Resistant oral opioid agonist formulations

ORAL MEDICINAL FORMS OF SUSTAINABLE MAOTIOID AGONIST Opioids, also known as opioid agonists, are a group of drugs that exhibit properties similar to those of opium or morphine. Opioids are initially used as moderate to severe pain but have numerous other pharmacological actions, including drowsiness, dyspnea insufficiency, mood swings, and blurring of the senses without causing loss of consciousness. Opioids act as agonists by interacting with hystereospecific and saturable binding sites of the brain and other tissues. Endogenous opioid-like peptides occur in particular in the areas of the central nervous system suspected of being associated with a sense of disorder; for movement, mood and behavior, and the refinement of neuroendocrine functions. Opium contains more than twenty different alkaloids. Morphine, codeine and papaverine are included in this group. In the middle of the nineteenth century, the use of pure alkaloids, like morphine, instead of raw opium preparations began to spread to the world of medicine. The parenteral use of morphine was intended to produce stronger varieties of compulsive medication than raw opium preparations. The problem of addictions to the hamopioids has stimulated the search for potential maladies that would be deprived of the likelihood of inducing accustomance. In 1967, the researchers concluded that complex interactions between morphine-like drug agents, antagonists and what was later termed the "agonist-antagonist mixture" can best be explained by the postulation of more than one type of opioid receptor and similar drugs. With the occurrence of new, totally synthetic units with morphine-like action, the term opioid is generally retained as a generic name for all exogenous substances that bind stereospecifically to any of several opioid receptors and produce agonist activity. While this great understanding pushes ahead pharmacological science, it does not lead to the development of opioid-free opioids released by potential abuse. The potential for the development of tolerance and physical dependence with repeated opioid use is a feature of all opioid drugs and the ability to develop 3 physiological dependence (i.e., addiction) is a primary concern in the use of pain medication, even by means of an atrogenic addiction. Another major concern associated with the use of opioids is the diversion of drugs from a patient's pain to another (non-patient) for illicit purposes, for example, impartial. The overall potential for abuse of an opioid is determined by a single factor. Instead, there are a number of factors, including the ability of the drug to produce a certain physical dependence, in which a withdrawal drug leads to sufficient suffering that leads to a drug-induced behavior; the ability to suppress withdrawal symptoms caused by other remedies; the extent to which it induces a shock, produced by morphine and other opioids; the pattern of toxicity that occurs when the drug is dosed above its normal therapeutic range; and physical characteristics of the drug, such as water solubility. Such physical characteristics may determine whether drug abuse is possible through parenteral administration. In the US, efforts to control users of compulsive medications include efforts to control accessibility of drugs by imposing prohibitions on the use of opioid pain relief for users of compulsive 4 medical devices. In practice, the doctor often chooses to use a strong opioid analgesic even for people who seem prone to develop psychological dependence, addiction to such drugs. In view of this problem, it was recommended that these patients should not be given an opioid when another non-abusive medical device may be sufficient; and in addition, these patients do not have to be provided with a single-dose form that can be misused parenterally, and should be delivered for several days at any given time. At least three patterns of opioid use and dependence have been identified. The first includes indi- viduals whose use of drugs starts in the context of a nursing treatment and who receive their initial delivery through legitimate sources, for example, physicians. DrugModel begins with experimental or use of a "relaxing" drug and progresses to more intense use. A third model includes users, which begin with one or the other of the previous models but later include oral opioids, such as methadone, obtained from licensed treatment programs for impotence. Tolerance refers to the need to exacerbate the dose of the opioid for a given period of time to achieve the same level of analgesia or euphoria, or the observation that re-administration of the same dose to reduced pain, euphoric, or other opioid effects. It has been found that a remarkable degree of tolerance develops against the effects of respiratory insufficiency, analgesia, sedative, emphatic opioid effect. However, the rate at which this tolerance may develop, be it impartial or in a patient in need of treatment, depends on the pattern of use. If the opioid is used frequently, it may be necessary to increase the dose. Tolerance does not develop equally or at the same rate for all opioid effects, and even users who are highly tolerant to the effects of respiratory insufficiency continue to exhibit myosis and constipation. Tolerance to opioids disappears when he or she completes the withdrawal syndrome. Physical dependence may develop recurrent administration or prolonged use of opioids. Physical dependence is gradually becoming apparent after opioid use or very quickly (for example, within a few minutes) following administration of a narcotic antagonist (referring to a "quick denial"). For the drug, to which dependence and duration of use and dose are established, withdrawal symptoms vary in number and type, duration, and severity. The most common symptoms of overdose syndrome, weight loss, pupil enlargement, frost, alternating with extreme sweating, abnormal clutter, lifting, vomiting, muscle spasms, over-irritability, crying, rhinorrhoea, bruising and rapid heartbeat. Natural abstinence syndromes 6 typically begin to appear 24-48 hours after the last dose, reaching peak intensity on the third day, and may not begin to reduce the adolescence week. Rapid withdrawal syndromes induced by the use of an opioid antagonist vary in intensity and duration depending on the dose of the specific antagonist but usually range from several minutes to several hours of duration. Physical dependence (ie, addictive) vacuolates is characterized by a search-of-drug behavior, aimed at achieving euphoria and rescuing, for example, psycho-economic pressures. One addict continues to use opioids for non-medical purposes and despite the self-deception. Previously, attempts have been made in the state of the art to control the abuse potentially associated with opioid analgesics. For example, the combination of pentazocin and naloxone has been used in commercially available tablets commercially available under the trade name Tawleynx of Sapoil-Wimmer. Teflin® Nx contains pentazocine hydrochloride equivalent to 50 mg of base and naloxone hydrochloride equivalent to 0.5 mg of base. Tamiflu is indicated for the incidence of moderate to severe pain. The amount of naloxone present in this combination has low activity when it is oral and minimally hinders the pharmacological action of pentazocine. However, this amount of naloxone, when parenterally administered, has a profound antagonistic effect on the narcotic analgesic agent. Thus, the inclusion of naloxone is expected to repel a form of abuse of oranapentazocin that occurs when the once-dosing formulation dissolves and is injected. Therefore, this dosage has a lower potential for parenteral abuse than the previous oral formulation of pentazocine. However, it is still subject to improper use by patients and abusive pathways, for example, by patients taking multiple dosages at once. Fixed combination therapy, including tritidine (50 mg) and naloxone (4 mg), is available in Germany for the treatment of severe pain since 1978 (Vardim®M, Oesbeech). The rationale for the combination of these drugs is effective pain relief and prevention of addiction to tilidine by naloxone-induced antagonism at the morphine receptor. A fixed combination of buprenorphine and naloxone was introduced in 1991 in New Zealand (Tetrahedron®Max, PeschK1 & Co.) for the treatment of pain. OBJECTS AND SUMMARY OF THE INVENTION It is an object of the present invention to provide an oral dosage form of an opioid agonist which is useful in detecting the potential for abuse of the opioid agonist contained therein. A preferred embodiment of the invention is to provide an oral opioid agonist oral dosage form, which is useful for reducing the potential abuse of the opioid agonist without affecting the opioid agonist's anesthetist activity or exposing the risk of accelerated withdrawal. It is an object of one preferred embodiment of the invention to provide an oral dosage form for the administration of an opioid agonist that is resistant to misuse or miscarriage, said resistance being independent of the individual patient-specific differences in co-administration of a mixture of an opioid agonist and antagonist. It is an object of one preferred embodiment of the invention to provide an effective oral dosage form comprising an effective dose of an opioid agonist together with a dose of an opioid antagonist that does not alter the analgesic efficacy of the opioid agonist, when the dosage form is administered orally intact, which can prevent abuse if the dosage form is mixed by interfering with the action of the opioid agonist. It is an object of a preferred embodiment of the invention to provide a method of preventing the use of an oral dosage unit form, since the dosage form also comprises a dose of a monopotassium antagonist which is separated, for example, not efficacious when the dose is administered intact but is efficacious when the dosage form is mixed with (e.g., an attempt to misuse the dose of opioid tampered means). It is another object of a preferred embodiment of the invention to provide single-dose oral dosage forms for which it is intended to be useful for controlling acute or chronic pain, wherein the change in the analgesic action of the opioid agonist should be avoided so that in the case of tolerance, physical dependence or individual variations, blackleg or physiology. It is another object of a preferred embodiment of the invention to provide a method of treating pain in a human oral dosage form for administering an opioid agonist while reducing its misuse by oral, parenteral, intranasal and / or nasal administration. Some or all of the above objectives, as well as others, are achieved by a preferred embodiment of the present invention directed in part to a single dose oral formulation comprising an opioid agonist and a opioid antagonist, wherein the opioid antagonist is present in a form that is substantially non- is separated (ie, "isolated"). In a preferred embodiment of the invention, the oral dosage form comprises an orally therapeutically effective amount of a opioid agonist, the single dosage form providing the desired analgesic effect. Since the opioidant is present in a form that is substantially non-separable, it does not substantially block the pain-inhibiting action of the opioid agonist when the once-injectable dosage form is administered orally intact and does not pose the risk of abrupt withdrawal in opioid-tolerant or opioid-dependent patients. In a preferred embodiment, the oral dosage form of the present invention is directed to an oral dosage form comprising (i) an opioid agonist in a release form and (ii) a separate opioid antagonist which is substantially non-releasable to the formulation intact, such that the ratio of the antagonist released from the dosage form after mixing with the amount of antagonist released in the dosage form is 4: 1 or more based on the in-situ dissolution for 1 hour of the indicated single dose formulation in 900 ml of simulated stomach by using U3P Touret II (mixer) apparatus at 75 rpm (rpm) at 37 degrees Celsius, since the agonist and antagonist are interdispersed and not isolated from each other in two separate layers. In another embodiment, the invention is directed to a single dose oral dosage form comprising (i) an opioid agonist in a release form and (ii) a separate opioid antagonist which is substantially non-separable when the dosage form is contacted so that the ratio of the amount of the antagonist, separated from the dosage form after mixing to the amount of antagonist, the release dosage form is approximately 4: 1 or more based on an in-vivo dilution for 1 hour of the once-dosed form in 900 ml of Simultaneous Gumat Liquid, using USP Tourell ) apparatus at 75 rpm (rpm) at 37 degrees Celsius, wherein the antagonist is in the form of a plurality of individual particles with an individual coating of a separating product that substantially prevents release of the antagonist. In another embodiment, the invention is directed to an oral dosage form comprising (i) an opioid agonist in a release form and (ii) a separate opioid antagonist which is substantially non-separable when the dosage form is applied in contact, so that the ratio of the amount of antagonist emitted from the dosage form after mixing to the amount of antagonist released from the intact dosage form is approximately 4: 1 or more based on in vitro dilution for 1 hour of the indicated single dose formulation in 900 ml Simulated Stomach , using a USP Toure II (stirrer) apparatus at 75 rpm (rpm) at 37 degrees Celsius, the antagonist being dispersed in a matrix comprising a product to be dispensed), which substantially prevents release of and the antagonist. In another embodiment, the invention is directed to an oral dosage form comprising (i) an opioid agonist in the release form and a separate opioid antagonist which is substantially non-separable when the dosage form is applied in contact, such that the ratio of the amount of antagonist contained in the intact dosage form to the amount of antagonist released from the intact dosage form after 1 hour is approximately 4: 1 or more based on the in-line dilution in 1 hour of the indicated dosage form 12 in 900 ml simulated stomach, using a C13P Tourette II agitator at 75 gpm (rpm) at 37 ° C, as the agonist and antagonist were inter-dispersed and not isolated from each other in two separate layers. In another embodiment, the invention is directed to an oral dosage form comprising (i) an opioid agonist in a release form and (ii) a separate opioid antagonist that is substantially non-separable when the dosage form is applied in contact, so that the ratio of the amount of the antagonist emitted from the intact single dose form after 1 hour is less than an amount equivalent to 0.25 mg of naltrexone, and the amount of the antagonist released after 1 hour of the dosage form after mixing is one amount bioequivalent to 0 , 25 mg of naltrexone or more, the dilution being based on a 1 hour dilution of the single dose formulation at 900 ml Simulated Stomach Thyroid using a C5P Toure II mixer at 75 rpm (rpm) at 37 degrees Celsius, the agonist and antagonist are interdispersed and are isolated from each other in two separate layers. Preferably, the amount of antagonist released after 1 hour of the mixed dosage form is one amount, bioequivalent to approximately 0, 5 mg of naltrexone or more and / or the amount of antagonist elicited after 1 hour of the once-ready dosage form represents an amount of 13 equivalents, bioequivalent to approximately 0.125 mg / dl of mettrexone or less. In another embodiment, the invention is directed to an oral dosage form comprising (i) an opioid agonist in a release form and (n) a separate naltrexone or a pharmaceutically acceptable salt thereof which is substantially non-excreted when the dosage form is co-administered in an intact, thus the amount of naltrexone separated from the intact form co-dosing after 1 hour is less than 0.25 mg and the amount of naltrexone released 1 hour after mixing is 0.25 mg or more, the release being at baseline for 1 hour of the single dose formulation in 900 ml Simulated Gut Liquid, using a USP Tourette II apparatus at 75 rpm at 37 degrees Celsius, wherein the antagonist and naltrexone are inter-dispersed and not isolated from each other in two separate layers. Alternatively, in this embodiment, the oral amount of an antagonist elicited after 1 hour of the mixed dosage co-dosing is approximately 0.5 mg of naltrexone or more and / or the amount of antagonist released after 1 hour of the single-dose dosage form is approximately 0.125 mg of naltrexone or - a little. In another embodiment, the invention is directed to an oral dosage form comprising (i) a therapeutic effect of an opioid agonist; and (i) a separate opioid antagonist such that 1 hour after oral administration, the intact dosage form releases 14 not more than about 25% of the antagonist, the dermal form provides an analgesic effect and the antagonist does not affect the analgesic effect since the agonist and antagonist are interdispersed and are not isolated from each other in two separate layers. Preferably, the intact dosage form is not more than about 12.5% ​​of the antagonist. In another embodiment, the invention is directed to an oral dosage form comprising: (i) an opioid agonist in a form which separates; and (ii) an opioid antagonist in a substantially releasable form, wherein the antagonist is in the form of a multiplicity of particles with an individual coating of material that substantially prevents the antagonist secretion. In another embodiment, the invention is directed to a single oral dosage form comprising (i) an opioid agonist in a form, which separates; and (ii) an opioid antagonist in a substantially releasable form, wherein the antagonist is dispersed in a matrix comprising a material that substantially prevents the release of an antagonist. In certain embodiments, the intact dosage form of the present invention removes some of the opioid antagonists contained therein for 1 hour after oral administration, for example, the once-dosage form releases at least 0.025 mg naltrexone or bioequivalent dose of the other antagonist after 1 hour. In these embodiments, the single dosage form provides an analgesic effect to the patient and the released antagonist does not affect the painful effect. In these embodiments, the single dose dosage form preferably does not release 0.25 mg or more naltrexone for 1 hour administration. The release of naltrexone from the intact dosage form can be measured for the purposes of these variants on the basis of in vitro dilution of the once-in-one dosage form for 1 hour in 900 ml of Simultaneous Gumat Liquid using a USP Tourell apparatus at 75 rpm , at 37 degrees C. In another embodiment, the invention is directed to an oral dosage form comprising an opioid agonist and naltrexone or a salt thereof in a substantially non-releasable form; wherein the agonist andaltrexone are at least partially interdispersed. In another embodiment, the invention is directed to an oral dosage form comprising an opioid agonist; and an oral bioavailable opioid antagonist in a form which is not substantially removed; the antagonist and the agonist are at least partially interdisciplined. In one embodiment of the invention, wherein the antagonist is in the form of a plurality of particles of a separating product, the plurality of particles may be in the form of inert beads, an antagonist coating