dosage form can provide once daily or twice daily dosing.
[0039] The term "controlled-release" encompasses "sustained release", "extended release", "delayed release" or any other modified (i.e., non-immediate) release.
[0040] The term "polyethylene oxide" is defined for purposes of the present invention as a composition of polyethylene oxide having a molecular weight of at least 25,000, based on rheological measurements, and preferably having a molecular weight of at least 100,000. Compositions with lower molecular weight are usually referred to as polyethylene glycols.
[0041] For purposes of the present invention, the term "opioid analgesic"
means one or more compounds selected from base opioid agonists, mixed opioid agonist-antagonists, partial opioid agonists, pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates and solvates thereof and mixtures thereof.
[0042] The term "patient" means a subject who has presented a clinical manifestation of a particular symptom or symptoms suggesting the need for treatment, who is treated preventatively or prophylactically for a condition, or who has been diagnosed with a condition to be treated.
[0043] The term "subject" is inclusive of the definition of the term "patient"
and does not exclude individuals who are entirely normal in all respects or with respect to a particular condition.
[0044] As used herein, the term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
[0045] As used herein, resistance to splitting, crushing, shearing, grinding and/or chewing results from a dosage form (or any portion thereof) having a preferable breaking strength of at least 400 Newtons.
[0046] The term "chiral center" refers to a carbon atom to which four different groups are attached.
[0047] The term "enantiomer" or "enantiomeric" refers to a molecule that is nonsuperimposable on its mirror image and hence optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction.
[0048] The term "racemic" refers to a mixture of enantiomers.
[0049] The term "resolution" refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.
BRIEF DESCRIPTION OF THE DRAWINGS
[0050] FIG. 1 is a graphical representation of a single coated core embodiment of the present invention.
[0051] FIG. 2 is a graphical representation of a multiparticulate embodiment of the present invention.
[0052] FIG. 3 is a graphical representation of a unitary core of the present invention.
[0053] FIG. 4 is a graphical representation of a core of the present invention having an inner component and an outer component.
DETAILED DESCRIPTION
[0054] In some instances, for particular medications, tablet splitting is condoned or even encouraged by physicians as a means of reducing the high cost of prescription drugs. Widespread use of tablet splitting, however, without consideration of the patient and the particular dosage form can have detrimental effect.
[0055] Potential detrimental effects include (i) an increased amount of drug released over a short period of time associated with splitting certain controlled release dosage forms (e.g., controlled release opioids); (ii) an upset stomach or foul taste in a patient's mouth with splitting dosage forms of foul tasting or gastro-irritative agents (e.g., ciprofloxacin, aspirin); (iii) unusable fragments with the attempted splitting of friable dosage forms such as sublingual nitroglycerin;
and (iv) uneven dosing with more drug in one half than in the other, which is a particular problem with drugs tablet which require a narrow therapeutic window for each individual patient (e.g., levothyroxine, warfarin and digoxin).
[0056] Splitting and crushing is also a methodology utilized by drug abusers in order to liberate active agent from a dosage form for illicit use (e.g., parenteral, nasal or oral abuse). This is a problem with both immediate release and controlled release dosage forms containing drugs susceptible to abuse (e.g., opioid analgesics or stimulants).
[0057] The present invention thus provides a solid oral dosage form that is resistant to tampering (e.g., splitting, crushing, shearing, grinding, chewing or a combination thereof) that might otherwise be carried out in order to liberate the active agent contained therein, thus reducing the likelihood of these associated detrimental effects.
[0058] Referring to Fig. 1, the dosage forms of the present invention may comprise an inert (i.e., without an active agent) tamper resistant core (10); and a coating surrounding the core (11), the coating comprising an active agent (12).
[0059] The dosage form can be a single coated core (e.g., in tablet form) which coating contains the entire intended dose as depicted in Fig. 1 or can be in the form of multiparticulates as depicted in Fig. 2, with a plurality of tamper resistant coated cores (20). The tamper resistant coated cores have an active agent coating surrounding each core, with the active agent divided among the plurality of coated cores. The multiparticulates can be contained in an optional pharmaceutically acceptable capsule (21).
[0060] As depicted in Figure 3, the inert tamper resistant core can be unitary (30) with a sufficient hardness in order to be tamper resistant or as depicted in Fig. 4, can have an inner component (40) which is tamper or non-tamper resistant, that is coated with a tamper resistant outer component (41) of a suitable hardness.
[0061] The coating on the inert tamper resistant cores can have a suitable amount of active agent to provide a therapeutic effect. Depending on the active agent, the amount can be, e.g., from about 0.1 mg to about 1 gram, about 1 mg to about mg, or about 10 mg to about 100 mg. Typically, the weight of the coating when applied to the inert cores is about 1% to about 25% of the total weight of the dosage form although this can be higher or lower depending on the load of active agent required for a therapeutic effect.
[0062] The tamper resistant cores of the present invention are of a sufficient hardness to present difficulty in splitting, crushing, shearing, grinding or chewing the final dosage form in an attempt to fragment the dosage form. Preferably, the tamper resistant core has a breaking strength of at least about 400Newtons, at least about 500 Newtons, at least about 600 Newtons, at least about 700 Newtons, at least about 800 Newtons or at least about 1 KiloNewton.
[0063] The present invention further provides a pharmaceutical package comprising a single or plurality of solid oral dosage forms, e.g., tablets, of the present invention. The package can be, e.g., a blister pack, bottle, tube, bags, vial, box, container or any other suitable packaging material. The container can hold an amount of dosage forms such as 1 to 5000, 1 to 1000, 1 to 500, 1 to 120, 1 to 100, 1 to 90, 1 to 60, 1 to 50, 1 to 30, 1 to 28, 1 to 21, 1 to 14, 1 to 7 or 1 to 5.
Specific amounts of dosage forms included in packaging materials include 1 (single dose), 7 (e.g., once daily dosing for one week), 14 (e.g., twice daily dosing for one week), 21 (e.g., three times daily dosing for 1 week), 28 (e.g., four times daily dosing for 1 week), 30 (e.g., once daily dosing for one month), 60 (e.g., twice daily dosing for one month), 90 (e.g., three times daily dosing for 1 month), 100 (typically a 1-3 month supply) or 120 (e.g., four times daily dosing for 1 month).
IMMEDIATE RELEASE DOSAGE FORMS
[0064] The solid oral dosage forms of the present invention can be in the form of an inert tamper resistant core coated with an immediate release coating of the active agent. Immediate release dosage forms of drugs susceptible to abuse are sometimes split or crushed in order for the drug to be readily available for parenteral or nasal abuse. Thus, the present invention may discourage the illicit use of immediate release formulations by inhibiting the ability to effectively split or crush the dosage form. The immediate release tamper resistant dosage forms of the present invention also discourage the splitting of dosage forms that can result in an overdose or underdose of the active agent contained therein.
[0065] The immediate release coating can be applied by various methodologies such as spray coating, dipping, powder layering or compression coating. In embodiments wherein the active agent does not provide the necessary bulk to process the immediate release coating, various excipients can be utilized in order to facilitate processing.
[0066] In spray coated dosage forms, the active agent is typically dissolved in solution and sprayed onto the inert cores of the present invention in either single or multiparticulate form. The process may include spraying of very finely atomized droplets of solution onto the inert cores in a stream of hot process air or other suitable gas. By having the drug in solution rather than suspension, improved uniformity of the coating can be achieved. The solution can be an aqueous or organic solvent and include various binders such as polyvinylpyrrolidone, natural and synthetic gums including gum arabic, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, methylcellulose, pullulan, dextrin, starch, polyvinyl alcohol among others.
[0067] In powder layering, inert tamper resistant cores of the present invention may be spray coated with a binder to provide tackiness. The active agent in powder form is then sprayed onto the binder coated inert cores. The spraying powder comprising the active agent may also include additional excipients, including glidants, diluents, stabilizers, coloring agents, and additional binders. Suitable glidants include, e.g., colloidal silicon dioxide and/or talc. Suitable diluents include, e.g., polysaccharides, monosaccharides, corn starch, and the like.
[0068] In compression coating, the active agent is combined with suitable excipients (e.g., glidants, diluents) and compression coated onto the inert tamper resistant cores of the present invention. In certain embodiments, a Manesty Dry-Cota press (e.g., Model 900) can be utilized. This apparatus consists of two side by side interconnected tablet presses where the inert core is made on one press and then mechanically transferred to the next press for compression coating. Each press has an independent powder feed mechanism so that the inert core blend is loaded on one machine, and the coating blend is loaded on the other machine. Mechanical transfer arms rotate between the machines to remove cores from the core press and transfer them to the coating press. Other presses which may be used to prepare the dosage forms of the present invention include Elizabeth Hata HT-AP44-MSU-C; Killian RLUD; and Fette PT 4090, each of which has a dual feed system for coating blend and pre-made cores.
[0069] In any of the above immediate release coating embodiments, a film coat (e.g., for taste, protective or cosmetic purposes) can be overcoated on the immediate release layer and/or utilized as an undercoat between the inert core and the active agent layer. An example of such a coating is Opadry .
CONTROLLED RELEASE DOSAGE FORMS
[0070] The solid oral dosage forms of the present invention can be in the form of an inert tamper resistant core coated with a controlled release coating of the active agent. Splitting controlled release dosage forms is subject to the same issues as immediate release dosage forms (e.g., parenteral and nasal abuse, non-uniform fragments). In addition, controlled release dosage forms are subject to oral abuse when an amount of drug intended for an extended period of time is liberated for immediate illicit use by splitting or crushing. Thus, the dosage forms of the present invention discourage the illicit use of controlled release formulations.
Further, if a patient administers a half tablet of many controlled release dosage forms (without illicit intent), often the integrity of the dosage form is compromised and a toxic amount of active agent can be released. The controlled release tamper resistant dosage forms of the present invention also discourage the splitting of dosage forms that can result in an overdose or underdose of the active agent contained therein.
[0071] In certain embodiments, an immediate release coating of the active agent is applied to the inert tamper resistant cores of the present invention (e.g., as disclosed above) followed by an application of a controlled release coating over the active layer. In other embodiments, the active agent can be included (i.e., dispersed) in controlled release excipients in the coating without a separate active agent layer and controlled release layer. The controlled release coating can be applied by various methodologies (e.g., spray coating and compression coating as discussed above) with the inclusion of excipient(s) to provide the desired release rate.
[0072] A non-limiting list of suitable controlled release materials which may be selected for inclusion in the controlled release layer according to the present invention includes hydrophilic and hydrophobic materials such as sustained release polymers, gums, acrylic resins, protein-derived materials, waxes, shellacs, and solid or semi-solid oils such as hydrogenated castor oil and hydrogenated vegetable oil.
More specifically, the controlled release materials can be, e.g., alkylcelluloses such as ethylcellulose, acrylic and methacrylic acid polymers and copolymers, and cellulose ethers, such as hydroxyalkylcelluloses (e.g., hydroxypropylmethylcellulose) and carboxyalkylcelluloses. Waxes include, e.g., natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures of the same (e.g., beeswax, carnauba wax, stearic acid and stearyl alcohol). Certain embodiments utilize mixtures of two or more of the foregoing controlled release materials in the matrix of the core. However, any pharmaceutically acceptable hydrophobic or hydrophilic controlled release material which is capable of imparting controlled release of the active agent may be used in accordance with the present invention. The controlled release coating may also contain suitable quantities of additional excipients, e.g., lubricants, binders, granulating aids, diluents, colorants, flavorants and glidants, all of which are conventional in the pharmaceutical art.
