MXPA00006261A - A method of preventing abuse of opioid dosage forms - Google Patents

Abstract

The invention relates in part to a method of reducing the abuse potential of an oral dosage form of an opioid analgesic, wherein an analgesically effective amount of an orally active opioid agonist is combined with an opioid antagonist into an oral dosage form which would require at least a two-step extraction process to be separated from the opioid agonist, the amountof opioid antagonist including being sufficient to counteract opioid effects if extracted together with the opioid agonist and administered parenterally.

Description

METHOD TO PREVENT THE ABUSE OF OPIOID DOSING FORMS Opioids, also known as opioid agonists, are a group of drugs that have properties similar to opium or morphine. Opioids are first used as analgesics ranging from moderate to strong, but which also have many other pharmacological effects, including drowsiness, respiratory depression, mood swings and mental nervousness without a resultant loss of consciousness. Consciousness, opioids act as agonists, interacting with stereospecific and saturable binding sites in the brain and other tissues. Peptides similar to endogenous opioids are present particularly in areas of the central nervous system that are presumed to be related to the perception of pain; movement, humor and behavior, and the regulation of neuroendocrinological functions. The opium continent more than twenty different alkaloids. Morphine, codeine and papaverine are included in this Group. By the middle of the nineteenth 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 had a tendency to produce a more severe variety of the use of compulsive drugs. The problem of opioid addiction stimulated an investigation for potent analgesics that would be free of the potential to produce addictions. By 1967, researchers had come to the conclusion that the complex interactions between morphine-like drugs, antagonists and what were then called "combined agonist-antagonists" would be better explained by postulating the existence of more than one type of receptor. for opioids and related drugs. With the advent of totally synthetic new entities with morphine-like actions, the term "opioid" was generally retained as a generic designation for all exogenous substances that were stereospecifically related to any of the various subspecies of opioid receptors and produced actions agonists ~ 7 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 (addiction) is one of the main concerns in the use of pain treatment. with .opioids, although iatrogenic addiction is really rare. Another major concern associated with the use of opioids is the diversion of these drugs from the patient suffering from pain to another (non-patient) for recreational purposes, for example, to an addict.