and an outer coating of a product, or alternatively a granular form comprising the antagonist, and product. Multiparticulates may be dispersed in a matrix containing the 16 opioid agonist or contained in a opioid antagonist capsule. In one embodiment of the invention, wherein the antagonist is dispersed in a matrix comprising a material which substantially prevents the release of the antagonist, the matrix may be the pellet subform. The pellets may be dispersed in another matrix comprising the opioid agonist or, to contain a opioid agonist capsule. In another embodiment, part of the antagonist is in the matrix and / or part of the antagonist is coated. In some embodiments of the invention which exhibit the above-described ratio of about 4: 1 or greater, with respect to the amount of antagonist emitted from the single dose formulation after mixing with the amount of said antagonist removed from the intact dosage form, the dilution baseline for 1 hour of the once-dosing formulation in 900 ml Simulated Gravity Liquid, using a USP Tourette II apparatus at 75 rpm (revolutions per minute) at 37 degrees C, the intact form together lt; RTI ID = 0.0 & gt; 22.5% & lt; / RTI & gt; or less of the antagonist after 1 hour, and the mixed single dose formulation forms 90% or more of the antagonist after 1 hour. In another embodiment, the single dose formulation releases 20% or less of the indicated antagonist after 1 hour, and the mixed dosage form of either 80% or more of the antagonist after 1 hour. In another embodiment, the intact single dose formulation separates 10% or less of the indicated antagonist after 1 hour, and the mixed dosage form of either 40% or more of the antagonist after 1 hour. In another implementation variant, the intact form for the intact dosage form releases 10% or less of the indicated antagonist after 1 hour and the mixed dosage form of either 40% or more of the antagonist after 1 hour. In another implementation variant, the intact form for the intact dosage form releases 10% or less of the indicated antagonist after 1 hour and the mixed dosage form of either 40% or more of the antagonist after 1 hour. In another implementation variant, the intact form forsingle-dose administration releases 5% or less of the indicated antagonist after 1 hour and the mixed dosage form of 20% or more of the antagonist after 1 hour. In some embodiments, the ratio of the amount of antagonist released from the once-dosed formulation after mixing to the amount of said antagonist administered in the single dose unit dose, based on the 1 hour dilution of the once-dose form in 900 μl Simulated Gut Liquid, The use of the IUDP Toure II (agitator) apparatus at 75 rpm (revolutions per minute) at 37 degrees C is 10: 1 or more, 50: 1 or more and 100: 1 or more. In some embodiments, the antagonist is naltrexone or a pharmaceutically acceptable salt thereof. In such embodiments, the intact dosage form preferably being less than 0.25 mg to prevent 0.125 mg or less naltrexone for 1 hour according to the above-mentioned dilution conditions. Preferably, the mixed dosage form together dispenses 0.15 mg or more naltrexone after 1 hour, under the same conditions. In some embodiments, the ratio of the amount of antagonist emitted from the once-once dosage form after mixing to the amount of the indicated antagonist, the single dose unit dosage form, the once-in-a-dose intact dosage form based on the dilution of the 1-fold, single dose 900 μl Simulated Liquid Liquid at 75 ° C (rpm) at 37 ° C is 10: 1 or more, 50: 1 or more or 100: 1 or more using a USP Touret II (agitator) apparatus. In some embodiments of the dosage form, the antagonist in a form which is not removed is adapted to release less than 15% by weight in vivo after 36 hours. In some embodiments of the dosage form, the antagonist in a substantially non-releasable form is admitted to release less than 8% by weight in vivo after 36 hours. In some embodiments of the dosage form, the antagonist in a form that does not separate is adapted to release less than 3% by weight in vivo after 36 hours. In some embodiments of the dosage form, the antagonist in a substantially non-secreted form is admitted to release less than 1% by weight in vivo after 36 hours. In some embodiments of the dosage form, the antagonist in a form, which does not dissolve, is adapted to release less than 0.5% by weight in vivo after 36 hours. The invention also relates to methods for preventing the abuse of an opioid agonist using the single dosage forms described in the present invention. The method may comprise administering the opioid antagonist in an oral dosage form together with an opioid agonist wherein the opioid antagonist is present in a form which is substantially free of mutilation when the integrity of the dosage form is maintained until digestion is started but which is bioavailable if subjected (e.g., crushing, forced shearing which disrupt the dosage form, etc., solvents or temperatures above 45 ° C). Another embodiment of the invention is directed to a method of reducing the abuse of a opioid agonist dosage form comprising the oral dosage unit form as hereinbefore described. For example, the method may include the preparation of a single dosage form comprising (i) an orally therapeutically effective amount of a opioid agonist and (ii) an opioid antagonist in a form which is not substantially removed so that said dosage form together provides the desired analgesic effect and said antagonist not to block the substantially opioid-like effect of the opioid agonist when the dosage form is co-administered intact. In a further alternative embodiment, the opioid antagonist effect is at least partially blocked when said single dose formulation is mixed with, for example, chewable, crushed or diluted in a solvent, and administered orally, intranasally, parenterally or subcutaneously. The invention further relates to a method of treating pain with the dosage forms described herein. The method may include providing a once-only dosage form comprising an opioidagonist in a form suitable for release and an opioid-antagonist form which is substantially not removed; and the intact dosage form is administered orally. A further embodiment of the invention relates to a method of treating pain with the described dosage forms in co-dosage. In some embodiments, the method of treating pain with a single-dose form in patients having a lower potential for abuse includes providing an oral dosage form comprising a dosage form, which can separate an opioid agonist and a form that can not be substantially separated from an opioid antagonist; and the oral dosage form is orally administered to provide the blood plasma glucagon agonist with the higher unmodified analgesic concentration of the opioid agonist. The invention also relates to methods for obtaining the dosage forms described herein. In some embodiments, the invention includes a method of preparing a single dose oral formulation comprising pretreatment of an opioid antagonist to make a subform which can not be substantially removed; and recombines the pretreated antagonist with a form that can be released into an opioid agonist in a manner that maintains the integrity of the form that can not be separated from the antagonist. Some embodiments of the invention are directed to dosage forms wherein the agonist antagonist is interdispersed and is not isolated from one another in two separate layers. However, in some embodiments, the agonist and antagonist are partially interdispersed. The term & quot; analgesic effect & quot; defines the aims of the present invention as satisfactory reduction or elimination of pain along with tolerable side effects as determined by the patient. Expression "does not block the substantially analgesic action of an opioid agonist" means that opioid agonist blocks the actions of the opioid agonist in a sufficient amount to make the once-dose dosage form therapeutically less effective for delivering a painful action. The expression "risk of speeding" that the actual action of the pharmaceutical form does not depend on the specific relationship of the agonist to the antagonist or the different metabolism of each. The term & quot; opioid antagonist in a form which can not be separated & quot; refers to an opioid antagonist that is not separated or substantially is not removed one hour after the oral single dose formulation containing both the opioid agonist and antagonist is administered orally (i.e., without being mixed up). For the purposes of the invention, the amount released after oral administration of an intact dosage form can be measured in vitro by digesting for 1 hour in 900 ml of Simultaneous Gumat Liquid using a USP Tourell apparatus at 75 rpm at 37 grams C. Such a once-off dosage form is also referred to as a & quot; separate antagonist & quot ;. Although the preferred embodiment of the invention includes an opioid antagonist in a form that completely prevents the release of an opioid antagonist, the invention also includes an antagonist in a substantially non-releasable form. The term & quot; which is not removed & quot; refers to the antagonist to be excreted in a small amount so long as the amount disposed does not interfere with, or does not interfere with, the analgesic effect when the dosage form is co-administered once in humans as expected . In some preferred embodiments, the substantially non-releasable form of the antagonist is resistant to laxatives (e.g., mineral oils), used to manage delayed bowel movements and states of chlorohydride (reduced hydrochloric acid). In some embodiments, the form that is not released into the opioid antagonist comprises an opioid antagonist that is formulated with one or more pharmaceutically acceptable hydrophobicidal material such that the antagonist is not removed or the substance is not removed during the passage through 23 gastrointestinal tract, when administered orally, as it was, without being mixed. In some embodiments of the present invention, the form which is substantially non-separable to the opioid antagonist is susceptible to mechanical, thermal and / or chemical mixing, e.g., mixing by means of crushing, shearing, milling, chewing and / or dissolving in a solvent in combination with heating (e.g., above about 45 ° C) of the oral dosage form in combination. When mixed in this way, the integrity of the opioid antagonist form which substance can not be separated will be compromised and the opioid antagonist will become available for release. In some embodiments, when the single dosage form is chewed, crushed, cut, or dissolved and heated in a solvent and administered orally, intranasally, parenterally or sublingually (sublingually), the analgesic or euphoric effect of the opioid is reduced or eliminated. In some embodiments, the action of the opioid agonist is at least partially blocked by the opioid antagonist. In some embodiments, the opioid agonist is substantially blocked by the opioid antagonist. The term & quot; mixing & quot; means any administration by mechanical, thermal and / or chemical agents that alters the physical properties of the dosage form, for example, to release opioid agonist immediately to release if in a delayed release form or to make the opioid agonist available for 24 inappropriate use, such as by alternate administration, e.g., parenterally. Mixing can be, for example, by shredding, shearing, grinding, chewing, dissolving in a solvent, heating (e.g., about 45 ° C) or any combination thereof. The term & quot; at least partially blocking the action of the opioid agonist & quot; is defined for the purposes of the present invention as meaning that the opioid agonist at least significantly blocks the euphoric action of the opioid agonist, thereby reducing the potential abuse of an opioid agonist in a single-dose form. In some preferred embodiments of the present invention, the form which can not be substantially removed from the opioid antagonist comprises particles of a opioid antagonist with a coating that substantially prevents antagonist secretion. In some preferred embodiments, the coating comprises one or more pharmaceutically acceptable hydrophobic materials. The coating is preferably an impenetrable opioid agonist which also contains an insoluble gastrointestinal system, thereby preventing the release of an opioid antagonist when the once-only dosage form is administered orally as intended. Accordingly, when the oral dosage form is not mixed, so as to compromise the integrity of the coating, the opioid antagonist contained will not be substantially removed during the first hour of 25 passage through the gastrointestinal system, and therefore will not be available for absorption. In certain preferred embodiments of the present invention, the hydrophobic material comprises a cellulose polymer or an acrylic polymer which is insoluble in gastrointestinal fluids and is impervious to the opioid antagonist. The term & quot; particles & quot; of an opioid antagonist as used herein refers to granules, spheroids, beads or pellets containing an opioid antagonist. In certain preferred embodiments, the opioid antagonist particles are less than about 0.2 to about 2 mm in diameter, more preferably about 0.5 to about 2 mm in diameter. In some embodiments of the present invention, the oral dosage form further comprises an opioid antagonist in a form which can be separated and thus the ophthalmic dosage form can be separated when administered orally, the ratio of the opioid agonist to the formulation which can be released to the opioid antagonist is such that the once-dosed form, when administered orally, has an analgesic effect. For example, when the opioid antagonist is substantially anti-secreted, and then mixed with an opioid agonist and compressed into tablets, known amounts of the coating may crack, thereby exposing the opioid-antagonist to release upon oral administration. Preferably, the opioid agonist used in the present invention, may be selected from the group consisting of morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, mepiridine, methadone, and mixtures thereof. Preferred examples of opioid antagonists used in the present invention include naltrexone, naloxone, nalmefene, cyclazocine, levalorphan, their pharmaceutically acceptable salts, and mixtures thereof. In some embodiments of the present invention, the ratio of the opioid agonist and the opioid antagonist present in the substantially non-releasable form is approximately 1: 1 to approximately 50: 1 weight, preferably approximately 1: 1, preferably 20: 1 by weight or 15 : 1 to about 30: 1. The ratio of the opioid agonist to the opioid antagonist as used in the present application relates to the weight of the active ingredients. For example, the weight of the opioid antagonist excludes the weight of the coating or matrix that makes the opioid antagonist in a substantially non-released form or other optional excipients associated with the antagonist particles. Some preferred embodiments are a ratio of approximately 1: 1 to approximately 10: 1 by weight. The steroidal antagonist is in a form which is substantially non-separable, the amount of such an antagonist in the dosage form may vary widely, then the opioid agonist / opioid antagonist combined dosage forms, both of which are in a form that is readily administration as long as the drug formulation is not dependent on the various metabolites or the red blood cell clearance for proper functioning. Security disclosures, the amount of opioid antagonist present in the form, which is essentially non-selective, is chosen not to be detrimental to humans, even if it is completely separated by mixing with the one-dose formulation. In certain preferred embodiments of the present invention, the opioid agonist comprises hydrocodone, oxycodone, or pharmaceutically acceptable salts thereof, and the opioid antagonist present in a form which is not substantially removed comprises naloxone, naltrexone, or pharmaceutically acceptable salts thereof. The single-dose oral dosage form comprising a opioid agonist in combination with a form that is substantially free of an opioid antagonist includes, but is not limited to, tablets or capsules. The single-dose formulations of the present invention may include any desired pharmaceutical excipient known to those skilled in the art. Oral dosage forms may, in addition, to provide immediate release of the opioid agonist. In certain embodiments, the oral dosage unit form of the present invention provides prolonged release of the opioid agonist contained therein. Oral dosage forms providing delayed release of the opioid agonist can be prepared according to pharmaceutical formulations / methods known to those skilled in the art of the formulation, for example, by incorporating a sustained release carrier into a matrix comprising the substantially non-releasable form naopioid antagonist; or by a delayed release matrix coating comprising the opioid agonist and the form to be secreted to the opioid antagonist. The benefits of the once-dose regimen of abuse are great in connection with oral dosage forms of strong opioid agonists (e.g., oxycodone or hydrocodone) which provide an anti-inflammatory effect but are susceptible of misuse thereof. This is particularly true for opioid-delayed release products that have a large dose of a cDNA agonist that is intended to be secreted for a prolonged period of time in any single-dose form. Drug abusers take on such delayed release products, and degrade, digest or otherwise injure the product so that the full content of the single-dose formulation becomes available for immediate absorption. Since such mixing of the dosage unit form, the invention results in, the opioid antagonist also is available for absorption, the present invention provides a means of preventing such abuse. Furthermore, the present invention is directed to the risk of overdosing ordinary patients from a "dump" effect of the full dose of the opioid agonist if the product inadvertently chews or breaks. The term & quot; delayed release & quot; is defined for the purpose of the present invention, wherein the release of the opioid agonist from the oral dosage form is at a rate in which blood levels (e.g., plasma) are maintained in therapeutic arms (above minimal effective pain reliever concentration or & quot; MEAS & quot;), but below the toxic levels over a period of 8 to 24 hours, preferably over a period of time, indicative of a twice-a-day or single-dose formulation. The invention may provide a safer product (e.g., less breathing insufficiency) if misused with the product, such as the one with less risk of abuse. In some embodiments, a combination of two opioid agonists is included in the dosage form. In other embodiments, one or more opioid antagonists are included, including also a non-opioid drug. Such non-opioid agents should preferably provide additional analgesia and include, for example, aspirin, acetaminophen, non-steroidal anti-inflammatory drugs ("NSAIDs"), NMDA antagonists, and inhibitors of cyclooxygenase-H ("COX-Ninhilters"). In other embodiments, can include non-opioid drugs which produce a desired effect other than an analgesic effect such as cough, expel, decongestant, or antihistamines, and the like. For the purposes of the present invention, the term "opioid agonist" is interchangeable with the term "opioid" or "opioid analgesic" and includes combinations of more than one opioid agonist, and also includes the base opioid, agonist-antagonist, partial agonist, acceptable salts, their