MXPA00006259A

MXPA00006259A - Opioid agonist/antagonist combinations

Info

Publication number: MXPA00006259A
Application number: MXPA/A/2000/006259A
Authority: MX
Inventors: Robert F Kaiko; D Colucci Robert
Original assignee: D Colucci Robert; Euroceltique Sa; Robert F Kaiko
Priority date: 1997-12-22
Filing date: 2000-06-22
Publication date: 2002-02-26

Abstract

The invention is directed in part to oral dosage forms comprising a combination of an orally analgesically effective amount of an opioid agonist and an orally active opioid antagonist, the opioid antagonist being included in a ratio to the opioid agonist to provide a combination product which is analgesically effective when the combination is administered orally, but which is aversive in a physically dependent subject. Preferably, the amount of opioid antagonist included in the combination product provides at least a mildly negative"aversive"experience in physically dependent addicts (e.g., precipitated abstinence syndrome).

Description

COMBINATIONS OF AGONISTS / OPIOID ANTAGONISTS Opioids, also known as opioid agonists, are a group of drugs that have properties similar to opium or morphine. Opioids are used primarily as moderate-to-strong analgesics, but they also have many other pharmacological effects, including dizziness, respiratory depression, mood swings, and mental turmoil, without causing loss of consciousness. Opioids act as agonists, interacting with stereospecific and saturable binding sites in the brain and other tissues. The endogenous opioid peptides are present particularly in areas of the central nervous system that are supposedly related to the perception of pain, to movement, mood and behavior, and to the regulation of neuroendocrine functions. Opium contains more than twenty different alkaloids. Morphine, codeine and papaverine are included in this group. In the middle of the 19th century, the use of pure alkaloids such as morphine, instead of raw opium preparations, began to spread throughout the medical world. The parenteral use of morphine tended to produce a more severe variety of compulsive drug use. The problem of opioid addiction stimulated a search for potent analgesics that were free of the potential for addiction. By 1967, the researchers concluded that the complex interactions between drugs and morphine-like antagonists, and what was then called a "mixed agonist-antagonist" could best be explained by postulating the existence of more than one type of receptor for opioids and related drugs. With the advent of new and fully synthetic entities with actions similar to morphine, the term "opioid" was retained as the generic designation of all exogenous substances that bind stereo-specifically to any of several subspecies of opioid receptors and produce agonist actions. The potential for the development of tolerance and physical dependence with the repeated use of opioids is a characteristic of all opioid drugs, and the possibility of developing psychological dependence (ie addiction) is one of the main concerns in the use of the treatment of pain with opioids, even when iatrogenic addiction is not common. Another important concern associated with the use of opioids is the diversion of these drugs from the patient who suffers from pain to another (who is not a patient) for recreational purposes, that is, to an addict. The overall potential abuse of an opioid is not established by a single factor. Instead, there is a composition of factors including the ability of the drug to produce the type of physical dependence in which abstinence from the drug causes sufficient alterations to produce the drug-seeking behavior, the ability to suppress withdrawal symptoms caused by abstinence. of other agents, the degree to which it induces euphoria similar to that produced by morphine and other opioids, the toxicity patterns that occur when the drug is dosed above its normal therapeutic range and physical characteristics of the drugs such as their water solubility . These physical characteristics can determine if the drug has possibilities of abuse by parenteral route. In the United States, activities to control the compulsive drug user include activities to control the availability of drugs by imposing restrictions on the use of opioids in the treatment of pain among compulsive drug users. In practice, the doctor often faces the alternative of administering powerful opioid analgesics even to people who seem predisposed to develop psychological dependence, ie addiction, of such drugs. In view of this problem, it is recommended that these patients do not receive an opioid when another drug without potential for abuse can suffice; and also, that these patients are not allowed to self-administer these drugs parenterally and that they are given a supply of a few days each time. At least three basic patterns of opioid use and dependence have been identified. The first involves individuals whose drug use begins in the context of medical treatment, and who obtain their initial supplies through doctors. Another pattern begins with the experimental or "recreational" use of drugs and advances to a more intensive use. A third pattern involves users who start from one or the other of the preceding forms, but then switch to oral opioids such as methadone, which they obtain from organized programs for the treatment of addictions. Tolerance refers to the need to increase the dose of the opioid over a period of time, in order to achieve the same level of analgesia or euphoria, or the observation that repeated administration of this same dose results in less analgesia, euphoria or other opioid effect. It was discovered that a remarkable degree of tolerance develops to the effects of respiratory depression, analgesics, sedatives, emetics and euphorigenics of opioids. However, the rate at which this tolerance can develop in an addict or patient that requires pain treatment depends on the pattern of use. If the opioid is frequently used, it may be necessary to increase the dose. Tolerance does not develop equally or at the same pace in all the effects of opioids, and even users who are highly tolerant of the effects of respiratory depression continue to have miosis and constipation. Tolerance to opioids disappears * mainly when the withdrawal syndrome ends. Physical dependence can develop through repeated administrations or the widespread use of opioids. Physical dependence manifests gradually after interrupting the use of opioids, or manifests precipitously (for example, within 20 minutes) after administering a narcotic antagonist (known as "precipitous abstinence"). Depending on the drug from which the dependence was established and the duration of use and dosage, withdrawal symptoms may vary in quantity and type, duration and severity. The most common symptoms of withdrawal syndrome include anorexia, weight loss, pupil dilation, chills alternating with excessive sweating, abdominal cramps, nausea, vomiting, muscle spasms, hyperirritability, tearing, runny nose, "goose bumps" and heart rhythm. increased. Withdrawal syndrome typically begins 24 to 48 hours after the last dose, and the syndrome reaches its maximum intensity by the third day, and can not decrease until the third week. The psychological dependence (ie, addiction) of opioids is characterized by a drug-seeking behavior aimed at achieving euphoria and escape from, for example, psychosocio-economic pressures. An addict will continue to administer opioids for non-medical purposes, and dealing damage to his person. Pharmacologically, opioid antagonists typically block or reverse all the effects of opioid agonists. One use of opioid antagonists is as once-a-day treatment of naltrexone to block the euphoric effects that could be obtained by administering opioids to addicts. Small doses of opioid antagonists have been used to determine if any person is physically dependent on opioids. More commonly, opioid antagonists are used to reverse the effects of opioids in people with overdoses of opioid agonist drugs. Previously there were attempts in the art to control the abuse potential associated with opioid analgesics. Typically, a particular dose of an opioid analgesic is more potent when administered parenterally compared to the same dose administered orally. Accordingly, a popular mode of abuse of oral medications involves the extraction of the opioid from the dosage form and the subsequent injection of the opioid (using any "suitable" vehicle for injection) in order to achieve "get in the mood". Accordingly, attempts to prevent abuse typically centered around the inclusion of the oral dosage form of an opioid antagonist that is not orally active which essentially blocks the analgesic effects of the opioid if an attempt is made to dissolve the opioid to parenterally administer it. For example, the combination of pentazocine and naloxone was used in tablets available in the United States, commercially available as Tal in®Nx from Sanofi- inthrop. Talwin®Nx contains pentazocine hydrochloride, equivalent to 50mm base, and naloxone hydrochloride equivalent to 0.5mg base. Talwin®Nx is indicated for the relief of moderate to severe pain. The amount of naloxone present in this combination produces no action if taken orally, and therefore does not interfere with the pharmacological action of pentazocine. However, this amount of naloxone administered by injection has a profound antagonistic action to narcotic analgesics. Therefore, the intention to include naloxone is to prevent a form of oral pentazocine abuse that occurs when the dose is dissolved and injected. Therefore, this dose has a lower potential for parenteral abuse than the previous oral pentazocine formulas. However, it is still subject to the use and abuse of patients orally, for example, when the patient takes multiple doses at the same time. Sunshine et al., In "Analgesic Efficacy of Pentazocine Versus Pentazocine-Naloxone Combination Following Oral Administration", Clin.J. Pain, 1988: 4: 35-40, reports the effect of adding 0.5mg of naloxone to the analgesic efficacy of 50mg of pentazocine. It was found that the combination is significantly less effective than pentazocine for the sum of pain intensity differences (SPID), and for the relief and difference of pain intensity (PID) at the fourth hour. For patients with moderate baseline pain, the combination produced significantly less pain relief than pentazocine for SPID and for relief and PID at the third and fourth hours. In patients with severe baseline pain, no significant difference was found between pentazocine and the combination of pentazocine with naloxone. Wang et al., In "Crossover and Parallel Study of Oral Analgesics", J. Clin Pharmacol 1981; 21: 162-8, studied the combination of 0.25mg of naloxone and Percodán® (composed of .5mg oxycodone HCl, 0.28mg of oxycodone terephthalate, 224mg of aspirin, 160mg of phenacetin and 32mg of caffeine) compared to Percodán® alone , and placebo in a crossover study in patients with chronic pain. The combination had lower mean scores than Percodán® only for most of the analgesic parameters per hour in the last hours of the study. However, for the summary variables, the combination showed no significant difference from placebo or Percodán®. In 1991, a fixed combination of buprenorphine and naloxone was introduced in New Zealand (Temgesic Nx®, Reckitt &Coleman) for the treatment of pain. A fixed therapeutic combination comprising tilidine (50mg) and naloxone (4mg) is available in Germany for the management of severe pain since 1978 (Valoron®N, Goedecke). The basis of the combination of these drugs is effective pain relief and prevention of tilidine addiction by antagonism induced by naloxone in the morphine receptor. U.S. Pat. No. 3,773,955 (Pachter et al.) Describes effective oral analgesic compositions that do not produce analgesia euphoria or physical dependence with parenteral administration, and therefore prevent parenteral abuse of analgesic agents. Such compositions contained from 0. lmg to about 10mg of naloxone per oral analgesic dose. This reference mentions the oral abuse of opioids. U.S. Pat. 3,493,657 (Lewenstein et al.) Describes compositions comprising naloxone and morphine or oxymorphone, whose compositions appear to provide a strong analgesic effect without the occurrence of undesirable side effects such as hallucinations. U.S. Pat. 4,457,933 (Gordon et al.) Describes a method to decrease the potential * of oral and parenteric abuse of strong analgesic agents such as oxycodone, propoxyphene and pentazocine, by combining an analgesic dose of the opioid with naloxone in a specific and relatively narrow range. The oxycodone-naloxone compositions with a ratio of 2.5-5: 1 parts by weight and compositions of pentazocine-naloxone with a proportion of 16-50: 1 parts by weight are preferred. The dose of naloxone that must be combined with the opioid is formulated to essentially eliminate the possibility of oral or parenteral abuse of the opioid, without essentially affecting its oral analgesic activity. U.S. Pat. No. 4,582,835 (Lewis) describes a method for treating pain by administering a sublingual effective dose of buprenorphine with naloxone. Lewis describes dose ratios of naloxone against buprenorphine between 1: 3 to 1: 1 for parenteral administration, and from 1: 2 to 2: 1 for sublingual administration. It is increasingly recognized in the art that oral opioid formulations are abused not only by parenteral route but also orally when the patient or addict orally self-administers more than the oral dose prescribed during any dose interval. There is therefore a need to develop a formula for the treatment of pain that is administered orally and that provides a lower potential for oral abuse. As far as the knowledge of the inventors is concerned, a proportion of opioid agonist with opioid antagonist that is analgesically effective when the combination is administered orally, but which is adverse in a subject with physical dependence, is not yet recognized. OBJECTS AND SUMMARY OF THE INVENTION It is an object of the present invention to provide an oral dosage form of an opioid analgesic that is subject to less potential for oral abuse than the above commercially available dosage forms. It is yet another object of the present invention to provide an oral dosage form of an opioid analgesic and a method that provides therapeutic analgesia and that also provides a negative or adverse experience when the physically dependent subject takes or administers a large amount of the opioid., for example 2 to 3 times the dose that is usually prescribed. It is yet another object of the present invention to provide an oral dosage form of an opioid analgesic and a method of administering therapeutic analgesia, so that it is not so positively reinforcing in subjects who are not physically dependent and who take more than the usual dose. it is prescribed, that is 2 to 3 times the dose that is usually prescribed for the opioid, compared to the same amount of the opioid without the antagonist. It is yet another object of the present invention to provide a method for treating pain in human patients with an oral dosage form of an opioid analgesic, while reducing the potential for oral abuse of the dosage form. It is yet another object of the present invention to manufacture an oral dosage form of an opioid analgesic so that it has less potential for oral abuse. These and other objects are achieved by the present invention, which is directed in part to the surprising finding that there is no proportion of opioid antagonist against opioid agonist (analgesic) that is analgesically effective when the combination is administered orally, but which is adverse effect in physically dependent subjects. As far as the knowledge of the inventor is concerned, this was not even considered by those who know the technique, ie addictologists, analgesiologists or clinical pharmacologists. It is surprising that a combination product (of antagonist / combined agonist) could in essence be therapeutic for a population (patients with pain), whereas it would be unacceptable (adverse) in a different population (ie, in physically dependent subjects) when it is administered at the same or greater dose than is generally prescribed, that is between 2 to 3 times the dose of opioid that is usually prescribed. The present invention is in part directed to an oral dosage form comprising an analgesically effective oral amount of an opioid agonist and an opioid antagonist in a proportion that maintains the analgesic efficacy of the opioid analgesic, but which may slightly decrease analgesia, depending on the evaluations of direct measurements in patients, or by the use of one or more substitute measures of opioid efficacy (analgesia) in human subjects. Substitute measures of opioid efficacy (analgesia) include sedation, respiratory rate or pupil size (by pupilometry) and visual analog scale ("VAS") for the "drug effect". These substitute measures are affected in a direction that indicates a reduction in the opioid effect compared to the same dose of opioid without the concomitant dose of opioid antagonist. In certain preferred embodiments wherein the opioid is hydrocodone and the antagonist is naltrexone, the oral dosage form includes hydrocodone in the form of its debitartrate salt and naltrexone in the form of its hydrochloride salt.