[0073] In any of the controlled release coating embodiments, a film coat (e.g., for taste, protective or cosmetic purposes) can be overcoated on the controlled release layer and/or utilized as an undercoat between the inert core and the active agent layer.
OTHER TAMPER RESISTANT EMBODIMENTS
[0074] In other embodiments, the inert tamper resistant dosage forms that are resistant to splitting, crushing, etc., can further include additional agents that are aversive to oral, parenteral and/or nasal abuse of the dosage form.
[0075] In certain embodiments of the present invention, the dosage form comprises a bittering agent in the inert core, in the coating, or in both the inert core and the coating, to discourage an abuser from tampering with the dosage form (e.g., by chewing, splitting or crushing) and thereafter inhaling or swallowing the tampered dosage form due to the resultant unpleasant taste. Various bittering agents can be employed including, for example and without limitation, natural, artificial and synthetic flavor oils and flavoring aromatics and/or oils, oleoresins and extracts derived from plants, leaves, flowers, fruits, etc., and combinations thereof.
Nonlimiting representative flavor oils include spearmint oil, peppermint oil, eucalyptus oil, oil of nutmeg, allspice, mace, oil of bitter almonds, menthol and the like. Useful bittering agents can be artificial, natural and synthetic fruit flavors such as citrus oils including lemon, orange, lime, grapefruit, and fruit essences and the like. Additional bittering agents include sucrose derivatives (e.g., sucrose octaacetate), chlorosucrose derivatives, quinine sulphate, and the like. The preferred bittering agent for use in the present invention is Denatonium Benzoate NF-Anhydrous, sold under the name Bitrex . (Macfarlan Smith Limited, Edinburgh, UK).
[0076] In certain embodiments of the present invention, the dosage form comprises an irritant in the inert core, in the coating, or in both the inert core and the coating, to discourage an abuser from tampering with the dosage form (e.g., by chewing, splitting or crushing) and thereafter inhaling or swallowing the tampered dosage form due to the resultant burning or irritating effect to the abuser upon inhalation, injection, and/or swallowing of the tampered dosage form. Various irritants can be employed including, for example and without limitation capsaicin, a capsaicin analog with similar type properties as capsaicin, and the like. Some capsaicin analogues or derivatives include for example and without limitation, resiniferatoxin, tinyatoxin, heptanoylisobutylamide, heptanoyl guaiacylamide, other isobutylamides or guaiacylamides, dihydrocapsaicin, homovanillyl octylester, nonanoyl vanillylamide, or other compounds of the class known as vanilloids.
[0077] In other embodiments, a gelling agent can be included in the inert core, in the coating, or in both the inert core and the coating, such that when the dosage form is tampered with, the gelling agent preferably imparts a gel-like quality to the tampered dosage form in the presence of a liquid (e.g., an extracting solvent or within the mucosa) to hinder the ability to inject or inhale the active agent.
Various gelling agents can be employed including, for example and without limitation, sugars or sugar derived alcohols, such as mannitol, sorbitol, and the like, starch and starch derivatives, cellulose derivatives, such as microcrystalline cellulose, sodium caboxymethyl cellulose, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose, attapulgites, bentonites, dextrins, alginates, carrageenan, gum tragacanth, gum acacia, guar gum, xanthan gum, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, the carbomers and carbopols, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, surfactants, mixed surfactant/wetting agent systems, emulsifiers, other polymeric materials, and mixtures thereof.
[0078] In other embodiments, opioid antagonists can be used in the present invention to discourage illicit use. The antagonist can be naltrexone, naloxone, nalmefene, nalide, nalmexone, nalorphine, nalorphine dinicotinate, cyclazocine, levallorphan, pharmaceutically acceptable salts thereof, and mixtures thereof.
The antagonist can be in the coating, the inert core, or in both the inert core and the coating. The antagonist (as well as the other aversive agents) can be releasable or sequestered, such that the agent is only releasable if the dosage form is tampered with. Sequestered dosage forms can be formulated in accordance with U.S.
Patent No. 6,696,088.
INERT TAMPER RESISTANT CORES
[0079] Non-limiting examples of suitable inert core materials include polymers such as polyalkylene oxides (e.g., polymethylene oxides, polyethylene oxides, polypropylene oxides) polyethylenes, polypropylenes, polyvinyl chlorides, polycarbonates, polystyrenes, polyacrylates, polycaprolactone, polymethacrylates copolymers thereof, and mixtures thereof.
[0080] A suitable inert core material can be processed to produce a tamper resistant core by heating the material (i.e., curing) to its melting (softening) point and then cooling the material. The heating may be monitored by a temperature measurement in the interior of a formed core using a temperature sensor. In other embodiments, the core can be subject to ultrasonic forces. Compressive force may optionally be applied, continuously or discontinuously, to form the core. The method of producing a tamper resistant core according to the invention may be accelerated by rapidly cooling formed cores after the application of heat. This may proceed, for example by conveying the formed cores through a cooling chamber or by placing them into a cooling medium, such as for example into a liquid gas. See, U.S. Patent Publication No. 2007/0003616.
[0081] In an aspect of the invention, a core is formed having a breaking strength of at least 400 Newtons. In another aspect of the invention, a core is formed having a breaking strength of at least 500 Newtons, at least 600 Newtons, at least 700 Newtons, at least 800 Newtons or at least 1 KiloNewton.
[0082] Cores of such breaking strength can be prepared by adapting the technologies described in the art to the presently disclosed invention. Non-limiting examples of such technologies are described in the following published US
patent applications: US 2005/0236741 and US 2008/0317854, which describe abuse-proof dosage forms that incorporate a binder having a breaking strength of 500 Newtons, and exposing the dosage forms to ultrasound and force; US 2006/0002859 and US
2008/0312264, which describe abuse-proof dosage forms having a breaking strength of 500 Newtons, produced by melt extrusion with a planetary-gear extruder; US
2006/0188447, US 2008/0311049, US 2009/0005408 and US 2007/0003616, which describe abuse-proof dosage having a polymer with a breaking strength of at least 500 Newtons; US 2006/0193782 and US 2008/0247959 which describe abuse-proof dosage forms having a polymer with a breaking strength of at least 500 Newtons and thermoformed without extrusion; US 2006/0193914, US 2008/0311187, and US
2010/0151028 which describe crush resistant dosage forms having a resistance to crushing of at least 400 Newtons and release of active agent that is at least partially delayed.
[0083] In order to achieve a core breaking strength according to the invention, the core can comprise at least one natural or synthetic wax with the specified breaking strength. Waxes with a softening point of at least 60 C are preferably used, for example, carnauba wax and beeswax. The wax can be used together with one or more suitable core polymers.
[0084] A tamper resistant core according to the invention can also be formed by coating a conventional core with a tamper resistant material such as cellulose acetate, such that the core is thereby rendered tamper resistant. The tamper resistant material may be coated onto a core using coating methods described above. The active agent coating (immediate or controlled release) can then be coated onto the tamper resistant coating of the inert core.
[0085] Splitting a dosage form can be more difficult when it has an asymmetrical shape. Splitting may also be more difficult if the dosage form has a shape that is roundish or spherical as compared to flattish, oval or longish.
[0086] Shaping of the tablet may be performed by applying force, e.g., a force of greater than or equal to 0.5 KiloNewton, preferably of 1 to 100 KiloNewton.
The force is preferably exerted with the assistance of a press, preferably a tablet press, with shaping rollers or shaping belts equipped with rollers. The formulation mixture may also be extruded with the assistance of an extruder to yield a strand which is singulated into formed articles having the desired size.
[0087] A suitable method for determining the breaking strength of a tablet core is published in the European Pharmacopoeia 1997, page 143, 144, method no. 2.9.8.
[0088] In other embodiments, the inert core material can include a natural or synthetic abrasive material such as metal oxides (e.g., alumina, ceria, silica, and zirconia), carbides (e.g., calcium carbide, silicon carbide (carborundum), tungsten carbide and cementite), nitrides (e.g., titanium nitride, aluminum nitride and gallium nitride) and co-formed products or combinations thereof. The abrasive material is preferably durable enough to inhibit splitting, crushing, shearing, grinding, or chewing of the dosage form, while also not presenting a safety/toxicity issue to the patient.
ACTIVE AGENTS
[0089] A solid oral dosage form of the present invention may include any drug, or combination of drugs, that can be incorporated into a coating for application directly over an inert tamper resistant core. The present invention is particularly suited to drugs that should not be administered in split or divided solid dosage forms.
Accordingly, the present invention is particularly suited to drugs such as, for example, antibiotics, opioids, hormones, anti-psychotic agents, stimulants, anti-hypertensive agents, and sedatives. More specific, non-limiting examples include controlled release verapamil, extended-release oxycodone, extended release morphine, coated aspirin, niroglycerin, digoxin, levothyroxine and warfarin.
[0090] The inert tamper resistant cores can be used to produce solid oral dosage forms according to the present invention that make drug abuse more difficult.
A drug abuser will find it more difficult to simply split or crush a solid oral dosage form according to the present invention to produce a powder suitable for nasal or intravenous administration. Accordingly, the instant invention is particularly suited to prepare oral dosage forms of commonly abused drugs such as, for example, opioids, tranquilizers, CNS depressants, CNS stimulants, anti-anxiolytics (e.g., benzodiazepines), sedatives, hypnotics, stimulants (including amphetamine, dextroamphetamine, dinoprostone, methylphenidate, modafinil, pemoline and appetite suppressants such as phenylpropanolamine), and cannabinoids, among others.
[0091] Opioids useful in the present invention include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts, stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof. Preferably, the opioid is selected from the group consisting of codeine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, tramadol, pharmaceutically acceptable salts, stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof.
[0092] In other embodiments, the active agent can be selected from barbiturates such as phenobarbital, secobarbital, pentobarbital, butabarbital, talbutal, aprobarbital, mephobarbital, butalbital, pharmaceutically acceptable salts thereof, and the like;
benzodiazepines such as diazepam, chlordiazepoxide, alprazolam, triazolam, estazolam, clonazepam, flunitrazepam, pharmaceutically acceptable salts thereof, and the like; stimulants such as gamma-hydroxybutyrate, dextroamphetamine, methylphenidate, sibutramine, methylenedioxyrnethamphetamine, pharmaceutically acceptable salts thereof, and the like; other agents such as marinol, meprobamate and carisoprodol; and all pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof.
[0093] In other embodiments, the active agent can be an anti-psychotic agent such as amisulpride, aripiprazole bifemelane, bromperidol, clozapine, chlorpromazine, haloperidol, iloperidone loperidone, olanzapine, quetiapine, fluphenazine, furnarate, risperidone, thiothixene, thioridazine, sulpride, ziprasidone, and all pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof.
[0094] In other embodiments, the active agent can be an anti-hypertensive agent such as beta adrenergic blockers (e.g., propranolol, metoprolol and timolol), calcium channel blockers (L-type and T-type; e.g., diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET
receptor antagonists (e.g., sitaxsentan, atrsentan, and compounds disclosed in U.S.
Pat. Nos. 5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compounds disclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat), nitrates and pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof.
[0095] In further embodiments, other therapeutically active agents may be used in accordance with the present invention. Examples of such therapeutically active agents include antihistamines (e.g., dimenhydrinate, diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate), non-steroidal anti-inflammatory agents (e.g., naproxen, diclofenac, indomethacin, ibuprofen, sulindac, Cox-2 inhibitors), acetaminophen, anti-emetics (e.g., metoclopramide, methylnaltrexone), anti-epileptics (e.g., phenyloin, meprobmate and nitrazepam), anti-tussive agents and expectorants, anti-asthmatics (e.g. theophylline), antacids, anti-spasmodics (e.g. atropine, scopolamine), antidiabetics (e.g., insulin), bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline, penicillins, cephalosporins, erythromycins), hormones (e.g., estrogens and progestins), anti-hemorrhoidals, psychotropics, anti-diarrheals, mucolytics, decongestants (e.g.
pseudoephedrine), laxatives, vitamins, and pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof.