stereoisomers, their enantiomers and esters, and mixtures thereof. For purposes of the present invention, the term & quot; opioid antagonist & quot; should include combinations of more than one opioid agonists and also contain the base, its pharmaceutically acceptable salts, its stereoisomers, its ethers and esters, and their mixtures. The invention described herein is intended to include all pharmaceutically acceptable salts of the disclosed opioid agonists and opioid antagonists. Pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, zeolite salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; salts of organic acids such as triethylamine salt, pyridine salt, picoline salt, hydrochloric acid ethanolamine, triethanolamine salt, dodecyclohexylamine salt, N, N'-dibenzylethylenediamine salt and the like; salts of inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate and the like, salts of organic acids such as formate, acetate, trifluoroacetate, maleate, tartrate and the like, sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; salts of amino acids such as arginate, aspartate, glutamate and the like. Some of the opioid agonists and antagonists described herein may contain one or more centers of asymmetry and may therefore give rise to enantiomeric, diastereomeric and other stereoisomeric forms. The present invention also includes all such possible forms as well as their racemic and otherwise dissolved forms and mixtures thereof. When the compounds described herein contain an olefinic double bond or other centers of geometric asymmetry, and if not elsewhere, it is assumed to include both the E and Z isomeric isomers. All tautomers are also contemplated to be encompassed by the present invention. As used herein, telmine "stereoisomers" is a generic term for all isomers of the individual molecules, which differ only in the swept spatial orientation of the atoms. It includes enantiomers and isomers of compounds with more than one chiral center which are not mirror images of each other (diastereomers). The term & quot; chiral center & quot; refers to a carbon atom to which four distinct groups are attached. The term & quot; enantiomer & quot; or & quot; enantiomeric & quot; refers to a molecule that can not overlap with its mirror image and therefore optically active, whereby the enantiomer rotates the plane of polarized light on its side, and its mirror image rotates polarized light in the opposite direction. The term & quot; racemic & quot; refers to a mixture of equal parts of enantiomers which is optically inactive. The term & quot; dissolution & quot; refers to the separation or concentration or depletion of one of the two enantiomeric forms of the molecule. The present invention furthermore relates to a method for reducing the potential for opioid analgesic abuse in single oral administration. The method includes providing an opioid agonist in an oral dosage form as described herein. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graphical representation of the results of Example 20. Figure 2 is a graphical representation of the results of Example 23. Figure 3 is a graphical representation of the results of Example 24. TECHNICAL NATURE OF THE INVENTION It is believed that there are at least three subspecies opioid receptors, referred to as opioid receptors. In this frame, The receptor is considered to be involved in the induction of spinal aesthetic, myositis and sedative action. The activation of gamma receptors causes dysphoric and healucinations, as well as respiratory and respiratory disorders, as well as respiratory depression, eosinophilia, and physical dependence. vasomotor 33 stimulatory effects. A receptor that differs from the tyreceptor and referred to as a gamma has been described in this example. aks, Issa, 1977, 267, 495-99. Opioidogonists are thought to exhibit their agonist activity predominantly at the th receptor and, to a lesser extent, to receptor the receptor. There are few drugs that appear to act as partial agonists in one or the other receptor type. Such drugs include butorphin, propiram, and buprenorphine. Other drugs also act as competitive antagonists at the thyreceptor and block the action of morphine-like drugs by exerting their effects on the kappa and the omega receptors. The term agonist-antagonist is designed to describe such a mechanism of action. The present invention relates to a controlled release opioid pain reliever such as an analgesic spectrum with existing controlled release painkillers which is administered in a dosage form to minimize misuse, misuse and abnormalities. In some embodiments, these characteristics are conferred by including an opioid antagonist, such as naltrexone HCl, which itself is formulated in a single matrix controlled release. The properties of this drug formulation evolve so as to release the antagonist in the conditional misuse or mixing of already insignificant amounts of antagonist that would be released (a single amount that does not affect the analgesic effect 34 tested by the patient) under the prescribed conditions of use. In some embodiments, the release of the antagonist component of the dosage form is expressed by the rate of release obtained after mixing, for example, by breakage or chewing, depending on the amount of intact drug release. The ratio is then expressed as [Crushed] / [Goals] and it is desirable that this ratio be at least 4: 1 or more (separated from the 1 hour split / intact for 1 hour). When the antagonist is naltrexone, the preferred contact dosage form is to release less than 0.25 mg, preferably 0.125 g or less in 1 h, with 0.25 mg or more of nelfrexon release after 1 hour when the formulation is coadministered or The deviation of these values ​​is described in Examples 17, 18 and 19. The present invention provides an oral dosage form together with an opioid agonist useful in illustrating the potential for opioid agonist abuse contained therein. The present invention includes a single-dose oral formulation comprising an orally therapeutically effective amount of an opioid agonist in combination with an opioid antagonist. The opioid antagonist is present in a form that is essentially not released. In some preferred embodiments, the opioid antagonist in a form, which essentially does not separately include opioid antagonist particles with coating, which substantially prevents excretion. Preferred variants, such a coating circumvents the particle of the antagonist and is impervious to the drug and is insoluble in the gastrointestinal system. When the once-only dosage form of the present invention is administered orally to humans, the opioid antagonist is not secreted from the coating and is therefore not available for absorption in the body. Thus, although the opioid antagonist, although present in the dosage form, does not substantially block the analgesic action of the opioid agonist. However, if the oral dosage form of the present invention is mixed, in the case of compromise of the entirety of the coating, the opioid antagonist contained therein, will become available to at least partially block the action of the opioid agonist. This characteristic reduces the potential for abuse or deviation of the opioid agonist in the oral dosage form. For example, if one attempts to abuse the drug containing the oral dosage form of the present invention by, for example, chewing, breaking, chewing or dissolving in a solvent of heat (e.g., greater than 45 ° C to about 50 ° C) , the coating will be damaged and will no longer protect the opioid antagonist release. Upon administration, the opioid antagonist will be excreted to block the euphoric effect of the opioid antagonist. In some embodiments, the ratio of the opioid agonist to the opioid 36-coated antagonist is such that, when the oral dosage form is mixed with the compromised integrity of the coating which renders the opioid antagonist substantially not separable, the euphoric action of the agonist would be abrogated by the opioid antagonist when misusing the subject, oral, parenteral, intranasal or sublingual. In some preferred embodiments of the invention, the euphoric action of the opioid agonist would be canceled by the opioid antagonist when misused parenterally or sublingually. The present invention also includes a single dose oral dosage form comprising a opioid antagonist form together with an opioid agonist and opioid antagonist coated particles such as an agonist to a non-coated opioid agonist is such that when administered orally as is front, oral dosage form is effective for the purpose of obesity. In some other embodiments of the present invention, the opioid agonist, in a form that is not removed, contains an opioid agonist dispersed in a matrix which makes the antagonist substantially free of the matrix comprising one or more pharmaceutically acceptable hydrophobic materials. The antagonist is substantially not removed from the matrix, as the bloodstream is not made available to be absorbed during passage through the gastrointestinal system. In some other embodiments of the invention, the opioid agonist in the matrix does not substantially release opioid antagonist contents dispersed in a molten extruded matrix, wherein the matrix contains one or more pharmaceutically acceptable hydrophobic materials. In preferred embodiments, opioid antagonists useful in the present invention include, but are not limited to, alfentanil, allylprodine, alfaprodine, anilridine, benzylmorphine, besitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dihydrochloride, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives, heroin, rophodone, hydromorphone, hydroxypetidine, isomethadone, ketobemidone, levorphanol, leuphenacylmorphan, lofentanil, mepiridine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narcine, nicomorphine, norbornophane, oxymorphone, papaveretum, pentazocine, fenadoxone, phenomorphan, pyritramine, phenazocine, profetazine, phenoperidine, promodil, pimidinine, propiperidine, propoxyphene, sufentanil, tilidine, tromadol, mixtures of which are the foregoing, salts of any of the foregoing, . In some embodiments, the amount of opioid agonist in the opioid 38 composition for which protection is desired may be approximately 75 to 750 mg. In some preferred embodiments, the opioid antagonist is selected from the group consisting of hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, mepiridine, methadone, oxymorphone, buprenorphine, fentanyl and derivatives derivatives, dipipanone, heroin, tramadol, etorphine, dihydroetorphine, butorphanol , levorphanol, or their salts or mixtures thereof. In some preferred embodiments, the opioid agonist is oxycodone or hydrocodone. Equial analgesic doses of these opioids compared to 15 mg hydrocodone are shown in the following Table 1: TABLE 1 Equimalgesic Opioid Doses Opioid Calculated Dose (mg) Oxycodone 13.5 Codeine 90.0 Hydroxycodone 15.0 Hydromorphone 3.375 Levorphanol 1.8 Mepiridine 135.0 Methadone 9.0 Morphine 27.0 Although oxycodone and hydrocodone are effective in controlling pain, there is an increase in malnutrition by people who are physically dependent on opioids or who misuse opioids for no therapeutic reasons. Previous experiments with other opioids have shown a diminishing potential for abuse when opioids are administered in combination with a narcotic antagonist, particularly in patients who are formerly addicted. in Coltina, in the case of Non-Drug, Ogid ApslAlsoOloprepse 1992; 30: 263-274; Meglendisch 3, eich auf der Werkzeugnung, einen Werkzeug und Werkzeugen in der Spiegelungen, Kunstwirtschaftliche Kunststoffe. 1996; 60: 105-114; both of which are incorporated herein by reference as a reference. However, these combinations do not contain an opioid antagonist which is in a substantially non-exuding form. Rather, the opioid antagonist is secreted into the gastrointestinal system when administered orally and becomes available for absorption, relying on the physiology of the host to differentially antagonize the agonist antagonist and to eliminate the agonist effect. Hydrocodone is a semisynthetic narcotic and anti-cough agent with numerous actions on the central nervous system of the gastrointestinal system. The chemical hydrocodone is 4, 5-epoxy-3-methyl-17-methylmorphinan-6-one and is also known as dihydrocodeinone. Like other opioids, hydrocodone can lead to a habit and may cause drug addiction to morphine-borne disease. In very large doses, hydrocodone, as other derivatives of opium, leads to respiratory depression. The oral form of hydrocodone is also available in Europe (Belgium, Germany, Greece, Italy, Luxembourg, 40 Norway and Switzerland) as an anti-cough agent. The parenteral formulation is also available in Germany as a cough remedy. For use as a contraceptive agent, hydrocodone bitartrate is commercially available in the United States only as a fixed combination with non-opiate drugs (i.e., ibuprofen, acetaminophen, aspirin, etc.) for the treatment of moderate to moderate severe pain. A conventional dosage form of the hydrocodone is in combination with acetaminophen and is available in the grid, for example as Loradab® in the US by and SBRIagar, Inc., with 2.5 / 500 mg, 5/500 mg, 7.5 / 500 mg, and 10 / 500 mg hydrocodone / acetaminophen tablets. The tablets are commercially available, also at a ratio of 7.5 mg dihydrocodone bitartrate and 650 mg acetaminophen and 7.5 mg dihydrocodone bitartrate and 750 mg acetaminophen. Hydrocodone in combination with aspirin is prescribed in adults as an oral dosage form, usually 1-2 tablets per day in 4-6 hours, if necessary pain relieving. The tablet formulation is 5 mg dihydrocodone betartrate and 224 mg aspirin with 32 mg caffeine or 5 mg hydrocodone bitartrate and 500 mg aspirin. An over-the-counter new formulation includes hydrocodibitrate and ibuprofen. X / JorgoTex®, available from the U.S. based trade network, of Rohol Lactobacillus, is a tablet formulation containing 7.5 mg of hydrocodone bitartrate and 200 mg of bibuprofen. It is believed that the present invention encompasses all such dosage forms with the inclusion of opioid antagonist particles with a coating which makes the antagonist not substantially removed. Oxycodone, known under the chemical name of 4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorfinan-6-one, is an opioid agonist whose main therapeutic effect is analgesia. Other therapeutic actions of oxycodone include anxiolysis (feeling of subtlety), euphoria and a sense of relaxation. The exact mechanism of the analgesic action is known, but specific opioid receptors of the Central Nervous System for opgenid compounds with opioid-like action have been identified in the brain and spinal cord and play a role in the analgesic action of the drugs. Oxycodone is commercially available in the United States, for example, Ouchodip® from Rigby Pharmaceuticals. P. as controlled release tablets for oral administration containing 10mg, 20mg40 mg or 80 mg of oxycodone hydrochloride, and OxyP®, also from Rigby Pharmaceuticals Ltd., such as snap-off capsules containing 5 mg of oxycodone hydrochloride. The present invention is considered to include all such dosage forms, including a opioid antagonist in a form that is substantially non-separable. In preferred embodiments, the opioid antagonist comprises naltrexone, nalmefene, cypazocine, levalofane and mixtures thereof. In some preferred embodiments, the opioid antagonist is naloxone or naltrexone. In some embodiments, the opioid 42 antagonist present in a substantially non-secreted form may be approximately 10 mg to 275 mg. Naloxone is an opioid antagonist that is free of agonist activity. Subcutaneous doses of up to 12 mg of naloxine produce no distinct subjective effects, (0.4-0.8 mg) of naloxone administered intramuscularly or intravenously in humans prevents or rapidly reverses the action of morphine-like opioid agonists. It has been reported that one ml of naloxone intravenously completely blocks the action of 25 mg of naloxone alone in mild drowsiness. heroin. The effects of naloxone are expressed almost immediately after intravenous administration. The drug is absorbed after oral administration, but it has been reported that it is rapidly metabolised by an inactive form in its first passage of the liver, as reported to be significantly weaker than if administered parenterally. For oral dosage form of over 1 g, it is reported that the seed is almost completely in less than 24 hours. It is reported that 25% of naloxone administered sublingually is absorbed. Meigegd, al. Aggression of the Territory of the United States of America, Tue. (1988); 44: 335-340. Other opioid antagonists, e.g., cyclazocine and naltrexone, both of which have cyclopropylmethyleurization on nitrogen, retain most of their efficacy through the oral route of administration and their duration of action is much greater, approaching 24 hours after the oral single dose formulation. In the treatment of opioid-dependent patients, naltrexone has been used in large oral dosages (over 100 mg) to prevent the euphoric effects of opioid agonists. Naltrexone has been reported to show a highly preferential blocking action against the 0e1a sites. Naltrexone is known as a synergistic combination of oxymorphone with opioid agonist properties, and differs in structure from the oxymorphone substitutions of the methyl group located on the nitrogen atom of the oxymorphone with the cyclopropylmethyl group. The naltrexone hydrochloride salt is soluble in water at approximately 10 mg / cc. The pharmacological pharmacokinetic properties of naltrexone have been evaluated in numerous animal studies. See, for example, Sogwagus. ЬР, е1 а1., Магейпепе: Алексей на КрПатассосултуассс! The Pharmaceutical Prevention and Rehabilitation Program will be held in the City of Opole. Ohrid 1988; 35: 192-213, incorporated herein by reference as a literary reference. Following oral administration, naltrexone is rapidly adsorbed (for 1 hour) and has an oral bioavailability ranging from 5% to 40%. Naltrexone binding of the proteins is approximately 21%, and the volume of distribution after single dose administration is 16.1 μg / kg. Naltrexone is commercially available from Peptide® for the treatment of alcohol dependence and for the blocking of exogenously administered opioids. See, for example, Pervy (tablets naltrexone hydrochloride). Heck Kegel 5151 et al., Molec / alle, N3. "Meson Esopotuz" 1997; 51: 957-959. a dose of 50 mg of Pseudo blocked the pharmacological action of 25 mg IV administered heroin for up to 24 hours. It is known that when co-administered with morphine, heroin or other chronic-opioid drugs, naltrexone blocks the development of physical dependence on opioids. It is believed that the method by which naltrexone blocks heroin action is by competitive binding of the sapoid receptors. Naltrexone has been used to treat narcotic dependence by fully blocking the action of opioids. It was discovered that the most successful use of naltrexone, Drug addicts are drug addicts, there are good predictions, part of the conscious work or rehabilitation program involves controlling controls or other methods that enhance the assertion. For the treatment of narcotic addiction, it is desirable for the patient to be opioid-free for a period of at least 7-10 days. The initial dose of naltrexone targeted was typically approximately 25 mg, and if signs of rejection occur, the dose may be increased to 50 mg per day. A 50 mg daily dose is considered to produce an adequate clinical blocking effect on parenteral opioids. Naltrexone