In certain preferred embodiments wherein the opioid is hydrocodone and the antagonist is naltrexone, the ratio of naltrexone to hydrocodone is preferably between 0.03-0.27: 1 by weight, and more preferably between 0.05-0.20: 1 by weight. The present invention is directed to a method for preventing a subject from orally abusing an oral opioid formulation, which comprises preparing oral dosage form comprising an analgesically effective oral amount of an opioid agonist and an opioid antagonist in a proportion that maintains efficacy analgesic of the opioid analgesic, but which can slightly decrease the analgesia when evaluated by direct measures in patients, or by the use of one or more substitute measures of the opioid effect in human subjects. When the oral dosage form is taken by a subject with physical dependence at a relatively large dose, ie between 2 to 3 times the dose that is usually prescribed, that use is adverse in physically dependent human subjects, and preferably not so positively reinforcing as the opioid (ingested by itself) in a human subject that is not physically dependent. The present invention is also directed to a method of treatment comprising the oral administration of an analgesically-effective oral amount of an opioid agonist together with an opioid antagonist in a proportion that retains the analgesic efficacy of the opioid analgesic, but which may slightly decrease the analgesia by direct measurements in patients, or by using one or * more substitute measures of opioid defect with human subjects. The present invention is also directed in part to oral dosage forms comprising a combination of an analgesically effective oral amount of an opioid agonist and an orally active opioid antagonist, where the opioid antagonist is included in an amount (i) that is not cause a reduction in the level of analgesia produced by the dosage form when administered orally at a non-therapeutic level and (ii) that provides at least a mildly negative or adverse experience in physically dependent subjects (ie, abrupt withdrawal syndrome) when subjects try to take at least twice the dose that is usually prescribed at a time (and often 2 to 3 times that dose, or more), compared to a comparable dose of opioid without the presence of the opioid antagonist. Preferably, the amount of naltrexone included in the oral dosage form produces less positive reinforcement (ie, less "like") to an addict with nonphysical dependence on the opioid, than a comparable oral dosage form without including the antagonist. Preferably, the formulation provides effective analgesia when administered orally. For purposes of the present invention, the phrase "which may slightly decrease analgesia when evaluated by direct measurements in patients, or by the use of one or more substitute measures of the analgesic efficacy of the opioid in human subjects" means that the patient with pain it may or may not notice appreciably the difference between the formulation administered according to the present invention (ie, the combination of opioid antagonists / agonists) and a similar formulation that includes the same dose of opioid agonist without the opioid antagonist, but which will obtain from the combination an analgesic effect. The pharmacodynamic effect (analgesia) of the formulations administered in accordance with the present invention can be described by, for example, ratings of the analgesia questionnaire reported by patients in serial lapses after administration of the dosage form. Summary measures of analgesia include the sum of pain intensity differences (SPID) and total pain relief (TOTPAR). In certain preferred embodiments, the amount of opioid antagonist included in the dosage form can cause a clinically significant reduction in the level of analgesia produced by the dosage form when administered orally., that is, measured by substitute measures such as the visual analogue scale ("VAS") for the "effect of the drug". In other modalities, the amount of opioid antagonist included in the oral dose form can produce a marked reduction in the level of analgesia produced by the dosage form when administered orally, although it does not reduce the level of analgesia that occurs at the oral level. Subtherapeutic Preferably, the amount of antagonist included in the oral dosage form has fewer positive reinforcers (ie, "like" less) for a subject with nonphysical opioid dependence, than a comparable oral dosage form without including the antagonist. The present invention is also directed to a method for preparing an oral dosage form of an opioid analgesic for the treatment of pain in human patients, so as to minimize the possibility of oral abuse of the dosage form, by combining an oral amount analgesically effective of an opioid agonist together with an opioid antagonist in a proportion that maintains the analgesic efficacy of the opioid analgesic, but which may slightly decrease analgesia when measured directly in patients, or by using one or more substitute measures of analgesia in human subjects. In certain embodiments, the combination, when administered orally, provides a clinically sigcant reduction in the level of analgesia produced by the dosage form when administered orally (as compared to the same dose of opioid alone), and supplies when less a mildly negative or adverse experience in a subject with physical dependence (ie precipitous abstinence syndrome) when the subject takes an opioid dose that is more than what is usually prescribed. The subject can be, for example, an addict trying to achieve euphoria ("get in the mood") by taking more than (ie, at least 2 to 3 times) the dose that is usually prescribed at a time. The amount of opioid antagonist that is included in the dosage form may or may not cause a marked reduction in the level of analgesia produced by the dosage form when administered orally, ie when measured with pharmacodynamic parameters such as the visual analogue scale ( "VAS") for the effect of the drug, but preferably allows the dosage form to produce effective analgesia. In certain preferred embodiments of the method, the dose of opioid antagonist appreciably affects a substitute measure of opioid analgesic effect. In certain preferred embodiments, the amount of antagonist included in the oral dosage form produces less positive (i.e., "like" less) reinforcement in a subject without physical dependence, than a comparable oral dosage form without including the antagonist. Oral pharmaceutical compositions containing the drug combination of the present invention may be in the form of tablets, liquids, lozenges, aqueous or oily suspensions, multi-particle formulations including dispersible powders, granules, spheroids or coated inert beads, emulsions, hard capsules or * soft or syrups and elixirs, microparticles (ie microcapsules, microspheres and the like), buccal tablets, etc. The dosage forms of the present invention can include any pharmaceutically acceptable excipient that is desired and known in the art. The dosage forms can also provide an immediate release of the opioid agonist and the opioid antagonist. In certain preferred embodiments, the dosage forms provide a sustained release of the opioid agonist and supply part or all of the dose of the opioid antagonist in (i) immediate release form, (ii) sustained release form, or (iii) form of release both immediate and sustained. These embodiments may further comprise a portion of the opioid agonist in the form of immediate release. Sustained release can be achieved in accordance with formulations / manufacturing methods known in the pharmaceutical formulating art, that is, by incorporating a sustained release vehicle into a matrix containing the opioid agonist and the opioid antagonist; or by a sustained release coating of a matrix containing the opioid agonist and the opioid antagonist. The present invention can provide a safer product (i.e., less respiratory depression) as well as a product with a slower rate of opioid tolerance and • development of physical dependence. In other preferred embodiments, the opioid included in the dosage form is an orally active opioid agonist which is not hydrocodone. The proportion of naltrexone included in these formulations can be easily determined on the basis of a simple calculation, taking into account the known equianalgesic doses of several opioid analgesics compared to hydrocodone. The equianalgesic doses of various opioid analgesics appear below, and are known in the art, ie from Foley, K. "The Treatment of Cancer Pain"; N. Engl. J. Med. 1985: 313: 84-95, incorporated herein by reference. In still other aspects of the present embodiment, naltrexone is replaced by a different opioid antagonist, using equiantagonist doses thereof. In certain embodiments, a combination of two opioid analgesics is included in the formulation. In yet other embodiments, one or more opioid analgesics is included and another non-opioid drug is included, in addition to the opioid antagonist. These non-opioid drugs would preferably provide additional analgesia and would include, for example, aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs ("NSAIDS"), NMDA antagonists, and cyclooxygenase-II inhibitors ("COX-II inhibitors"). In still other embodiments, an opioid np drug * may be included that provides a desired effect in addition to analgesia, for example antitussive, expectorant, decongestant or antihistaminic, and the like. The term "parenteric," as used herein, includes subcutaneous, intravenous, intramuscular, intrasternal or infusion techniques. The term "effective analgesia" is defined for purposes of the present invention as a satisfactory reduction, or elimination, of pain, together with a tolerable level of side effects, as determined by the human patient. The term "sustained release" is defined for purposes of the present invention as the release of the drug (opioid analgesic) from the oral formulation at a rate such that the concentrations (levels) in the blood (ie in plasma) fall within the therapeutic range (above the minimum effective analgesic concentration or ("MEAC") but below the toxic levels for an idle time of a formulation once or twice a day.The term "stable state" refers to the time in which the rate of elimination of a drug is equal to the rate of absorption of this drug in the body For purposes of the present invention, the term "opioid agonist" is interchangeable with the term "opioid" or "opioid analgesic" and includes the base of the opioid, mixture of agonist-antagonists, partial agonists, pharmaceutically acceptable salts thereof, stereoisomers thereof, ethers and esters thereof, and mixtures thereof. BRIEF DESCRIPTION OF THE DRAWINGS The following drawings illustrate the embodiments of the present invention, and are not intended to limit the scope of the present invention, as it is encompassed in its claims. Figure 1 shows the antagonism of VAS naltrexone (visual analog scale) of the "drug effect" induced by hydrocodone for example 1. Figure 2 shows naltrexone antagonism of pupil constriction induced by hydrocodone for the example 1. Figure 3 presents the mean VAS rating of the "drug effect" with respect to time for each of the treatments of example 2. Figure 4 presents the average pupillary diameters of the "drug effect" with respect to time for each one of the treatments of example 2. Figures 5 and 6 present the corresponding maximum mean VAS scores of the "drug effect" (+ 95% CI) and the mean minimum pupillary diameter (± 95% CI) against >; the logarithm of each dose of naltrexone in example 2. Figure 7A illustrates the ability of subjects to feel the effect of hydrocodone in the presence of varying amounts of naltrexone in Example 3. Figures 7B and 7C illustrate the experiences subjective or unfavorable subjective subjects with hydrocodone in the presence of varying amounts of naltrexone, respectively, for example 3. Figure 8 illustrates the subject's perception of abstinence from the effect of hydrocodone in the presence of varying amounts of naltrexone in Example 3 Figure 8B illustrates the subjective experience of discomfort in the presence of various amounts of naltrexone, in example 3. Figure 9A illustrates the effect on the size of the pupils produced by hydrocodone in the presence of various amounts of naltrexone in Example 3 Figure 9B illustrates the apparent abstinence measure of the effect of hydrocodone in the presence of various amounts of naltre xona in Example 3, from the perspective of the observer. Figures 10A-C present the areas under the curves presented in Figures 7A-C, integrated over an observation period of 6 hours, as a function of the dose of naltrexone and 95% confidence levels for the placebo reaction to the naltrexone (30mg hydrocodone, Omg naltrexone). Figures 11A-C present the areas under the curves presented in Figure 8A-B and Figure 9A, integrated over a 6-hour observation period, as a function of naltrexone dose and 95% confidence levels for the reaction Placebo of naltrexone (30mg hydrocodone, Omg naltrexone). DETAILED DESCRIPTION OF THE INVENTION It was postulated that there are at least three subspecies of opioid receptors, designated mu, kappa and delta. Within this frame of reference, the mu receptor is considered to be the one involved in the production of superespinal analgesia, respiratory depression, euphoria and physical dependence. The kappa receptor is considered to be involved in the induction of spinal analgesia, miosis and sedation. Activation of gamma receptors causes dysphoria and hallucinations, as well as respiratory and vasomotor stimulation effects. A receptor other than the mu and gamma receptors has been described in the deferent channel of mice, Lord et al. Nature, 1977, 267, 495-99. It is thought that opioid agonists exert their agonist actions primarily on the mu receptor, and to a lesser extent on the kappa receptor. There are few drugs that seem to act as partial agonists in one or the other type of receptor. These drugs have a ceiling effect. These drugs include nalorphine, propiram and buprenorphine. Other drugs act as competitive antagonists in the mu receptor, and block the effects of drugs similar to morphine, exerting agonist actions in the kappa and omega receptors. The term "agonist-antagonist" evolved to describe such mechanisms of action. The concept of antagonism to the actions of opioids is considered to be very complex. It was discovered in the administration of opioid agonist-antagonists and partial agonists that tolerance develops to the effects of the agonist, although not to the antagonistic effects of the drugs. Even after prolonged administration of high doses, discontinuing naloxone is not characterized by a recognizable withdrawal syndrome, and abstinence from naltrexone, another relatively pure opioid antagonist, produces very few signs and symptoms. However, after prolonged administration of high doses, the abrupt discontinuation of the opioid agonist-antagonist nalorphine or cyclazocine causes a characteristic withdrawal syndrome that is similar for both drugs. Naloxone is an opioid antagonist almost devoid of agonist effects. Subcutaneous doses of up to 12 mg of naloxone do not produce discernible subjective effects, > and 24mg of naloxone produce only a slight numbness. Reduced doses (0.4-0.8mg) of intramuscular or intravenous naloxone in men prevent or rapidly reverse the effects of the opioid agonist similar to morphine. It was reported that one mg of intravenous naloxone completely blocks the effect of 25mg of heroin. The effects of naloxone are noticed almost immediately after intravenous administration. The drug is absorbed after oral administration, although it is reported that it is metabolized in an inactive form quickly when first passed through the liver, in such a way that it is reported that it has one fifth of its potency when it is administered parenterally. It was reported that the oral dose of more than one gram is metabolized almost completely in less than 24 hours. Other opioid antagonists, for example cyclazocine and naltrexone, where both have substitutions of cyclopropylmethyl nitrogen, retain much of its effectiveness orally and its duration of action is much longer, approaching 24 hours after the oral dose. A preferred opioid antagonist is naltrexone. However, the equiantagonistic oral doses of other opioid antagonists, including but not limited to naloxone, nalmefene, cyclazocine and levalorphane can be used in accordance with the present invention. The proportion of these antagonists to a particular opioid agonist can easily be determined without undue experimentation by the person skilled in the art who wishes to use an opioid antagonist in addition to naltrexone, whose proportion to the opioid agonist is exemplified and discussed in detail herein. Those skilled in the art can determine these proportions of other antagonists against opioid agonists by performing clinical studies similar or similar to those appearing in the examples appended hereto. Accordingly, combinations of opioid antagonists / opioid agonists that are orally administered in proportions equivalent to the ratio of, for example, naltrexone to hydrocodone specified herein are considered to be within the scope of the present invention and within the scope of the invention. of the appended claims. For example, in certain embodiments of the present invention naloxone is used as an opioid antagonist, where the amount of naloxone included in the dosage form is large enough to provide an equiantagonistic effect that resembles that of naltrexone if it were included in the combination . In the treatment of previously addicted patients. opioids, naltrexone was used in large oral doses (more than 10Omg) to prevent euphorigenic effects of opioid agonists. It was reported that naltrexone exerts strong preferential blocking actions against the mu cycle, above the delta site. Naltrexone is known as the synthetic congener of oxymorphone without opioid agonist properties, and its structure of oxymorphone differs by substituting a methyl group located on the nitrogen atom of oxymorphone with a cyclopropylmethyl group. Naltrexone hydrochloride salt is soluble in water up to about 100 mg / cc. The pharmacological and pharmacokinetic properties of naltrexone were evaluated in multiple animal and clinical studies. See, for example, Gonzales JP et al., Naltrexone: A review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Efficacy in the Management of Opioid Dependence. Drugs 1988; 35: 