[0096] Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like;
organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts such as arginate, asparaginate, glutamate and the like; metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; and organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like.
[0097] The tamper resistant dosage forms can be used to treat any disease or condition requiring pharmacological therapy. Such disease states include without limitation, pain and anti-psychotic disorders.
[0098] Pain syndromes include but are not limited to acute or chronic pain that is either nociceptive (for example somatic or visceral) or non-nociceptive (for example neuropathic or sympathetic) in origin. In some embodiments, the pain is nociceptive pain including, but not limited to, surgical pain, inflammatory pain such as that associated with inflammatory bowel syndrome or rheumatoid arthritis, pain associated with cancer, and pain associated with osteoarthritis. In some embodiments, the pain is non-nociceptive pain including, but not limited to, neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia, focal peripheral nerve injury, anesthesia clolorosa, central pain (for example, post-stroke pain, pain due to spinal cord injury or pain associated with multiple sclerosis), and peripheral neuropathy (for example, diabetic neuropathy, inherited neuropathy or other acquired neuropathies).
[0099] Psychotic disorder include but are not limited to psychotic depression, postpartum depression, affective disorder, schizoaffective disorder, schizophreniform disorder, schizophrenia, delusional disorder, brief psychotic disorder, shared psychotic disorder, borderline personality disorder, manic-depressive disorder, obsessive-compulsive disorder, Huntington's Disease, Tourette's syndrome and tic disorder.
[00100] The following examples are set forth to assist in understanding the invention and should not be construed as specifically limiting the invention described and claimed herein. Such variations of the invention, including the substitution of all equivalents now known or later developed, which would be within the purview of those skilled in the art, and changes in formulation or minor changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein.
1001011 This application claims priority from U.S. Provisional Application Serial No. 61/426,903, filed December 23, 2010, the disclosure of which is hereby incorporated by reference.
Examples The following examples are provided to illustrate, but not to limit, the present invention.
Prophetic Example 1 A tablet may be constructed using the following materials and processes:
Core Polyethylene oxide 149 mg Magnesium stearate 1 mg Total 150 mg Coating Active pharmaceutical ingredient (API) 5 mg HPMC 10 mg Overcoat HPMC 10 mg Manufacturing process I. Blend the polyethylene oxide with the magnesium stearate.
11. Compress into round 7mm tablet cores using a rotary tablet press to achieve a target weight of 150mg.
111. Cure the cores in a conventional tablet coater by heating to an exhaust temperature of 72C for 15 minutes.
IV. Allow the tablets to cool while continuously rotating the tablet bed.
Add a dusting of magnesium stearate, if necessary, to prevent the cores agglomerating.
V. Disperse the active ingredient and HPMC for the active coating in water to a solids content of 10-15%.
VI. Apply the active ingredient-containing coating to the tablet cores using the tablet coater to a target weight gain of 15mg/tablet.
VII. Disperse the HPMC (for the overcoat) in water to a solids content of 15%.
VIII. Apply the overcoat to the active ingredient-coated cores in the tablet coater to achieve a target weight gain of 10mg/tablet.
Prophetic Example 2 I. An inert tablet was prepared using 200 mg of high molecular weight polyethylene oxide (PEO 303 ¨ MW 7,000,000), as set forth below.
II. To prepare the core, a single station Manesty Type F 3 tablet press is equipped with 7.94 mm, round, standard concave plain tooling. A powdered aliquot of the PEO, was weighed out to target weight of 200 mg, charged into the die, and compressed to form the inert.
III. Several compression inert tablets prepared as above are placed onto a tray, which are placed in a Hotpack model 435304 oven targeting 72 C for 30 minutes to cure.
IV. Thereafter, 20 mg of hydrocodone bitartrate are spray coated onto the inert core in a hydroxypropylmethycellulose solution.
[001001 The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.
Claims (51)
1. A solid oral dosage form comprising:
(a) an inert tamper resistant core having a breaking strength of at least 400 Newtons;
and (b) a coating surrounding the core, the coating comprising active agent.
(a) an inert tamper resistant core having a breaking strength of at least 400 Newtons;
and (b) a coating surrounding the core, the coating comprising active agent.
2. The solid oral dosage form of claim 1, wherein the tamper resistant core is resistant to splitting, crushing, shearing, grinding, chewing or a combination thereof.
3. The solid oral dosage form of claim 2, wherein the tamper resistant core is resistant to splitting.
4. The solid oral dosage form of claim 2, wherein the tamper resistant core is resistant to crushing.
5. The solid oral dosage form of any one of claims 1 to 4, wherein the tamper resistant core has a breaking strength of at least 500 Newtons, at least 600 Newtons, at least 700 Newtons, at least 800 Newtons or at least 1 KiloNewton.
6. The oral solid dosage form of any one of claims 1 to 5, wherein the tamper resistant core comprises a metal oxide, a carbide, a nitride or a combination thereof.
7. The sold oral dosage form of any one of claims 1 to 6, wherein the inert tamper resistant core comprises an inner component and an outer component surrounding the inner component.
8. The solid oral dosage form of claim 7, wherein the inner component is tamper resistant, the outer component is tamper resistant or both the inner and outer components are tamper resistant.
9. The solid oral dosage form of claim 8, wherein the outer component is tamper resistant.
10. The solid oral dosage form of any one of claims 1 to 9, wherein the coating provides an immediate release of the active agent.
11. The solid oral dosage form of any one of claims 1 to 9, wherein the coating provides a controlled release of the active agent.
12. The solid oral dosage form of any one of claims 1 to 11, wherein the coating further comprises a pharmaceutically acceptable excipient.
13. The solid oral dosage form of claim 12, wherein the excipient is an immediate release excipient.
14. The solid oral dosage form of claim 13, wherein the immediate release excipient is selected from the group consisting of hydroxypropylmethylceluose, polyvinyl alcohol, and a combination thereof.
15. The solid oral dosage form of claim 12, wherein the excipient is a controlled release excipient.
16. The solid oral dosage form of claim 15, wherein the controlled release excipient is selected from the group consisting of a cellulosic material, an acrylic polymer, and a combination thereof.
17. The solid oral dosage form of any one of claims 12 to 16, wherein the active agent is dispersed in the excipient.
18. The solid oral dosage form of any one of claims 12 to 16, wherein the active agent is layered on the core and the excipient is layered on the active agent.
19. The solid oral dosage form of any one of claims 1 to 18, wherein the core comprises a pharmaceutically acceptable excipient.
20. The solid oral dosage form of any one of claims 1 to 19, wherein the core comprises a bittering agent.
21. The solid oral dosage form of any one of claims 1 to 20, wherein the core comprises an irritant.
22. The solid oral dosage form of claim 17, wherein the excipient comprises a material selected from the group consisting of a polyalkylene oxide, a polymethylene oxide, a polyethylene oxide, a polypropylene oxide, a polyethylene, polypropylene, a polyvinyl chloride, a polycarbonate, a polystyrene, a polyacrylate, copolymers thereof, and mixtures thereof.
23. The solid oral dosage form of claim 22, wherein the excipient comprises polyethylene oxide.
24. The solid oral dosage form of any one of claims 1 to 23, wherein the core is cured.
25. The solid oral dosage form of any one of claims 1 to 24, wherein the core is subject to ultrasonification.
26. The solid oral dosage form of any one of claims 1 to 25, wherein the excipient is extruded and compressed.
27. The solid oral dosage form of any one of claims 1 to 26 comprising a plurality of active agents.
28. The solid oral dosage form of claim 27, wherein the plurality of active agents are coated on the same inert core
29. The solid oral dosage form of claim 27, wherein the plurality of active agents are coated on different inert cores.
30. The solid oral dosage form of any one of claims 1 to 29, wherein at least one active agent is susceptible to abuse.
31. The solid oral dosage form of claim 30, wherein the at least one active agent is selected from the group consisting of opioid analgesics, tranquilizers, CNS
depressants, CNS stimulants, sedatives, hypnotics, stimulants and cannabinoids.
depressants, CNS stimulants, sedatives, hypnotics, stimulants and cannabinoids.
32. The solid oral dosage form of claim 31, wherein the at least one active agent is an opioid analgesic selected from the group consisting of codeine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, tramadol, pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof.
33. The solid oral dosage form of claim 30, wherein the at least one active agent is selected from the group consisting of secobarbital, phenobarbital, clonazepam, diazepam, estazolam, lorazepam, midazolam, mitrazepam, oxazepam, triazolam, temazepam, chlordiazepoxide, and alprazolam.
34. The solid oral dosage form of any one of claims 1 to 29, wherein at least one active agent is selected from the group consisting of nitroglycerin, digoxin, levothyroxin, and warfarin.
35. The solid oral dosage form of any of claims 1 to 34, comprising a plurality of inert cores.
36. The solid oral dosage form of claim 35, wherein at least one inert core is coated with at least one active agent.
37. The solid oral dosage form of claim 35, wherein each inert core is coated with at least one active agent.
38. The solid oral dosage form of any one of claims 35 to 37, wherein the plurality of coated cores are contained in a pharmaceutically acceptable capsule.
39. The solid oral dosage form of any one of claims 1 to 38, having an asymmetrical shape.
40. A method of preparing a solid oral dosage form comprising:
surrounding an inert tamper resistant core having a breaking strength of at least 400 Newtons with a coating comprising an active agent.
surrounding an inert tamper resistant core having a breaking strength of at least 400 Newtons with a coating comprising an active agent.
41. A method of preparing a solid oral dosage form comprising:
(a) preparing an inert tamper resistant core having a breaking strength of at least 400 Newtons; and (b) surrounding the core with a coating comprising an active agent.
(a) preparing an inert tamper resistant core having a breaking strength of at least 400 Newtons; and (b) surrounding the core with a coating comprising an active agent.
42. A method of treating a patient for a disease or condition comprising administering to a patient in need thereof, a solid oral dosage form of any of claims 1-39.
43. A method of treating a pain comprising administering to a patient in need thereof, a solid oral dosage form of claim 32.
44. A method of reducing the incidence of overdosing, comprising dispensing a solid oral dosage form of any of claims 1-39.
45. A method of reducing the incidence of underdosing, comprising dispensing a solid oral dosage form of any of claims 1-39.
46. A method of reducing the abuse potential of an active agent susceptible to abuse comprising dispensing a solid oral dosage form of claim 30.
47. A method of reducing the incidence of overdosing, comprising preparing a solid oral dosage form of any of claims 1-39.
48. A method of reducing the incidence of underdosing, comprising preparing a solid oral dosage form of any of claims 1-39.
49. A method of reducing the abuse potential of an active agent susceptible to abuse comprising preparing a solid oral dosage form of claim 30.
50. The use of an active agent susceptible to abuse in the preparation of a tamper resistant solid oral dosage form, the dosage form comprising:
(a) an inert tamper resistant core having a breaking strength of at least 400 Newtons;
and (b) a coating surrounding the core, the coating comprising the active agent.
(a) an inert tamper resistant core having a breaking strength of at least 400 Newtons;
and (b) a coating surrounding the core, the coating comprising the active agent.