has also been used to treat alcoholism as a complement to social and psychotherapeutic methods. In some embodiments of the invention, the ratio of the opioid agonist to the form, which is not removed from the opioid antagonist in the oral dosage form, is such that the action of the opioid agonist is at least partially blocked when the single dosage form is chewed, broken or dissolved in a solvent and heated and administered orally, intranasally, parenterally or sublingually. Once the oral dosage form of the present invention, when properly administered as intended, does not bind the utility of opioid agonist release, the amount of the antagonist may vary more widely than if the opioid antagonist is available to be excreted in the gastrointestinal system upon oral administration. For reasons of safety, the amount of antagonist present in a substantially non-releasable form should not be injurious to humans, even when fully released. The ratio of a certain opioid agonist to an antagonist can be determined without unnecessary experimentation with the subject in the art. In some embodiments of the present invention, the ratio of the opioid agonist and the opioid antagonist that is present in a substantially non-separable form is approximately 1: 1 to about 50: 1 by weight, preferably from about 20: 1 by weight. In some preferred embodiments, the ratio is desirably 1: 1 to about 10: 1 by weight. In a preferred embodiment of the invention, the opioid agonist contains oxycodone or hydrocodone and is present in an amount of approximately 15-45 mg, and the opioid antagonist contains naltrexone and is present at approximately 0.5 - 5 mg. The oral dosage form of the present invention may, furthermore, include, in addition to an opioid agonist and antagonist, one or more drugs that can act or act synergistically with them. Thus, in certain embodiments of the invention, a combination of two opioid antagonists may be included in the single dose formulation in addition to the opioid antagonist. For example, the dosage form may include a two-agent agonist having different properties such as half-life, solubility, strength, and a combination of the above. In another embodiment, one or more opioid antagonists are included, non-opioid agent in addition to the opioid antagonist. Such non-opioid drugs would preferably provide additional analgesic action and include, for example, aspirin, acetaminophen; non-steroidal anti-inflammatory drugs (& quot; NSAID & quot;), e.g., ibuprofen, ketoprofen, etc .; N-methyl-O-aspartate (NMDA) receptor antagonist, for example, morphinan, dextromethorphan or dextrofan or ketamine, cyclooxygenase-II inhibitors ("COX-H inhibitors"); and / or antagonist antagonist. In certain preferred embodiments of the present invention, the invention relates to the use of low doses of opioid analgesics by the addition of an additional neopioid agonist such as NSAID or COX-2 inhibitors. By using low amounts of one or two drugs, the side effects 47 associated with the effectiveness of controlling pain in the ear are reduced. Suitable non-steroidal anti-inflammatory agents include ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fluprofen, trioxaphene, indoprofen, pyroprofen, carprofen, oxaprozine, susprofen, fluprofen, pramoprofen, aminoprofen, murophefen, thioxaprofen, thiaprofenic acid, dexpinax, mephenamatic acid, meclofenamic acid, flufenamic acid, nuflemic acid, tolfenamic acid, diffursin, flufenisal, piroxicam, sudoxicam or isooxicam and the like. Useful formulations for single-dose administration of these drugs are well known to those skilled in the art. N-methyl-D-aspartate receptor (NMDA) receptor antagonists are well known in the art and include, for example, morphinans such as dextromethorphan or dextrorphan, ketamine, 6-methadone or a pharmaceutically acceptable carrier thereof. For the purposes of the present invention, the term "NMDA antagonist" is intended to include pharmaceutical agents that block the major intracellular effect of NMDA receptor activation, for example, ganglioside, such as CM- [beta] or CTLb phenothiazine such as trifluoroperazine or naphthalenesulfonamide, such as N- -aminotexyl) -5-chloro-1-naphthalenesulfonamide. These drugs are thought to inhibit the development of 48 tolerance to and / or dependence or drug addiction, e.g., narcotic analgesics such as morphine, codeine, and the like. U.S. Patent Nos. 5,321,012 and 5,556,838 (both owned by Mauer, et al.), Both of which are incorporated herein by reference in their entirety. NMDA antagonist may be included alone or in combination with topical anesthesia, such as lidocaine, as described in the Mauer et al. The treatment of chronic pain by using a glycine receptor antagonist and the identification of such drugs is described in U.S. Patent No. 5,514,680, incorporated herein by reference. COX-2 inhibitors have been reported in the state of the art and many chemical structures are known to produce inhibition of cyclooxygenase-2. COX-2 inhibitors are described, for example, in U.S. Patent No. 5,616,601; 5,604,260; 5,593,994; 5,550142; 5,536,752; 5,521,213; 5,475,995; 5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,436,265; 5,409,944; and 5,130,311, all of which are incorporated herein by reference. Some preferred COX-2 inhibitors include celecoxib (5C-58635), DUF-697, flusulide (CCP-28238), meloxicam, 6-methoxy-2 naphthylacetic acid (6MCA), MK-966 nabumetone (6-MCA precursor), nimesulide, N5-398, 5C-5766, 5C-58215, T-614; or combinations thereof. The dosage level of the COX-2 inhibitor of approximately 0.005 mg, approximately 140 mg per kilogram body weight per day, is 49 therapeutically effective in combination with an opioid pain killer. Alternatively, approximately 0.25 mg to approximately 7 g per patient per day of a COX-2 inhibitor is administered in combination with an opioid pain killer. In another embodiment, a non-opioid drug may be provided which delivers a different effect than an analgesic, e.g., anaplastic, expectoral, decongestant, antihistamine, local anesthetics, and the like. OBTAINING OPIOID ANTAGONIST IN FORM, Which in principle is not separated. In certain embodiments of the present invention, an opioid antagonist in a form which is not secreted can be produced by a combination antagonist with one or more pharmaceutically acceptable hydrophobic materials. For example, opioid antagonist particles may be coated with a coating layer which substantially prevents the release of the antagonist, the coating comprising the hydrophobic material (s). Another example would be an opioid antagonist which is a dispersed matrix which makes the antagonist in a form which is not removed, such as the matrix comprising hydrophobic material (s). In certain embodiments, the pharmaceutically acceptable hydrophobic materials include a cellulose polymer selected from the group consisting of ethylcellulose, cellulose acetate, propionate 50 cellulose (low, medium or high molecular weight), cellulose acetate propionate, acetate butyrate cellulose, acetate phthalate cellulose and cellulose acetate triacetate. An example of ethyl cellulose has an ethylic content of 44% to 55%. Ethylcellulose can be used in the form of a alcoholic solution. In some other embodiments, the hydrophobic material includes polylactic acid, polyglycolic acid or copolymer of polylactic acid and polyglycolic acid. In some embodiments, the hydrophobic material may include a cellulosic polymer selected from the group consisting of cellulose ether, cellulose ester, cellulose ester ether and cellulose. The cellulose polymer has a substitution step of 0.3 on an anhydroglucose unit of more than zero and up to and including 3. By degree substitution is meant the average number of hydroxyl groups, present on the anhydroglucose unit, including the cellulose polymer, which are substituted by substituent groups. Representative materials include a polymer selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono, di, tricellulose alkanylates, mono-, di- and tri-cellulose arolates and mono, di tri-cellulose alkenylates. Exemplary polymers include cellulose acetate having a D.5. and acetyl content to 21%; cellulose acetate having an acetyl content of up to 32 to 39.8%; cellulose acetate having 0.5. from 1 to 2 and an acetyl content of 21 to 35%; acetate 51 cellulose having 0.5. from 2 to 3 and an acetyl content of 35 to 44.8%. More typical cellulosic polymers include propionate cellulose having 0.5. of 1.8 and a propylene content of 39, 2 to 45 and a hydroxyl content of 2.8 to 5.4%; acetate butyrate cellulose having 0.8. of 1.8, an acetyl content of 13 to 15% and a butyryl content of 34 to 39%; acetate butyrate cellulose having an acetyl content of 2 to 29%, butyryl content and 17 to 53% and a hydroxyl content of 0.5 to 4.7%; cellulose triacylate having U.5. from 2.9 to 3, such as cellulose triacetate, cellulose trivalerate, cellulosic trilaurate, cellulose tripalmitate, cellulose; trisuccinate, and cellulose dextrotoate; cellulose diacylate having a D.S. from 2.2 to 2.6, such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose dipentanoate, and cellulose esters, such as cellulose acetate butyrate, acetate octanoate and acetate propionate cellulose. The additional cellulose polymers used to prepare an opioid antagonist in a form, which does not release, include acetaldehyde dimethylacetate cellulose, cellulose acetate ethyl acarbamate, cellulose acetate methylcarbamate, and cellulose acetate dimethylaminocellulose acetate. An acrylic polymer used in the preparation of a opioid antagonist in a substantially non-separable form includes, but is not limited to, acrylic resins including copolymers synthesized from acrylic acid esters (for example, the copolymers of a lower alkyl ester of acrylic acid and lower alkyl ester methacrylic acid) containing from 0.02 to 0.03 moles of the three (lower alkyl) ammonium group per mole of the acrylic and methacrylic monomers used. A suitable acrylic resin example is a polymer produced Horn Powder String, and marketed under the trademark Elizabeth® H5. Preference is given to Epsilon K53C10. Esidar® K5 is a water-insoluble copolymer of ethyl acrylate (EA), methyl methacrylate (MM) and trimethylammoniummethyl methacrylate chloride (TAM), in which the molar ratio of TAM to the other ingredients (EA and MM) is 1:40. Acrylics such as Estelle® can be used in the form of aqueous suspensions. In certain embodiments, the acrylic polymer may be selected from the group consisting of acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly (acrylic acid), poly (methacrylic acid), copolymer of alkylamide methacrylic acid, poly (methyl methacrylate), polymethacrylate, poly (methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic acid anhydride) acrylate. When the opioid antagonist in a form which is not removed includes opioid antagonist particles coated with a coating which makes the antagonist substantially removed and when a cellulosic polymer or acrylic polymer is used to prepare the coating composition 53 suitable plasticizers, acetyl triethyl citrate / or acetyl tributyl citrate may also be mixed with the polymer. The coating layer may also include additives such as coloring agents, talc and / or magnesium stearate, which are well known from the prior art coatings. The coating composition may be applied to the particles of the opioid antagonist by spraying on the particles using suitable spraying equipment known in the state of the art. For example, a fluidized bed system in which airflow, with bottom injection, fluidizes the coating material and is dried while the insoluble coating polymer layer is sprayed on top. The thickness of the coating depends on the characteristics of the particular coating composition to be used. However, it is within the capabilities of one skilled in the art to determine by circumutinous experiments the optimal thickness of the particular coating layer required for a particular dosage form of the present invention. The pharmaceutically acceptable hydrophobic material useful for producing an opioid antagonist in a substantially non-releasable form comprises a biodegradable copolymer comprising poly (lactic / glycolic acid) ("PLA"), polylactide, polyglycolide, polyanhydride, polyorthoester, polycaprolactones, polyphosphazenes, polysaccharides, protein polymers, polyesters, polydioxanone, polygluconate, copolymers of polylactic acid-polyethylene oxide, poly (hydroxybutyrate), polyphosphate ester or mixtures thereof or mixtures thereof. In some embodiments, the biodegradable polymer comprises poly (lactic / glycolic acid), a lactic-glycolic acid copolymer having a molecular weight of from about 2,000 to about 500,000 daltons. The ratio of lactic acid to glycolic acid is from about 100: 0 to about 24: 75, with a ratio of lactic acid to glycol of 65: 35 is preferred. The poly (lactic / glycolic acid) can be obtained by the methods set forth in U.S. Patent No. 4,293,539, the disclosure of which is incorporated herein by reference in its entirety as a reference. In short, The copolymer is obtained by condensing lactic acid and glycolic acid in the presence of a readily removable polymerization catalyst (e.g., strong acidic ion exchange resin, such as Dowex HCP-VH2-H). the amount of catalyst is not critical for the polymerization, but is typically from about 0.01 to about 20 weight parts, based on the total volume of combinational lactic acid and glycolic acid. The polymerization reaction can be carried out without a solvent having a temperature of from about 100 ° C to about 250 ° C for from about 48 hours to about 96 hours, preferably under reduced pressure, to facilitate separation of the water and by-products. Then, poly (lactic / glycolic acid) is extracted by filtering the molten reaction mixture in an organic solvent, such as 55 dichloromethane or acetone, and subsequent filtration to separate the catalyst. Once the opioid antagonist is obtained, in a substantially non-releasable form, it is possible to combine a tacoid agonist with conventional conventional ingredients known in the art to achieve the oral dosage form of the present invention. In some embodiments, the oral dosage form is a capsule or tablet. When formulated in the form of a tablet, the opioid antagonist and agonist can be combined with sine or more inert, non-toxic pharmaceutical ingredients which are suitable for the manufacture of tablets. Such excipients include, for example, an inert diluent, such as lactose; granulating and disintegrating agents such as corn starch; a binding agent such as an anesthetic; and a lubricant such as magnesium stearate. The oral dosage form of the present invention may be administered in a medicament form to release the opioid agonist which is contained therein. In yet another embodiment of the invention, however, the oral dosage form provides prolonged release of the opioid agonist. In some embodiments, the oral dosage form co-dosing providing prolonged release of the opioid agonist can be obtained by mixing an opioid antagonist in a form that does not substantially release the sagostante and acceptable pharmaceutical excipients to provide a tablet, a coating was coated onto the tablet, which coating was extended. In some embodiments of the invention, extended release opioid agonist tablets may be prepared by mixing the formulation which is substantially free of the opioid antagonist with the opioid antagonist vamatrix which provides the extended release tablet. A detailed description of the preparation of the oral extended release single dose oral dosage form according to the present invention is set forth below. PREPARATION OF SINGLE DOSAGE FORMS CONTROLLED DEPARTURE CONTAINING THE OPIOID AGONIST AND FORM OF OPIOID ANTAGONISTE WHICH DOES NOT BE DISTRIBUTED A combination of an opioid agonist and an opioid antagonist in a substantially non-releasable form can be formulated as an oral dosage form, co-dosing with controlled or prolonged release in any suitable tablet, coated tablet or multiparticulate, known specialists in the field. The sustained-release oral dosage form may optionally include a sustained release carrier which is incorporated in matrix together with the opioid agonist and an inaccessible form of the opioid antagonist or may be administered as a sustained release coating. In some embodiments, wherein the opioidant includes hydrocodone, the oral extended release co-dosage formulation may contain a dose of doses ranging from about 8 mg to about 50 mg of single dose hydrocodone. In the oral dosage forms, a prolonged release coadministration in which hydromorphone is the therapeutically active opioid agonist, it is combined in an amount of approximately 2 mg of approximately 64 mg hydromorphone hydrochloride. In a further embodiment, the opioid agonist comprises a morphine, and the oral dosage form of sustained release of the present invention comprises from about 2.5 mg to about 800 mg morphine and oral sustained release sustained release formulations of the present invention comprise from about 2.5 mg to about 800 mg morphine-specific. In another embodiment of the invention, the opioid agonist comprises oxycodone and a once-divided, prolonged release oral dosage form comprising from about 2.5 mg to about 800 mg of doxycodone. In some preferred embodiments, the oral extended release oral dosage form comprises from about 20 mg to about 30 mg of oxycodone. Controlled oxycodone releases are known from the state of the art. The following documents describe various controlled release oxycodone formulations for use in the invention described herein, and methods for their preparation: U.S. Patent No. 5,266,331; 5,549,912; 58 5,508,042; and 5,656,293. The opioid agonist may include madol, and the single-dose sustained release sustained release formulations comprise from approximately 25 mg of approximately 800 mg tramadol per dosage unit. The single dose dosage form may comprise a more ophthalmide opioid agonist to deliver a substantially equivalent therapeutical effect. Alternatively, the single-dosage form may contain molar equivalent amounts of other opioid agonist salts useful in the present invention. In a preferred embodiment of the present invention, the oral extended release oral dosage form comprises those particles comprising an opioid agonist wherein the particles have a diameter of about 0.1 mm to about 2.5 mm, preferably from about 0.5 mm to about 2 mm. The opioid agonist particles are preferably coated with a product which allows release of the opioidogonist at a slow rate in an aqueous medium. This film coating is chosen so as to achieve, in combination with other established properties, desired in vitro release rate. The extended release single dose formulations of the present invention should be capable of producing a strong, continuous film which is smooth and elegant, capable of supporting pigments and other coating additives, non-toxic, inert and non-stick. Dosage forms include an opioid antagonist and an opioid antagonist in substantially 59 non-secreted form may optionally be coated with one or more of the materials suitable for regulating the opioid agonist release or for preserving the dosage form. In one embodiment, the coatings are provided so as to allow both pH-dependent and irn-independent separation, for example, when exposed to the gastrointestinal fluid. The pH-dependent coating serves to separate the opioid into desired areas of the gastrointestinal (C1) tract, for example the stomach or intestine, so as to provide an absorption profile capable of providing at least approximately eight hours or, preferably, approximately twelve hours, to approximately twenty-four hours, an analgesic effect on the patient. When a pH-independent coating is desired, the coating is designed to achieve optimal release of the opioid, regardless of the pH change in the surrounding fluid, e.g., the gastrointestinal tract. It is also possible to receive a dosage form of compositions which release a portion of the dose at a specific site of the gastrointestinal tract, for example the stomach, and release the remainder of the dose from the gastrointestinal tract, for example, the thinner. Pharmaceutical formulations according to the invention which use pH-dependent coatings to produce drug formulations also give a repetitive action in which the uncoated drug formulation is coated over the inner coating and separates in the stomach while the remainder that is protected by the 60 inner coating is separates down the gastrointestinal tract. Coatings, which are pH-dependent, can be used according to the present invention include shellac, cellulose acetate phthalate (SAP), polyvinyl acetate phthalate (PVP), hydroxypropylmethylcellulose phthalate, and copolymers of the ester-methacrylic acid ester, zein and the like. In some preferred embodiments, the substrate (e.g., tablet core beads, matrix particles) containing the opioid analgesic agent (with or without a COX-2 inhibitor) is coated with a dehydrophobic material selected from (i) alkylcellulose; (ii) an acrylic polymer; or (iii) a mixture thereof. The coating may be in the form of an organic or aqueous solution or dispersion. The coating may be applied so as to achieve a weight gain of approximately 2 to 25% of the substrate in order to obtain the desired prolonged release profile. Coatings, which are derived from aqueous dispersions described in detail, for example, in U.S. Patent Nos. 5,273,760 and 5,286,493, filed to the Applicant of the present invention and are incorporated herein by reference in their entirety. Other examples of drug formulations and sustained release coatings which may be used according to the present invention include patents No. 5,324,351; 5,356,467, and 5,472,712, incorporated herein by reference, as a reference. 