192-213, incorporated herein by reference. After oral administration, naltrexone is rapidly absorbed (within 1 hour) and has an oral bioavailability ranging from 5 to 40%. The protein binding of naltrexone is approximately 21%, and the volume of the distribution after the single dose administration is 16.1 L / kg. Naltrexone is commercially available in the form of a tablet (Revia®, DuPont) for the treatment of alcohol dependence and for the blockade of exogenously administered opioids. See for example, Revia (naltrexone hydrochloride tablets). Physician's Desk Reference, 51st edition, Montvale, Nj, USA "Medical Economics" 1997; ' 51: 957-959. A 50mg dose of ReVia® blocks the pharmacological effects of 25g of intravenously administered heroin for up to 24 hours. It is known that when coadministered with morphine, heroin or other opioids chronically, naltrexone blocks the development of physical dependence on opioids. It is thought that the method by which naltrexone blocks the effects of heroin is by competitively binding with opioid receptors. Naltrexone is used to treat narcotic addiction by completely blocking the effects of opioids. It was discovered that the most effective use of naltrexone for narcotic addiction is with narcotic addicts with good prognosis as part of a complete occupational or rehabilitation program that includes behavior control and other methods to increase compliance. For the treatment of narcotic dependence with naltrexone, it is desirable that the patient be free of opioids for at least 7 to 10 days. The initial dose of naltrexone for such purposes is typically about 25mg, and if withdrawal symptoms do not occur, the dose may be increased to 50mg daily. It is considered that a daily dose of 50 mg produces an adequate clinical blockade of the actions of the parenteral administration opioids. Naltrexone was also used for the treatment of alcoholism along with social and psychotherapeutic methods. In the dosage forms and methods of the present invention, the amount of naltrexone included is significantly lower than the above commercially available doses. This is partly because the use of naltrexone is different in the present invention: the objective is not to block the opioid effects but rather to produce a negative and adverse experience when a subject with physical dependence takes or administers a large amount of the drug. combination product, that is 2 to 3 times more than the dose that is usually prescribed. Accordingly, in formulations of the present invention wherein the opioid is 15 mg of hydrocodone bitartrate, the amount of naltrexone hydrochloride that is included in the formulation is between 0.5 mg to about 4 mg, and preferably 0.75 mg to about 3 mg. of naltrexone for every 15mg of hydrocodone. Opioid analgesics which are useful in the present invention include all opioid agonists or mixtures of agonists-antagonists, partial agonists, including but not limited to alfentanil, allylprodine, alphaprodin, anileridin, benzylomorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocin, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimetheptanol, dimethyl-thiambutene, dioxafethyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypentidine, isomethadone, ketobemidone, levorphanol, levofenac-morphine, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, mirofin, narcein, nicomorphine, norlevofanol, normetadone, nalorphine, nalbufen, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, fenadoxone, fenomorphan, phenazocine, phenoperidine, piminodine, piritramide, profeptazine, promedol, properidin, propoxyphene, sufentanil, tilidine, tramadol, mixtures of any of the above salts, salts of any of the foregoing and the like. In certain preferred embodiments, the opioid or analgesic agonist is selected from the group consisting of hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone or salts and mixtures thereof. In certain preferred embodiments, the opioid agonist is hydrocodone. In Table 1 below, equianalgesic doses of these opioids are described, compared to a dose of 15 mg of hydrocodone: Table 1: Eguianalgesic Doses of Opioids Based on the preferred ratio of naltrexone in an amount of between 0.5 to about 4 mg per 15 mg of hydrocodone, the approximate ratio of naltrexone to each mg of each opioid is described in Table 2: Table 2: Weight Ratio of Naltrexone Per Dose of Opioid Based on the most preferred ratio of approximately 0.75mg against approximately 3mg naltrexone for each 15mg naltrexone hydrocodone, the approximate ratio of naltrexone to each mg of each opioid is specified in Table 3: Table 3: Weight proportion of Naltrexone by Opioid Dosage Although hydrocodone is effective in pain management, there was an increase in its abuse by individuals who are psychologically dependent on opioids, or who misuse opioids for non-therapeutic reasons. Previous experience with other opioids demonstrated a decrease in the abuse potential when opioids are > administered in combination with a narcotic antagonist especially in patients who are ex-addicts. Weinhold LL and collaborators. Bupremorphine Alone and in Combination with Naltrexone in Non-Dependent Humans, Drug and Alcohol Dependence 1992; 30: 263-274; Mendelson J et al., Buprenorphine and Naloxone Interactions in Opiate-Dependent Volunteers, Clin Pharm Ther 1996; 60: 105-114; where both are incorporated herein by reference. Hydrocodone is a semisynthetic and antitussive narcotic analgesic with several gastrointestinal actions and in the central nervous system. Chemically, hydrocodone is 4,5-epoxy-3-methoxy-17-methyl-morphinan-6-one, and is also known as dihydrocodeinone. Like other opioids, hydrocodone can induce habit and can lead to drug dependence of the morphine type. Excessive doses of hydrocodone, like other opiate derivatives, depress respiration. Oral hydrocodone is also available in Europe (Belgium, Germany, Greece, Italy, Luxembourg, Norway and Switzerland) as an antitussive agent. In Germany, a parenteral formulation is also available as an antitussive agent. To be used as an analgesic, hydrocodone bitartrate is commercially available only in the United States as a fixed combination with non-opiate drugs (ie, ibuprofen, acetaminophen, aspirin, etc.) for moderate to moderately severe relief. A common dosage form of hydrocodone is in combination with acetaminophen, and is commercially available as Lortab® in the USA. from UCB Pharma, Inc as tablets of 2.5 / 500mg, 5 / 500mg, 7.5 / 500mg and 10 / 500mg of hydrocodone / acetaminophen. The tablets are also available in a ratio of 7.5mg of hydrocodone bitartrate and 650mg of indolene aceto and 7.5mg of hydrocodone bitartrate and 750mg of acetaminophen. Hydrocodone in combination with aspirin is given in oral dosage form for adults, usually in 1 or 2 tablets every 4 to 6 hours, as needed to relieve pain. The tablet form is 5mg of hydrocodone bitartrate and 224mg of aspirin with 32mg of caffeine; or 5mg of hydrocodone bitartrate and 50Omg of aspirin. A relatively new formulation comprises hydrocodone bitartrate and ibuprofen. Vicoprofen®, commercially available in the USA from Knoll Laboratories, is a tablet that contains 7.5mg of hydrocodone bitartrate and 20mg of ibuprofen. It is contemplated that the present invention encompasses all of these formulations, including the oral active opioid antagonist within the amounts of the invention as specified herein. The potential abuse of opioid analgesics such as hydrocodone is surprisingly limited by the combinations of the present invention. More particularly, it was found that it is possible to combine in a single oral dose an opioid analgesic together with a small amount of opioid antagonist to obtain a product that continues to produce analgesia but that essentially denies the possibility that a physically dependent human subject continues to abuse the drug. when taking more than one tablet at a time, for example 2 to 3 times more than the dose that is usually prescribed. The oral dosage forms of the present invention comprise a therapeutically effective oral amount of an opioid agonist, together with an opioid antagonist such as naltrexone in an amount (i) that does not cause a reduction in the level of analgesia produced by the dose when administered by orally at a non-therapeutic level; and (ii) that produces at least a mildly negative or adverse experience in physically dependent human subjects, such as, for example, physically dependent addicts (ie, abrupt withdrawal syndrome) when taking more than the dose per dose. which is usually prescribed. Preferably, the amount of antagonist included in the oral dosage form has (iii) less positive reinforcement (i.e., "like" less) for a human subject without physical dependence, i.e. an opioid addict, than an oral dosage form comparable without including the antagonist. The amount of antagonist that is useful for achieving parameters (i) - (iii) that are specified in the previous paragraph can be determined at least in part, for example, by the use of "substitute" tests, such as a VAS scale ( where the subject qualifies their perception of the effect of the dosage form) or by a measurement such as the size of the pupil (measured by pupilometry). These measurements allow the person skilled in the art to determine the dose of antagonist with respect to the dose of agonist that causes a decrease in the opiate effects of the agonist. Subsequently, the skilled artisan can determine the level of opioid antagonist that causes adverse effects in physically dependent subjects, as well as the level of opioid antagonist that minimizes the "taste ratings" or opioid reinforcing properties in addicts without physical dependence. Once these levels of opioid antagonist are determined, it is then possible to determine the dose range of antagonist at or below this level that would be useful to achieve the parameters (i) - (iii) specified in the previous paragraph. The combination of opioid agonist and opioid antagonist can be used in mixtures with conventional excipients, i.e. pharmaceutically acceptable organic or inorganic vehicles, and suitable for oral administration as is known in the art. Pharmaceutically acceptable carriers include, but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatos, carbohydrates such as lactose, amylose or starch, talc magnesium stearate, silicic acid, viscous paraffin, perfume oil, monoglycerides and diglycerides of fatty acids, fatty acid esters of pentaerythritol, hydroxymethylcellulose, polyvinylpyrrolidone, etc. The pharmaceutical preparations can be sterilized and, if desired, mixed with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, colors, flavors, aromatic substances and the like. They can also be combined, when desired, with other active agents, ie other analgesic agents. For oral administration, tablets, dragees, liquids, drops, suppositories or capsules are particularly suitable. The compositions intended for oral use can be prepared according to any method known in the art, and such compositions can contain one or more agents selected from the group consisting of inert and non-toxic pharmaceutical excipients which are suitable for the manufacture of tablets. Such excipients include, for example, an inert diluent such as lactose.; granulation and disintegration agents such as corn starch; binding agents such as starch; and agents > lubricants like magnesium stearate. The tablets may be uncoated, or they may be coated by known techniques to obtain elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules, where the active ingredient is mixed with an inert diluent. The aqueous suspensions contain the above identified drug combination, and that mixture has one or more suitable excipients as suspending agents, for example pharmaceutically acceptable synthetic gums such as hydroxypropylmethylcellulose or natural gums. Oily suspensions may be formulated by suspending the drug combination previously identified in a vegetable or mineral oil. Oily suspensions may contain a thickening agent such as wax or cetyl alcohol. A syrup or elixir can be used, where a sweetened vehicle is used. Injectable suspensions may also be prepared, in which case suitable liquid carriers, suspending agents and the like may be used. The method of treatment and the pharmaceutical formulations of the present invention may further include one or more drugs in addition to the opioid analgesic and the opioid antagonist, wherein the additional drugs may or may not act synergistically with each other. Accordingly, in certain embodiments, a combination of two opioid analgesics may be included in the formulation, in addition to the opioid antagonist. For example, the dosage form may include two opioid analgesics with different properties, such as half-life, solubility, potency and combination of any of the foregoing. In still other embodiments, one or more opioid analgesics and a non-opioid drug are included, in addition to the opioid antagonist. These non-opioid drugs preferably produce additional analgesia and include, for example, aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs ("NSAIDS"), for example ibuprofen, ketoprofen, etc; N-methyl-D-aspartate (NMDA) receptor antagonists, for example a morphinan such as dextromethorphan or dextrorphan, or ketamine; cyclooxygenase-II inhibitors ("COX-II inhibitors") or glycine receptor antagonists. In certain preferred embodiments of the present invention, the invention allows the use of lower doses of the opioid analgesic by virtue of including an additional non-opioid agonist, such as an NSAID or a COX-2 inhibitor. By using smaller amounts of one or both drugs, the side effects associated with the effective management of pain in humans are reduced. Suitable non-steroidal anti-inflammatory agents include ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carpofrene, oxaprozin, pramofreno, muroprofen, trioxaprofen, suprofreno, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepiraco, thiopinaco, zidometacin, acemetacin, fentiazaco, clidanaco, oxpinaco, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, and the like. The useful doses of these drugs are well known in the art. N-methyl-D-aspartate (NMDA) receptor antagonists are well known in the art and encompass, for example, orfinans such as dextromethorphan or dextrorphan, ketamine, d-methadone or pharmaceutically acceptable salts thereof. For purposes of the present invention, the term "NMDA antagonist" is also considered to include drugs that block a greater intracellular consequence of NMDA receptor activation, for example a gangliocide such as G io G b, a phenothiazine such as trifluoperazine or a naphthalenesulfonamide such as N - (6-aminotexyl) -5-chloro-1-naphthalenesulfonamide. These drugs inhibit the development of tolerance to, or dependency, to addictive drugs, for example narcotic analgesics such as morphine, codeine, etc., in US Pat. 5,321,012 and 5,56,838 (both by Mayer et al.) And as chronic pain treatment in U.S. Pat. 5,502,058 (Mayer et al.) All incorporated herein by reference. The NMDA antagonist can be included alone, or in combination with a local anesthetic such as lidocaine, as described in these Mayer et al. Patents. The treatment of chronic pain by the use of glycine receptor antagonists and the identification of these drugs is described in U.S. Pat. 5,514,680 (Weber et al.), Incorporated herein by reference. COX-2 inhibitors have been reported in the art and many chemical structures that produce the inhibition of cyclooxygenase-2 are known. COX-2 inhibitors are described, for example, in U.S. Pat. 5,616,601; 5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,475,995; 5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,409,944 and 5,130,311, all incorporated herein by reference. Preferred COX-2 inhibitors include celecoxib (SC-58635), DUP-697, fluosulide (CGP-28238), meloxicam, 6-methoxy-2 naphthyl ocetic acid (6-MNA), MK-966, nabumetone (prodrug for 6-) MNA), nimesulide, NS-398, SC-5766, SC-58215, T-614 or combinations of these. The dose levels of the COX-2 inhibitors are in the order of between 0.005mg to * about 14Omg per kilogram of body weight per day, which are therapeutically effective in combination with an opioid analgesic. Alternatively, they are administered between 0.25mg to about 7g per patient per day of COX-2 inhibitor in combination with an opioid analgesic. In other embodiments, a non-opioid drug that produces a desired effect in addition to analgesia may be included, for example antitussives, expectorants, decongestants, antihistamines, local anesthetics and the like. An oral dosage form according to the present invention can be provided as, for example, granules, spheroids, beads, fragments (hereinafter collectively referred to as "multiparticles"). An amount of multiparticles effective to produce the desired dose of opioid over time can be placed in a capsule or can be incorporated in any other suitable oral solid form. Alternatively, the oral dosage form may be in the form of a tablet. DOSAGE FORMS OF CONTROLLED RELEASE The opioid agonist / opioid antagonist combination can be formulated as a sustained or controlled oral formulation in any suitable tablet, coated tablet or multiparticulate formulation known in the art. The sustained release dosage form may optionally include a sustained release vehicle that is incorporated in a matrix together with the opioid agonist and the opioid antagonist, or it may be applied as a sustained release coating. In embodiments where the opioid analgesic comprises hydrocodone, sustained release oral dosage forms may include analgesic doses of between 8 mg to about 50 mg of hydrocodone per unit dose. In sustained release oral dosage forms, where the therapeutically active opioid is hydromorphone, 64 mg of hydromorphone hydrochloride is included in an amount of between 2 mg to sustained release oral dosage forms. In another embodiment, the opioid analgesic comprises morphine, and the sustained release oral dosage forms of the present invention include between 2.5mg to about 80Omg of morphine by weight. In yet another embodiment, the opioid analgesic comprises oxycodone, and sustained release oral dosage forms include between 2.5 mg and approximately 800 mg oxycodone. The opioid analgesic may comprise tramadol, and the sustained release oral dosage forms may include between 25mg to 80Omg of tramadol per unit dose. The dosage form may contain more than one opioid analgesic to produce an essentially equivalent therapeutic effect.

