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.
This application is a division of U.S. patent application Ser. No. 13/997,560 filed on Sep. 23, 2013, which is a national stage entry of PCT Application No. PCT/IB2011/003162 filed on Dec. 22, 2011, which claims the benefit of U.S. Provisional Application No. 61/426,903.
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.
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.
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.
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.
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.
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.
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.
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.
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.
All references disclosed herein are incorporated by reference in their entireties for all purposes.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
The term "controlled-release" encompasses "sustained release", "extended release", "delayed release" or any other modified (i.e., non-immediate) release.
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.
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.
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.
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.
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).
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.
The term "chiral center" refers to a carbon atom to which four different groups are attached.
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.
The term "racemic" refers to a mixture of enantiomers.
The term "resolution" refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.
FIG. 1 is a graphical representation of a single coated core embodiment of the present invention.
FIG. 2 is a graphical representation of a multiparticulate embodiment of the present invention.
FIG. 3 is a graphical representation of a unitary core of the present invention.
FIG. 4 is a graphical representation of a core of the present invention having an inner component and an outer component.
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.
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).
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).
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.
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).
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).
As depicted in FIG. 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.
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 500 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.
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 400 Newtons, 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.
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).
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.
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.
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.
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.
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.
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®.
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.
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.
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.
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.
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.
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).
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.
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.
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. Pat. No. 6,696,088.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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, fumarate, risperidone, thiothixene, thioridazine, sulpride, ziprasidone, and all pharmaceutically acceptable salts, complexes, stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof.
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.
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.
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.
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.
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).
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.
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.
This application claims priority from U.S. Provisional Application Ser. No. 61/426,903, filed Dec. 23, 2010, the disclosure of which is hereby incorporated by reference.
The following examples are provided to illustrate, but not to limit, the present invention.
I. Blend the polyethylene oxide with the magnesium stearate.
II. Compress into round 7 mm tablet cores using a rotary tablet press to achieve a target weight of 150 mg.
III. Cure the cores in a conventional tablet coater by heating to an exhaust temperature of 72 C 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 15 mg/tablet.
VII. Disperse the HPMC (for the overcoat) in water to a solids content of 10-15%.
VIII. Apply the overcoat to the active ingredient-coated cores in the tablet coater to achieve a target weight gain of 10 mg/tablet.
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.
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.
wherein the solid oral dosage form is a tablet comprising a single coated core that comprises a therapeutically effective amount of the opioid analgesic.
3. The method of claim 1, wherein the tamper resistant core comprises a gelling agent.
4. The method of claim 3, wherein the gelling agent is selected from the group consisting of sugar, sugar derived alcohols, mannitol, sorbitol, starch, microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, attapulgite, bentonite, dextrin, alginate, carrageenan, gum tragacanth, gum acacia, guar gum, xanthan gum, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, carbomer, carbopol, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, surfactant, mixed surfactant/wetting agent, emulsifier and mixtures thereof.
5. The method of claim 4, wherein the gelling agent is selected from the group consisting of sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, alginate, carrageenan, gum tragacanth, gum acacia, guar gum, xanthan gum, pectin, polyethylene oxide, polyvinyl alcohol and mixtures thereof.
6. The method of claim 5, wherein the gelling agent comprises alginate.
7. The method of claim 5, wherein the gelling agent comprises xanthan gum.
8. The method of claim 5, wherein the gelling agent comprises hydroxypropylmethylcellulose.
9. The method of claim 5, wherein the opioid analgesic comprises morphine sulfate or oxycodone hydrochloride.
11. The method of claim 10, wherein the gelling agent further comprises an agent selected from the group consisting of sugar, sugar derived alcohols, mannitol, sorbitol, starch, microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, attapulgite, bentonite, dextrin, alginate, carrageenan, gum tragacanth, gum acacia, guar gum, xanthan gum, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, carbomer, carbopol, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, surfactant, mixed surfactant/wetting agent, emulsifier and mixtures thereof.
12. The method of claim 11, wherein the gelling agent further comprises an agent selected from the group consisting of sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, alginate, carrageenan, gum tragacanth, gum acacia, guar gum, xanthan gum, pectin, polyethylene oxide, polyvinyl alcohol and mixtures thereof.