51. The use of an inert tamper resistant core having a breaking strength of at least 400 Newtons in the preparation of a tamper resistant solid oral dosage form, the dosage form comprising:
(a) the inert tamper resistant core having a breaking strength of at least 400 Newtons;
and (b) a coating surrounding the core, the coating comprising at least one active agent susceptible to abuse.
(a) the inert tamper resistant core having a breaking strength of at least 400 Newtons;
and (b) a coating surrounding the core, the coating comprising at least one active agent susceptible to abuse.
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Families Citing this family (56)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040253310A1 (en) | 2001-09-21 | 2004-12-16 | Gina Fischer | Morphine polymer release system |
WO2003024429A1 (en) | 2001-09-21 | 2003-03-27 | Egalet A/S | Polymer release system |
US7776314B2 (en) | 2002-06-17 | 2010-08-17 | Grunenthal Gmbh | Abuse-proofed dosage system |
EP1610767B1 (en) | 2003-03-26 | 2011-01-19 | Egalet A/S | Morphine controlled release system |
US20070048228A1 (en) | 2003-08-06 | 2007-03-01 | Elisabeth Arkenau-Maric | Abuse-proofed dosage form |
DE10336400A1 (en) | 2003-08-06 | 2005-03-24 | Grünenthal GmbH | Anti-abuse dosage form |
DE10361596A1 (en) | 2003-12-24 | 2005-09-29 | Grünenthal GmbH | Process for producing an anti-abuse dosage form |
DE102005005446A1 (en) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Break-resistant dosage forms with sustained release |
DE102004032049A1 (en) | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Anti-abuse, oral dosage form |
DE102005005449A1 (en) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Process for producing an anti-abuse dosage form |
AU2008258596B2 (en) | 2007-06-04 | 2013-02-14 | Egalet Ltd | Controlled release pharmaceutical compositions for prolonged effect |
AU2009207796B2 (en) | 2008-01-25 | 2014-03-27 | Grunenthal Gmbh | Pharmaceutical dosage form |
EP2393484A1 (en) | 2009-02-06 | 2011-12-14 | Egalet Ltd. | Immediate release composition resistant to abuse by intake of alcohol |
CA2766179A1 (en) | 2009-06-24 | 2010-12-29 | Egalet Ltd. | Controlled release formulations |
RU2015138422A (en) | 2009-07-22 | 2018-12-25 | Грюненталь Гмбх | STABLE DURING OXIDATION, STRONG-BREAKED DOSAGE FORM |
CA2765971C (en) | 2009-07-22 | 2017-08-22 | Gruenenthal Gmbh | Hot-melt extruded controlled release dosage form |
WO2012028318A1 (en) | 2010-09-02 | 2012-03-08 | Grünenthal GmbH | Tamper resistant dosage form comprising an anionic polymer |
PL2611426T3 (en) | 2010-09-02 | 2014-09-30 | Gruenenthal Gmbh | Tamper resistant dosage form comprising inorganic salt |
JP5638151B2 (en) | 2010-12-23 | 2014-12-10 | パーデュー、ファーマ、リミテッド、パートナーシップ | Tamper resistant solid oral dosage form |
US10201502B2 (en) | 2011-07-29 | 2019-02-12 | Gruenenthal Gmbh | Tamper-resistant tablet providing immediate drug release |
EP2736497B1 (en) | 2011-07-29 | 2017-08-23 | Grünenthal GmbH | Tamper-resistant tablet providing immediate drug release |
MX347961B (en) * | 2011-09-16 | 2017-05-19 | Purdue Pharma Lp | Tamper resistant immediate release formulations. |
US20130225697A1 (en) | 2012-02-28 | 2013-08-29 | Grunenthal Gmbh | Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer |
TWI522101B (en) | 2012-04-17 | 2016-02-21 | 普渡製藥有限合夥事業 | Systems and methods for treating an opioid-induced adverse pharmacodynamic response |
MX362357B (en) | 2012-04-18 | 2019-01-14 | Gruenenthal Gmbh | Tamper resistant and dose-dumping resistant pharmaceutical dosage form. |
US10064945B2 (en) | 2012-05-11 | 2018-09-04 | Gruenenthal Gmbh | Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc |
EP2877161A1 (en) | 2012-07-06 | 2015-06-03 | Egalet Ltd. | Abuse deterrent pharmaceutical compositions for controlled release |
BR112015000320B1 (en) | 2012-07-12 | 2023-03-07 | SpecGx LLC | ABUSE DETERRENT PHARMACEUTICAL COMPOSITIONS AND THEIR PREPARATION PROCESS |
US10751287B2 (en) | 2013-03-15 | 2020-08-25 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
WO2014191397A1 (en) | 2013-05-29 | 2014-12-04 | Grünenthal GmbH | Tamper-resistant dosage form containing one or more particles |
AR096439A1 (en) | 2013-05-29 | 2015-12-30 | Gruenenthal Gmbh | DOSAGE METHOD RESISTING TO INDEED USE CONTAINING ONE OR MORE PARTICLES |
US20150017236A1 (en) * | 2013-07-09 | 2015-01-15 | Jefferson J. Gregory | Pharmaceutical compositions of thyroid hormone |
EA032465B1 (en) | 2013-07-12 | 2019-05-31 | Грюненталь Гмбх | Tamper-resistant oral pharmaceutical dosage form containing ethylene-vinyl acetate polymer and process for the production thereof |
AU2014306759B2 (en) | 2013-08-12 | 2018-04-26 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded immediate release abuse deterrent pill |
US9770514B2 (en) | 2013-09-03 | 2017-09-26 | ExxPharma Therapeutics LLC | Tamper-resistant pharmaceutical dosage forms |
CN105934241B (en) | 2013-11-26 | 2020-06-05 | 格吕伦塔尔有限公司 | Preparation of powdered pharmaceutical composition by cryogenic grinding |
WO2015095391A1 (en) | 2013-12-17 | 2015-06-25 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
US9492444B2 (en) | 2013-12-17 | 2016-11-15 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
JP2017518980A (en) | 2014-05-12 | 2017-07-13 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | Anti-modification immediate release capsule formulation containing tapentadol |
WO2015181059A1 (en) | 2014-05-26 | 2015-12-03 | Grünenthal GmbH | Multiparticles safeguarded against ethanolic dose-dumping |
WO2016010771A1 (en) | 2014-07-17 | 2016-01-21 | Pharmaceutical Manufacturing Research Services, Inc. | Immediate release abuse deterrent liquid fill dosage form |
US9849124B2 (en) | 2014-10-17 | 2017-12-26 | Purdue Pharma L.P. | Systems and methods for treating an opioid-induced adverse pharmacodynamic response |
EP3209282A4 (en) | 2014-10-20 | 2018-05-23 | Pharmaceutical Manufacturing Research Services, Inc. | Extended release abuse deterrent liquid fill dosage form |
EP3285745A1 (en) | 2015-04-24 | 2018-02-28 | Grünenthal GmbH | Tamper-resistant dosage form with immediate release and resistance against solvent extraction |
EP3346991A1 (en) | 2015-09-10 | 2018-07-18 | Grünenthal GmbH | Protecting oral overdose with abuse deterrent immediate release formulations |
EP3181124A1 (en) * | 2015-12-16 | 2017-06-21 | Universität Basel | Abuse deterrent pharmaceutical dosage forms |
JP2019524761A (en) | 2016-08-12 | 2019-09-05 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | Anti-modification preparation of ephedrine and its derivatives |
WO2019073408A1 (en) * | 2017-10-10 | 2019-04-18 | Douglas Pharmaceuticals Ltd. | Extended release pharmaceutical formulation and methods of treatment |
US10441544B2 (en) | 2017-10-10 | 2019-10-15 | Douglas Pharmaceuticals, Ltd. | Extended release pharmaceutical formulation |
US10869838B2 (en) | 2017-10-10 | 2020-12-22 | Douglas Pharmaceuticals, Ltd. | Extended release pharmaceutical formulation |
US11471415B2 (en) | 2017-10-10 | 2022-10-18 | Douglas Pharmaceuticals, Ltd. | Extended release pharmaceutical formulation and methods of treatment |
CN111465396A (en) * | 2017-12-20 | 2020-07-28 | 普渡制药公司 | Abuse-resistant morphine sulfate dosage forms |
TW202002957A (en) | 2018-02-09 | 2020-01-16 | 德商歌林達有限公司 | Tamper resistant formulation of ephedrine and its derivatives comprising a conversion inhibitor |
WO2020081762A1 (en) * | 2018-10-19 | 2020-04-23 | Temple University-Of The Commonwealth System Of Higher Education | Tamper-resistant drug dosage forms and methods of making and use thereof |
MX2021010207A (en) * | 2019-03-25 | 2021-09-21 | Douglas Pharmaceuticals Ltd | Extended release pharmaceutical formulation. |
CN114366720B (en) * | 2021-12-11 | 2023-07-21 | 江苏恩华药业股份有限公司 | Abuse-proof triazolam oral tablet and preparation method thereof |
Family Cites Families (304)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3096248A (en) | 1959-04-06 | 1963-07-02 | Rexall Drug & Chemical Company | Method of making an encapsulated tablet |
US3065143A (en) | 1960-04-19 | 1962-11-20 | Richardson Merrell Inc | Sustained release tablet |
US3173876A (en) | 1960-05-27 | 1965-03-16 | John C Zobrist | Cleaning methods and compositions |
NL271831A (en) | 1960-11-29 | |||
US3260646A (en) | 1962-10-19 | 1966-07-12 | Ferring Ab | Medication with mechanism to prevent overdosage |
US3276586A (en) | 1963-08-30 | 1966-10-04 | Rosaen Filter Co | Indicating means for fluid filters |
US3400197A (en) | 1965-01-26 | 1968-09-03 | Robins Co Inc A H | Compressible sustained release pharmaceutical tablet lipid-colloidal silica gel matrix fragment granules |
NL6714885A (en) | 1967-11-02 | 1969-05-06 | ||
US3541006A (en) | 1968-07-03 | 1970-11-17 | Amicon Corp | Ultrafiltration process |
US3541005A (en) | 1969-02-05 | 1970-11-17 | Amicon Corp | Continuous ultrafiltration of macromolecular solutions |
US3879555A (en) | 1970-11-16 | 1975-04-22 | Bristol Myers Co | Method of treating drug addicts |
GB1405088A (en) | 1971-06-03 | 1975-09-03 | Mundipharma Ag | Slow release formulation |
US3965256A (en) | 1972-05-16 | 1976-06-22 | Synergistics | Slow release pharmaceutical compositions |
US3845770A (en) | 1972-06-05 | 1974-11-05 | Alza Corp | Osmatic dispensing device for releasing beneficial agent |
US3980766A (en) | 1973-08-13 | 1976-09-14 | West Laboratories, Inc. | Orally administered drug composition for therapy in the treatment of narcotic drug addiction |
US3916889A (en) | 1973-09-28 | 1975-11-04 | Sandoz Ag | Patient ventilator apparatus |