Alternatively, the dosage form may contain molarly equivalent amounts of other salts of the opioids useful in the present invention. In a preferred embodiment of the present invention, the sustained release dosage form comprises particles containing the active ingredient, wherein the particles have diameters from O.lmm to about 2.5mm, preferably from 0.5mm to about 2mm. The particles are preferably coated with a film of a material that allows the release of the opioid agonist / antagonist combination at a sustained rate in an aqueous medium. The coating film is chosen to obtain, in combination with other properties, a desired invitro release rate. The sustained release coating formulations of the present invention should be capable of producing a continuous and resistant film that is smooth and elegant, capable of supporting pigments and other additives, as well as being non-toxic and inert. In certain embodiments, the particles comprise normal release matrices containing the opioid analgesic with the opioid antagonist.

COATINGS The oral dosage forms of the present invention may optionally be coated with one or more materials suitable for the regulation of the release or for the protection of the formula. In one embodiment, coatings are provided that allow a dependent or independent release of the pH, i.e., upon exposure to gastrointestinal fluids. A pH-dependent coating functions to release the opioid in desired areas of the gastrointestinal tract (Gl), ie the stomach or small intestine, in such a way that an absorption profile capable of producing at least 8 hours is produced, and preferably 12 hours, and up to 24 of analgesia for a patient. When a pH independent coating is desired, the coating is designed to achieve optimum release regardless of changes in the pH of the surrounding fluid, for example the Gl tract. It is also possible to formulate compositions that release a portion of the dose in a desired area of the Gl tract, for example the stomach, and release the remainder of the dose in another area of the Gl tract, for example the small intestine. The formulations according to the present invention which use pH dependent coatings to obtain formulations can also produce a repeated action effect, wherein the unprotected drug is coated on the enteric layer and is released into the stomach, while the rest , being protected by the enteric coating, is released further down the gastrointestinal tract. Coatings which are pH dependent include shellac, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulphthalate and copolymers of methacrylic acid esters, zein and the like can be used according to the present invention. . In certain preferred embodiments the substrate (i.e. the core of the tablet, the matrix particle) containing the opioid analgesic (with or without the COX-2 inhibitor) is coated with a hydrophobic material selected from (i) an alkylcellulose; (ii) an acrylic polymer or (iii) mixtures thereof. The coating can be applied in the form of an organic or aqueous solution or dispersion. The coating can be applied to obtain a weight gain of between 2 to about 25% of the substrate, to obtain the desired profile of sustained release. Coatings derived from aqueous dispersions are described in detail in U.S. Pat. 5,273,760 and 5,286,493 assigned to the assignee of the present invention, and which are incorporated herein by reference. Other examples of sustained release formulations and coatings that may be used in accordance with the present invention include U.S. Pat. Assignee 5,324,351; 5,356,467, and 5,472, 712, incorporated in their entirety by reference herein. Alkylcellulose Polymers Cellulose materials and polymers, including alkylcelluloses, produce hydrophobic materials suitable for coating the beads according to the present invention. Simply by way of example, a preferred alkylcellulosic polymer is ethylcellulose, although one of ordinary skill in the art will appreciate that other cellulose or alkylcellulose polymers can be readily used, alone or in combination, as all or part of a hydrophobic coating in accordance with the present invention. A commercially available aqueous dispersion of ethylcellulose is Aquacoat® (EMC Corp, Philadelphia, Pennsylvania, USA). Aquacoat® is prepared by dissolving the ethylcellulose in an organic solvent not immiscible with water, and then emulsifying it in water in the presence of a surfactant and a stabilizer. After homogenizing it to generate smaller drops to a miera, the organic solvent is evaporated under vacuum to form a pseudolatex. During the manufacturing stage, the plasticizer is not incorporated into the pseudolatex. Therefore, before using it as a coating, it is necessary to intimately mix the Aquacoat® with a suitable plasticizer before it is used. Another commercially available ethylcellulose dispersion is Surelease® (Colorcon, Inc., West Point, Pennsylvania, USA). This product is prepared at '. Incorporate a plasticizer in the dispersion during the manufacturing process. A hot melt is prepared from a polymer, plasticizer (dibutyl sebacate) and a stabilizer (oleic acid) as a homogeneous mixture which is then diluted with an alkaline solution to obtain an aqueous dispersion that can be applied directly to substrates. Acrylic Polymers In other preferred embodiments of the present invention, the hydrophobic material comprising the controlled release coating is a pharmaceutically acceptable acrylic polymer, including, but not limited to, copolymers of acrylic and methacrylic acid, copolymers of methyl methacrylate, methacrylate of ethoxyethyl, cyanoethyl methacrylate, poly (acrylic acid), poly (methacrylic acid), methacrylic acid alkyl amide copolymer, poly (methyl methacrylate), polymethacrylate, poly (methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer , poly (methacrylic acid anhydride), and glycidyl methacrylate co-polymers. In certain preferred embodiments, the acrylic polymer comprises one or more copolymers of ammonium methacrylate. Ammonium methacrylate copolymers are known in the art and are described in NF XVII as fully polymerized copolymers such as esters of acrylic or methacrylic acid with low content of quaternary ammonia groups. In order to obtain a desirable dissolution profile, it may be necessary to incorporate two or more copolymers of ammonium methacrylate with different physical properties, such as different molar proportions of the quaternary ammonia groups against neutral (meth) acrylic esters. Certain polymers of the methacrylic acid ester type are useful for preparing pH-dependent coatings that can be used in accordance with the present invention. For example, there is a family of synthesized copolymers of diethylaminoethyl methacrylate and other neutral methacrylic esters, also known as methacrylates copolymers or methacrylic acid polymers, commercially available as Eudragit® from Rohm Tech, Inc. There are several different types of Eudragit®. For example, Eudragit® E is an example of a methacrylic acid copolymer that swells and dissolves in an acid medium. Eudragit® L is a methacrylic acid copolymer that does not swell at a pH < 5.7 and that it is soluble at about pH > 6_. Eudragit® S does not swell at a pH < 6.5, and it is soluble at approximately pH >; 7. Eudragit® RL and Eudragit® RS swell in water and the amount of water absorbed by these polymers depends on the pH, although dosage forms coated with > . Eudragit® RL and RS are independent of pH. In certain preferred embodiments, the acrylic coating comprises a blend of two acrylic resin lacquers commercially available from Rohm Pharma under the trademarks Eudragit® RL30D and Eudragit® RS30D, respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylic esters with low content of ammonia quaternary groups, where the molar ratio between the ammonia groups versus the remaining neutral (meth) acrylic esters is 1:20 in Eudragit® RL30D and 1:40 on Eudragit® RS30D. The average molecular weight is about 150,000. The code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents. The mixtures of Eudragit® RL / RS are insoluble in water and in digestive fluids. However, the coatings formed therefrom swell and are permeable in aqueous solutions and digestive fluids. The Eudragit® RL / RS dispersions of the present invention can be blended in any desired ratio to obtain a sustained release formulation having a desirable dissolution profile. Desirable sustained-release formulations can be obtained, for example, with a retardation coating derived from 100% Eudragit® RL, 50% Eudragit® RL and 50% Eudragit® RS and 10% Eudragit® RL: Eudragit® 90% RS . Of course, the artisan will recognize that other acrylic polymers can be used, such as, for example, Eudragit® RL. Plasticizers In some embodiments of the present invention wherein the coating comprises an aqueous dispersion of a hydrophobic material, including an effective amount of a plasticizer in the aqueous dispersion of the hirophobic material will further improve the physical properties of the sustained release coating. For example, since ethylcellulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, it is preferable to incorporate a plasticizer in an ethylcellulose coating containing a sustained release coating before using it as a coating material. . In general, the amount of plasticizer included in a coating solution is based on the concentration of the film former, i.e., often between 1 to about 50% of the weight of the film former. However, the concentration of the plasticizer can be determined appropriately only after careful experimentation with the particular coating solution and the method of application. Examples of suitable plasticizers for ethylcellulose include water-insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and triacetin, it is possible to use other water-insoluble plasticizers (such as acetylated monoglycerides, phthalate esters). , resin oil, etc). Triethyl citrate is a plasticiser especially preferable for the aqueous dispersions of ethylcellulose of the present invention. Examples of suitable plasticizers for the acrylic polymers of the present invention include, but are not limited to, citric acid esters such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene glycol. Other plasticizers that were found to be suitable for increasing the elasticity of films formed from acrylic films such as lacquer solutions Eudragit® RL / RS includes polyethylene glycols, propylene glycol, diethyl phthalate, castor oil and triacetin. Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention. It was further discovered that adding small amounts of talc reduces the tendencies of aqueous dispersions to stick during the process, and acts as a polishing agent. PROCESSES FOR PREPARING COVERED ACCOUNTS When a hydrophobic material is used to coat pharmaceutically inert beads such as beads. nu pariel 18/20, the plurality of resulting solid controlled release beads can be placed in a gelatin capsule in sufficient quantity to deliver an effective dose of controlled release upon ingestion and contact with a surrounding fluid, i.e. gastric fluid or means of dissolution. The controlled release account formulations of the present invention slowly release the therapeutically active agent, i.e., when ingested and exposed to gastric fluids, and then to intestinal fluids. The controlled release profile of the formulations of the present invention can be altered, for example, by varying the amount of coating with the hydrophobic material, altering the way in which the plasticizer is added to the hydrophobic material, varying the amount of plasticizer relative to the hydrophobic material, by including additional ingredients or excipients, altering the manufacturing method, etc. The dissolution 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 the therapeutically active agent are prepared, for example by dissolving the therapeutically active agent in water and then spraying the solution on a substrate, for example nu pariel 18/20 beads using a Wuster insert. Optionally, additional ingredients may be added before coating the beads in order to aid in the agglutination of the opioid to the beads, to color the solution, etc. For example, a product that includes hydroxypropylmethylcellulose, etc., with or without a dye (ie, Opadry®, commercially available from Colorcon, Inc.) can be added to the solution, and mixed (i.e., for about 1 hour) before application. to the accounts. The resulting coated substrate, which in this example are beads, can optionally be coated with a barrier agent to separate the therapeutically active agent from the hydrophobic controlled release coating. An example of a suitable barrier agent is one comprising hydroxypropylmethylcellulose. However, any film former known in the art can be used. It is preferred that the barrier agent does not affect the rate of dissolution of the final product. The beads can then be coated with an aqueous dispersion of the hydrophobic material. The aqueous dispersion of the hydrophobic material preferably includes an effective amount of plasticizer, for example triethyl citrate. Aqueous dispersions preformulated with ethylcellulose can be used, such as Aquacoat® or Surelease®. If Surelease® is used, it is not necessary to separately add a plasticizer. Alternatively, preformulated aqueous dispersions of acrylic * polymers such as Eudragit® can be used. The coating solutions of the present invention preferably contain, in addition to the film former, plasticizer and a solvent system (ie water), a colorant to give elegance and distinction to the product. Instead, color can be added to the solution of the therapeutically active agent, or in addition to the aqueous dispersion of the hydrophobic material. For example, color can be added to the Aquacoat® using color dispersions based on alcohol or propylene glycol, ground aluminum and opacifiers such as titanium dioxide, adding color with grinding to solutions of water-soluble polymers, and then using low grinding in the plasticized Aquacoat®. Alternatively, any suitable method can be used to color the formulations of the present invention. Suitable ingredients for coloring the formulation when an aqueous dispersion of an acrylic polymer is used include titanium dioxide and pigments, such as iron oxide pigments. However, the incorporation of pigments increases the retardation effect of the coating. Plasticized hydrophobic materials may be applied to the substrate, comprising the therapeutically active agent by spraying any suitable spray equipment known in the art. In a preferred method, a Wurster fluidized bed system is used wherein an air jet, injected from below, fluidizes the core material and effects drying while spraying the acrylic polymer coating. Preferably, a sufficient amount of the hydrophobic material is applied to obtain a predetermined controlled release of the therapeutically active agent when the coated substrate is exposed to the aqueous solutions, for example gastric fluids, taking into account the physical characteristics of the therapeutically active agent, the manner in which that the plasticizer is incorporated, etc. After coating with the hydrophobic material, an additional layer of a film former, such as Opadry®, is optionally applied to the beads. If this layer is supplied, it is to essentially reduce the agglomeration of the accounts. The release of the therapeutically active agents from the controlled release formulation of the present invention can be further influenced by adjusting them at a desired rate by adding one or more release modifying agents, or by providing one or more passages through the coating. The proportion of hydrophobic material against water-soluble material is determined by, among other factors, the rate of release required and the solubility characteristics of the selected materials. Release modifying agents that function as pore formers can be organic or inorganic, and