13. The method of claim 10, wherein the gelling agent further comprises alginate.
14. The method of claim 13, wherein the gelling agent further comprises hydroxypropylmethylcellulose.
15. The method of claim 10, wherein the active agent comprises morphine sulfate or oxycodone hydrochloride.
16. The method of claim 10, wherein the inert tamper resistant core has a breaking strength of at least 400 Newtons.
18. The method of claim 17, wherein the inert tamper resistant core has a breaking strength of at least 400 Newtons.
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Perry-Eaton Takes Fifth In One-Meter Diving At NCAA Championships
WEST LAFAYETTE, Ind. – Notre Dame fifth-year senior Meghan Perry-Eaton (Brandon, Fla./Bloomingdale H.S.) finished fifth in one-meter diving to be named an All-American for the second straight year, while sophomore Katie Carroll (Toledo, Ohio/Notre Dame Academy) was again honorable mention All-America in the 200-yard individual medley with a 14th-place result in Thursday-evening action at the 2005 NCAA Division I Women's Swimming and Diving Championships in the Boilermaker Aquatic Center. Both improved two positions from their qualifying spots, while the veteran notched the third-highest finish ever for a Notre Dame competitor in the meet. They combined to score 17 points, putting the Irish in 18th place after the first of three days of action.
After qualifying seventh with a score of 287.15 points, Perry-Eaton accumulated a total of 303.00 points in the evening to finish .35 ahead of Miami's Jenna Dreyer, who qualified fourth and was 17th at the Athens Olympics off the springboard last summer. She also beat NCAA zone C champion Christina Loukas of Indiana, who was sixth in prelims, as well as another Hoosier, Lisa Silvestri.
Qiong Jie Huang of Hawai'i, a native of China and the only diver other than Perry-Eaton to have been named an All-American off the one-meter board in both 2004 and '05, was the national champion with a score of 327.00 points. The runner-up was USC's Blythe Hartley, who took fifth in last year's Athens Olympics in springboard action and was a bronze medalist in synchronized platform competition. She had 324.90 points after being the top scorer in prelims. Iowa's Nancilea Underwood took third with 321.40, while Purdue's Carrie McCambridge ended up fourth with 314.40 points. The NCAA's zone C – which includes most of the Big Ten schools, as well as others in the area, including Notre Dame – dominated the event, taking six of the top nine positions.
The only higher finishes by Notre Dame competitors in the NCAA Championships were Perry-Eaton's third-place result in one-meter diving in 2004 and a fourth-place finish by current assistant coach Carrie Nixon in the 50-meter freestyle in 2000. The current Irish senior, three times the BIG EAST Championships Most Outstanding Diver, became just the third Notre Dame student-athlete – and first diver – to be a multiple-time All-American on the Division I level, joining five-time All-American Tanya Williams (also four honorable mentions) and Nixon, who was a two-time All-American (10-time honorable-mention selection). Perry-Eaton will conclude her career with each of the top three finishes ever by Irish student-athletes in one-meter diving at the NCAAs. In 2003, she just missed the championship final, ending ninth. The top finish by any other Notre Dame diver in the event was a 12th-place result by Heather Mattingly in 2002. Perry-Eaton's score on Thursday night also stands as the sixth-highest in a championship-style meet off the one-meter board since the current six-dive format was adopted in 2000-01. The product of the Jetstream Diving Club ends her career owning each of the top 16 one-meter, championship-meet scores in Irish history.
Perry-Eaton concludes the 2004-05 season having been beaten in one-meter action by just five divers at any point in the campaign: McCambridge (three times), Loukas, Huang, Hartley, and Underwood. In 2003-04, she was defeated by only three divers: national champion Allison Brennan of South Carolina, NCAA runner-up Lane Bassham of Alabama, and Tealin Keleman from Michigan, whom she also beat three times.
Carroll, who was seeded 26th heading into the meet, moved up to 16th in prelims and then rose another two spots to 14th in finals. After going 2:00.74 in the morning, she turned in a time of 2:00.75 in the evening, finishing ahead of Auburn freshman Julie Stupp (2:00.93 after qualifying 14th) and Tennessee's Megan Tomes (2:01.58 after being tied for 10th in prelims). Michigan freshman Justine Mueller won the heat in a time of 1:59.07.
The product of the Greater Toledo Aquatic Club was one of just five swimmers to earn evening appearances in the 200 IM in both of the last two years. Carroll, the 2004 and '05 BIG EAST champion in the race, was 11th in prelims last year in the 200 IM before going on to take ninth in the evening. She now has both of the top two finishes ever by Irish swimmers at the NCAAs in the 200 IM. The best result prior to her swim last year was 18th by Tanya Williams in 1992. Williams twice was named honorable mention All-America in the 200 IM (1992 and '93), when competitors placing 17th-32nd gained the distinction. The current rules award the swimmers finishing ninth-16th with honorable mention All-America. Carroll became the ninth Irish student-athlete to gain All-America mention on three or more occasions.
Carroll's finals time is the fifth-fastest swim in the race ever by a Notre Dame competitor, behind only three of her times from her rookie campaign and her Thursday prelims performance. The top two marks in school history – 1:58.52 and 1:59.55 – came from the 2004 NCAAs and are converted from short-course meters times. Carroll's 2:00.65 from last year's BIG EAST Championships is the fastest-ever yards time by a Notre Dame swimmer. In addition to the top five marks, Carroll boasts seven of the top 11 times in the 200 IM in Irish history.
The Irish sophomore continued a trend of moving up considerably from her seeding in big meets. At the 2004 NCAAs, she was seeded 22nd in the 200 IM before taking ninth, while rising 21 spots from her seeding (35th) in the 400 IM to finish 14th. At the 2004 United States Olympic Trials, Carroll rose 12 spots from her seeding (35th) to finish 22nd in the 200 IM.
Notre Dame has scored 11 or more points in all 10 years since current head coach Bailey Weathers took over the program. The Irish got 14 from Perry-Eaton and three from Carroll on Thursday. A year ago, Notre Dame finished 25th with 28 points.
The Irish will have a full day of action on Friday, as Carroll will swim the 400-yard individual medley (seeded 19th), Perry-Eaton will take part in three-meter diving, and junior Christel Bouvron (Singapore, Singapore/Raffles Girls' Secondary School) will make her NCAA Championships debut, swimming the 100 butterfly (seeded 40th). Swimming prelims begin at 11 a.m. (EST), while diving starts at 1 p.m.
For complete results of the NCAA Championships, please see http://www.ncaasports.com/swimming/womens/championship-results/2005/d1.
Swimming and Diving Straub, Flaute, Gillilan Earn ACC Weekly Honors
Swimming and Diving Irish Women Upset Louisville, Men Fall Narrowly to Cardinals
Swimming and Diving Irish Open 2021 Hosting Cardinals