61 Alkyl Cellulose Polymer Cellulosic materials and polymers, including alkyl cellulose, provide hydrophobic materials which suitably apply to the coating of the beads according to the invention. By way of example, a preferred alkylcellulosic polymer is ethylcellulose, although the person skilled in the art would appreciate, that other cellulosic and / or alkylcellulose polymers can be easily used, alone or in many combinations, as a whole or part of a hydrophobic coating according to the invention. An aqueous dispersion, commercially available from ethyl cellulose, is Acacia® (EMC Co., Inc., Inc., Rep. & Lt; RTI ID = 0.0 & gt; 7 & apos; Acacia is produced by dissolving ethylcellulose in a water-miscible organic solvent, then emulsified in water, optionally with surfactants and stabilizers. After homogenization to form submicrons, the organic solvent is evaporated under vacuum to give forms pseudolatex. The plasticizer is not included in the injection phase during the manufacturing phase. Thus, before using the same as the coating, it is necessary to intimately mix Aciasso! ® with a suitable plasticizer prior to use. Another aqueous dispersion of ethylcellulose is disclosed as Ziegelase® (Coomasson, Inc., Wisconsin, Rep., Inc., and 3.A.). This product is obtained by incorporating a plasticizer in the dispersion during the manufacturing process. A hot melt of polymer, 62 plasticizer (dibutyl sebacate) and stabilizer (oleic acid) is obtained as a homogeneous mixture which is then diluted with an alkaline solution to give a water dispersion that can be applied directly to the substrates. Acrylic Polymers In another preferred embodiment of the present invention, the hydrophobic material comprising the controlled release coating is a pharmaceutically acceptable acrylic polymer including, but not limited to, acrylic acid copolymers of methacrylic acid, copolymers of methyl methacrylate, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly (acrylic acid), poly (methacrylic acid), methacrylic acid alkylamide copolymer, poly (methyl methacrylate), polymethacrylate, copolymer of napoly (methyl methacrylate), polyacrylamide, , poly (methacrylic acid anhydride), and glycidyl methacrylate copolymers. In some preferred embodiments, the acrylic polymer consists of one or more copolymers of ammonium methacrylate. The ammonio methacrylate copolymers are well known in the state of the art and are described in NP XII as fully polymerized copolymers of acrylic acid-ascorbic acid esters with low quaternary ammonium groups. In order to achieve the desired degradation profile, it may be necessary to include two or more ammonio methacrylate copolymers having different physiological properties as well as a different molar ratio of the quaternary ammonium groups to the unsaturated (meth) acrylate esters. Some polymers of the methacrylic acid ester type are useful for preparing pH-dependent coatings which can be used according to the present invention. For example, there is a family of copolymers synthesized from diethylaminoethyl methacrylate and other non-nitrile methacrylic esters, also known as methacrylic acid copolymer or polymeric methacrylates, commercially available such as Eibagan® from Rock Tech. 1ps. There are several different Eibadan®. For example, Eibagan® E is one example of a substituted acrylic acid copolymer, which swells and dissolves an acidified environment. Is a methacrylic acid copolymer which does not melt at approximately pH & lt; 5.7 and is soluble at about pH 6. The pH of the reaction is not melted at approximately pH & lt; 6.5 and dissolves at ca. Eggagrid® K and Eibagid® K3 swell in water, the amount of water absorbed by these polymers is pH-dependent, however, the single dose dosage forms with Eidag® P1 and K5 are pH-independent. In certain preferred embodiments, the acrylic coating comprises a mixture of two acrylic emulsifiers commercially marketed by Roll Plastas 64 under the trade names of Aldrich® PL30D and Aldrich® GCl3C10, respectively. Eryldithromycans and Esidar® K83C10 are copolymers of acrylic and methacrylic esters with low content of quaternary ammonium groups, the molar ratio of the ammonium groups to the remaining neutral (meth) acrylic esters is 1:20 at Eudragit® Pb300 and from 1: 40 in the Aldrich® P330O. The average molecular weight is approximately 150,000. The code name P1 (high permeability) and P3 (transmittance) refers to the degree of permeability of these agents. The Eibag® Rb / P3 mixtures are insoluble in water and in ingestible liquids. However, coatings formed by it may be swallowed and are soluble in aqueous solutions and digestive fluids. The Aigadic® P1 / P3 dispersion of the present invention may be mixed together in any desired relationship in order to impart a sustained release dosage form having the desired dilution profile. The desired dosage forms, in combination with a prolonged release, can be obtained, for example, of a delayed coating derived from 100% of Eudragit®, 4L, 50% of Eudragit® PI- and 50% of Eggard® P3, and 10% of Eggard® P1: Eggard®® 90% P3. Of course, one skilled in the art would recognize that other acrylic polymers may also be used, such as, for example, Eudragit®. 65 Plasticizers In the embodiments of the present invention, wherein the coating comprises an aqueous dispersion of extrudable matrix, incorporating an effective amount of a plasticizer into the aqueous suspension of the boron material will further improve the physical properties of the extended release coating. For example, since ethylcellulose has a relatively high glass transition temperature and does not form soft-film under normal coating conditions, it is preferable to incorporate a plasticizer, the cellulosic coating, containing release coating prior to use as a coating material. Typically, the amount of plasticizer incorporated in the backing solution is based on the film-forming concentration, for example very often from about 1 to about 50 weight percent of the film-former. The concentration of the plasticizer, this can accurately determine, after carefully experimenting, a certain solution and method of administration. Examples of suitable plasticizers for ethylcellulose include water-insoluble plasticizers, such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin, although other plasticizers (such as acetylated monoglycerides, phthalatonsters, beaver oil, etc.) may be used. Triethyl citrate is a particularly preferred plasticizer for aqueous dispersions of ethylcellulose of the present invention. Examples of suitable plasticizers for acrylic polymers of the present invention include, but are not limited to, citric acid esters such as NE XVI, tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene glycol. Other plasticizers that have proven to be suitable for enhancing the elasticity of filmsacrylic foams are formed, such as Eggardi® H1 / P3 glazing solutions include polyethylene glycols, propylene glycol, diethyl phthalate, beer oil, and triacetin. Triethyl citrate is a preferred plasticizer for the aqueous dispersions of the cellulose of the present invention. It has later been discovered that the addition of a talc of a small amount reduces the tendency of the aqueous dispersions to adhere during the process, and acts as a polishing agent. METHODS FOR OBTAINING COVERED PEARLS When a hydrophobic material is used for controlled coating of inert-pharmaceutical beads, 18/20 beads which are already coated with an opioid agonist, the majority of the controlled release pearled solid beads can then be placed in a gelatin capsule sapoid antagonist in a form that is substantially non-separable. The single dosage form provides a controlled release dose of controlled opioid agonist when ingested and brought into contact with surrounding liquids such as a gastrointestinal fluid or degradation medium. The drug formulations of controlled release beads of the present invention slowly release the opioid agonist, for example, when digested and exposed to gastrointestinal fluids. The controlled release profile of the dosage form of the invention may be altered by, for example, changing the amount of cover with hydrophobic material, modifying the manner in which the plasticizer is added to the hydrophobic material by varying the amount of plasticizer relative to the hydrophobic material by incorporating additional ingredients or by other parties, by changing production methods, and other. The dilution profile of the final product can also be modified, for example, by increasing or decreasing the thickness of the retardant coating. Spheroids or beads coated with an opioid agonist can be prepared by, for example, reconstituting the drug into water and then spraying the solution onto a substrate, for example, using 18/20 beads, using a wax insert. If desired, additional ingredients are also included before coating the beads in order to promote binding of the opioid agonist to the beads, and / or to color the solution, and the like. For example, a product which includes hydroxypropyl methyl cellulose, etc., with or without a coloring agent (e.g., Opradon®, marketed by Co. Ltd., Inc.) can be added to the solution and the solution mixed (e.g., for approximately 1 hour) before applying the same on the beads. The resulting substrate 68 coated, in this example, the beads, can then be optionally coated with a separating agent to separate the therapeutically active agent from the hydrophobic coating by controlled release. An example of a suitable resolution agent is one which contains hydroxypropylmethyl cellulose. However, any known film-forming agent may be used. It is preferred that the differentiation does not affect the rate of dilution of the final product. Pearls may then be coated with a hydrophobic material substrate dispersion. The water dispersibility of the hydrophobic material preferably also includes an effective amount of a plasticizer, for example, triethyl citrate. Pre-formulated aqueous dispersions of ethylcellulose, such as Acacia® or Siegelase®, may also be used. If Sepharose® is used, it is not necessary to add a separate plasticizer. Alternatively, preformed formulations of an aqueous dispersion of acrylic polymers such as Eidagrid® may be used. The roofing solutions of the present invention preferably contain, in addition to the film-forming, plasticizer and solvent system (i.e., water), a colorant to provide product elegance and degradability. The colorant may be added to the solvent of the therapeutically active agent instead of or in addition to an aqueous dispersion of the hydrophobic material. For example, a dye can be added to Acioia! By using an alcohol or propylene glycol dispersion of the colorant, milled aluminum lacquers and matting agents such as titanium dioxide by the addition of a colorant to a water-soluble polymer solution and subsequent use of an ebony displacement of the Accioal® plasticizer. Alternatively, any suitable method may be employed to provide a colorant to the dosage forms of the present invention. Suitable ingredients for providing color to the pharmaceutical form when the aqueous dispersion of acrylic copolymer is used, including titanium dioxide and pigments, such as pigments of iron oxide. The incorporation of pigments may, however, increase the coating's coating effect. The plasticizing hydrophobic material may be applied to the substrate, including the therapeutically active compound, by spraying, in use, and is a suitable spray device known in the state of the art. In one preferred method, the fluidized bed bead system is used in which an airflow injected from below upstream fluidises the core material and activates the drying while dispersing the polymeric coating overhead. A sufficient amount of the hydrophobic material for the preparation of a predetermined controlled release of said therapeutically active agent when the coated substrate is exposed to aqueous solutions, e.g. gastrointestinal fluids, is preferably administered, given the physical characteristics of the therapeutically active agent, the route of incorporation the plasticizer, and the like. After application of the hydrophobic material coating, if desired, a further coating of a film-former, such as Opradon®, is applied to the girders. This envelope is provided, if at all, in order to significantly reduce the agglomeration of the beads. The separation of the therapeutically active agent controlled release formulation of the present invention may be further influenced, i.e., brought to the desired rate, by adding one or more release modifying agents, or by providing one or more modes of passage cover. The ratio of the hydrophobic material to the water-soluble material is determined by, among other factors, the rate of release required and the solubility characteristics of the selected materials. The release modifying agents acting as pore-forming agents may be organic or non-organic, which can be solubilized, extracted or recovered from the coating in the environment used. Pore-forming agents may include one or more hydrophilic materials such as hydroxypropylmethyl cellulose. The extended release coating of the present invention may also include aiding agents, such as starch and resins. The extended release coatings of the present invention may also include materials which are useful for producing a microporous laminate used in the surrounding environment, such as polycarbonates consisting of linear polyesters of carbonic acid in which carbonate groups reappear in the polymer chain. The release modifying agents also include a semi-permeable polymer. In certain preferred embodiments, the release modifying agents are selected from the group consisting of & lt; RTI ID = 0.0 & gt; consisting of hydroxypropylmethylcellulose, lactose, metallic stearates, and mixtures of any of the foregoing. The extended release coatings of the present invention may also include a one-way passageway comprising at least one aperture or the like. The aperture may be formed by such methods as those described in U.S. Patent Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864, all of which are incorporated herein by reference. The hole may be of any shape, such as round, triangular, square, elliptical, irregular, etc. MATRIX MEDICINAL FORMS In other embodiments of the present invention, the sustained release dosage form is a matrix having a prolonged release coating as indicated above. The present invention also includes, sustained release tablets containing an opioid agonist and opioid antagonist particles that make the antagonist substantially not cleared, wherein the agonist and antagonist are dispersed in a controlled release matrix that provides a rate of in vivo dilution of the opioid agonist at preferred ranges, and which elicits the opioid agonist in a pH-dependent or pH-independent manner. Materials suitable for inclusion in a controlled release matrix depend on the offset used to form the matrix. For example, a matrix, in addition to the opioid agonist, a substantially opioid opioid antagonist can include: hydrophilic and / or hydrophobic materials such as resins, cellulose ethers, acrylic resins, materials derived from proteins, the list not being claims to be exequatur, any pharmaceutically acceptable hydrophobic material hydrophilic material which is capable of conferring controlled release of the opioid may be used in the present invention. C8-C50, especially C12-C40, hydrocarbons saturated or unsaturated, such as fatty acids, fatty alcohols, fatty acid glyceryl esters, mineral and vegetable oils and waxes, and isaryl alcohol; and polyalkylene glycols. Of these polymers, the acrylic polymers are especially preferred, in particular Eibag® P5PO-cellulose ethers, in particular hydroxyalkylcellulose and carboxyalkylenecellulose. The oral dosage form may contain between 1% and 80% (by weight) of at least one hydrophilic or hydrophobic material. When the hydrophobic material is a hydrocarbon, the hydrocarbon preferably has a melting point of between 25 ° C and 90 ° C. Among the hydrocarbon materials a long chain is preferred fatty (aliphatic) alcohols. The oral dosage form may contain up to 60% (by weight) of the at least one digestible, hydrocarbon long chain. Preferably, the oral dosage form contains up to 60% (by weight) of at least an indole alkylene glycol. The hydrophobic material is preferably selected from the group consisting of alkyl cellulose, polymers and copolymers of acrylic and methacrylic acids, shellac, zein, hydrogenated beer oil, hydrogenated vegetable oil, or mixtures thereof. In some preferred embodiments for carrying out the present invention, the hydrophobic product is a pharmaceutically acceptable acrylic polymer, but are not limited to polymers and copolymers of acrylic and methacrylic acids, methyl methacrylate, copolymers of methyl methacrylate, ethoxyl methacrylates, cyanoethyl methacrylate, aaminoalkyl methacrylate copolymer, poly (acrylic acid), poly (methacrylic acid), alkyl methacrylic acid copolymer, ), poly (methacrylic acid) anhydride, polymethacrylate, polyacrylamide, poly (methacrylic acid anhydride) and glycidyl methacrylate copolymers. In other embodiments, the hydrophobic material is selected from amongst 74 materials such as hydroxyalkyl cellulose, such as hydroxypropylmethyl cellulose and mixtures of the foregoing. Preferred