include materials that can be dissolved, removed or filtered from the coating into the environment of use. The pore formers may comprise one or more hydrophilic materials such as hydroxypropylmethylcellulose. The sustained release coatings of the present invention can also include erosion promoting agents, such as starch and gums. The sustained release coatings of the present invention may also include materials useful for making microporous sheets in the environment of use, such as polycarbonates comprised of linear carbon acid polyesters where carbonate groups reoccur in the polymer chain. The release modifying agent may also comprise a semipermeable polymer. In certain preferred embodiments, the release modifying agent is selected from hydroxypropylmethylcellulose, lactose, metal stearates and mixtures of any of the foregoing. The sustained release coatings of the present invention may also include an output device comprising at least one passage, orifice or the like. The passage may be formed by the methods disclosed in U.S. Pat. 3,845,770; 3,916,889; 4,063,064 and 4,088,864 (all incorporated herein by reference). The passage can have any shape, and can be round, triangular, square, elliptical, irregular, etc. FORMULATIONS FOR MATRIX ACCOUNTS In other embodiments of the present invention, the controlled release formula is achieved by a matrix having a controlled release coating as specified above. The present invention also utilizes a controlled release matrix that allows rates of invitro dissolution of the opioid within the preferred ranges and that releases the opioid in a pH-dependent or pH-independent manner. Suitable materials for inclusion in a controlled release matrix will depend on the method used to form the matrix. For example, a matrix in addition to the opioid analgesic and (optionally) COX-2 may include: hydrophilic and / or hydrophobic materials, such as gums, cellulose ethers, acrylic resins, protein derived materials; the list is not intended to be exclusive, and any hydrophobic or hydrophilic pharmaceutically acceptable material which is capable of imparting a controlled release of the active agent and which melts (or softens to the extent necessary to be effective) can be used in accordance with the present invention. extruded). Long chain digestible hydrocarbons (Cs-Cso, especially C12-C40). substituted or unsubstituted, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, oils and mineral and vegetable waxes and stearyl alcohol; and polyalkylene glycols. Of these polymers, acrylic polymers, especially Eudragit® RSPO, cellulose ethers, especially hydroxyalkylocelluloses and carboxyalkylocelluloses are preferred. 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 hydrocarbon, the hydrocarbon preferably has a melting point of between 25 and 90 ° C. Among the long chain hydrocarbon materials, fatty alcohols (aliphatic) are preferred. The oral dosage form can contain up to 60% (by weight) of at least one digestible and long chain hydrocarbon. Preferably, the oral dosage form contains up to 60% (by weight) of at least one polyalkylene glycol. The hydrophobic material is preferably selected from the group consisting of alkyl celluloses, polymers and copolymers of acrylic and methacrylic acids, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil or mixtures thereof. In certain preferred embodiments of the present invention, the hydrophobic material is a pharmaceutically acceptable acrylic polymer, including but not limited to copolymers of acrylic and methacrylic acids, methyl methacrylate, copolymers of methyl methacrylate, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly (acrylic acid), poly (methacrylic acid), alkylamino copolymer of methacrylic acid, poly (methyl methacrylate), poly (methacrylic acid) (anhydride), polymethacrylate, polyacrylamide, poly (methacrylic acid anhydride), and glycidyl methacrylate copolymers. In other embodiments, the hydrophobic material is selected from materials such as hydroxyalkylocelluloses such as hydroxypropylmethylcellulose and mixtures of the foregoing. The preferred hydrophobic materials are insoluble in water with hydrophobic or hydrophilic tendencies more or less pronounced. Preferably, the hydrophobic materials useful in the present invention have a melting point of between 30 to about 200 ° C, preferably 45 to 90 ° C. Specifically, the hydrophobic material may comprise natural or synthetic waxes, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl, or preferably keto stearyl alcohol), fatty acids, including but not limited to fatty acid esters, fatty acid glycerides. (mono-, di-, and tri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol and hydrophobic and hydrophilic materials with hydrocarbon main structures. Suitable waxes include, for example, beeswax, glycerin wax, castor wax and carnauba wax. For purposes of the present invention, a solid substance is defined as any material that is normally solid at room temperature and having a melting point of between 30 and about 100 ° C. Suitable hydrophobic materials that can be used in accordance with the present invention include digested, long chain (Cs-Cso, especially C 2 -C 40), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of acids fatty, mineral and vegetable oils and natural and synthetic waxes. Hydrocarbons with melting points between 25 and 90 ° C are preferred. Of the long chain hydrocarbon materials, fatty alcohols (aliphatic) are preferred in certain embodiments. The oral dosage form can contain up to 60% (by weight) of at least one digestible and long chain hydrocarbon. Preferably, they are included in the formulations of. the matrix a combination of two or more hydrophobic materials. If an 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 wax, stearic acid and stearyl alcohol. This list is not intended to be exclusive. A suitable matrix in particular comprises at least one hydroxyalkyl cellulose soluble in water, at least one C2-C36 aliphatic alcohol. preferably C14-C22 and, optionally, at least one polyalkylene glycol. The at least one hydroxyalkyl cellulose is preferably an alkyl hydroxy (Ci to Ce) cellulose, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and, especially, hydroxyethylcellulose. The amount of the at least one hydroxyalkyl cellulose in the present oral dosage form will be determined by the precise rate of opioid release that is required. The at least one aliphatic alcohol can be, for example, lauryl alcohol, myristyl alcohol, or stearyl alcohol. However, in particularly preferred embodiments of the present oral dosage form, the at least one aliphatic alcohol is cetyl alcohol or cetostearyl alcohol. The amount of at least one aliphatic alcohol in the present oral dosage form will be determined, as previously done, by the precise rate of opioid release that is required. It will also depend on whether or not at least one polyalkylene glycol is present in the oral dosage form. In the absence of at least one polyalkylene glycol, the oral dosage form preferably contains between 20 and 50% by weight of at least one aliphatic alcohol. If at least one polyalkylene glycol is present in the oral dose form, then the combined weight of the at least one aliphatic alcohol and at least one polyalkylene glycol preferably constitutes between 20 and 50% of the weight of the total dose. In one embodiment, the ratio of 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 release of the opioid from the formulation. A ratio of 1: 2 and 1: 4 of the at least one hydroxyalkyl cellulose to the at least one aliphatic alcohol / polyalkylene glycol is preferred, wherein a ratio of between 1: 3 and 1: 4 is particularly preferred. The at least one polyalkylene glycol can be, for example, polypropylene glycol or, which is preferable, polyethylene glycol. It is preferred that the average molecular weight of the at least one polyalkylene glycol is between 1000 and 15,000, and especially between 1,500 and 12,000. Another suitable controlled release matrix could comprise an alkylcellulose (especially ethylcellulose), an aliphatic alcohol C_2 to C36 and, optionally, a polyalkylene glycol. In another preferred embodiment, the matrix includes a pharmaceutically acceptable combination of at least two hydrophobic materials. In addition to the above ingredients, a controlled release matrix can also contain adequate amounts of other materials, ie diluents, lubricants, binders, granulation aids, dyes, flavorings and others that are conventional in the pharmaceutical art. PROCESSES FOR PREPARING MATRIX BASED ACCOUNTS In order to facilitate the preparation of a solid oral dosage form and controlled release according to the present invention, any method for preparing a matrix formulation known in the art can be used. For example, incorporation into the matrix can be effected by forming (a) granules comprising at least one hydroxyalkyl cellulose soluble in water and an opioid or opioid salt.; (b) mixing the hydroxyalkyl cellulose containing granules with at least one C2-C3e aliphatic alcohol; and (c) optionally compressing and forming the granules. Preferably, the granules are formed by wet granulating the hydroxyalkyl cellulose and the opioid with water. In a particularly preferred embodiment of this process, the amount of water added during the wet granulation step is preferably between 1.5 and 5 times, especially between 1.75 and 3.5 times the dry weight of the opioid. In other alternative embodiments, a sphering agent, together with the active ingredient, can be spherized to form spheroids. Microcrystalline cellulose is preferred. A suitable microcrystalline cellulose is, for example, the material sold under the trademark Avicel PH 101 (Trade Mark, FMC Corporation). In such embodiments, in addition to the active ingredient and the sphering agent, the spheroids may also contain a binder. Suitable binders, such as low viscosity and water soluble polymers. However, water-soluble low alkyl hydroxy-celluloses, such as hydroxypropylcellulose, are preferred. Additionally (or alternatively) the spheroids may contain a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer such as ethyl acrylate-methacrylic acid copolymer, or ethyl cellulose. In such embodiments, the controlled release coating will generally include a hydrophobic material such as (a) a wax, either on its own or mixed with a fatty alcohol; or (b) shellac or zein. Fusion extrusion matrix Sustained release matrices can also be prepared by melt blending or melt extrusion techniques. Generally, melt blending techniques involve melting a normally solid hydrophobic material, for example a wax, and incorporating a powder drug therein. To obtain a sustained release dosage form, it may be necessary to incorporate an additional hydrophobic substance, for example ethylcellulose or a water-insoluble acrylic polymer in the hydrophobic material of melted wax. Examples of sustained release formulations prepared by granule fusion techniques can be found in U.S. Pat. 4,861,598, assigned to the assignee of the present invention, and incorporated in its entirety to the present pro reference. The additional hydrophobic material may comprise one or more water-insoluble waxy thermoplastic substances, possibly mixed with one or more waxy thermoplastic substances less hydrophobic than one or more water-insoluble waxy substances. In order to achieve constant release, each waxy substance in the formulation must be essentially non-degradable e. insoluble in gastrointestinal fluids during the initial stages of release. The most useful water-insoluble waxy substances can be those with a solubility in water of less than about 1: 5,000 (by weight). In addition to the above ingredients, a sustained release matrix may also contain suitable amounts of other materials, for example diluents, lubricants, binders, granulation aids, colorants, flavors and stabilizers conventional in the pharmaceutical art, in amounts up to about 50% of the weight of the particles, if desired. In the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986), incorporated herein by reference, specific examples of pharmaceutically acceptable carriers and excipients that can be used to formulate oral dosage forms are described. Fusion Extrusion Multiparticles The preparation of a suitable melt extrusion matrix according to the present invention can, for example, include the steps of mixing the analgesic opioid together with at least one hydrophobic material and preferably the additional hydrophobic material to obtain a homogeneous mixture. The homogeneous mixture is then heated to a temperature sufficient to at least soften the mixture sufficiently to extrude it. The resulting homogeneous mixture is then extruded to form beads. The extrudate is preferably cooled and cut into multiparticulates by any form known in the art. The beads are cooled and cut into multiple particles. The multiparticles are then divided into unit doses. The extrudate preferably has a diameter of between 0.1 to about 5mm and provides a sustained release of the therapeutically active agent for a period of between 8 to about 24 hours. An optional process for preparing the melt extrusions of the present invention includes directly measuring an hydrophobic material in an extruder., a therapeutically active agent and an optional binder; heat the homogeneous mixture; Extract the homogeneous mixture to form beads; cool the beads that contain the homogeneous mixture; cut the beads into particles to have a size between 0.1 to about 12mm; and divide these particles into unit doses. In this aspect of the present invention, a relatively continuous manufacturing process is performed. The diameter of the extruder outlet opening or door can also be adjusted to vary the thickness of the extruded beads. In addition, the outlet part of the extruder nc needs to be round; It can be oblong, rectangular, etc. Outgoing beads can be reduced to particles using a hot wire cutter, guillotine, etc. The melt-extruded multiparticulate system may have, for example, granule or spheroidal form, depending on the exit hole of the striker. For purposes of the present invention, the terms "melt extruded multiparticles" and "melt extruded multiparticulate systems" and "melt extruded particles" refer to a plurality of units, preferably within a range of similar size or shapes , and containing one or more active agents and one or more excipients, preferably including a hydrophobic material as described herein. In this regard, the multiparticulas extruded by fusion will be in a range of between 0.1 to approximately 12mm in length, and with a diameter of between 0.1 to approximately 5mm. In addition, it will be understood that melt extruded multiparticles can have any geometric shape within this range of sizes. Alternatively, the extrudate can simply be cut into the desired lengths and divided into unit doses of the therapeutically active agent, without the need for the sphering step. In a preferred embodiment, oral dosage * forms are prepared to include an effective amount of multiparticulates extruded by fusion within a capsule. For example, a plurality of melt extruded multiparticles may be placed in a gelatin capsule in sufficient quantity to produce an effective sustained release dose when ingested and in contact with the gastric fluid. In another preferred embodiment, a suitable amount of the multiparticulate extrudate is compressed into an oral tablet using conventional equipment for tablets, and using conventional techniques. The techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are also described in Remington's Pharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980), incorporated herein by reference. reference. Still another preferred embodiment, the extrudate can be molded into tablets as set forth in U.S. Pat. 4,957,681 (Klimesch et al.), Described above with additional details and which is incorporated herein by reference.