redpajama_set_name: RedPajamaCommonCrawl


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EarthSeal Zero should not be used for exterior applications as the sunlight will rapidly degrade the product. It should not be used where foam will stay submerged in water. Applicable codes must be strictly adhered to.


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Монголы в Чешской Республике () формируют одну из меньших этнических групп страны. Рабочие из Монголии составляют 3,6 % иностранной рабочей силы, начиная с 2008 года, доставлялись домой, в Монголию.

История миграций
По данным местной полиции, на 2005 год в Чехии проживало всего 1900 монголов. К 31 марта 2006 года их число выросло до 2607 человек, из них 2051 рабочих и 213 бизнесмена. На следующий год произошел существенный рост монгольского населения, которое почти утроилось до 7515 человек к июню 2007 года. С июля 2008 года, еще около тридцати — сорока монголов прибывали в Чехию для работы каждую неделю, многие на поезде. Число монголов, как ожидается, продолжит расти быстрыми темпами, так как Монголия, наряду со Вьетнамом, была выбрана в 2008 году в качестве одной из стран, снабжающих трудовыми ресурсами Чехию, с целью замены северокорейских иностранных рабочих, визы которых не были обновлены после международного беспокойства, что их заработная плата конфисковалась северокорейским правительством и использовалась для поддержки ядерной программы.