GB1478759A (en) | 1974-11-18 | 1977-07-06 | Alza Corp | Process for forming outlet passageways in pills using a laser |
DE2530563C2 (en) | 1975-07-09 | 1986-07-24 | Bayer Ag, 5090 Leverkusen | Analgesic drugs with reduced potential for abuse |
US4077407A (en) | 1975-11-24 | 1978-03-07 | Alza Corporation | Osmotic devices having composite walls |
US4063064A (en) | 1976-02-23 | 1977-12-13 | Coherent Radiation | Apparatus for tracking moving workpiece by a laser beam |
US4175119A (en) | 1978-01-11 | 1979-11-20 | Porter Garry L | Composition and method to prevent accidental and intentional overdosage with psychoactive drugs |
NO154582C (en) | 1978-10-20 | 1986-11-05 | Ferrosan Ab | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE DIPHENYL-DIBUTYLPIPERAZINE CARBOXAMIDS. |
US4200098A (en) | 1978-10-23 | 1980-04-29 | Alza Corporation | Osmotic system with distribution zone for dispensing beneficial agent |
US4285987A (en) | 1978-10-23 | 1981-08-25 | Alza Corporation | Process for manufacturing device with dispersion zone |
US4293539A (en) | 1979-09-12 | 1981-10-06 | Eli Lilly And Company | Controlled release formulations and method of treatment |
IE49324B1 (en) | 1979-12-19 | 1985-09-18 | Euro Celtique Sa | Controlled release compositions |
US4457933A (en) | 1980-01-24 | 1984-07-03 | Bristol-Myers Company | Prevention of analgesic abuse |
US4424205A (en) | 1982-03-18 | 1984-01-03 | The Procter & Gamble Company | Hydroxyphenylacetamides having analgesic and anti-irritant activity |
US4389393A (en) | 1982-03-26 | 1983-06-21 | Forest Laboratories, Inc. | Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose |
US4443428A (en) | 1982-06-21 | 1984-04-17 | Euroceltique, S.A. | Extended action controlled release compositions |
IL70071A (en) | 1982-11-01 | 1987-12-31 | Merrell Dow Pharma | Multilayered sustained release pharmaceutical tablets having non-uniform distribution of active ingredient |
US4459278A (en) | 1983-03-07 | 1984-07-10 | Clear Lake Development Group | Composition and method of immobilizing emetics and method of treating human beings with emetics |
US4765989A (en) | 1983-05-11 | 1988-08-23 | Alza Corporation | Osmotic device for administering certain drugs |
US4612008A (en) | 1983-05-11 | 1986-09-16 | Alza Corporation | Osmotic device with dual thermodynamic activity |
US4681897A (en) | 1984-01-16 | 1987-07-21 | The Procter & Gamble Company | Pharmaceutical products providing enhanced analgesia |
US4599342A (en) | 1984-01-16 | 1986-07-08 | The Procter & Gamble Company | Pharmaceutical products providing enhanced analgesia |
US4629623A (en) | 1984-06-11 | 1986-12-16 | Biomatrix, Inc. | Hyaluronate-poly (ethylene oxide) compositions and cosmetic formulations thereof |
US4588580B2 (en) | 1984-07-23 | 1999-02-16 | Alaz Corp | Transdermal administration of fentanyl and device therefor |
US4610870A (en) | 1984-10-05 | 1986-09-09 | E. R. Squibb & Sons, Inc. | Controlled release formulation |
US4806341A (en) | 1985-02-25 | 1989-02-21 | Rutgers, The State University Of New Jersey | Transdermal absorption dosage unit for narcotic analgesics and antagonists and process for administration |
US4666705A (en) | 1985-06-03 | 1987-05-19 | E. R. Squibb & Sons, Inc. | Controlled release formulation |
US4764378A (en) | 1986-02-10 | 1988-08-16 | Zetachron, Inc. | Buccal drug dosage form |
ES2058111T3 (en) | 1986-06-10 | 1994-11-01 | Euro Celtique Sa | COMPOSITION OF CONTROLLED RELEASE OF DIHYDROCODEIN. |
US4785000A (en) | 1986-06-18 | 1988-11-15 | The Rockefeller University | Method of treating patients suffering from chronic pain or chronic cough |
US4769372A (en) | 1986-06-18 | 1988-09-06 | The Rockefeller University | Method of treating patients suffering from chronic pain or chronic cough |
US4861598A (en) | 1986-07-18 | 1989-08-29 | Euroceltique, S.A. | Controlled release bases for pharmaceuticals |
US4970075A (en) | 1986-07-18 | 1990-11-13 | Euroceltique, S.A. | Controlled release bases for pharmaceuticals |
GB8626098D0 (en) | 1986-10-31 | 1986-12-03 | Euro Celtique Sa | Controlled release hydromorphone composition |
GB8727504D0 (en) | 1987-11-24 | 1987-12-23 | Glaxo Group Ltd | Chemical compositions |
DE3812567A1 (en) | 1988-04-15 | 1989-10-26 | Basf Ag | METHOD FOR PRODUCING PHARMACEUTICAL MIXTURES |
EP0361910B1 (en) | 1988-09-30 | 1994-06-29 | Rhone-Poulenc Rorer Limited | Granular pharmaceutical formulations |
US4939149A (en) | 1988-10-24 | 1990-07-03 | The United States Of America As Represented By The Department Of Health And Human Services | Resiniferatoxin and analogues thereof to cause sensory afferent C-fiber and thermoregulatory desensitization |
US5026556A (en) | 1988-11-10 | 1991-06-25 | Norwich Eaton Pharmaceuticals, Inc. | Compositions for the transdermal delivery of pharmaceutical actives |
US5403868A (en) | 1988-12-23 | 1995-04-04 | Sandoz Ltd. | Capsaicin derivatives |
US5202128A (en) | 1989-01-06 | 1993-04-13 | F. H. Faulding & Co. Limited | Sustained release pharmaceutical composition |
US5330766A (en) | 1989-01-06 | 1994-07-19 | F. H. Faulding & Co. Limited | Sustained release pharmaceutical composition |
US5059600A (en) | 1989-03-31 | 1991-10-22 | Yale University | Treating habit disorders |
US5114942A (en) | 1989-03-31 | 1992-05-19 | Yale University | Treating habit disorders |
US4992277A (en) | 1989-08-25 | 1991-02-12 | Schering Corporation | Immediate release diltiazem formulation |
US5169645A (en) | 1989-10-31 | 1992-12-08 | Duquesne University Of The Holy Ghost | Directly compressible granules having improved flow properties |
US5232685A (en) | 1989-11-03 | 1993-08-03 | Schering Aktiengesellschaft | Nonionic x-ray contrast medium with high iodine content |
GB8926612D0 (en) | 1989-11-24 | 1990-01-17 | Erba Farmitalia | Pharmaceutical compositions |
US5240711A (en) | 1989-11-29 | 1993-08-31 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Transdermal therapeutic system comprising as active component buprenorphine |
IT1237904B (en) | 1989-12-14 | 1993-06-18 | Ubaldo Conte | CONTROLLED SPEED RELEASE TABS OF ACTIVE SUBSTANCES |
KR950005865B1 (en) | 1990-04-23 | 1995-06-02 | 데이진 가부시끼가이샤 | Plaster |
FR2661324B1 (en) | 1990-04-25 | 1994-09-16 | Didier Bernardin | DISPLAY OF OBJECTS IN A LINE. |
US5679650A (en) | 1993-11-24 | 1997-10-21 | Fukunaga; Atsuo F. | Pharmaceutical compositions including mixtures of an adenosine compound and a catecholamine |
US5069909A (en) | 1990-06-20 | 1991-12-03 | Cygnus Therapeutic Systems | Transdermal administration of buprenorphine |
US5246698A (en) | 1990-07-09 | 1993-09-21 | Biomatrix, Inc. | Biocompatible viscoelastic gel slurries, their preparation and use |
US5113585A (en) | 1990-09-28 | 1992-05-19 | The Gillette Company | Shaving system |
US5300302A (en) | 1990-10-04 | 1994-04-05 | Nestec S.A. | Pharmaceutical composition in gel form in a dispensing package |
FR2669336B1 (en) | 1990-11-20 | 1993-01-22 | Adir | NOVEL OXAZOLO PYRIDINES DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
US5273758A (en) | 1991-03-18 | 1993-12-28 | Sandoz Ltd. | Directly compressible polyethylene oxide vehicle for preparing therapeutic dosage forms |
US5149538A (en) | 1991-06-14 | 1992-09-22 | Warner-Lambert Company | Misuse-resistive transdermal opioid dosage form |
US5215758A (en) | 1991-09-11 | 1993-06-01 | Euroceltique, S.A. | Controlled release matrix suppository for pharmaceuticals |
EP0623155A4 (en) | 1991-09-18 | 1995-01-11 | Transcontinental Marketing Gro | One coat protective system for a surface. |
DE69229881T2 (en) | 1991-10-04 | 1999-12-09 | Yoshitomi Pharmaceutical | DELAYED RELEASE TABLET |
EP0546593B1 (en) | 1991-10-30 | 1997-09-03 | Glaxo Group Limited | Multi-layered compositions containing histamine or serotonin antagonists |
US5656295A (en) | 1991-11-27 | 1997-08-12 | Euro-Celtique, S.A. | Controlled release oxycodone compositions |
US5266331A (en) | 1991-11-27 | 1993-11-30 | Euroceltique, S.A. | Controlled release oxycodone compositions |
US5580578A (en) | 1992-01-27 | 1996-12-03 | Euro-Celtique, S.A. | Controlled release formulations coated with aqueous dispersions of acrylic polymers |
US5273760A (en) | 1991-12-24 | 1993-12-28 | Euroceltigue, S.A. | Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer |
US5478577A (en) | 1993-11-23 | 1995-12-26 | Euroceltique, S.A. | Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level |
US5958459A (en) | 1991-12-24 | 1999-09-28 | Purdue Pharma L.P. | Opioid formulations having extended controlled released |
US5286493A (en) | 1992-01-27 | 1994-02-15 | Euroceltique, S.A. | Stabilized controlled release formulations having acrylic polymer coating |
US5681585A (en) | 1991-12-24 | 1997-10-28 | Euro-Celtique, S.A. | Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer |
US5472712A (en) | 1991-12-24 | 1995-12-05 | Euroceltique, S.A. | Controlled-release formulations coated with aqueous dispersions of ethylcellulose |
US5968551A (en) | 1991-12-24 | 1999-10-19 | Purdue Pharma L.P. | Orally administrable opioid formulations having extended duration of effect |
AU658271B2 (en) | 1992-03-26 | 1995-04-06 | Tanabe Seiyaku Co., Ltd. | Butadiene derivatives and process for preparing the same |
CA2138026C (en) | 1992-06-22 | 2003-09-09 | Eckard Weber | Novel 1,4-dihydroquinoxaline-2,3-diones and uses therefor as glycine receptor antagonists |
US5232934A (en) | 1992-07-17 | 1993-08-03 | Warner-Lambert Co. | Method for the treatment of psychomotor stimulant addiction |
US5324351A (en) | 1992-08-13 | 1994-06-28 | Euroceltique | Aqueous dispersions of zein and preparation thereof |