Optionally, the sustained release fusion extruded multiparticulate tablets or systems may be coated, or the gelatin capsule may be further coated with a sustained release coating such as the sustained release coatings described above. These coatings preferably include a sufficient amount of hydrophobic material to obtain a weight gain level of between 2 to about 30%, although overcoating may be greater depending on the physical properties of the particular opioid analgesic compound being used and the rate of desired release, among other things. The melt extruded unit dose forms of the present invention may further include combinations of melt extruded multiparticles containing one or more of the therapeutically active agents previously disclosed before being encapsulated. In addition, unit dosage forms can also include an amount of an immediate release therapeutically active agent for rapid therapeutic effect. The immediate release therapeutically active agent can be incorporated, for example, as separate granules within the gelatin capsule, or they can be coated on the surface of the multiparticulas after the preparation of dosage forms (i.e., controlled release coating). or of matrix ba.se). The unit dosage forms of the present invention may also contain a combination of the controlled release beads and matrix multiparticles to achieve a desired effect. The sustained release formulations of the present invention preferably stop the release of the therapeutically active agent, i.e., when ingested and exposed to gastric fluids, and then to intestinal fluids. The sustained release profile of the extruded formulations according to the present invention can be altered, for example, by varying the amount of the retarder, ie the hydrophobic material, by varying the amount of plasticizer relative to the hydrophobic material, by including ingredients or additional excipients, altering the manufacturing method, etc. In other embodiments of the present invention, the melt extrudate is prepared without including the therapeutically active agent, which is subsequently added to the extrudate. In these formulations, the therapeutically active agent is typically mixed with the extruded matrix material, and then the mixture is formed into tablets to produce a slow release formulation. Such formulations can be helpful, for example, when the therapeutically active agent included in the formulation is sensitive to temperatures necessary to soften the hydrophobic material or the retardant material. DETAILED DESCRIPTION OF THE PREFERRED MODALITIES The following examples illustrate various aspects of the present invention. They should not be interpreted in any way * as limitations on claims. A direct comparison of the competitive antagonist properties of naltrexone after co-administration with various opioid agonists was not performed prior to the present invention, as far as the inventors' knowledge is concerned. However, dose range studies were conducted to evaluate the properties of opioid antagonists in subjects who were challenged with heroin or morphine. In general, the pre-administration of 50mg naltrexone 24 hours before receiving 25mg of intravenous heroin completely blocked or attenuated the effects of the opioid agonist. See, Gonzalez JP, Brogden RN. "Naltrexone: A Review of its Pharmacodynamic and Pharmacokinetik Properties and Therapeutic Efficacy in the Management of Opioid Dependence." Drugs 1988; 35: 193-213: Resnick RR, Valavka J, Freedman AM, Thomas M. "Studies of EN-1639A (Naltrexone): A New Narcotic Antagonist" Am. J. Psychiatry 1974; 131: 646-650, where both rejoin to the present by reference. EXAMPLE 1 In Example 1, a randomized, blinded, placebo-controlled, single-dose, four-way crossover study was conducted, which evaluated whether an oral 6.4mg naltrexone solution could block the opioid agonist properties of 15mg hydrocodone in six normal and healthy volunteers. »The study population included only women because previous observations indicate that women are more sensitive to opioid agonist effects, compared to men. The four treatments were HYIR / APAP (2 tablets of 7.5mg of hydrocodone and 750mg of acetominophen, Vicodin ES®) and an oral solution of 3.2mg of naltrexone, HYIR / APAP (2x7.5mg) and an oral solution of 6.4mg of naltrexone , comparator tablets HYIR (2 tablets of 750mg of Trilisat®) and an oral solution of naltrexone (placebo), and HYIR / APAP (2 tablets of Vicodin ES®) and oral solution of naltrexone (placebo). All treatments were administered on an empty stomach. A period of 48 hours between doses occurred. Subjects were randomly assigned four treatment sequences from the four treatment groups. The subjects reported to the study facility one night before the first dose and remained confined until the evaluation of 24 hours post-dose at the last dose. The safety measures consisted of reports of adverse events, vital signs, abnormal laboratory values, abnormal physical exams and ECG results. Pharmacodynamic parameters (pupil size and modified questionnaire on specific effects of drugs) were also evaluated. Test Treatments The four treatments were: tablets of * immediate release of hydrocodone (2x7.5mg) and naltrexone 3.2 mg oral solution. Hydrocodone immediate release tablets (2x7.5mg) and 6.4mg naltrexone oral solution. Comparison tablets of immediate release of hydrocodone and naltrexone oral placebo solution. Hydrocodone immediate-release placebo tablets (2x7.5mg) and naltrexone oral solution placebo. Test products The products evaluated in the present study included Vicodin ES® (7.5mg hydrocodone bitartrate and 75Omg acetaminophen, Knoll Pharmaceuticals), Trilisalato® (750mg magnesium trisalicylate, Purdue Frederick) that worked as a comparator, and naltrexone powder. Vicodin ES® was selected as an active ingredient since the acetaminophen portion in this product may not have an effect on the central nervous system or pupillary measurement. Trilisalate was selected as "comparator" because its physical appearance is similar to Vicodin ES® and has no effect on the central nervous system or pupillary measurement. A powdered naltrexone formula was selected instead of the commercially approved tablet formulation (Revia® 50mg tablets, DuPont) to improve the overall decision in the preparation of the oral solution. An on-site research pharmacologist reconstituted the oral solution from the naltrexone powder in a sterile environment using appropriate pharmaceutical techniques. Naltrexone powder (Mallinckrodt Chemical) was used to formulate the naltrexone solution. Individual solutions of naltrexone were prepared using a modification of the method proposed by Tsang and Holtsman. Tsang BK, Holtsman R. "Room Temperature Stability of Liguid Naltrexone." Anesthesiology 1995: 83: A864, incorporated herein by reference. Immediately before (<minutes) at each dose period, naltrexone solution was prepared by weighing 32mg and 64mg of naltrexone powder. Each of these portions was dissolved in 50 mL of distilled water and 50 mL of simple syrup, NF to obtain a final volume of 100 mL. The concentration of the final solutions was 0.32mg / mL (32mg / 100 mL) and 0.64mg / mL (64mg / 100mL), respectively. These concentrations allowed the same volume (lOmL) of oral naltrexone solution to be administered during each dosing period. The naltrexone oral solution placebo was prepared in the same vehicle as the active solution. A bitter agent, Bitterguard (denatonium benzoate, NF) was added to produce a flavor similar to the active solution. Pharmacodynamic measurements. to. Pupillary size - measured by pupilometry Pupil diameter measurements were made with the Polaroid CU-5 camera with a 75 mm lens and electronic flash built using Polacolor ER 669 instant film. This method is accepted as a safe and accurate way to study the pupils , and is commonly considered as only inferior to the infrared television pupilometric technique (a much more versatile and sophisticated method, but also more expensive and cumbersome). It is said that the Polaroid Cu-5 method has an accuracy of up to O.lmm. See Czarnecki JS. Pilley SF, Thomson HS. "The Use of Photography in the Clinical Evaluation of Unequal Pupils" Cañad. J. Ophtal. 1979; 14: 297-302; incorporated herein by reference. The pupillary diameters were measured as follows: the chamber was modified by covering two small sections of the flash at 3 and 9 o'clock, so that the reflection of the flash produced by the cornea did not obscure the horizontal pupillary margin. The camera was placed in front of the subject's face about 8cm in front of the lateral orbital basins and the eyes occupying the upper part of the field (to minimize looking up). The subject was asked to look towards the camera and fix the view on an object at a distance, thereby minimizing the near reflection. With the volunteer eyes fixed on the distance, the photograph was taken. All the photographs were taken with constant ambient light. The pupil latency was such that the flash did not affect the pupillary diameter. Tonic constriction of the pupil occurs after the flash, but it is of short duration; therefore, it did not interfere with the measurements necessary for this study. See Smith SA, Dewhist RR. "A Single Diagnostic Test for Pupillary Abnormality in Diabetic Autonomic Neuropathy". Diabetic Medicine 1988; 3: 38-41; incorporated herein by reference. Reveal the photograph during the recommended time period (approximately 1 minute, which varies with the ambient temperature) will produce a photograph in one-to-one proportion of the middle part of the volunteer's face, where the pupils are at the top of the photograph. The horizontal pupillary diameter is then measured using a simple magnifying glass with an interconstructed grating calibrated at 0.1 mm. Only the left eye was used to measure the pupillary effects in each lapse, as specified in the protocol, b) Modified questionnaire of specific effects of drugs. Questionnaire is a questionnaire modification of 22 questions used by Jasinski and Preston. See, Jasinski DR.