Однако, в начале 2009 года, чешское правительство решило, что они больше не будут предоставлять рабочие визы для монгольских или вьетнамских рабочих, в ответ на экономический спад, оставивший 380 000 чешских граждан без рабочих мест. Выдача виз официально прекратилась 1 апреля того же года. Правительство заявило, что этот процесс возможно возобновится в будущем. Они также объявили о своем плане предложить 500€ и бесплатный авиабилет назад, в Улан-Батор, для любых монгольских рабочих, находящихся в Чехии и потерявших свои рабочие места. Представитель Министерства внутренних дел заявил, что этот план был предназначен для того, чтобы в стране не осталось нелегальных безработных иностранных рабочих. С февраля по апрель, монголы составляли 66 % от 1345 иностранцев, которые использовали в своих интересах такое предложения от чешского правительства.

Демография и распространенность
Помимо монгольской общины в Праге, численностью около 500 человек, монголы проживают так же в Южноморавском крае, в городе Бланско, и несколько сотен насчитывается в Пльзене. В марте 2007 года город Бланско стал мишенью протестов, организованных группой националистов, один из которых был арестован за нацистское приветствие. Однако, несмотря на напряженные отношения между монголами и гражданами города, несколько местных жителей, фактически участвовали в этих протестах. Демонстранты были описаны как неонацисты из других регионов Чешской Республики.

Нелегальные миграции
Проблема с торговлей людьми и нелегальной иммиграцией из Монголии в Чехии растет. Монголы составляют одну из самых многочисленных групп незаконных мигрантов, задержанных на границе со Словакией. Раньше одним из главных источников нелегальных иностранных работников на территории Чешской Республики была Украина, но многие из них переехали ещё западнее, в другие страны Европейского Союза, в поисках более высокой заработной платы. Монголы были одной из основных групп, заменивших их. Правительство Чехии в борьбе с незаконной миграцией работает вместе с Правительством Монголии, и они действуют по программе, похожей на те, по которым Чехия сотрудничала с правительствами Молдовы, Армении, Украины.

В Чехии в настоящий момент работает пятнадцать учреждений, занятых вопросами работников из Монголии. Однако, только два таких учреждения имеют разрешение правительства Монголии на работу на её территории, остальные же не имеют такого разрешения. Это отсутствие регистрации является причиной того, что чешское правительство завышает количество мигрантов из Монголии, которых в общей сложности в 2007 году оно насчитывало 2 000 человек, в то время как правительство Монголии говорит о небольшом числе трудящихся, отправившихся в Чешскую Республику.

Примечания

Литература

Народы Чехии
Монгольская диаспора

redpajama_set_name: RedPajamaWikipedia


So, there's been a change of plans! I've been thinking of doing a Homestuck-style animation for the big climactic battle, but had my doubts as to whether I could pull it off (animation, as you probably know, is hard as heck, and I've never done a project quite of this magnitude). I was going to just keep the regular comic updates going, but now that I've reached the point in the story which I'd been thinking of animating, I realized I'd regret not going for it.
The bad news: this is going to take a while. I've got about 2 minutes of animating to do, and the first four seconds in the above teaser took two days to put together (though I'll be speeding up considerably as I get more into it). That said, I don't want you guys to be waiting too long, so I'll be putting everything I have into this. I'll see if I can get this all done by January 17th. Until then, Silent Pirate is taking a hiatus.
Thanks (in advance) for your patience. I'll try my best to put something really amazing together.
Looks absolutely brilliant. It's been an amazing comic, and take your time. You don't want to rush the ending.
I heartily agree with Pedro; I look forward to seeing the results.
Dude. Go for it. Seriously!
GIF animation is the bane of my life. Great job! It's a pain to do without animation software.
Thanks, everyone, for understanding. I'm making progress, slowly but surely. I've got 10 seconds or so finished so far, but I'm speeding up!