CA2144077C (en) | 1992-09-18 | 2005-05-24 | Kazuhiro Sako | Hydrogel-type sustained-release preparation |
US5472943A (en) | 1992-09-21 | 1995-12-05 | Albert Einstein College Of Medicine Of Yeshiva University, | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other opioid agonists |
IT1256393B (en) | 1992-11-17 | 1995-12-04 | Inverni Della Beffa Spa | MULTI-LAYER MATERIAL FORMS FOR THE CONTROLLED RELEASE OF ACTIVE INGREDIENTS |
US5604260A (en) | 1992-12-11 | 1997-02-18 | Merck Frosst Canada Inc. | 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2 |
US5321012A (en) | 1993-01-28 | 1994-06-14 | Virginia Commonwealth University Medical College | Inhibiting the development of tolerance to and/or dependence on a narcotic addictive substance |
CA2115792C (en) | 1993-03-05 | 2005-11-01 | David J. Mayer | Method for the treatment of pain |
US5409944A (en) | 1993-03-12 | 1995-04-25 | Merck Frosst Canada, Inc. | Alkanesulfonamido-1-indanone derivatives as inhibitors of cyclooxygenase |
US5474995A (en) | 1993-06-24 | 1995-12-12 | Merck Frosst Canada, Inc. | Phenyl heterocycles as cox-2 inhibitors |
US5436265A (en) | 1993-11-12 | 1995-07-25 | Merck Frosst Canada, Inc. | 1-aroyl-3-indolyl alkanoic acids and derivatives thereof useful as anti-inflammatory agents |
IL110014A (en) | 1993-07-01 | 1999-11-30 | Euro Celtique Sa | Solid controlled-release oral dosage forms of opioid analgesics |
US5879705A (en) | 1993-07-27 | 1999-03-09 | Euro-Celtique S.A. | Sustained release compositions of morphine and a method of preparing pharmaceutical compositions |
EP1442745A1 (en) | 1993-10-07 | 2004-08-04 | Euro-Celtique | Orally administrable opioid formulations having extended duration of effect |
US6210714B1 (en) | 1993-11-23 | 2001-04-03 | Euro-Celtique S.A. | Immediate release tablet cores of acetaminophen having sustained-release coating |
US5891471A (en) | 1993-11-23 | 1999-04-06 | Euro-Celtique, S.A. | Pharmaceutical multiparticulates |
KR100354702B1 (en) | 1993-11-23 | 2002-12-28 | 유로-셀티크 소시에떼 아노뉨 | Manufacturing method and sustained release composition of pharmaceutical composition |
US5500227A (en) | 1993-11-23 | 1996-03-19 | Euro-Celtique, S.A. | Immediate release tablet cores of insoluble drugs having sustained-release coating |
GB9401894D0 (en) | 1994-02-01 | 1994-03-30 | Rhone Poulenc Rorer Ltd | New compositions of matter |
US5843480A (en) | 1994-03-14 | 1998-12-01 | Euro-Celtique, S.A. | Controlled release diamorphine formulation |
US5411745A (en) | 1994-05-25 | 1995-05-02 | Euro-Celtique, S.A. | Powder-layered morphine sulfate formulations |
US5567439A (en) | 1994-06-14 | 1996-10-22 | Fuisz Technologies Ltd. | Delivery of controlled-release systems(s) |
US5460826A (en) | 1994-06-27 | 1995-10-24 | Alza Corporation | Morphine therapy |
US5914131A (en) | 1994-07-07 | 1999-06-22 | Alza Corporation | Hydromorphone therapy |
US5529787A (en) | 1994-07-07 | 1996-06-25 | Alza Corporation | Hydromorphone therapy |
US5616601A (en) | 1994-07-28 | 1997-04-01 | Gd Searle & Co | 1,2-aryl and heteroaryl substituted imidazolyl compounds for the treatment of inflammation |
EP0783343A4 (en) | 1994-08-22 | 1999-02-03 | Iomed Inc | Iontophoretic delivery device with integral hydrating means |
US5612359A (en) | 1994-08-26 | 1997-03-18 | Bristol-Myers Squibb Company | Substituted biphenyl isoxazole sulfonamides |
US5521213A (en) | 1994-08-29 | 1996-05-28 | Merck Frosst Canada, Inc. | Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2 |
US5593994A (en) | 1994-09-29 | 1997-01-14 | The Dupont Merck Pharmaceutical Company | Prostaglandin synthase inhibitors |
US5965161A (en) | 1994-11-04 | 1999-10-12 | Euro-Celtique, S.A. | Extruded multi-particulates |
IL116674A (en) | 1995-01-09 | 2003-05-29 | Mendell Co Inc Edward | Microcrystalline cellulose-based excipient having improved compressibility, pharmaceutical compositions containing the same and methods for the preparation of said excipient and of solid dosage form thereof |
US5552422A (en) | 1995-01-11 | 1996-09-03 | Merck Frosst Canada, Inc. | Aryl substituted 5,5 fused aromatic nitrogen compounds as anti-inflammatory agents |
US5676972A (en) | 1995-02-16 | 1997-10-14 | The University Of Akron | Time-release delivery matrix composition and corresponding controlled-release compositions |
US5945125A (en) | 1995-02-28 | 1999-08-31 | Temple University | Controlled release tablet |
US5695781A (en) | 1995-03-01 | 1997-12-09 | Hallmark Pharmaceuticals, Inc. | Sustained release formulation containing three different types of polymers |
US6348469B1 (en) | 1995-04-14 | 2002-02-19 | Pharma Pass Llc | Solid compositions containing glipizide and polyethylene oxide |
US5686106A (en) | 1995-05-17 | 1997-11-11 | The Procter & Gamble Company | Pharmaceutical dosage form for colonic delivery |
US5604253A (en) | 1995-05-22 | 1997-02-18 | Merck Frosst Canada, Inc. | N-benzylindol-3-yl propanoic acid derivatives as cyclooxygenase inhibitors |
US5639780A (en) | 1995-05-22 | 1997-06-17 | Merck Frosst Canada, Inc. | N-benzyl indol-3-yl butanoic acid derivatives as cyclooxygenase inhibitors |
US5510368A (en) | 1995-05-22 | 1996-04-23 | Merck Frosst Canada, Inc. | N-benzyl-3-indoleacetic acids as antiinflammatory drugs |
US5654005A (en) | 1995-06-07 | 1997-08-05 | Andrx Pharmaceuticals, Inc. | Controlled release formulation having a preformed passageway |
US5762963A (en) | 1995-06-07 | 1998-06-09 | Emory University | Method and compositions for controlling oral and pharyngeal pain using capsaicinoids |
US5811388A (en) | 1995-06-07 | 1998-09-22 | Cibus Pharmaceutical, Inc. | Delivery of drugs to the lower GI tract |
US5811126A (en) | 1995-10-02 | 1998-09-22 | Euro-Celtique, S.A. | Controlled release matrix for pharmaceuticals |
US5773031A (en) | 1996-02-27 | 1998-06-30 | L. Perrigo Company | Acetaminophen sustained-release formulation |
PT914097E (en) | 1996-03-12 | 2002-06-28 | Alza Corp | COMPOSITION AND DOSAGE FORM COMPREHENDING OPIOIDE ANTAGONIST |
US5766623A (en) | 1996-03-25 | 1998-06-16 | State Of Oregon Acting By And Through The Oregon State Board Of Higher Education On Behalf Of Oregon State University | Compactable self-sealing drug delivery agents |
DE69723248T2 (en) | 1996-04-10 | 2004-05-27 | Warner-Lambert Co. Llc | COMPOSITIONS FOR SYMPATHOMIMETIC AMINE SALT |
WO1997045091A2 (en) | 1996-05-31 | 1997-12-04 | Euro-Celtique, S.A. | Sustained release oxycodone formulations with no fed/fast effect |
US6440464B1 (en) | 1996-06-10 | 2002-08-27 | Viva Life Science | Nutritive composition for cardiovascular health containing fish oil, garlic, rutin, capsaicin, selenium, vitamins and juice concentrates |
DE69739343D1 (en) | 1996-06-26 | 2009-05-14 | Univ Texas | HOT-MOLLY EXTRUDABLE PHARMACEUTICAL FORMULATION |
US5788987A (en) | 1997-01-29 | 1998-08-04 | Poli Industria Chimica Spa | Methods for treating early morning pathologies |
TW536540B (en) | 1997-01-30 | 2003-06-11 | Bristol Myers Squibb Co | Endothelin antagonists: N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide and N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-4'-(2-oxazolyl)[1,1'-biphe |
US5837379A (en) | 1997-01-31 | 1998-11-17 | Andrx Pharmaceuticals, Inc. | Once daily pharmaceutical tablet having a unitary core |
US5948787A (en) | 1997-02-28 | 1999-09-07 | Alza Corporation | Compositions containing opiate analgesics |
US6120751A (en) | 1997-03-21 | 2000-09-19 | Imarx Pharmaceutical Corp. | Charged lipids and uses for the same |
US6124282A (en) | 1997-05-22 | 2000-09-26 | Sellers; Edward M. | Drug formulations |
JP2002514221A (en) | 1997-05-27 | 2002-05-14 | アルゴス ファーマシューティカル コーポレーション | Analgesic composition containing capsaicinoid and enhancer thereof |
US6153621A (en) | 1997-06-23 | 2000-11-28 | The University Of Kentucky Research Foundation | Combined antagonist compositions |
RS49982B (en) | 1997-09-17 | 2008-09-29 | Euro-Celtique S.A., | Synergistic analgesic combination of opioid analgesic and cyclooxygenase-2 inhibitor |
US5891919A (en) | 1997-09-19 | 1999-04-06 | Burlington Bio-Medical & Scientific Corp. | Denatonium capsaicinate and methods of producing the same |
US6294194B1 (en) | 1997-10-14 | 2001-09-25 | Boehringer Ingelheim Pharmaceuticals, Inc. | Method for extraction and reaction using supercritical fluids |
US6066339A (en) | 1997-10-17 | 2000-05-23 | Elan Corporation, Plc | Oral morphine multiparticulate formulation |
EP1035834B1 (en) | 1997-12-05 | 2002-04-17 | Alza Corporation | Osmotic dosage form comprising first and second coats |
US6485748B1 (en) | 1997-12-12 | 2002-11-26 | Andrx Pharmaceuticals, Inc. | Once daily pharmaceutical tablet having a unitary core |
US20030059471A1 (en) | 1997-12-15 | 2003-03-27 | Compton Bruce Jon | Oral delivery formulation |
HUP0100310A3 (en) | 1997-12-22 | 2002-11-28 | Euro Celtique Sa | A method of preventing abuse of opioid dosage forms |
DK1041987T3 (en) | 1997-12-22 | 2006-08-21 | Euro Celtique Sa | Oral pharmaceutical dosage form comprising a combination of an opioid agonist and naltrexone |
US6375957B1 (en) | 1997-12-22 | 2002-04-23 | Euro-Celtique, S.A. | Opioid agonist/opioid antagonist/acetaminophen combinations |
US6251430B1 (en) | 1998-02-04 | 2001-06-26 | Guohua Zhang | Water insoluble polymer based sustained release formulation |
US6245357B1 (en) | 1998-03-06 | 2001-06-12 | Alza Corporation | Extended release dosage form |
US6365185B1 (en) | 1998-03-26 | 2002-04-02 | University Of Cincinnati | Self-destructing, controlled release peroral drug delivery system |
US6372254B1 (en) | 1998-04-02 | 2002-04-16 | Impax Pharmaceuticals Inc. | Press coated, pulsatile drug delivery system suitable for oral administration |