"Assessment of the Abuse Potential of Morphine-Like Drugs (methods used in man)." In: Drug Addiction I (Martin, W.R, ed.), 1997: 197-258. Springer- Verlag, New York; Preson KL, Jasinski DR, Testa M. "Abuse Potential and Pharmacological, Comparison of Tramadol and Morphine." Drug and Alcohol Dependence 1991; 27: 7-17; both incorporated herein by reference. The present questionnaire consisted of 10 questions rated by the subject 10 minutes before taking blood samples. The questions are related to signs of opioid agonist drugs, and it was the following: questions for the subject 1) Do you feel any effect for the drugs ?, 2) Do you feel itching on the skin? 3) Do you feel calm ?, 4) Are you sleepy ?, 5) Do you feel drunk ?, 6) Do you feel nervous ?, 7) Do you feel full of energy ?, 8) Do you feel you need to talk ?, 9) Do you feel sick to your stomach? 10) Do you feel dizzy? The subject qualified the question by placing a vertical mark on a visual analog scale (VAS) of 100mm set at one end in "for nothing" and at the other end in "very much". The size of the pupils of the left eye was measured at the baseline (30 minutes before the dose), and at 0.5,1,2,4,6,9 and 12 hours after the dose, and the subject rated the effect of the drug based on a visual analogue scale for the Modified Drug Specific Effects Questionnaire ("MSDEQ") at baseline, and at 0.5.1,2,4,6,9 and 12 hours after dosing. We visually and statistically examined separate graphs of the 11 responses (MSDEQ questions and pupillary diameter measurements) against the dose of naltrexone, to determine the nominal effective dose of naltrexone in combination with the dose of hydrocodone used in the study. The adverse events that were reported were those commonly associated with the administration of opioid analgesics, and most were classified as "mild". No serious adverse events or deaths occurred, and no patient in the study was discontinued due to adverse events. The results are presented in Figures 1 and 2. Figure 1 shows the antagonism of naltrexone of the VAS (visual analogue scale) of the "drug effect" induced by hydrocodone. This refers to the first question of the Modified Specified Drug Effect Questionnaire in which the subjects were asked "Do you feel any effect of the drug?". The results suggest that there is a dose-response effect for naltrexone; increasing the dose of naltrexone decreased the VAS of the "drug effect" of hydrocodone. "The 6.4mg dose of naltrexone antagonized the effects of a dose of 15 mg hydrocodone to a greater extent than the 3.2 mg dose of naltrexone. Hydrocodone opioid was not completely blocked by the naltrexone dose of 6.4mg Figure 2 shows naltrexone antagonism of the hydrocodone-induced pupil constriction These results also suggest a dose-response effect for naltrexone; the dose of naltrexone caused less pupillary constriction in subjects who received 15 mg hydrocodone.The 6.4mg dose of naltrexone antagonized the pupil constriction induced by hydrocodone to a greater extent than the dose of 32mg of naltrexone.The pupil constriction of hydrocodone was not completely blocked by the 6.4mg dose of naltrexone.The minimal pupillary constriction occurred in the placebo group.The group of hydrocodone and Naltrexone placebo experienced the greatest pupillary constriction and, consequently, had the lowest pupil diameter measurements. EXAMPLE 2 In Example 2, a ten-period, randomized, crossover, blinded study was conducted that evaluated the proportion of oral naltrexone against oral hydrocodone that would nominally minimize the opioid agonist effects in normal and healthy volunteers. 21 subjects were enrolled in the study, and 16 completed it. The ten treatments included HYIR / APAP (2 tablets of 7.5 hydrocodone and 750 mg of acetaminophen per tablet, Vicodin ES®) with the following doses of naltrexone oral solution: 0.4mg / 1Om, 0.8mg / 10mL, l.mg / lOmL, 3.2mg / 10mL, 4.8 mg / 10mL, 6.4mg / 10mL, 9.6 mg / lOmL, 12.8mg / 10mL, and a naltrexone oral solution placebo, as well as immediate-release hydrocodone comparison tablets (2 tablets of Trilisate® 750mg) with a placebo of naltrexone oral solution. All treatments were administered on an empty stomach. There was an interval of 48 hours between doses. The subjects were randomly assigned to 10 treatment sequences from the 10 treatment groups. Subjects were reported to the testing facility one night before the first dose, and remained confined until the evaluation was completed 24 hours after the last dose. The safety measures consisted of reports of adverse events, vital signs, abnormal laboratory values, abnormal physical examination and ECG results. Levels of hydrocodone, naltrexone and 6-β-naltrexol were obtained in plasma, and pharmacokinetic values were calculated and analyzed. The pharmacodynamic parameters (pupil size and Modified Drug Specific Effects Questionnaire) were also evaluated. Dosage Regimen The dose regimen was as follows: hydrocodone immediate release tablets (placebo) were administered with an oral lOmL solution of naltrexone (placebo) at approximately 08:00 on the day of dose in periods 1 and up 10, after a fast of 8 hours. Fasting continued for an additional 4 hours after the dose. Immediate-release tablets of hydrocodone (2x7.5mg) were administered with 10L of naltrexone oral solution (placebo) at approximately 08:00 on the day of dose in periods 1 and 10, after an 8-hour fast. . Fasting continued for an additional 4 hours after the dose. hydrocodone (2x7.5mg) with lOmL of naltrexone oral solution (0.4mg) at approximately 08:00 on the day of dose in periods 1 and up to 10, after an 8-hour fast. Fasting continued for an additional 4 hours after the dose. hydrocodone (2x7.5mg) with lOmL of naltrexone oral solution (0.8mg) at approximately 08:00 on the day of dose in periods 1 and up to 10, after an 8-hour fast. Fasting continued for an additional 4 hours after the dose. hydrocodone (2x7.5mg) with 10mL naltrexone oral solution (l.dmg) at approximately 08:00 on the day of dose in periods 1 and 10, after an 8-hour fast. Fasting continued for 4 additional hours after the dose hydrocodone (2x7.5mg) with 10mL of naltrexone oral solution (3.2mg) at approximately 08:00 on the day of dose in periods 1 and up to 10, after an 8-hour fast. Fasting continued for 4 additional hours after the dose hydrocodone (2x7.5mg) with 10ml naltrexone oral solution > (4.8mg) at approximately 08:00 on the day of dose in periods 1 and up to 10, after a fast of 8 hours. Fasting continued for an additional 4 hours after the dose. hydrocodone (2x7.5mg) with 10mL of naltrexone oral solution (6.4mg) at approximately 08:00 on the day of dose in periods 1 and 10, after an 8-hour fast. Fasting continued for an additional 4 hours after the dose. hydrocodone (2x7.5mg) with 10mL naltrexone oral solution (9.6mg) at approximately 08:00 on the day of dose in periods 1 and 10, after an 8-hour fast. Fasting continued for an additional 4 hours after the dose. hydrocodone (2x7.5mg) with lOml of naltrexone oral solution (12.8mg) at approximately 08:00 on the day of dose in periods 1 and 10, after an 8-hour fast. Fasting continued for an additional 4 hours after the dose. Subjects observed a fasting of 8 preceding hours and fasted for four hours after each dose administration of the assigned drug during each dose day. A baseline blood sample (for hydrocodone, naltexone and 6-ß-naltrexol in plasma) was obtained before administering the dose (within 30 minutes) of the initial dose (Ohr) and 0.5.1.2 , 4,6 and 9 hours after the dose. HE; They took samples within a period of ± 2 minutes of the scheduled time. Measurements of the following pharmacodynamic parameters were made just before blood samples were taken at the baseline (within 30 minutes before the dose), and at 0.5hr, 1hr, 2hr, 4hr, 6hr and 9hr after the dose . Immediately after each dose period, 8 individual solutions of naltrexone were prepared weighing 4, 8,16,32,48,64,96 and 128mg / mL. Each of these portions was dissolved in 50 ml of distilled water and 50 ml of simple syrup. The final solution was 100mL at concentrations of 0.04.0.08,0.16,0.32,0.48,0.96 and 1.28mg / mL. These concentrations allowed the same volume (lOml) of naltrexone solution to be administered during each dose period. The naltrexone placebo solution was prepared in the same vehicles as the active solution. A bitter agent, Bitterguard Powder (denatonium bensoate) was added to produce a flavor similar to the active solution. Pharmacodynamic measurements Pharmacodynamic measurements were obtained for Example 2 in accordance with the procedures specified in Example 1.