hydrophobic materials which are unsaturated, with less or more marked hydrophilic and / or hydrophobic features. Preferably, the hydrophobic materials useful in the invention, has a melting point of from about 30 ° C to about 200 ° C, preferably from about 45 ° C to about 90 ° C. In particular, the hydrophobic materials can include natural or synthesized waxes, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or, preferably, cetostearyl alcohol), fatty acids including but not limited to fatty acid esters, fatty acid glycerides (mono-, di-, yttriumglycerides, hydrogenated oils, hydrocarbons, normal waxes, stearic acid, stearyl alcohol hydrophobic and hydrophilic materials having a carbon backbone, etc. Suitable waxes include, for example, bee For the purposes of the present invention, a wax-like substance is defined as any material, such as a wax- which is usually a solid at room temperature and has a melting point of from about 30 ° C to about 100 ° C. Suitable hydrophobic materials to be used in accordance with the present invention include digestible, long chain (C8-C50, especially C12-C40), substituted or unsubstituted hydrocarbons such as fatty acids, fatty alcohols, fatty acid glyceryl esters, mineral and vegetable oils, and natural isynthetic waxes. Hydrocarbons having a melting point between 25 ° C and 90 ° C are preferred. Long chain dewatering materials are preferred in some embodiments of fatty (aliphatic) alcohols. The oral dosage form may contain up to 60 ° C (by weight) of at least one long chain digestible hydrocarbon. Preferably, a combination of two or more hydrophobic materials are included in the matrix formulations. If one additional hydrophobic material is included, it is preferably selected from natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof. Examples include beeswax, carnauba, stearic acid and stearyl alcohol. The list is not supposed to be exclusive. A particular suitable matrix comprises at least one water-soluble hydroxyalkyl cellulose, at least one C14-C22 aliphatic alcohol and, if desired, at least one polyalkylene glycol. This at least one hydroxyalkylcellulose is preferably hydroxy (C1 to C6) alkylcellulose, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and, in particular, hydroxyethylcellulose. The amount of the at least one hydroxyalkyl cellulose present in the oral dosage form is determined by, inter alia, the precise rate of opioid release. At least one aliphatic alcohol may be, for example, lauryl alcohol, 76 myristyl alcohol or stearyl alcohol. In the most preferred embodiments of the present oral dosage form, however, the aliphatic aliphatic aliphatic compound is cetyl alcohol or acetyl stearyl alcohol. The amount of at least one non-aliphatic alcohol in the present oral dosage form is determined as above, by the precise rate of release of the required opioid. It will also be appreciated that a polyalkylene glycol is present in or absent the topical dosage form. In the absence of a polyalkylene glycol, the oral dosage form preferably comprises between 20% and 50% (by weight) of said at least one aliphatic alcohol. When at least one polyalkylene glycol is present in the single dose oral formulation, then the combined weight of the aliphatic alcohol and the at least one polyalkylene glycol preferably comprise between 20% and 50% by weight of the total dosage unit form. In one embodiment, the ratio of, for example, the at least one hydroxyalkyl cellulose or acrylic resin to the at least one aliphatic alcohol / polyalkylene glycol determines to a considerable extent the rate of opioid release from the dosage form. With respect to the at least one hydroxyalkyl cellulose, one aliphatic alcohol / polyalkylene glycol of between 1: 2 and 1: 4 is preferred, with a ratio of 1: 3 and 1/4 being particularly preferred. At least one polyalkylene glycol may be, for example, propylene glycol or, which is preferred, polyethylene glycol. The average molecular weight of the at least one polyalkylene glycol is preferably between 1,000 and 15,000, in particular between 1,500 and 12,000. Another suitable matrix for controlled release includes alkylcellulose (especially ethyl cellulose), C12-C36 aliphatic alcohol and, if desired, polyalkylene glycol. In another preferred embodiment, the matrix comprises a pharmaceutically acceptable combination of two hydrophobic materials. In addition to the above constituents, the controlled release matrix may include appropriate quantities of other materials, for example, diluents, lubricants, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art. METHODS FOR OBTAINING THE MATRIX BASES In order to facilitate the preparation of a solid, a controlled-release oral dosage form according to the present invention, any method known to those skilled in the art can be used to obtain a dosage form with the matrix. For example, incorporation into the matrix may be accomplished, for example, by (a) forming granules comprising at least one soluble hydroxyalkyl cellulose or opioid salt; (B) mixing a hydroxyalkyl cellulose containing granules with at least one C12-C35 aliphatic alcohol; and (c) if desired, compressing and shaping the granules. Preferably, the granules are formed by wet-wetting the hydroxyalkyl cellulose / opioid with water. In a particularly preferred embodiment of the tomato, the amount of water, which is added during the wet granulation step is preferably between 1.5 and 5 times, particularly between 1.75 and 3.5 times the dry weight of the opioid. In another embodiment, spheres forming agent together with the active ingredient may be spherical in order to form spheroids. Microcrystalline cellulose is preferred. Suitable microcrystalline cellulose is, for example, the material marketed as Avicel PH 101 (Tagebe Magic, RMC Corporation). In this embodiment, in addition to the active ingredient and the spheroidal formulating agent, the spheroids can also contain a binder. Suitable binders, such as low viscosity, water-soluble polymers, are well known to those skilled in the pharmaceutical arts. However, a water-soluble hydroxylated alkyl cellulose, such as hydroxypropylcellulose, is preferred. Additionally (or alternatively) the spheroids can include a water-insoluble polymer, in particular an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer or ethyl cellulose. In addition, the extended release coating generally includes a hydrophobic material such as (a) wax), either alone or in admixture with a fatty alcohol; or (b) shellac or zein. Expanded Matrix Extrusion Extended release matrices can also be prepared by melt granulation or melt extrusion techniques as long as the techniques used do not impair the integrity of the form of the opioid antagonist which is substantially not removed during the preparation of the matrix to the extent that a sufficient amount of the opioid antagonist becomes available, to separate into the gastrointestinal system upon oral administration. Alternatively, the melt extrusion step can be carried out with the opioid agonist to produce prolonged release agonist particles which can then be combined with the opioid antagonist form that is not substantially removed. Typically melt reeling techniques include melting a normally solid material, for example wax, and incorporating a drug into a powdered state. In order to obtain a sustained release single dose form, it may be necessary to incorporate an additional hydrophobic substance, e.g., ethyl cellulose or water-insoluble acrylic polymer, the infused waxy hydrophobic material. Examples of sustained release formulations obtained by melt techniques are disclosed in U.S. Pat. No. 4,861, 598 discloses the applicant of the present invention and is therefore included in its present scope. The additional hydrophobic material may comprise one or more water-insoluble wax-like 80 thermoplastic materials, possibly mixed with one or more wax-like thermoplastic materials, which are less hydrophobic than the one or more water-insoluble wax-like thermoplastic materials. In order to achieve a sustained release, the individual-like thermoplastic materials in the dosage form must be substantially non-degradable and insoluble in gastrointestinal fluids during the initial release phases. Polyvalent wax-like thermoplastic materials may be those with a water solubility that is greater than about 1: 5,000 (w / w). In addition to the above constituents, the sustained release matrix may also contain suitable quantities of other materials, for example, diluents, lubricants, binders, granulating agents, coloring agents, flavoring agents and glidants which are conventional in the art. The amounts of these additional materials should be sufficient to give the desired effect of the desired dosage form. In addition to the above ingredients, a matrix comprising a meltblown multiple particle may also contain suitable quantities of other materials, for example, diluents, lubricants, binders, granulating aids, coloring agents, flavoring agents, and glidants, which are conventional in the pharmaceutical state of the art up to 50% by weight of the particles as desired. Specific examples of pharmaceutically acceptable carriers and excipients which can be used to bring the oral dosage forms into the dosage form are described in U.S. Pat. Exophilis, Atespap Pandemicus Azolabia (1986), incorporated herein by reference. Multiple Particle Melt Extrusion The preparation of a melt-extruded substrate extruded according to the present invention may, for example, comprise the steps of mixing the opioid tampering agent together with at least one hydrophobic material and, preferably, a hydrophobic material to form a homogeneous mixture. After this homogeneous mixture is heated to a temperature, sufficient homogeneous mixture is then extruded to form a homogeneous mixture. Preferably, the extrudate is cooled and cut into a plurality of particles by any known method of the state of the art. The threads are cooled and cut into multiple pieces. Multiple particles are then mixed with opioid antagonist particles with coating, which makes the antagonist substantially not separated and divided into single doses. The extrudate is typically a dialysis of approximately 0.1 to approximately 5 mm and provides prolonged release of the opioid agonist for a period of time of from about 8 to about 24 hours. An optimal method for preparing an extrusion melt of the present invention includes directly loading into an extruder a hydrophobic material, a therapeutically active agent, and an optimal binder; heating the homogeneous mixture; extruding the homogeneous mixture to form filaments; cooling the nozzles containing the homogeneous mixture; cutting the fiber particles with a size of approximately 0.1 mm, approximately 12 mm; and combining particles with a particulate opioid antagonist with coating and separating them into a single dose. In this aspect of the invention, a relatively continuous production process is realized. The diameter of the extruder or exit aperture can also be adjusted to vary the thickness of the extruded filaments. In addition, the outlet portion of the extruder does not need to be round; it may be round, lawful, etc. The outgoing threads can be reduced by using a cut with hot wire, guillotine, and the like. The melt extrusion system of a plurality of ** particles may be, for example, in the form of granules, spheroids or pellets, depending on the extruder outlet. For the purposes of the present invention, the terms & quot; melt extruded multiparticulates & (i) multiparticulate melt extrusion and melt extrusion particles should refer to a plurality of units, preferably within a range of similar size and / or shape, and containing one or more active agents and one or more excipients including In this regard, the melt extruded 83 multiplicity of particles are in the range of approximately 0.1 to approximately 5 mm. It is further understood, the melt-extruded multi-particle may be rocked and geometric in the range of this dimension. Alternatively, the extrudate can simply cut the desired length and divide in unit doses co-dosing of the therapeutically active agent unnecessary from the spheroid stage. In a preferred embodiment, single dose oral forms are prepared such that they comprise an effective amount of the extruded multiparticulates in capsules. For example, a plurality of melt extruded particles can be placed in a gelatin capsule in an amount sufficient to provide an effective dose with extended release when absorbed into contact with gastric fluid. In another preferred embodiment, suitably quantitatively from the multiparticulate extrudate is combined with opioid antagonist particles coated and pressed into an oral tablet using conventional tabletting equipment using standard techniques. Techniques and compositions for preparing tablets (compressed and cast), capsules (hard and soft gelatin), and pills are also described in U.S. Pat. No. 5,153,153 (1980), incorporated herein by reference . In another embodiment, the coated opioid antagonist particles are added during the extrusion process and the extrudate can be given a 84 tablet formulation as disclosed in U.S. Patent No. 4,957,681 (U.S. Patent No. 4,957,681) in more detail above and incorporated herein by reference. Upon request, melt-extruded, elongated release tablets or tablets may be coated or gelatin capsules may be coated with a sustained release coating as the extended release coatings described above. Such coatings preferably comprise a sufficient amount of hydrophobic material to provide a level of growth of approximately 2 to approximately 30 percent, although the backing layer may strongly depend on the physical properties of the particular opioid analgesic agent employed and the desired rate of release, among others. The melt-extruded single-dosage forms of the present invention may also comprise melt-extruded multiparticulates containing one or more therapeutically active agents described above before and after washing them. Furthermore, dosage forms may also include a certain amount of opioid antagonist released release for rapid therapeutic effect. The immediate release opioidantonist can be incorporated, for example, by separating pellets in a gelatin capsule, or coated onto the surface of a plurality of particles after receiving the co-dosing forms (e.g., a controlled release or matrix based coating). The co-dosing formulations of the present invention may also comprise a combination of controlled release beads and a plurality of particle matrix to achieve the desired effect. The sustained release formulations of the present invention preferably provide a slow release of the agonist, for example, when digested or exposed to gastric juices, and then to the guts. The prolonged release profile of the melt-extruded formulations of the invention can be resolved by, for example, changing the amount of disintegrating agent, i.e. hydrophobic material, by varying the amount of plasticizer relative to the hydrophilic material by introducing additional constituents or excipients , through a change in the production method, and others. In another embodiment of the invention, melt-extruded material is obtained without contacting the opioid agonist and / or coated opioidantonist particles which are added after extrusion. Such formulations typically have drug compositions which are blended together with the extruded matrix material, after which the mixture is tabletted in order to ensure a slow release of the opioid agonist. Such pharmaceutical forms may be advantageous, for example, when the therapeutically active ingredient included in the formulation is sensitive to the temperatures required to soften the hydrophobic material and / or the release material. 86 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples illustrate various aspects of the present invention. They should not be construed as limiting patent claims in any way. EXAMPLE 1 In Example 1, a dosage form which is substantially free of an opioid antagonist (naltrexone HCl) is obtained by coating a particle of alaltrexone, the coating causing the antagonist not to separate substantially. FORMULA: Ingredients At1 / Units Apply Naltrexone HCl 5.0 Sugar Spheres (30/35 Mesh) 50.0 Orang White Y-5-7068 2.5 Purified Water 42, 5 * Coating Orangut white Y-5-7068 3.02 Purified water 17.11 * Non-separating coating (to avoid removal of the substantially opioid agonist) Example 12 Sodium triethyl citrate 2.42 87 Talc 4 , 82 Purified water 49,21 * Orangut white coating Y-5-7068 4,12 Purified water 23,35 * Total 84,0 * Remains in the product only as residual moisture. METHOD:

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1. Preparation of the solution 2. Application 3. Coating 4. Delaying coating Naltrexone HC! is dissolved in purified water. Orangut white is then added and mixing is continued to form a homogeneous dispersion. The above dispersion is applied to the saccharine spheres using a fluid bed coating device. Prepare a solution of a coating by dispersing Orrabug white in purified water. This dispersion is applied to the Naltrexone HCl sugar spheres using a fluidized bed coating device. Preparation of the non-stick coating solution by admixing with Eggardi K3 C1010, triethyl citrate, talc and purified water. This dispersion is applied to the coated coated bead spheres using a fluidized bed coating device 88. 5. Coating A second coating solution is prepared by coating dispersion of Oracil white in purified water. This dispersion is applied by using a fluidized bed coating device. 6. Treatment Spheres were treated at 45 ° C for approximately 48 hours. EXAMPLE 2 In Example 1, a non-substantially releasable opioid antagonist (naltrexone HCl) is formulated by coating Naltrexone HCl on granules. The granulate consists of naltrexone HCl dispersed in a matrix that makes the antagonist not separate substantially. FORMULA: Ingredients At / Unit Naltrexone HCl 5.0 Dicalcium Phosphate 53.0 Poly (D1-lactide-Co-glycolide) polymer (PUA) MV ~ 100,000 12.0 Ethyl acetate Total 70.0 * for administration of a PGAA polymer. 89 METHOD: 1. Preparation of PI. 6A is dissolved in ethyl acetate by solution mixing. 2. Granulation Naltrexone HCl and Dicalcium Phosphate are placed through a fluid bed coating device and seeded by spraying the above solution. EXAMPLE 3 In Example 3, a dosage form of an opioid antagonist (naltrexone HCl) which is substantially non-eliminated is obtained in the form of extruded pellets of naltrexone HCl. FORMULA: Ingredients At1 / Unit Naltrexone HCl 5.0 Amino HZPO 180.0 Stearyl Alcohol 55.0 Total 240.0 90 METHOD: Grinding Sterile alcohol flakes are passed through a mill. Mixing Naltrexone HCl, Escherichi, and milled stearyl alcohol are mixed in a dual jacketed mixer. Extrusion The blended material is continuously fed into a twin screw extruder and the resulting fibers of the conveyor are collected. Cooling The threads are allowed to cool on the conveyor. Pelletizing The cooled strands are cut into pellets by using a Reagent Screening. The pellets are screened and harvested through a sieve of an ordered size. EXAMPLE 4 Controlled release hydrocodone bitartrate tablets with naltrexone HCl beads Ingredients At1 / unit Hydrocodone bitartrate 30.0 Stearyl alcohol 44.0 Anhydrous dicalcium phosphate (powdered) 62.0 Microcrystalline cellulose 62.0 Glyceryl behenate 20.0 Naltrexone HCl beads 84 , 0 91 (Example 1) Magnesium stearate 2.0 Orbug red 10.0 Dicalcium phosphate 53.0 Purified water 56.7 * Total 314.0 * Remains in the product only as residual moisture.