DE69940063D1 (en) | 1998-07-06 | 2009-01-22 | Bristol Myers Squibb Co | BIPHENYLSULFONAMIDE AS A DOUBLE-ACTIVE RECEPTOR ANTAGONIST OF ANGIOTENSIN AND ENDOTHELIN |
US6541520B1 (en) | 1998-08-05 | 2003-04-01 | Brookhaven Science Associates | Treatment of addiction and addiction-related behavior |
US8293277B2 (en) | 1998-10-01 | 2012-10-23 | Alkermes Pharma Ireland Limited | Controlled-release nanoparticulate compositions |
EP1005863A1 (en) | 1998-12-04 | 2000-06-07 | Synthelabo | Controlled-release dosage forms comprising a short acting hypnotic or a salt thereof |
US6419960B1 (en) * | 1998-12-17 | 2002-07-16 | Euro-Celtique S.A. | Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations |
US20030170181A1 (en) | 1999-04-06 | 2003-09-11 | Midha Kamal K. | Method for preventing abuse of methylphenidate |
BE1012795A3 (en) | 1999-07-23 | 2001-03-06 | Barco Elbicon N V | Use of optical waveguide technology in a sort device. |
CA2379987A1 (en) | 1999-07-29 | 2001-02-08 | Roxane Laboratories, Inc. | Opioid sustained-released formulation |
WO2001013909A2 (en) | 1999-08-25 | 2001-03-01 | Cooper Barrett R | Compositions and methods for treating opiate intolerance |
KR101216270B1 (en) | 1999-10-29 | 2012-12-31 | 유로-셀티크 소시에떼 아노뉨 | Controlled release hydrocodone formulations |
AR031682A1 (en) | 1999-11-19 | 2003-10-01 | Reckitt Benckiser Helthcare Uk | PHARMACEUTICAL COMPOSITIONS |
US6352721B1 (en) | 2000-01-14 | 2002-03-05 | Osmotica Corp. | Combined diffusion/osmotic pumping drug delivery system |
US6491949B2 (en) | 2000-01-14 | 2002-12-10 | Osmotica Corp. | Osmotic device within an osmotic device |
ATE340563T1 (en) | 2000-02-04 | 2006-10-15 | Depomed Inc | SHELL AND CORE TYPE DOSAGE FORM WITH A RELEASE OF ACTIVE INGREDIENTS APPROACHING TO THE ZERO ORDER |
RS50407B (en) | 2000-02-08 | 2009-12-31 | Euro-Celtique S.A., | Tamper-resistant oral opiod agonist formulations |
US20010036943A1 (en) | 2000-04-07 | 2001-11-01 | Coe Jotham W. | Pharmaceutical composition for treatment of acute, chronic pain and/or neuropathic pain and migraines |
US6761895B2 (en) | 2000-04-17 | 2004-07-13 | Yamanouchi Pharmaceutical Co., Ltd. | Drug delivery system for averting pharmacokinetic drug interaction and method thereof |
US20020028240A1 (en) | 2000-04-17 | 2002-03-07 | Toyohiro Sawada | Timed-release compression-coated solid composition for oral administration |
US6955821B2 (en) | 2000-04-28 | 2005-10-18 | Adams Laboratories, Inc. | Sustained release formulations of guaifenesin and additional drug ingredients |
US6419954B1 (en) | 2000-05-19 | 2002-07-16 | Yamanouchi Pharmaceutical Co., Ltd. | Tablets and methods for modified release of hydrophilic and other active agents |
AU2002227383B2 (en) | 2000-10-30 | 2004-07-08 | Euro-Celtique S.A. | Controlled release hydrocodone formulations |
US6559159B2 (en) | 2001-02-01 | 2003-05-06 | Research Triangle Institute | Kappa opioid receptor ligands |
US6656882B2 (en) | 2001-02-28 | 2003-12-02 | Oms Investments, Inc. | Controlled release products and processes for the preparation thereof |
JP2004529902A (en) | 2001-03-13 | 2004-09-30 | ペンウェスト ファーマシューティカルズ カンパニー | Chronotherapeutic dosage forms containing glucocorticosteroids |
US20020187192A1 (en) | 2001-04-30 | 2002-12-12 | Yatindra Joshi | Pharmaceutical composition which reduces or eliminates drug abuse potential |
DE60216078T2 (en) | 2001-05-11 | 2007-07-05 | Endo Pharmaceuticals Inc. | OPIOID CONTAINING ARZNEIFORM AGAINST MISUSE |
US20030035839A1 (en) | 2001-05-15 | 2003-02-20 | Peirce Management, Llc | Pharmaceutical composition for both intraoral and oral administration |
US20030064122A1 (en) | 2001-05-23 | 2003-04-03 | Endo Pharmaceuticals, Inc. | Abuse resistant pharmaceutical composition containing capsaicin |
US20030091625A1 (en) | 2001-06-25 | 2003-05-15 | Madhusudan Hariharan | Method and device for producing compression coated tablets |
WO2003002100A1 (en) | 2001-06-26 | 2003-01-09 | Farrell John J | Tamper-proof narcotic delivery system |
US20030021841A1 (en) | 2001-07-02 | 2003-01-30 | Matharu Amol Singh | Pharmaceutical composition |
ATE376832T1 (en) | 2001-07-06 | 2007-11-15 | Penwest Pharmaceuticals Co | DELAYED RELEASE FORMULATIONS OF OXYMORPHONE |
US7157103B2 (en) | 2001-08-06 | 2007-01-02 | Euro-Celtique S.A. | Pharmaceutical formulation containing irritant |
US20030044458A1 (en) | 2001-08-06 | 2003-03-06 | Curtis Wright | Oral dosage form comprising a therapeutic agent and an adverse-effect agent |
DE20220910U1 (en) | 2001-08-06 | 2004-08-05 | Euro-Celtique S.A. | Anti-abuse compositions for opioids |
WO2003015531A2 (en) | 2001-08-06 | 2003-02-27 | Thomas Gruber | Pharmaceutical formulation containing dye |
US7144587B2 (en) | 2001-08-06 | 2006-12-05 | Euro-Celtique S.A. | Pharmaceutical formulation containing opioid agonist, opioid antagonist and bittering agent |
US20150031718A1 (en) | 2001-08-06 | 2015-01-29 | Purdue Pharma L.P. | Pharmaceutical Formulation Containing Opioid Agonist, Opioid Antagonist and Gelling Agent |
US7332182B2 (en) | 2001-08-06 | 2008-02-19 | Purdue Pharma L.P. | Pharmaceutical formulation containing opioid agonist, opioid antagonist and irritant |
US7842307B2 (en) | 2001-08-06 | 2010-11-30 | Purdue Pharma L.P. | Pharmaceutical formulation containing opioid agonist, opioid antagonist and gelling agent |
US20030068375A1 (en) | 2001-08-06 | 2003-04-10 | Curtis Wright | Pharmaceutical formulation containing gelling agent |
US7141250B2 (en) | 2001-08-06 | 2006-11-28 | Euro-Celtique S.A. | Pharmaceutical formulation containing bittering agent |
US20030068276A1 (en) | 2001-09-17 | 2003-04-10 | Lyn Hughes | Dosage forms |
US20030092724A1 (en) | 2001-09-18 | 2003-05-15 | Huaihung Kao | Combination sustained release-immediate release oral dosage forms with an opioid analgesic and a non-opioid analgesic |
US20040253310A1 (en) | 2001-09-21 | 2004-12-16 | Gina Fischer | Morphine polymer release system |
US20030091635A1 (en) | 2001-09-26 | 2003-05-15 | Baichwal Anand R. | Opioid formulations having reduced potential for abuse |
US6723340B2 (en) | 2001-10-25 | 2004-04-20 | Depomed, Inc. | Optimal polymer mixtures for gastric retentive tablets |
US20030091630A1 (en) | 2001-10-25 | 2003-05-15 | Jenny Louie-Helm | Formulation of an erodible, gastric retentive oral dosage form using in vitro disintegration test data |
JP2005035888A (en) | 2001-10-25 | 2005-02-10 | Ta Stevia Co Ltd | Substance for ameliorating anaphylactic type allergic symptom and method for producing the same |
US20030125347A1 (en) | 2001-11-02 | 2003-07-03 | Elan Corporation Plc | Pharmaceutical composition |
US20040126428A1 (en) | 2001-11-02 | 2004-07-01 | Lyn Hughes | Pharmaceutical formulation including a resinate and an aversive agent |
WO2003057136A2 (en) | 2001-12-24 | 2003-07-17 | Teva Pharmaceutical Industries Ltd. | Dosage form with a core tablet of active ingredient sheathed in a compressed annular body of powder or granular material, and process and tooling for producing it |
TW573259B (en) | 2001-12-28 | 2004-01-21 | Admtek Inc | LIFM algorithm for security association database lookup in IPSec application |
US8323692B2 (en) | 2002-02-21 | 2012-12-04 | Valeant International Bermuda | Controlled release dosage forms |
AU2003220551A1 (en) * | 2002-03-26 | 2003-10-13 | Euro-Celtique S.A. | Sustained-release gel coated compositions |
FR2838647B1 (en) | 2002-04-23 | 2006-02-17 | PROLONGED RELEASE PARTICLES, PROCESS FOR THEIR PREPARATION AND TABLETS CONTAINING SAME | |
ES2320435T3 (en) | 2002-04-29 | 2009-05-22 | Alza Corporation | METHOD AND DOSAGE FORMS FOR THE CONTROLLED ADMINISTRATION OF OXICODONE. |
US20060034872A1 (en) | 2002-04-29 | 2006-02-16 | Woolf Clifford J | Compositions and methods for preventing abuse of orally administered medications |
US20050106249A1 (en) | 2002-04-29 | 2005-05-19 | Stephen Hwang | Once-a-day, oral, controlled-release, oxycodone dosage forms |
WO2003101431A1 (en) | 2002-06-04 | 2003-12-11 | J.B. Chemicals & Pharmaceuticals Ltd. | Pharmaceutical composition for controlled drug delivery system |
US7776314B2 (en) | 2002-06-17 | 2010-08-17 | Grunenthal Gmbh | Abuse-proofed dosage system |
EP1594467A4 (en) | 2002-07-05 | 2008-10-22 | Collegium Pharmaceutical Inc | Abuse-deterrent pharmaceutical compositions of opioids and other drugs |
US20050020613A1 (en) | 2002-09-20 | 2005-01-27 | Alpharma, Inc. | Sustained release opioid formulations and method of use |
PT1551372T (en) | 2002-09-20 | 2018-07-23 | Alpharma Pharmaceuticals Llc | Sequestering subunit and related compositions and metohds |
US8487002B2 (en) | 2002-10-25 | 2013-07-16 | Paladin Labs Inc. | Controlled-release compositions |
DE10250084A1 (en) | 2002-10-25 | 2004-05-06 | Grünenthal GmbH | Dosage form protected against abuse |
US20050186139A1 (en) | 2002-10-25 | 2005-08-25 | Gruenenthal Gmbh | Abuse-proofed dosage form |
WO2004045551A2 (en) | 2002-11-15 | 2004-06-03 | Branded Products For The Future | Pharmaceutical composition |
US20040110781A1 (en) | 2002-12-05 | 2004-06-10 | Harmon Troy M. | Pharmaceutical compositions containing indistinguishable drug components |
CA2510465A1 (en) | 2002-12-18 | 2004-07-08 | Pain Therapeutics | Oral dosage forms with therapeutically active agents in controlled release cores and immediate release gelatin capsule coats |
US7524515B2 (en) | 2003-01-10 | 2009-04-28 | Mutual Pharmaceuticals, Inc. | Pharmaceutical safety dosage forms |
EP1610767B1 (en) | 2003-03-26 | 2011-01-19 | Egalet A/S | Morphine controlled release system |