text:
Gerontology Research Centre
Combined GRC Annual Report (Sept. 2016–March 2019)
Theodore D Cosco
Andrew Wister
Sarah Canham
Ian Fyffe
Lillian Hung
Gloria Gutman
Sharon Koehn
Habib Chaudhury
John R. Best
Department of Gerontology
Gerontology Research Centre / Research Staff / Habib Chaudhury
Email: chaudhury@sfu.ca
Dr. Habib Chaudhury, Chair and Professor in the Department of Gerontology, has extensive research experience in the field of environmental gerontology. He conducts research and consulting work in the following areas: physical environment for people with dementia in long-term care facilities, memories of home and personhood in dementia, community planning and urban design for active aging, and dementia-friendly communities. Projects have been funded by Canadian Institute of Health Research (CIHR), Social Science and Humanities Research Council (SSHRC), Canada Mortgage and Housing Corporation (CMHC), CapitalCare Foundation and the Centre for Health Design. He has published over 60 peer-reviewed journal articles, book chapters and monographs. Published books include: Environments in an Aging Society: Autobiographical Perspectives in Environmental Gerontology (Annual Review of Gerontology and Geriatrics, Vol 38, 2018; co-edited with F. Oswald), Remembering Home: Rediscovering the Self in Dementia (Johns Hopkins University Press, 2008) and Home and Identity in Later Life: International Perspectives (Springer Publications, 2005; co-edited with G. Rowles). Dr. Chaudhury conducts research consulting with various national and international organizations in the areas of planning and design of seniors housing and long-term care facilities. He is also affiliated with the Centre for Research on Personhood in Dementia at the University of British Columbia, Vancouver and Alzheimer Catalonia, Barcelona, Spain. He serves as the Editor-in-Chief of the Journal of Housing for the Elderly.
Dr. Chaudhury received the Excellence in Teaching Award at Simon Fraser University in 2013. He has supervised over forty graduate (MA and PhD) students in gerontology and/or social science disciplines. His students have received external support and recognitions that include: the SSHRC Graduate Scholarship, Michael Smith Foundation Graduate Trainee Award, Best Research Poster Award from the Canadian Association on Gerontology and Best Research Poster Award from the CIHR.


In a large pot or skillet over med heat, use a wooden spoon to brown & break up ground meat. When browned drain any liquid, and return to heat adding the olive oil. Next add the celery & onion and stir to combine. Add cayenne pepper, chili powder, ground cumin, dried oregano, and salt to the pot and stir. Allow it to simmer on med heat for about 10 min. Rinse & drain your canned beans. Add the beans and give it a good stir. Allow the chili to simmer another 10 min to warm the beans. After the 10 min check the celery to verify it's done, it should be tender and this will be your signal that the chili is done. Top w/diced onions and shredded cheese and serve w/warm cornbread. Tastes even better the next day!
It's was spicy, but I added lots of cheese & sour cream!!!
Check out the CaveMan or Paleo recipes, they're usually gluten- and dairy-free.