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METHOD: 1. Grinding 2. Mixing 3. Extruding 4. Cooling 5. Grinding 6. Mixing 7. Pressing Sterile alcohol flakes are passed through an oxidation mill. Hydrocodone bitartrate, milled stearic alcohol, anhydrous Dicalcium phosphate, microcrystalline cellulose, and glyceryl behenate are mixed in a mixing apparatus with a double sheath. The mixed material is continuously drilled into a twin screw extruder and the resulting heated material of the conveyer is collected. the material is left to cool the conveyer. The cooled extrudate is milled using an oxylating mill. Mix milled extrudate, Naltrexone HCl peroxide (from example 1) and magnesium stearate. Treat the resulting granules using a tablet press. 92 8. Application A film coating solution is prepared by dispersing ORABUG in purified water and applied to the tablet core. EXAMPLE 5 Controlled release tablets of hydrocodonitartrate with granulated naltrexone HCl Ingredients Amt / unit Hydrocodone bitartrate 30.0 Stearyl alcohol 44.0 Anhydrous dicalcium phosphate (powdered) 62.0 Microcrystalline cellulose 62.0 Glyceryl behenate 20.0 Naltrexone HCl granulate (Example 2) 70.0 Magnesium stearate 2.0 Orbug red 10.0 Purified water 56.7 * Total 300.0 * Remains in the product as residual moisture. METHOD 1. Grinding 2. Mixing Sterile alcohol flakes are passed through an oxidation mill. Hydrocodone bitartrate, milled stearyl 93 3. Extrusion 4. Cooling 5. Grinding 6. Mixing 7. Compression 8. Coating of anhydrous alcohol Dicalcium phosphate, microcrystalline cellulose and Glyceryl behenate are mixed in a dual-shear mixer. The mixed material is continuously drilled into a twin screw extruder and the resulting heated material of the conveyer is collected. The extrudate is allowed to cool off the conveyer. The cooled extrudate was milled using an oxidizing mill. It was mixed with a milled extrudate, Naltrexone HCl granulate (from Example 2) and magnesium stearate. Compress the resulting granules by using a tablet press. A solution of a film coating is prepared by dispersing ORABUG in the purified water and applied to the core of the tablets. 94 A solution of a film coating is prepared by dispersing ORABUG in the purified water and applied to the core of the tablets. 94 A solution of a film coating is prepared by dispersing ORABUG in the purified water and applied to the core of the tablets. 94

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EXAMPLE 6 Controlled Release Tablets Oxycodone HCl Sinaltrexone HCl Pearls Ingredients Antigens per Unit Oxycodone HCl 20.0 Lactose Spray Dried 59.25 Povidone 5.0 Egggard P5 30D (Dry Weight) 10.0 Triacetin 2.00 Stearyl Alcohol 25, 00 Talc 2.50 Magnesium stearate 1.25 Naltrexone HCl beads (example 1) 84.00 Orbug pink 6.00 Purified water 34.00 * Total 215.00 * A product remains in oneas residual moisture. METHOD: 1. Preparation of the solution 2. Granulation Plasticize Azeptan with triacetin by mixing. Place Oxycodone HCl, dry dispersion of lactose and povidone fluid bed granulator and apply the solution. 95 3. Grinding 4. Drying 5. Coating 6. Cooling 7. Grinding 8. Mixing 9. Pressing 10. Covering The granulate is passed through a rotary impeller mill. The granulate squeezes if the moisture content is very high. Stearic alcohol and wax from the above granulate are melted by adding stearylic alcohol to the granule during mixing. The coated granulate is cooled in a fluidized bed dryer. The cooled, fermented granulate is passed through a rotary impeller mill. Mix ground fermented granulate, talc, magnesium stearate and Naltrexone HCl perl (Example 1). Compress the resulting granules by using a tablet press. A solution of a film coating is prepared by dispersing ORABUG in the purified water and applied to the core of the tablets. EXAMPLE 7 Controlled Release Tablets Oxycodone HCl Sinaltrexone HCl 89 Ingredients Amount of Oxycodone HCl 20.0 Lactose Spray Dried 59.25 Povidone 5.0 Eggad H3 30D (Dry Weight) 10.0 Triacetin 2.00 Stearyl Alcohol 25.00 Talc 2.50 Magnesium Stearate 1.25 Naltrexone HCl Granulate (Example 2) 70.00 Orbug Pink 6.00 Purified Water 34.00 * Total 201.00 * Remains in the product only as residual moisture. METHOD: 1. Preparation of the solution 2. Granulation Plasticizer is mixed with triacetin by mixing. Place Oxycodone HCl, spray-dried lactose and povidone fluid bed granulator and apply the solution. 97 3. Grinding 4. Drying 5. Refining 6. Cooling 7. Grinding 8. Mixing 9. Compression 10. Covering The granulate is passed through a rotary impeller mill. The granulate squeezes if the moisture content is very high. Stearyl alcohol and wax from the above granulate are melted by adding stearylic alcohol to the granulate at the time of mixing. The granulated ointment is cooled in a fluid bed dryer. The chilled granulate is passed through a rotary impeller mill. Mix ground fermented granulate, talc, magnesium stearate and Naltrexone HC1 granulate (from example 2). Compress the resulting granules by using a tablet press. A solution of a film coating is prepared by dispersing ORABUG in the purified water and applied to the core of the tablets. Example 8 Hydrochloroprene HCl Controlled Hematopoietic Sodium Salt Shotratron HCl Extruded Pellets Ingredient Amount Hydromorphone HCl 12.0 Lactose Spray Dried 59.25 Aldrich Ac K3 SUC (Dry Weight) 76.5 Ethyl Cellulose 4.5 Stearyl Alcohol 27.0 Naltrexone HC1 pellets (Example 3) 240.0 Solid gelatin capsules V Total 360.00 * Remains in the product only as residual moisture. METHOD: Grinding stearic alcohol flakes are passed through a hammer mill. Mixing Hydromorphone HCl, Eggardi, ethylcellulose and ground stearyl alcohol are mixed in a double sheath mixer. Extrusion The blended material is continuously fed into a twin screw extruder and the resulting fibers of the conveyor are collected. Cooling The threads are allowed to cool on the conveyor. 99 5. Pelleting 6. Screening 7. Encapsulation The cooled strands are cut into pellets using a Pelletizator. The pellets are screened and collected through a sieve of a regular size. The extruded pellets hydromorphone HCl are filled at 120 mg and Naltrexone HCl pellets (Example 3) at 240 mg in solid gelatin capsules. Example 9 Hydrocodonitrate Controlled Tablets with Naltrexone HCl Pearles Ingredients Acts / Unit Hydrocodone Bitartrate 30.0 Stearyl Alcohol 44.0 Anhydrous Dicalcium Phosphate (Powder) 62.0 Microcrystalline Cellulose 62.0 Glyceryl Behexate 20.0 Naltrexone HC1 pearls (Example 1) 84.0 Magnesium stearate 2.0 Orbug red 10.0 Purified water 56.7 * Total 314 * Remains in the product as residual moisture. 100 METHOD: 1. Grinding 2. Mixing 3. Extrusion 4. Cooling 5. Grinding 6. Mixing 7. Compression 8. Coating Stearyl alcohol flakes are omitted from a mill. Hydrocodone bitartrate, ground stearic alcohol, anhydrous dicalcium phosphate, microcrystalline cellulose, and glyceryl behenate are mixed in a mixing apparatus with a double sheath. Mixed material is continuously sampled into a double screw extruder and the resulting heated material of the conveyer is collected. The extrudate is allowed to cool off the conveyer. Cool the extrudate using an oxylating mill. Mix milled extrudate, Naltrexone HCl beads (from Example 1) and magnesium stearate. Compress the resulting granules by using a tablet press. Prepare a film coating solution by dispersing ORABUG in the purified water and apply to the core of the tablets. 101 Example 10 Controlled release of hydrocodontetarate with naltrexone HC1 granulate Ingredients At / Unit Hydrocodone bitartrate 30.0 Stearyl alcohol 44.0 Anhydrous dicalcium phosphate (powdered) 62.0 Microcrystalline cellulose 62.0 Glyceryl behenate 20.0 Naltrexone HC1 / granulate (Example 2) 70.0 Magnesium stearate 2.0 Orbug red 10.0 Purified water 56.7 * Total 300.5 * Remains in the product only as residual moisture. METHOD: 1. Grinding 2. Mixing 3. Extrusion Stearyl alcohol flakes are passed through a mill. Hydrocodone bitartrate, ground stearic alcohol, anhydrous dicalcium phosphate, microcrystalline cellulose, and glyceryl behenate are mixed in a mixing apparatus with a double sheath. Mixed material continuously 102 4. Cooling 5. Grinding 6. Mixing 7. Compression 8. Coating is fed into a double screw extruder and the resulting heated material of the conveyor is collected. The extrudate is allowed to cool on the conveyor. Cool the extrudate using the oxidation mill. Mix milled extrudate, Naltrexone HCl granulate (from Example 2) and magnesium stearate. Compress the resulting granules by using a tablet press. Prepare a film coating solution by dispersing ORABUG in the purified water and apply to the core of the tablets. EXAMPLES Controlled Release Tablets Oxycodone HCl Sinaltrexone HCl Pearles Ingredients At1 / Unit Oxycodone HCl 20.0 Lactose Dried Suspension 58.75 Povidone 5.0 Egggard P3.300 (Dry Weight) 10.0 Triacetin 2.00 103 Stearyl Alcohol 25, 00 Talc 2,50 Magnesium Stearate 1,25 Naltrexone HCl Pearls (Example 1) 84,00 Orbug Pink 6,00 Purified Water 34,00 * Total 215,00 * Remains in the product only as residual moisture. METHOD: 1. Preparation of the solution 2. Granulation 3. Grinding 4. Drying 5. Coating 6. Cooling 7. Grinding Plasticized with triacetin by dilution. Place Oxycodone HCl, Spray Spray Lactose and Povidone Fluorinator and apply the solution. The granulate is passed through a rotational mill pile mill. The granulate is dried if the impurity content is very high. Stearyl alcohol and wax from the above granulate are melted by adding stearylic alcohol to the granulate at the time of mixing. The coated granulate is cooled in a fluidized bed dryer. The chilled granulate is passed through a rotary impeller mill. 8. Mix Mixed waxy granulate, talc, magnesium stearate and Naltrexone HCl beads (from Example 1). 9. Compression Compress the resulting granules using a tablet press. 10. Applying A solution of a film-coated coating is prepared by dispersing Oracil in purified water and applied to the core of the tablets. EXAMPLE 12 Controlled Release Tablets Oxycodone HCl Sinaltrexone HCl Granulate Ingredients At1 / Unit Oxycodone HCl 20.00 Lactose Dried Suspension 58.75 Pyridone 5.00 Excipient K5 30D (Dry Weight) 10.00 Triacetin 2.00 Stearyl Alcohol 25, 00 Talc 2,50 Magnesium Stearate 1,25 Naltrexone HCl Granule (Primer 2) 70,00 Orbage Pcc 6,00 105 Purified Water 34,00 * 34,00 Total 210,00 * Remains in the product only as residual moisture. METHOD: 1. Preparation of the solution 2. Granulation 3. Grinding 4. Drying 5. Oversing 6. Cooling 7. Grinding 8. Mixing 9. Compression Plasticize Aigabald with triacetin by mixing. Place Oxycodone HCl, spray dried lactose and povidone fluid bed granulator and the topical solution is applied. The granulate is passed through a rotational mill pile mill. The granulate is dried if the impurity content is very high. Stearyl alcohol and wax from the above granulate are melted by adding stearylic alcohol to the granulate at the time of mixing. The fermented granulate is cooled in a fluid bed dryer. The cooled, fermented granulate is passed through a rotary impeller mill. Mix ground fermented granulate, talc, magnesium stearate and Naltrexone HC1 granulate (from example 2). Compress the resulting granules by using a tablet press. 106 10. Application A solution of film-coated coating is prepared by dispersing ORABUG in purified water and applied to the core of the tablets. EXAMPLE 13 Controlled release capsules of hydromorphone HCl sinaltrexone HCl extruded pellets CH * - FORMULA: Ingredients Amt / Unit Hydromorphone HC1 12.0 mg Al2 O6 H3 O 76.0 Ethyl cellulose 4.5 Stearyl alcohol 27.0 Naltrexone HC1 pellets (Example 3) 240.0 Solid gelatin capsules V Total 360.00 * Remains in the product only as residual moisture. METHOD: 1. MNH 2. Mixing 3. Extrusion Stearyl alcohol flakes are passed through a mill. Hydromorphone HCl, Ethylglycol, Ethylcellulose, Milled Stearyl Alcohol are mixed in a double jacketed mixing apparatus. The mixed material is continuously cooled. 4. Cooling 5. Pelleting 6. Screening 7. Encapsulation is fed into a twin screw extruder and the resulting fibers of the conveyor are collected. The threads are allowed to cool on the conveyor. The cooled filaments are cut into pellets using Pelletizator. The pellets were screened and harvested and harvested through a sieve of theoretical size. Extruded pellets hydromorphone HCl are filled at 120.0 mg and Naltrexone HCl pellets (from Example 3) at 240 mg in hard gelatin capsules. EXAMPLE 14 10 mg of oxycodone hydrochloride controlled release organically produced oxycodone hydrochloride (10 mg / tablet) and spray-dried lactose (71.25 mg / tablet) were transferred to a suitable size mixer for approximately 6 minutes. Eibadik® P5 PM powder (6 mg / tablet) is dispersed in ethanol. While the powders are mixed, they are granulated with the dispersion and mixing continues to produce a wet granular mass. Additional ethanol is added if necessary to reach the end point of the granulation. The granulate is transferred to a fluidized bed dryer and dried at 30 ° C, the following is passed through a 12-mesh sieve. The remaining Eibagid® R5 PM (9 mg / tablet) is dispersed in a solvent of 90 parts ethanol and 10 parts purified water; and sprayed 108 on the fluid bed granules in a granulator / dryer at 30 ° C. The granulate is then passed through a 12-mesh sieve. Stearin alcohol (25 mg / tablet) melts at approximately 60-70 ° C. The hot granules are returned to the mixer. During the mixing process, melt alcohol is added. The coated pellets are removed from the mixer and allowed to cool. After that, they are passed through a 12-mesh sieve. The granulate then blends with naloxone particles (approximately 1-5 mg of a tablet) with a coating which makes the naloxone substantially removed, pharmaceutically acceptable excipients, tabletting, e.g. talc and magnesium stearate, a suitable blender, and are compressed into tablets. The naloxone particles have a diameter of approximately 0.5 to 2 mils. The coated naloxone particles which can not substantially be released from the canaloxone can be produced by spraying on the particles of the roofing composition comprising a cellulosic polymer or an acrylic polymer that is water-insoluble and impervious to naloxone. Suitable particles include granules, pellets, spheroids, containing naloxone. When the particles are pearls or pellets, they can be obtained by dissolving a naloxone solution and spraying it onto inert beads or pellets. Preferably, the coating composition includes Eudragit® GC5, which may be used in the form of a water suspension and in combination with a plasticizer, such as, for example, acetyl triethyl citrate and / or tributyl citrate. Preferably, the coating composition includes Eudragit® P5 which can be used in the form of a water suspension and in combination with a plasticizer such as acetyl triethyl citrate and / or acetyl tributyl citrate. EXAMPLE 15 The oral dosage form of the present invention can be administered to a patient to provide relief of pain. The oral dosage form of the oral dosage form may comprise an orally effective amount of an opioid agonist and an opioid antagonist which is made to separate. When the dosage form is administered orally and delivered to the gastrointestinal tract in the patient in need of pain relief therapy, the opioid agonist is detached from the single-dosing regimen during normal digestion, thereby delivering a pain-relieving effect to the patient. Nog opioid antagonist, since it is made not to be separated essentially, it is not released essentially during its passage through the gastrointestinal system. Preferably, the form of the antagonist that is not removed is laxative-resistant (mineral oil) used to control delay in gastric passage or chloride state. Patients who take the oral dosage form as prescribed without mixing with (for example, by mechanical shaking or dissolving in a solvent) can not afford an opioid antagonist absorbed at a sufficient amount of I 10 at any time during the dosing of the drug so that the efficacy of the opioid agonist is reduced or eliminated by the antagonist. In other words, the amount of opioid antagonist, (when administered orally in an intact state) absorbed by the gastrointestinal tract and the patient's stoma accumulated does not reach the level that significantly affects or alters the pain-relieving effect of the