US20040202717A1 (en) * | 2003-04-08 | 2004-10-14 | Mehta Atul M. | Abuse-resistant oral dosage forms and method of use thereof |
KR101192722B1 (en) | 2003-04-24 | 2012-10-18 | 자고텍 아게 | Delayed release tablet with defined core geometry |
US8906413B2 (en) | 2003-05-12 | 2014-12-09 | Supernus Pharmaceuticals, Inc. | Drug formulations having reduced abuse potential |
AU2003243068A1 (en) * | 2003-05-21 | 2004-12-13 | Ramhuset Dala-Speglar Ab | A method and a device for removing vehicle windows |
US20040241234A1 (en) | 2003-06-02 | 2004-12-02 | Alpharma, Inc. | Controlled release press-coated formulations of water-soluble active agents |
US20060165790A1 (en) | 2003-06-27 | 2006-07-27 | Malcolm Walden | Multiparticulates |
DE10361596A1 (en) | 2003-12-24 | 2005-09-29 | Grünenthal GmbH | Process for producing an anti-abuse dosage form |
ES2289542T3 (en) * | 2003-08-06 | 2008-02-01 | Grunenthal Gmbh | PHARMACEUTICAL FORM PROTECTED AGAINST POSSIBLE ABUSE. |
US8075872B2 (en) | 2003-08-06 | 2011-12-13 | Gruenenthal Gmbh | Abuse-proofed dosage form |
DE10336400A1 (en) | 2003-08-06 | 2005-03-24 | Grünenthal GmbH | Anti-abuse dosage form |
DE102004020220A1 (en) | 2004-04-22 | 2005-11-10 | Grünenthal GmbH | Process for the preparation of a secured against misuse, solid dosage form |
DE102005005446A1 (en) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Break-resistant dosage forms with sustained release |
DE102004032051A1 (en) | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Process for the preparation of a secured against misuse, solid dosage form |
US20070048228A1 (en) | 2003-08-06 | 2007-03-01 | Elisabeth Arkenau-Maric | Abuse-proofed dosage form |
CN1882316A (en) | 2003-09-19 | 2006-12-20 | 宾韦斯特医药公司 | Delayed release dosage forms |
US20050118267A1 (en) | 2003-09-19 | 2005-06-02 | Penwest Pharmaceuticals Co. | Chronotherapeutic dosage forms |
NZ546182A (en) | 2003-09-26 | 2009-08-28 | Alza Corp | Controlled release formulations of opioid and nonopioid analgesics such as hydrocodone and acetaminophen |
EP1684732A2 (en) | 2003-11-12 | 2006-08-02 | Ranbaxy Laboratories Limited | Ibuprofen-containing soft gelatin capsules |
US7201920B2 (en) | 2003-11-26 | 2007-04-10 | Acura Pharmaceuticals, Inc. | Methods and compositions for deterring abuse of opioid containing dosage forms |
AU2004296404A1 (en) | 2003-12-09 | 2005-06-23 | Spherics, Inc. | Bioadhesive polymers with catechol functionality |
US7867511B2 (en) | 2004-01-23 | 2011-01-11 | Travanti Pharma Inc. | Abuse potential reduction in abusable substance dosage form |
TW200533391A (en) | 2004-03-25 | 2005-10-16 | Sun Pharmaceutical Ind Ltd | Gastric retention drug delivery system |
EP1740156B8 (en) | 2004-04-22 | 2012-07-11 | Grünenthal GmbH | Method for the production of an abuse-proof, solid form of administration |
EP1604666A1 (en) | 2004-06-08 | 2005-12-14 | Euro-Celtique S.A. | Opioids for the treatment of the Chronic Obstructive Pulmonary Disease (COPD) |
DE102004032103A1 (en) | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Anti-abuse, oral dosage form |
DE102004032049A1 (en) | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Anti-abuse, oral dosage form |
AR049562A1 (en) | 2004-07-01 | 2006-08-16 | Gruenenthal Gmbh | ORAL PHARMACEUTICAL FORMS, WITH CONTROLLED OPIOID RELEASE, PROTECTED AGAINST ABUSE AND PROCEDURE FOR PREPARATION |
US20060018837A1 (en) | 2004-07-26 | 2006-01-26 | Victory Pharma, Inc. | Pharmaceutical compositions and methods for the prevention of drug misuse |
US20080311191A1 (en) | 2004-08-27 | 2008-12-18 | Avinash Nangia | Multi-Layer Tablets and Bioadhesive Dosage Forms |
GB2418854B (en) | 2004-08-31 | 2009-12-23 | Euro Celtique Sa | Multiparticulates |
DE102005005449A1 (en) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Process for producing an anti-abuse dosage form |
WO2006099618A1 (en) | 2005-03-16 | 2006-09-21 | Dr. Reddy's Laboratories Ltd. | Delivery system for multiple drugs |
FR2883179B1 (en) * | 2005-03-18 | 2009-04-17 | Ethypharm Sa | COATED TABLET |
US9149439B2 (en) | 2005-03-21 | 2015-10-06 | Sandoz Ag | Multi-particulate, modified-release composition |
CA2615802C (en) | 2005-07-07 | 2015-10-06 | Farnam Companies, Inc. | Sustained release pharmaceutical compositions for highly water soluble drugs |
US8652529B2 (en) * | 2005-11-10 | 2014-02-18 | Flamel Technologies | Anti-misuse microparticulate oral pharmaceutical form |
US9289583B2 (en) * | 2006-01-06 | 2016-03-22 | Acelrx Pharmaceuticals, Inc. | Methods for administering small volume oral transmucosal dosage forms using a dispensing device |
US20090022798A1 (en) * | 2007-07-20 | 2009-01-22 | Abbott Gmbh & Co. Kg | Formulations of nonopioid and confined opioid analgesics |
FR2898056B1 (en) * | 2006-03-01 | 2012-01-20 | Ethypharm Sa | SQUEEZE-RESISTANT TABLETS TO PREVENT UNLAWFUL MISUSE |
US7722898B2 (en) | 2006-04-26 | 2010-05-25 | Supernus Pharmaceuticals, Inc. | Modified-release preparations containing oxcarbazepine and derivatives thereof |
PL2457563T3 (en) | 2006-05-09 | 2017-09-29 | Mallinckrodt Llc | Zero-order modified release solid dosage forms |
US9023400B2 (en) | 2006-05-24 | 2015-05-05 | Flamel Technologies | Prolonged-release multimicroparticulate oral pharmaceutical form |
EP2526932B1 (en) * | 2006-06-19 | 2017-06-07 | Alpharma Pharmaceuticals LLC | Pharmaceutical composition |
KR20090024284A (en) | 2006-06-23 | 2009-03-06 | 엘란 파마 인터내셔널 리미티드 | Compositions comprising nanoparticulate naproxen and controlled release hydrocodone |
MX2008016115A (en) | 2006-06-23 | 2009-01-20 | Elan Pharma Int Ltd | Compositions comprising nanoparticulate meloxicam and controlled release hydrocodone. |
JP5228291B2 (en) * | 2006-07-06 | 2013-07-03 | 日産自動車株式会社 | Manufacturing method of semiconductor device |
JP2009543780A (en) | 2006-07-11 | 2009-12-10 | ミューチュアル ファーマシューティカル カンパニー,インク. | Controlled release formulations and kits |
US8703191B2 (en) | 2006-07-25 | 2014-04-22 | Intelgenx Corp. | Controlled-release pharmaceutical tablets |
SA07280459B1 (en) * | 2006-08-25 | 2011-07-20 | بيورديو فارما إل. بي. | Tamper Resistant Oral Pharmaceutical Dosage Forms Comprising an Opioid Analgesic |
EP2063872B2 (en) | 2006-08-30 | 2019-12-04 | Jagotec AG | Controlled release oral dosage formulations comprising a core and one or more barrier layers |
PE20081457A1 (en) * | 2006-10-06 | 2008-10-18 | Organon Nv | ASENAPIN AMORPHA, PROCESSES TO PREPARE THEM AND ITS USE TO TREAT DISORDERS OF THE CENTRAL NERVOUS SYSTEM |
CN101631536A (en) | 2007-01-12 | 2010-01-20 | 惠氏公司 | Tablet-in-tablet compositions |
US20080176955A1 (en) | 2007-01-16 | 2008-07-24 | Victory Pharma, Inc. | Combined administration of benzonatate and guaifenesin |
DE102007011485A1 (en) * | 2007-03-07 | 2008-09-11 | Grünenthal GmbH | Dosage form with more difficult abuse |
WO2009008006A2 (en) | 2007-07-06 | 2009-01-15 | Lupin Limited | Pharmaceutical compositions for gastrointestinal drug delivery |
PL2187873T3 (en) | 2007-08-13 | 2019-01-31 | Abuse Deterrent Pharmaceutical Llc | Abuse resistant drugs, method of use and method of making |
US8415401B2 (en) | 2007-12-06 | 2013-04-09 | Durect Corporation | Oral pharmaceutical dosage forms |
US8372432B2 (en) | 2008-03-11 | 2013-02-12 | Depomed, Inc. | Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic |
AU2009223061B2 (en) | 2008-03-11 | 2014-10-09 | Depomed Inc. | Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic |
US8133506B2 (en) * | 2008-03-12 | 2012-03-13 | Aptalis Pharmatech, Inc. | Drug delivery systems comprising weakly basic drugs and organic acids |
AU2009282376A1 (en) | 2008-08-12 | 2010-02-18 | Inspirion Delivery Technologies, Llc | Pharmaceutical compositions configured to deter dosage form splitting |
CA2750144C (en) | 2008-12-31 | 2016-10-25 | Upsher-Smith Laboratories, Inc. | Opioid-containing oral pharmaceutical compositions and methods |
WO2010141505A1 (en) | 2009-06-01 | 2010-12-09 | Protect Pharmaceutical Corporation | Abuse-resistant delivery systems |
RU2015138422A (en) | 2009-07-22 | 2018-12-25 | Грюненталь Гмбх | STABLE DURING OXIDATION, STRONG-BREAKED DOSAGE FORM |
CA2991217C (en) * | 2010-12-22 | 2020-06-09 | Purdue Pharma L.P. | Encased tamper resistant controlled release dosage forms |
JP5638151B2 (en) | 2010-12-23 | 2014-12-10 | パーデュー、ファーマ、リミテッド、パートナーシップ | Tamper resistant solid oral dosage form |
US20140056979A1 (en) | 2011-03-25 | 2014-02-27 | Purdue Pharma L.P. | Controlled Release Pharmaceutical Dosage Forms |
WO2013171146A1 (en) | 2012-05-15 | 2013-11-21 | Lts Lohmann Therapie-Systeme Ag | Oral film containing enteric release opiate resinate |
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WO2012085657A2 (en) | 2012-06-28 |
KR20140075807A (en) | 2014-06-19 |
US9707180B2 (en) | 2017-07-18 |
CN107412173A (en) | 2017-12-01 |
US20160120812A1 (en) | 2016-05-05 |
IL227113B (en) | 2018-04-30 |
ES2581323T3 (en) | 2016-09-05 |
KR101458334B1 (en) | 2014-11-04 |
BR112013015939A2 (en) | 2020-08-04 |
HK1189510A1 (en) | 2014-06-13 |
ZA201305461B (en) | 2014-08-27 |
JP2014500305A (en) | 2014-01-09 |
CA2822769C (en) | 2016-10-04 |
NZ612996A (en) | 2015-05-29 |
US20160143858A1 (en) | 2016-05-26 |
AU2011346758C1 (en) | 2015-09-03 |
US20170020820A1 (en) | 2017-01-26 |
US20140010874A1 (en) | 2014-01-09 |
CN103327969A (en) | 2013-09-25 |
KR20130103797A (en) | 2013-09-24 |
US9895317B2 (en) | 2018-02-20 |
EP2654733A2 (en) | 2013-10-30 |
EP2654733B1 (en) | 2016-04-06 |
JP5638151B2 (en) | 2014-12-10 |
AU2011346758A1 (en) | 2013-05-02 |
AU2011346758B2 (en) | 2015-06-11 |
US9233073B2 (en) | 2016-01-12 |
WO2012085657A3 (en) | 2012-08-30 |
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