text:
Tag: J. Brown
#metoo, Activism, Articles, Audio, Charismatic Abuse, Cult dynamics, Gurus, Patriarchy, Press & Interviews, rape culture, social justice, Trauma, Yoga, Yoga culture, Yoga pedagogy May 16, 2018 August 7, 2018
"From Somatic Dominance to Trauma Awareness" – Interview with J. Brown (Transcript)
Image: myself and Diane Bruni at the #WAWADIA event on May 29, 2014. I refer to this event in the interview. The write-up and (unfortunately) butchered video is here. I love how Diane is looking at me here, trying to figure out how full of shit I am.
Thank you to J. Brown for having me on his podcast, as part of his series about current news in the Ashtanga world. You can also tune in to his talks with Kino MacGregor, Scott Johnson, and Sarai Harvey-Smith.
Here's our talk. Resources and transcript (trimmed of intro/outro) below.
Karen Rain's writings on her experience with Pattabhi Jois and Ashtanga Yoga can be found here. I interview her at length here.
I've updated my WAWADIA project plans here. My article on Pattabhi Jois and sexual assault, featuring Karen's voice and the voices of eight other women, can be found here.
Here's where I've quoted Theodora Wildcroft on the fear of contagion elicited by the voice of the victim.
Here's my conversation with Colin Hall and Sarah Garden.
I've posted the classic "Deception, Dependence, and Dread" summary from cult researcher Michael Langone here.
Matthew Remski:
Jason Brown:
I'm good, I'm good. I just listened to your intro to Scott Johnson. I didn't listen to what Scott had to say, but I really appreciated the intro, it was good.
Well, thanks. There was still some debate about it, I guess. I just default to transparency and not everybody always thinks that's a good idea. But for me, it's where I feel most comfortable. So, thanks. But what else, what's been going on, how's your day going? It's the middle of the day for you too, right?
It is. And I just got up from a nap with alongside the almost two-year-old, Owen. And that was really good because I was up until about 1:30 in the morning after doing another interview with my friends Colin Hall and Sarah Garden at Bodhi Tree in Regina. It took me a while to come down off of that. But the sun is shining, we got some backyard cleaning done over the weekend, we emptied out the basement. Things are heading in an upward arc it feels in many ways.
Yeah. You know what, you mentioned two and a half years for your son and-
Almost two, he's going to be two on May 17th.
Well, we last spoke, the last time you were on the podcast was May 2016.
Oh, my goodness. Was he born or not?
I guess he wouldn't have been born because it's exactly two years ago. But we spoke about that book that you wrote with Michael Stone about becoming fathers and stuff. I remember that. I can't believe it's been two years.
Yeah, it's been a long time. We've been in touch since. The difference between the podcast and being on the phone is a little bit thin.
That's true actually. That's a good point because sometimes, I had Peter Blackaby on and I had not had other conversations with him other than the two that you hear on the podcast, but you and I had had many conversations. There is a three line there. And gosh, so much has happened. When we last spoke, we were talking about WAWADIA still. And right at the end of that, we were saying, "Oh, it's going in different directions." And people were sort of, I think upset back then and maybe still that it was started out as what poses hurt you, what poses don't hurt you. People wanted to sort of have some how to practice safe in clear, simple answers. And you were like, "I looked at it and I don't know that pose exists. And you were saying that it was going in this direction of the interpersonal dynamics that were going on.
Yeah. That's a good summary actually. It took about two years to figure out that I was barking up kind of a dissociative tree, that when the hard data is really laid out as I think you yourself suggested those years ago and perhaps before that as well, we don't really see that yoga is any more damaging physically to anybody than any other physical activity. In fact, it's probably safer. When that was clear, for a moment I held on to this notion that the problem with yoga injuries is the problem of expectation, that people get involved in this practice for therapy and spiritual healing. And why it seems very bizarre that they would hurt themselves, that they would develop repetitive stress or chronic pain.
I held on to that for a while. But trying to hang a research narrative on that premise became a lot less important than realizing the kinds of stories I was overlooking or I was papering over in the midst of all of the interviews that I was doing with people who had injured themselves or who had been injured by teachers. And a couple of key things happened that kind of spun me around. And one of them was that Diane Bruni was an early supporter of the work and she was one of my first interviews. And she told me about the correlation between overuse, repetitive stress and her hip injury coming out of the Ashtanga world.
And I interviewed her, it was a really compelling interview. She loved the project, she was a big supporter and she wanted to host this event at her home studio in Parkdale here in Toronto. We advertised it, it was going to be under the banner / branding of WAWADIA or my project. And 60 people showed up, and she was going to speak on her injury experience. I was going to give my initial research that was related to psychosocial dynamics of injury. And then we had also a sports medicine doctor who was going to come, and he was going to do a little bit of statistical analysis on who got hurt when and where and how. And Diane was going first, and she just did not follow the plan. That's not really her jam.
It wasn't unexpected, but at the same time, what she began talking about was really outside of what I felt the scope of my project should be. She started talking about the whisper network that she had encountered in the late 1990s that informed her that Pattabhi Jois was allegedly assaulting female students. And she described how that led her into a kind of crisis of faith and professional choices like how was she going to associate herself with a system where this was true? And the information that she had was credible. She told the story, and I was sitting there gripping my meditation cushion listening to her say it and thinking, "This wasn't in the program, this wasn't part of the deal."
Continue reading ""From Somatic Dominance to Trauma Awareness" – Interview with J. Brown (Transcript)"
Articles, Blog, Featured, Poetry September 7, 2016 July 6, 2017
The Love Songs of J. Brown Yogi
I grow old … I grow old …
I shall wear the bottoms of my trousers rolled.
— Eliot, "Love Song of J. Alfred Prufrock"
J. Brown makes transparency in the yoga biz bittersweet. He consistently points to the sorrow in the shadow of yoga marketing: perpetual change, impossible economics, anxious upselling, getting older, seeing through the dross, living with pain.
Continue reading "The Love Songs of J. Brown Yogi"