opioid agonist included in the dosage form. EXAMPLE 16 Method for the Prevention of Opioid Disease The oral dosage form of the present invention can be used to prevent the potential abuse of an opioid antagonist contained therein. The oral dosage form co-dosing contains an opioid agonist in a combination somotibody antagonist. The opioid antagonist is present in a form that is essentially not removed during ingestion. Therefore, When the oral dosage form is co-dosed to the gastrointestinal tract orally, as expected, without being mixed with, the antagonist is substantially prevented from being separated in the gastrointestinal system. However, if the oral dosage form has been mixed with, for example, mechanical shaking (e.g., crushing, shearing, milling), heated (e.g., temperatures exceeding 45 ° C, preferably between 45 and 50 ° C) or disintegration of the dosage unit (with or without heating), the single dose formulation is stained by the opioid antagonist which is now available to soften the opioid action. Thus, when the dosage form is chewed, broken or dissolved in a solvent, and then administered orally, intranasally, parenterally or under the tongue, the action of the opioid agonist is at least partially blocked by the opioid antagonist. EXAMPLE 17 In this human study, 12 morphine-dependent subjects were evaluated for rapid withdrawal after administration of immediate release hydrocodone tablets co-administered with naltrexone doses of 0.25 to 8 mg. The experimental single dose, single-dose, placebo-controlled, noltrexone dose-response experiment. Following administration of the investigational drugs, subjective phisiological measurements of misuse of responsiveness and discarding were made at the 32-fold dose of dosinaltraxone. The data suggest that a dose of 1 mg of naltrexone, opioid-dependent subjects demonstrated a lesser agonist with respect to the combination with placebo and plasma sedation concentration of 50% of the maximal effect of the withdrawal symptom. Example 18 This is a randomized, double-blind, placebo controlled trial investigating the immediate-release immediate release delayed-release threshold of 12 subjects in methadone. While the study was performed, an interim analysis showed that 0.5 mg of naltrexone was able to cause the signs and symptoms of the withdrawal in this population. These studies suggest that the dose of naltrexone that is required to induce withdrawal symptoms in opioid dependent subjects is between 0.25 and 1 mg. EXAMPLE 19 This is a randomized, single-blind, single dose, placebo-controlled, 10-fold crossover trial examining the effect of naltrexone on the subjective and physiological effects of 15 mg of hydrocodone in 16 normal subjects. Naltrexone dosages range from 0.4 to 12.8 mg. In this study 0, 4 mg of naltrexone is able to exhibit an antagonistic action against several of the centrally mediated opioid effects of the hydrocodone, including the pupil. Based on these data, significantly lower doses of less than 0.25 mg naltrexone show a tendency to antagonize the concomitant agonist. This was sustained by the absence of signs of withdrawal observed in subjects of Example 17 who received 0.25 mg. Clinical data for Examples 17, 18 and 19 suggest that circulating, immediate-release doses of 0.125 mg of naltrexone (or equivalent release from a once-controlled release single dose regimen) did not affect the pain-relieving effect to any significant extent, whereas greater rapid release of bioavailable drugs (0.25 mg or more) do it. These clinical data, that the loading of the naltrexone opiate matrix for this example, at a ratio of 1: 15 to 1:30 mg of naltrexone / mg hydrocodone, and that the mixed / interstitial separation ratio is at least 4: 1 and preferably higher. Alternatively, it can be inferred that less than 0.25 mg of naltrexone is released from the single dose unit dose and 0.25 mg or more of naltrexone from the crushed dosage form. EXAMPLE 20 Naltrexone HCl beads FORMULA: Ingredients At1 / Unit (mg) Step 1. Drug layers Naltrexone HC1 0,6 Ioprage 1 pearls (30/35 mesh) 61,4 Arabugum (hydroxypropylmethylcellulose) 0,6 water 114 Stage 2. anionic polymer coating Eibadium LD30 (dry) 6,3 Tributyl citrate 1,6 Talc 3, 1 Water (evaporated during the process) Step 3: Extended release coating Enzyme P830O (dry) 17.9 Tributyl citrate 4.5 Talc 8, 8 Water (evaporated during the process) Stage 4. Oreguage (hydraxypropylmethyl cellulose) sealing layer 3.2 Water (evaporated during the process) Total (on a dry basis) 108 Method of production of pearls 1. Naltrexone HCl and Orrabug cary are dissolved in water. The pharmaceutical solution is sprayed over a polypropylene in a fluidized bed coater with a wound dressing. 2. Disperse Aldrich 1300, tributyl citrate and talc in water. The dispersion is sprayed over the drug coated beads in a fluid bed coating device. 3. Disperse EpiPAD P330O, tributyl citrate and talc of water. The dispersion is sprayed over a pearly coated coating in a fluid bed coating device. 4. Dissolve Oropagu in water. The solution is sprayed with a bead of pearls in a fluid bed coating device. 5. Treat the beads at 60 ° C for 24 hours. Dilution Method 1. Type II Apparatus (IIPPP) Apparatus, 75 rpm at 37 ° C 2. Sample Time: 1, 2, 4, 8, 12, 24, 36 3. Medium: this analytical method: Highly Effective Liquid Chromatography Results and discussion: Pearls are found to have decomposition results: (108 mg) give the following Time (hours) 1 2 4 12 24 36 Medium% pP pP pP 6.0 10.0 dissolution nR = not measured The dilution results show that only about 10% of naltrexone HC1 (0.06 mg) of naltrexone HCl are removed after 36 hours in the dilution bath. These beads 116 will not be bioavailable unless they are orally shed. Naltrexone HCl is highly water-soluble. It tends to migrate through the extended release film during the water coating process (step 3). Immigration takes place during this coating step, the film will become porous during embedding and the rate of drug release would be relatively high. The anionic coating (step 2) forms a water-insoluble complex layer of the spontaneous salt of naltrexone HCl and would prevent the migration of the drug over the subsequent release coating. Dilution of Broken Pearls Simulated Mixing Method Approximately 108 mg of naltrexone beads are ground in a powder coating to investigate the dilution. Dilution Method - as above Results and Discussion: Broken beads (108 mg) are found to cause the following decomposition results: Time (hours) 0.25 0.5 1 Average% 91 100 104 Disintegration Tak can be seen , that at hour 1 of the intact beads there was no detectable release of NTX, whereas when crushed, 117 all NTX, 0.6 mg was removed. This is represented graphically in Figure 1. Therefore, the whipped / intact ratio at hour 1 is 100: 0 and this is more than the criterion &amp; gt; 4: 1, as can be seen from examples 17, 18 and 19. EXAMPLE 21 Oxycodone IP capsules with pearls naltrexone FORMULA: Compounds Acts / Unit * (mg) Stage 1. Drug layers Oxycodone HCl 5.0 Non-rag pellets (30/35 mesh) 1.25 Hydroxypropyl methyl cellulose (HPMC) 54.35 Water (evaporated during the process) Step 2 Film coating Orrabug VioletCoIg 1.2 Water (evaporated during the process) Step 3. Encapsulate OhuIP pearls (step 2) 62.5 Naltrexone beads (Example 20 ) * 108 * To protect Ohu1P beads, naltrexone beads will need to be used as a sealant as a seal coating in step 4, Example 20. 118 Production method 1. OCH1B HCl and HPMC are dissolved in water. The drug solution is sprayed onto a polygranular bead in a fluidized bed topcoat with a Warmer insert. 2. Dissolve the colored gum in water. A pearl drug is coated with a film-coated backing fluid bed device. 3. Mix equal amounts of OhuIP pearls and naltrexperperlites. They are encapsulated in hard gelatin capsules. EXAMPLE 22 FORMULA:

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Ingredients Month (mg) Stage 1. Drug loading Morphine sulphate 60.0 Non-lactose insoluble 12.0 Antibodies 1.55D 2.0 Polyamide 3.5 Migraine P6 30/35 16.8 Capsules 4.9 Water Step 2 (Step 1) 99.2 Elucid P30D 4.712 Aldrichx Pd30.0 (dry) 0.248 119 Triethyl citrate 0.992 Talc 1.884 Orbital bile 5.639 Water Step 3. Incubation of MOSC beads (above) 212 Naltrexone beads (Example 20 ) * 108 * For the protection of MASCG beads, the naltrexone pearls will need to use OracleBL as the seal coating in Step 4, Example 22. Production method 1. Dispense Poneidone and Eggardi P53ClO in water. Mix morphine sulphate and lactose. 2. Pearls are loaded onto a rotor processor. Rapid powder and the binding solution of pearls. 3. Apply a film coating on the top pearls in a rotary processor. 4. Disperse Aldrich, P330C, KL30D, triethyl citrate, talc and in water. Upper upper beads are coated with a fluidized bed coater. 5. Processed beads (M5SP pearls). 6. Mix equal amounts of M5CH beads and naltrexperperlites. They are encapsulated in hard gelatin capsules. 120 EXAMPLE 23 Naltrexone HCl Extruded Pellets Formulations: Ingredients At / Unit * (mg) Naltrexone beads 2.0 Aldrichon PBSO 88.0 Stearyl alcohol 15.0 Stearyl acid 15.0 BUTYL HYDROTULOUNEEN (BHT) 1.0 Total 121.0 Method : 1. Grinding Stearyl alcohol flakes are passed through a mill. 2. Mixing Naltrexone HCl, Eidagand, milled stearyl alcohol, stearic acid and BHT are mixed in a dual jacketed mixing apparatus. 3. Extrusion The blended material is continuously fed into a twin screw extruder and the resulting fibers of the conveyor are collected. 4. Cooling The threads are allowed to cool on the conveyor. 5. Pelleting The cooled strands are cut into 1 mm of pellets using Pelletizator. 6. Screening The pellets are screened and assembled 121 'Will the desired portions through a sieve of a regular size. Dilution method 1. Apparatus-type II airship (Rasuleu), 75 rpm at 37 ° C 2. Sample time: 1,2,4,8,12,24,36 3. Medium: 5CP for one hour / 8IP after 4. Analytical Method: High Performance Liquid Chromatography Results: Pearls (108 mg) are found to give the following decomposition results: Time 1 (hours) 2 4 8 12 24 36 Average% of 1.3 dissolution 2.6 2.9 3.6 4.0 5.2 6, 2 Simulated mixing process Naltrexone pellets are ground in a mortar with pestle to investigate the dilution. Dilution method: as above Results: Time (hours) Mean% of dissolution 1 33.5 122 EXAMPLE 24 Naltrexone HCl Extruded Pellets Formulations: Ingredients At1 / Unit * (mg) Naltrexone beads 2.0 Aigard P5PO 96.0 Stearyl alcohol 22,0 Dibasic calcium phosphate 6,0 Bottled hydroxytoluene (BHT) 1,0 Total 127,0 Method: Grinding Stearyl alcohol flakes are passed through a mill. Mixing Naltrexone HCl, Eggardi, milled stearyl alcohol, dibasic calcium phosphate and BHT were mixed in a dual jacketed mixer. Extrusion The blended material is continuously fed into a twin screw extruder and the resulting fibers of the conveyor are collected. Cooling The threads are allowed to cool on the conveyor. Pelletize The cooled strands are cut into 1 mm pellets using Pelletizator. 123 6. Screening The pellets are screened and collected portions through a sieve of a regular size. Dilution method 1. Apparatus-type II airspeed (75 ° C) at 37 ° C 2. Sample time: 1, 2, 4, 8, 12, 24, 36 3. Medium: (108 mg) gave the following decomposition results: Time 1 (hours) 2 4 8 12 24 36 Average% of 3.1 dissolution 5.9 8 , 9 12,2 14,7 19,9 24,6 Simulated mixing process Naltrexone pellets are ground in a mortar with pestle to investigate the dilution. Dilution method: as above Results: Time (hours) 1 Average% dissolution 36.4 Therefore, the separation from intact pellets is 0.062t at hour 1 and when broken is 0, 728 mg at hour 1. This 124 ratio of broken to incontinent is also greater than 4: 1. is presented in Figure 24 in Figure 24. EXAMPLE 25 Probable Hydromorphone HC1 CP Capsules with Naltrexone HCl Extruded Pellets FORMULA: Ingredients Atm / Unit (mg) Hydromorphone HCl 12.0 Excipient P5PO 76.5 Ethyl Cellulose 4.5 Stearyl Alcohol 27.0 Naltrexone HCl Pellets (Example 23) 121.0 Solid Gelatin Capsules V Total 241.0 Method: 1. Grinding 2. Mixing 3. Extrusion 4. Cooling The stearyl alcohol flakes are passed through a mill. Hydromorphone HCl, Ethylglycol, ethylcellulose, the milled stearyl alcohol is mixed with a mixed dual wrapper. The mixed material continuously drilled into a twin screw extruder and the resulting yarns of the conveyor are collected. The chips are allowed to cool to 125 ° C. 5. Pelletizing 6. Screening 7. Incapping the conveyor. The cooled filaments are cut into pellets using Pelletizator. The pellets are screened and harvested and harvested through a sieve sized portion. Extruded pellets hydromorphone HCl are filled at 120.0 mg and Naltrexone HCl pellets (from Example 23) in 121 mg hardened gelatin capsules. EXAMPLE 26 Probable Hydromorphone HC1 CP Capsules With Naltrexone HCl Extruded Pellets FORMULA: Ingredients Atomidine Hydromorphone HCl 12.0 Excipient P5PO 76.5 Ethyl Cellulose 4.5 Stearyl Alcohol 27.0 Naltrexone HCl Pellets (Example 24) 127.0 Solid Gelatin Capsules V Total 247,00 Method: 1. Grinding Stearyl alcohol flakes are passed 126 2. Mixing 3. Extrusion 4. Cooling 5. Pelleting 6. Screening 7. Incapping through a mill. Hydromorphone HCl, Eudragit, ethylcellulose, milled stearyl alcohol are mixed in a dual-shear mixer. The mixed material is continuously drilled into a twin screw extruder and the resulting yarns of the conveyor are collected. The chips are allowed to cool off the conveyor. The cooled filaments are cut into pellets using Pelletizator. The pellets are screened and harvested and harvested through a sieve sized portion. The extruded pellets hydromorphone HCl are filled at 120.0 mg and Naltrexone HC1 pellets (from Example 24) in 127 mg hardened gelatin capsules. EXAMPLE 27A Naltrexone CP Pearls Naltrexone controlled release beads were developed so that they could be incorporated into a controlled release lecithinopopioide, after which the mixture was compressed into tablets. Oxycodone HCl granulate controlled release is used with naltrexone beads as an example. 127 · Formulation 27A Ingredients * (mg) Step 1 Drug layers Naltrexone HCl 3, 3 Non-rag pellets (14/18 mesh) 95.0 Purified water WHO 1.5 Talc 0.2 Water Stage 2. Oreguard Cure (Hydroxypropylmethyl Cellulose) Sealing Coating 5.0 Water Step 3. Prolonged Release Coating Epsilon P530D (dry) 17.63 Tributyl citrate 3.53 Lime 80 0.04 Talc 8.81 Water Stage 4. Oreguard Cure (Hydroxypropylmethyl Cellulose) Sealing Coating 5.0 Water (evaporated during the process) Total 140 128 Method of Production of pearls 1. Naltrexone HCl and HPMC are dissolved in water. The pharmaceutical solution is dispersed over the supernatant beads in a fluidized bed coater with a wound dressing. 2. Disperse Aldrich 1, tributyl citrate and tallow oil. The dispersion is sprayed over a pearly coated coating in a fluid bed coating device. 3. Disperse Aigabak K8, tributyl citrate and talc of the inlet. The dispersion is sprayed over a pearly coated coating in a fluid bed coating device. 4. Dissolve HMPC in water. The solution is sprayed onto beads in a fluidized bed coater. 5. Treat the beads at 60 ° C for 24 hours. Dilution Method 1. Type-IIP Type II Apparatus (Rabbit), 75 rpm at 37 ° C 2. Sample Time: 1, 2, 4, 8, 12, 24, 36 3. Medium: 5CE for one hour / 4. Hours (hours) 4 8 12 24 36 Average% 2 dissolution 2 2 5 6 33 Naltrexone discontinuation from broken beads Time (hours) 1 Average% Dissolution 100 FORMULA27B Ohu / NX CP Tablets. Ingredients At (Unit *) (Stage 1) Step 1. Purification Oxycodone HCl 10.0 Dry Lactose Spread 69.25 Povidone 5.0 Essential P530D (Dry) 10.0 Triacetin 2, 0 Stearyl alcohol 25.0 Talc 2.5 Magnesium 1.25 Water Stage 4. Opadrum cation (hydroxypropylmethyl cellulose) sealing coating 5.0 130 Step 2. Combined tablets Auchmann granulate (supra) 125 Naprexxone CP (formula 27A) 140 Method of Production of (Ohu / NX CP Tablets) 1. A dispersion / triacetin dispersion is sprayed onto oxycodone HCl, sprayed dry lactose and ground, using a fluidized bed granulator. 2. Removal of the granule and passing through the mill. 3. Stirring the stearin alcohol and adding the granulated granulate using a mill. Allow to cool. 4. Cool the granulate through a mill. 5. The granulate is lubricated with talc and magnesium stearate. A mixer is used. 6. Mix the beads of naltrexone with the top granulate and compress into tablets. g Dilution Method 1. Type II Apparatus II (Rasillet),