Figures 3 and 4 show, respectively, the average VAS score of the "drug effect" and the pupil diameter with respect to time for each of the treatments. In general, single-dose administration of »immediate release» hydrocodone / acetaminophen ("HYIR / APAP") with dose increases of naltrexone (in a range of Omg to 12.8mg) resulted in a general decrease in the VAS rating of " drug effect "and decrease in pupillary constriction. Figures 5 and 6 show the corresponding average maximum of the VAS rating "of the drug effect" (± 95% CI) and mean minimum pupillary diameter (± 95% CI) against the logarithm of each dose of naltrexone.

Both figures suggest a dose-reaction relationship with the pupillary effect, which shows a higher dose-reaction relationship compared to the VAS reaction of the "drug effect". The results suggest that even including 0.4mg of naltrexone, there was a decrease in the pharmacological effects of the hydrocodone dose. Approximately 0. mg of naltrexone minimally antagonized the dose of 15 mg of hydrocodone. Doses higher than 0. mg of naltrexone began to show a greater decrease in the dose effect of hydrocodone. Adverse events reported were those commonly associated with the administration of opioid analgesics, and most were classified as "mild". A total of five subjects (5/21) discontinued the study. Three subjects were discontinued due to adverse events. Two of these subjects suffered adverse events that were classified as non-severe. One subject developed anemia that was classified as severe, and required iron therapy. Two other subjects were discontinued from the study because their doctors thought there was information in their medical file that did not allow them to participate. No deaths occurred in this study. In general, the administration of single doses of 15mg hydrocodone immediate-release tablets, with dose increases with naltrexone oral solution (Omg-12.8mg range) resulted in a general decrease in the VAS rating of "drug effect" and an increase in the diameter of the pupils. . EXAMPLE 3 Example 3 presents the results of a study that evaluated abstinence precipitated in morphine-dependent volunteers who received immediate-release tablets of hydrocodone and naltrexone oral solution. The study was blinded, single dose, placebo controlled and with dose increases of naltrexone in physically dependent opioid subjects. The experimental subjects (5) were found to be dependent on opioids as determined by the Narcan test, index scores of addiction severity, physical examination, observation and urine drug test results, and that they were not seeking treatment for their addiction. To evaluate abstinence * precipitated after coadministration of immediate-release hydrocodone and naltrexone, a dose of 3Omg of immediate-release hydrocodone was selected to simulate a dose level used by individuals abusing hydrocodone. This was also a dose that is considered as equianalgesic to other opioids commonly used in patients unaware of opioids. It is thought that the relative analgesic potency of hydrocodone is similar to that of oxycodone and paroxytely twice as much as oral morphine. Test Treatments The treatments were the following: Tablets 3mg of hydrocodone / acetaminophen immediate release (HYIR / APAP) of 30 mg (Lortab®3x10mg) and dose increase of naltrexone oral solutions of 0.25mg, 0.5mg, 1. Omg and 2. Omg. Hydrocodone / acetaminophen immediate release tablets (HYIR / APAP) of 30mg (Lortab®3xl0mg) and naltrexone oral solution placebo. The naltrexone oral solution and the oral placebo solution were prepared according to examples 1-2. The subjects were stabilized for 5 days by administering 15 mg of intramuscular morphine sulfate at regular intervals: 6 and 10 A.M. and 4 and 10P.M. Fifteen mg of intramuscular morphine sulfate is equivalent to 30 mg of oral hydrocodone. The study medications were administered after stabilization at 10AM on the * days when the dose of study medication was given, and observations were made during the following six hours. After six hours, if precipitated abstinence syndrome was observed, the administration of 15mg of intramuscular morphine sulfate at the 4pm dose was resumed. The subjects were stabilized 48 hours before the next administration of the study drug. After each treatment (1-4), if the abstinence syndrome was precipitated, the patient received medication from the study of the following treatment in the following ascending order: Treatment No. 1: HYIR / APAP 30mg tablets (Lordtab®3x10) administered placebo of naltrexone oral solution (lOml) at approximately 10:00 on the day of dosing after an 8-hour fast. The fasting continued for an additional 4 hours after the dose. Treatment: 2 HYIR / APAP 30mg tablets (Lordtab®3x10) administered oral 0.25mg naltrexone solution (lOml) at approximately 10:00 on the day of dosing after an 8-hour fast. The fasting continued for an additional 4 hours after the dose. Treatment: 3 3Omg HYIR / APAP Tablets (Lordtab®3x10) administered with 0.5mg naltrexone oral solution (lOml) at approximately 10:00 on the day of dosing after an 8-hour fast. The fasting continued for an additional 4 hours after the dose.; Treatment 4: 30mg HYIR / APAP tablets (Lordtab®3xl0) administered oral solution of 1. Omg naltrexone (lOml) at approximately 10:00 on the day of dosing after an 8-hour fast. The fasting continued for an additional 4 hours after the dose. Treatment 5: 30mg HYIR / APAP Tablets (Lordtab®3xl0) administered oral solution of 2. Omg naltrexone (lOml) at approximately 10:00 on the day of dosing after an 8-hour fast. The fasting continued for an additional 4 hours after the dose. • Blood samples were taken 0.5 hours before the dose, and at 0.5, 1, 2, 4, and 6 hours after the dose. Pupillary diameter measurements were obtained using a pupilskan pupilometer and recorded in millimeters, up to the nearest millimeter. There was an interval of 48 hours after each trial period. Four subjects completed the study, and one subject was discontinued. The effect of nalterexone was a slight withdrawal (symptoms of withdrawal syndrome) at one and two mg. The protocol was modified and 12 experimental subjects participated in the protocol, which was identical to the study described above, except for a higher proportion of naltrexone. The doses of naltrexone in the revised protocol were 0.1, 2, 4, and 8 mg. Eight of the experimental subjects completed the study, while four discontinued it. The vital signs of each subject were followed up, and the subjects were followed up with signs and symptoms of opioid abstinence. The signs of withdrawal include catarrh, tearing, yawning, sweating, tremor, vomiting, piloerection, midreasis, irritability and restlessness. Withdrawal symptoms include a sensation of change in temperature, pain in the joints, bones or muscles, abdominal cramps, skin reactions, nausea and the fact that the subject reports subjective experiences of these symptoms. To give a measure to the subjective experience of the drug combination, the subjects answered questionnaires during the study period. The answers to the questions were rated on the visual analog scale described in example 1. The subjective experiences that were evaluated were the following: liking / not liking the drug, ability to perceive the effect of the drug, sweating, restlessness, tremor, tearing, goose bumps, stomach discomfort, nasal congestion, drowsiness, feeling cold, feeling hot, muscle pain, tension or relaxation, confusion, fear, irritability, talkativeness, feeling of withdrawal, feeling sick. He also kept the subjects under observation, looking for the following symptoms: bozteso, itching, relaxation, nasal congestion, irritability abstinence. In addition, blood pressure, pulse, respiratory rate, pupillary size and body temperature were monitored. Below are the data of five of the subjects. Figures 7A-C illustrate the mean scores of the subjective perception of hydrocodone from the questionnaires, plotted as a function of time and as a function of the dose of naltrexone. Figure 7A illustrates the ability of subjects to feel the effect of hydrocodone in the presence of varying amounts of naltrexone. Figures 7B and 7C illustrate subjective favorable or unfavorable subjective experiences of subjects with hydrocodone in the presence of various amounts of naltrexone, respectively. Figures 8A and B illustrate the mean scores for the subjective perception of the effects of hydrocodone, plotted as a function of the time intervals administered, and as a function of the dose of naltrexone. Figure 8A illustrates the perception of subjects of abstinence from the effect of hydrocodone in the presence of varying amounts of naltrexone. Figure 8B illustrates the subjective experience of feeling sick in varying amounts of naltrexone. Figure 9A illustrates the effect produced by hydrocodone on the pupillary size in the presence of varying amounts of naltrexone. Figure 9 B illustrates the apparent measure of abstinence from >; effect of hydrocodone in the presence of varying amounts of naltrexone, from the perspective of the observer. Figures 10A-C present the areas under the curves presented in Figures 7A-C, integrated during a 6-hour observation period as a function of the dose of naltrexone, and the 95% confidence levels for the placebo response of naltrexone (30mg of hydrocodone, Omg of naltrexone). Figure 10A illustrates that up to 8mg of naltrexone does not make the subject's ability to perceive the effect of hydrocodone disappear: the experimentally determined AUC (0 to 6 hours) observed for each dose of naltrexone is completely within the confidence limits of 95 % for the naltrexone placebo reaction. Figure 10B illustrates the AUC (0 to 6 hours) for the subjective experience favorable to hydrocodone as a function of the dose of naltrexone. Figure 10B illustrates that the favorable subjective experience decreases for > 1 mg of naltrexone, that is, the experimentally determined AUC (0 to 6 hours) decreased below the 95% confidence limits for naltrexone placebo to approximately 1 mg of naltrexone. Figure 10C illustrates that the unfavorable subjective experience increases for > 1 mg naltrexone, that is, the experimentally determined AUC (0 to 6 hours) increased above the 95% confidence limits for naltrexone placebo to approximately 1 mg of naltrexone. Figures 11A-C present the areas under the curves presented in Figures 8A-B and Figure 9A, integrated over the 6-hour observation period, as a function of the dose of naltrexone, and the 95% confidence levels for the naltrexone placebo response (30 mg hydrocodone, 0 mg naltrexone). Figure 11A illustrates the AUC (0 to 6 hours) for the subjective experience of withdrawal syndrome in the presence of varying amounts of naltrexone. Figure 11A demonstrates that doses of naltrexone greater than about 0.75 mg produce a subjective experience of discomfort: the experimentally determined AUC (0 to 6 hours) observed in Figure 8A for each dose of naltrexone increases above the confidence limits of the 95% for the placebo reaction of naltrexone at approximately 0.75 mg of naltrexone. Figure 11B illustrates the AUC (0 to 6 hours) for the perception of discomfort of the subjects in the presence of variable amounts of naltrexone. Figure 11B demonstrates that doses of naltrexone greater than about 0.75 mg result in the subjective experience of discomfort: the experimentally determined AUC (0 to 6 hours) observed in Figure 8B for each dose of naltrexone increases above the confidence limits 95% for naltrexone placebo reaction at approximately 0.75 mg naltrexone. Figure 11C illustrates the AUC (0 to 6 hours) of the experimentally determined change in the size of the pupils as a function of the dose of naltrexone. Figure 11C demonstrates that up to 8 mg of naltrexone does not abolish the mycosis effect of hydrocodone: the experimentally determined AUC (0 to 6 hours) observed in Figure 9A for each dose of naltrexone falls well within the confidence limits of 95 % for the placebo reaction of naltrexone. The clinical study shows that hydrocodone, in combination with naltrexone, has an onset of < 0.5 hours, has its maximum within a period of 0.5 to 1 hours, and decreases sharply within a period of 3 to 4 hours. A rather flat dose-reaction curve was observed. The addition of naltrexone decreased the subjective favorable experience of hydrocodone, increased the subjective experience of dislike for hydrocodone and increased the subjective experience of discomfort and abstinence from the effects of hydrocodone. These experiences are clearly adverse. While the present invention was described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art will appreciate that obvious modifications can be made without departing from the spirit and scope of the present invention. Such variations are contemplated within the scope of the appended claims.

Claims

CLAIMS 1. An oral dosage form, comprising: a therapeutically effective amount of an opioid agonist, and an opioid antagonist, wherein the ratio between opioid antagonist and opioid agonist produces a combination product that is analgesically effective when the combination is administered orally , but which is adverse in physically dependent human subjects when administered at the same or more dose than generally prescribed for the opioid agonist.
2. The oral dosage form of claim 1, wherein the amount of antagonist included in the oral dosage form causes adverse experience in physically dependent addicts taking 2 to 3 times the dose of opioid that is generally prescribed.
3. The oral dosage form of claim 1, further comprising one or more inert pharmaceutically acceptable excipients.
4. The oral dosage form of claims 1 to 3, further comprising a sustained release vehicle, wherein the dosage form is administrable twice a day or once a day.
5. The oral dosage form of claims 1 to 4, wherein the opioid agonist is hydrocodone and the opioid antagonist is naltrexone, wherein the ratio of naltrexone to hydrocodone is between 0.03: 1 to about 0.27: 1.
6. The oral dosage form of claims 1 to 4, wherein the opioid agonist is hydrocodone and the '. Opioid antagonist is naltrexone, where the ratio of naltrexone to hydrocodone is between 0.05: 1 to about 0.20: 1.
7. The oral dosage form of claims 1 to 4, wherein the opioid or analgesic agonist is selected from the group consisting of morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, methadone and mixtures thereof; and the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, cyclazocine, levalorphan and mixtures thereof.
8. The oral dosage form of the claims 1 to 4, where the opioid agonist is naltrexone. The oral dosage form of claims 1 to 8, further comprising a non-opioid additional drug selected from the group consisting of an NSAID, a COX-2 inhibitor, acetaminophen, aspirin, an NSAID receptor antagonist, an antitussive, an expectorant, a decongestant, an antihistamine and mixtures of these. 10. The oral dosage form of claims 1 to 4 and 9, wherein the opioid antagonist is naltrexone and the opioid agonist is selected from the group consisting of hydrocodone in a naltrexone / hydrocodone ratio of between 0.03: 1 to 0.27: 1; oxycodone in a ratio of naltrexone / oxycodone from 0.037: 1 to 0.296: 1; codeine in a ratio of naltrexone / codeine between 0.005: 1 to '0.044: 1; hydromorphone in a naltrexone / hydromorphone ratio of 0.148: 1 to 1185: 1; levorphanol in a ratio of naltrexone / levorphanol between 0.278: 1 to 2222: 1; meperidine in a ratio of naltrexone / meperidine between 0.0037: 1 to 0.0296: 1; methadone in a naltrexone / methadone ratio between 0.056: 1 to 0.444: 1; and morphine in a naltrexone / morphine ratio of between 0.018: 1 to 0.148: 1. 11. The oral dosage form of claims 1 to 4 and 9, wherein the opioid antagonist is naltrexone and the opioid agonist is selected from the group consisting of hydrocodone in a naltrexone / hydrocodone ratio of between 0.05: 1 to 0.20: 1; oxycodone in a ratio of naltrexone / oxycodone from 0.056: 1 to 0.222: 1; codeine in a ratio of naltrexone / codeine between 0.0083: 1 to 0.033: 1; hydromorphone in a ratio of naltrexone / hydromorphone of between 0.222: 1 to 1.889: 1; levorphanol in a ratio of naltrexone / levorphanol between 0.417: 1 to 1.667: 1; meperidine in a ratio of naltrexone / meperidine from 0.0056: 1 to 0.022: 1; methadone in a ratio of naltrexone / methadone from 0.083: 1 to

0. 333: 1; and morphine in a ratio of naltrexone / orphine between 0.028: 1 to 0.111: 1. 12. A method to prevent oral abuse of an oral opioid formulation, which comprises preparing an oral dosage form comprising an orally analgesically effective amount of an opioid agonist and incorporating therein an opioid antagonist in a proportion against the opioid agonist so that the oral dosage form is analgesically effective when administered orally. , but it is adverse in physically dependent subjects when administered at the same dose or at higher doses than those generally prescribed for the opioid agonist. The method of claim 12, wherein the amount of antagonist included in the oral dosage form causes adverse experience in physically dependent addicts taking 2 to 3 times the dose of opioid that is generally prescribed. The method of claim 12, wherein the opioid agonist is hydrocodone and the opioid antagonist is naltrexone. The method of claim 12, wherein the opioid agonist is hydrocodone and the opioid antagonist is naltrexone, wherein the ratio of naltrexone to hydrocodone is between 0.03: 1 to about 0.27: 1. The method of claim 12, wherein the opioid agonist is hydrocodone and the opioid antagonist is naltrexone, wherein the ratio of naltrexone to hydrocodone is between 0.05: 1 to about 0.20: 1. 17. The method of claim 12, wherein the; Opioid agonist or analgesic is selected from the group consisting of morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, methadone and mixtures thereof; and the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, cyclazocine, levalorphan and mixtures thereof. The method of claim 12 to 17, further comprising a non-opioid additional drug selected from the group consisting of an NSAID, a COX-2 inhibitor, acetaminophen, aspirin, an NSAID receptor antagonist, a drug that blocks a consequence important intracellular activation of the NMDA receptor, an antitussive, an expectorant, a decongestant, an antihistamine and mixtures of these. The method of claims 12 to 18, further comprising preparing the oral dosage form with a sustained release vehicle such that the dosage form can be administered twice a day or once a day. The method of claims 12 and 17 to 19, wherein the opioid antagonist is naltrexone and the opioid agonist is selected from the group consisting of hydrocodone in a naltrexone / hydrocodone ratio of between 0.03: 1 to 0.27: 1; oxycodone in a ratio of naltrexone / oxycodone from 0.037: 1 to 0.296: 1; codeine in a ratio of naltrexone / codeine between 0.005: 1 to 0.044: 1; hydromorphone 'in a ratio of naltrexone / hydromorphone between 0.148: 1 to 1.185: 1; levorphanol in a ratio of naltrexone / levorphanol between 0.278: 1 to 2222: 1; meperidine in a ratio of naltrexone / meperidine between 0.0037: 1 to 0.0296: 1; methadone in a naltrexone / methadone ratio between 0.056: 1 to 0.444: 1; and morphine in a naltrexone / morphine ratio of between 0.018: 1 to 0.148: 1. The method of claims 12 and 17 to 19, wherein the opioid antagonist is naltrexone and the opioid agonist is selected from the group consisting of hydrocodone in a naltrexone / hydrocodone ratio of between 0.05: 1 to 0.20: 1; oxycodone in a ratio of naltrexone / oxycodone from 0.056: 1 to 0.222: 1; codeine in a ratio of naltrexone / codeine between 0.0083: 1 to 0.033: 1; hydromorphone in a ratio of naltrexone / hydromorphone of between 0.222: 1 to 1.889: 1; levorphanol in a ratio of naltrexone / levorphanol between 0.417: 1 to 1.667: 1; meperidine in a ratio of naltrexone / meperidine from 0.0056: 1 to 0.022: 1; methadone in a naltrexone / methadone ratio between 0.083: 1 to 0.333: 1; and morphine in a naltrexone / morphine ratio between 0.028: 1 to 0.111: 1. The present invention is directed in part to oral dosage forms comprising a combination of an orally analgesically effective amount of an opioid agonist * and an active oral opioid antagonist, where the opioid antagonist is included in a proportion against the opioid agonist to produce an opioid agonist. combination product that is analgesically effective when the combination is administered orally, but which is adverse in a physically dependent subject. Preferably, the amount of opioid antagonist included in the combination product produces an "adverse" experience at least slightly negative in physically dependent addicts (i.e., precipitous abstinence syndrome). • v ^ ii ^ ¿> ^ ° -