The Caching framework backend implementation \TYPO3\CMS\Core\Cache\Backend\ApcBackend has been removed. The APCu PHP extension has superseded in PHP 7.x.
The PHP APC extension works until PHP 5.x. APCu can be used as "drop-in" replacement since TYPO3 8 LTS which supports PHP 7.0+.
Any installation which has been updated, and any legacy APC cache backend is configured (see LocalConfiguration).
Use APCu implementation, which is implented via \TYPO3\CMS\Core\Cache\Backend\ApcuBackend instead of \TYPO3\CMS\Core\Cache\Backend\ApcBackend in your caching framework configuration.


text:
Issue 59: Shano and Marico
An accident is an opportunity which can be grasped or misused.
We will continue Praja's dream further on, but first I like to tell you another story about Shano.
(Shano and Marico)
Shano and Marico
As an example I will tell you another story of the past lives of Shano, some ten lifetimes or more than four thousand years ago, long before the life in which he committed suicide.
Shano was living in a village of only a few hundred houses in a faraway country, where his father was a carpenter. It was quite a good business, because there was hardly a day when nobody needed anything made of wood. Shano's father was a good carpenter, though somewhat hot-tempered at times, when he would be unnecessarily disturbed in his concentration. Then he would not say a word to his wife for the rest of the day. No human being is perfect. Besides making furniture he could also help in house construction. His furniture was characterized by wonderful woodcarvings. The carvings were mostly round interlaced figures, but he could also make the most beautiful birds and plant ornaments, or beings that perhaps only existed in human fantasy, or even fishes – though the ocean was so far away from the village that most people knew it only from hearsay. He applied his woodwork for backs of chairs or benches or beds, or for frames of pictures. But this type of work was time consuming and therefore expensive, and you needed the best types of wood for it. Most of his work consisted therefore in the coarser work of providing beams for houses, and making simple tables and stools. Mother was often singing (usually about some deity, or songs everyone knew). She was good in preparing delicious sweets, which she also provided to the other villagers, especially children. Her cooking was also really delightful, and the meals, though very simple as to ingredients, were a moment of joy for the family each day. They had two boys, the younger one, Shano, and one three years older, Marico. When still young they learned the skills of woodwork from their father and both where proud of what they accomplished – though clients coming to the shop always smiled, but rarely bought any of their creations, and if they did, these were always Marico's. Shano always hid his anger. When they became a little older they became both good toy makers, and before long all the children in the village were playing with their toys: wooden horses or camels or elephants on wheels, toy houses of which the little doors could be opened and closed, and even miniature furniture – many things painted in bright colors, others just as the wood was. Shano was also quite good in making such things, but he could never surpass his brother – after all he was three years younger. Father and mother were also proud of their energetic, skillful and optimistic sons. The only thing that worried mother was that Shano was rather hot-tempered at times, especially towards his elder brother. On the other hand, when Shano was hurt by his brother, he would not easily forgive him – but that was inside himself: he would never show it. Instead he would go outside and do something nasty, like throwing dung at buffaloes, and once by "mistake" – he hit an old lady, which invited the shouting of that ugly, very irritable witchlike old granny, of whom all the children were afraid. The fact was that she was crazy, and possessed some witchcraft also, but knew a lot about herbs and some magic spells to heal small ailments. Marico was calmer and was on a whole more contained in his emotions, like his mother.
But altogether they were a happy family and they had a lot of fun together. Mother had, under a kind of wooden roof on the back corner of the house, a number of goats – some black, others white and black. They provided milk for the family, and mother used it for all kinds of dishes. When Shano was only five years old he loved to take the goats out to the trees outside the village where they could feed on some hardy leaves. Because the country in which they lived was dry for most of the year, and either very hot of quite cold, there wasn't much for the goats, but goats always manage somehow. Shano followed them, carrying a long stick – at least three times as long as himself – with a hook at the end, so that he could pull down branches for the goats which otherwise they couldn't reach even when stretching themselves on their hind legs. Goats are not shy and very trusting, and they mostly followed little Shano without any problems. Occasionally one would escape and bleat desperately, or be caught in a narrow space, and Shano had to save her. But normally he only had to call 'how' … 'how' – the only words goats can apparently understand, but they know the meaning of very well. It means: "Stay together and remain reassured. Care is taken of you."
Then there was a cow – a completely white cow. Some other people had one or a few black buffaloes, but Shano's family had a tender white cow. Everyone loved her. She was very kind, never angry, and provided delicious milk which the children could drink directly from her udder. The milk was also collected in wooden buckets (made by father), but was never collected before the calf of the cow had been given the chance to take enough for herself. The cow could walk around freely, but she remained near the house most of the time where there were some shadowy trees, and where she would be given fodder brought by father of mother or what the children collected for her, and also buckets of water. She seemed to feel best when she was bound to a pole by a cord. Children she would allow to climb on her back and sit there as if they were driving a horse. It was on a whole a peaceful rural atmosphere.
There was, between the edge and the center of the village, a small temple, standing at a sandy square with in the middle a big tree which was at least a hundred years old. Under the tree people had make a bench of stones and clay in a circle around the stem, so that everyone could sit there in the shadow when it was too warm to work, or to chat together in the evenings. Shano liked the temple. Inside there was a stone statue, not very refined, rather like a standing black stone with orange painted eyes and some strips of cloth wrapped around it. It was the sacred place of the village. The statue represented the protecting deity of the village, and people believed that he lived around the village in the fields, and kept an eye on whatever invisible intruder might come to the village (especially at night) who might cause disease or mishap or misfortune, and he had some powers to chase them away. Some stories of miracles went around, and people believed things that can never be true. Like some old farmer's wife, then a widow, who lived eighty years ago and received a coin of money everyday from the deity; or a married couple who got a still-born child because they had not cared to do the right ritual at their marriage. But such things as giving coins gods rarely do, if at all, and gods certainly don't take revenge or let children die before being born to punish their mother or father. That absolutely can not happen with a god. They can not prevent accidents, nor determine what goes on in the people's minds and what history-threads they spin for themselves. Nobody had ever seen that deity, but some felt his presence, they said. Every inhabitant of the village would regularly go to the temple to bring some offering to the god – some grains of wheat, or fruits, or milk. They were really only offerings to their own fantasies. They never saw anything special happen there, but it always strengthened the people's devotion – and devotion one could feel in the atmosphere inside the temple. But if you could have seen it, you would have known that there really was something there. The temple was several generations old, but looked very tidy and attractive. Always people kept the place proper, and went there to wish good things – or if they were in a bad mood, they would usually come out in a calm and happy mood. When the temple had been consecrated, some generations ago, just after it had been build, an unknown but wise priest had arrived from elsewhere without having announced his coming. But people felt at ease with him, and he had the knowledge about how to perform rituals. First the priest had meditated in the temple for three days, while fasting, and then had said only a few holy words while his appearance was so quiet that everyone who had some problem in his mind and feelings, became quiet. The priest had left and never returned. But something of his atmosphere seemed still to reside there. In this way evil influences kept away from the village, because they just didn't feel at home.
[The Boys' village life]
Shano was a sensitive boy when he was seven or eight, and he felt always some special feeling when he was in that temple – where he preferred to sit alone on the floor.


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