The potential for total abuse of an opioid is not established by a single factor. Instead, there is a compound of factors, including the ability of the drug to produce the kind of physical dependence in which withdrawal of the drug causes sufficient distress to create a drug-seeking behavior; the ability to suppress the withdrawal symptoms caused by the withdrawal of the same from 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 the physical characteristics of the drugs such as the solubility of water. These physical characteristics can determine whether the drug is likely to be abused through a parenteral route. In the United States, the effort to control the compulsive consumer of drugs includes efforts to control the availability of drugs by placing restrictions on the use of opioids for the treatment of pain in compulsive drug users. It is often faced with a choice to administer potent opioid analgesics even to people who seem predisposed to developing a psychological dependence, for example, addiction, on such drugs.In view of this problem, it has been recommended that these drugs should not be used in these patients. administer an opioid when another drug without a potential for abuse is sufficient; and also that these patients should not be allowed to administer such drugs parenterally and that they will only be given a supply of these a few days and one at a time. At least three basic patterns have been identified. Opioid use and dependence. The first includes people whose use of drugs begins in the context of medical treatment and who obtain initial supplies through, for example, doctors. Another pattern begins with the use of experimental or "recreational" drugs and progress for more intensive use. A third pattern includes consumers who begin in one or the other of the above-mentioned forms but who then switch to oral opioids, such as methadone, which is obtained from organized addiction treatment programs. 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 the same dose results in decreased analgesia, euphoria or other opioid effects. It has been discovered that a remarkable degree of tolerance develops for the respiratory, analgesic, sedative, emetic and euphorigenic effects of opioids. However, the percentage at which this percentage can be developed either in an addict or in a patient that requires treatment for pain, depends on the pattern of use. If the opioid is used frequently, it may be necessary to increase the dose. Tolerance does not develop equally or at the same rate as all the effects of opioids, and even consumers who are highly tolerant of respiratory depressant effects continue to have miosis and constipation. Tolerance to opioids disappears widely when the withdrawal of the symptom is complete. Physical dependence can develop based on repeated administrations or the widespread use of opioids. L physical dependence manifests gradually after stopping the use of opioids or manifests precipitously (for example, within 20 minutes) after the administration of a narcotic antagonist (referred to "precipitate withdrawal"). Depending on the drug to which dependence has been established and the duration of use and dosage, withdrawal symptoms vary in number and class, duration and severity. The most common symptoms of withdrawal syndrome include anorexia, weight loss, dilation of pupils, chills, alternating with excessive sweating, abdominal cramps, nausea, vomiting, muscle spasms, hyperirritability, lacrimation, rhinorrhea, chicken meat and accelerated heart rate. Abstinence from the syndrome commonly begins to occur 24-48 hours after the last dose, and the syndrome reaches its maximum intensity around the third day and may not begin to decrease until the third week. Psychological dependence (ie, addiction) in opioids is characterized by drug seeking behavior aimed at achieving euphoria and escape from, for example, psychosocioeconomic pressures. An addict will continue to administer opioids for non-medicinal purposes and to deal with the damage itself. Pharmacologically, opioid antagonists commonly block or reverse the full effect of opioid agonists. The use of an opioid antagonist is a once-daily treatment of naltrexone to block the euphoric effects that can otherwise be obtained with the administration of opioids to the addicts. Small doses of opioid antagonists have been used to determine whether people are physically dependent on the opibids. Most commonly, opioid antagonists are used to reverse the effects of opioids in people who have received an overdose of opioid agonist drugs. There have previously been attempts in the art to control the potential abuse associated with opioid analgesics. Commonly a particular dose of an opioid analgesic is more potent when administered parenterally as compared to the same dose administered orally. Therefore a popular form of abuse of oral medications involves the extraction of the opioid from the dosage form, and the subsequent injection of the opioid (using an "adequate" vehicle for injection) to achieve a "high" effect. Attempts to reduce abuse have commonly focused around the inclusion in the oral dosage form of an opioid antagonist which is not orally active, but will substantially block the opioid's analgesic effects if one tries to dissolve the opioid and administer it parenterally. For example, the combination of pentazocine and naloxone has been used in tablets available in the United States, commercially available as Tal in®Nx from Sanofi-Winthrop. Talwin®Nx contains pentazocine hydrochloride equivalent to a 50 mg base and naloxone hydrochloride equivalent to a 0.5 mg base. Tal in®Nx is indicated for pain relief ranging from moderate to severe. The amount of _naloxone present in this combination has no action when taken orally, and will not interfere with the pharmacological action of pentazocine. However, this amount of naloxone that is administered by injection has a profound antagonistic action to narcotic analgesics. Therefore, the inclusion of naloxone is intended to control a form of oral pentazocine misuse, which occurs when a dosage form is solubilized and injected. Therefore this dosage has a lower potential for parenteral misuse than previous oral pentazocine formulas. However, this is still subject to misuse and abuse of the patient by the oral route, for example, that the patient take multiple doses at a time. _ Sunshine, et al. "Analgesic Efficacy of the Pentazocine in Comparison with a Combination of Pentazocine-Naloxone After Oral Administration "Clin.

J. Pain, 1988: 4: 35-40, reported on the effect of adding 0.5 mg of naloxone to the efficacy of 50 mg of pentazocine. It was observed that the combination was significantly less efficient than the pentazocine for the sum of the pain intensity difference (SPID of the acronym in English), and for the relief and difference of pain intensity (PID) at the fourth hour. For patients with moderate pain, the combination produced significantly less pain relief than pentazocine for SPID and for relief and PID at hours 3 and 4. In patients who presented severe pain, there was no significant difference. Among the pentazocine and the combination of pentazocine plus naloxone.

Wang, et al. "Cross-over and Parallel Study of Oral Analgesics", J. Clin Pharmacol 1981; 21: 162-8, studied the combination of 0.25 mg naloxone and Percodan® (composed of 4.5 mg oxycodone HCl, oxycodone terephthalate 0.28 mg, aspirin 224 mg, phenacetin 160 mg, and caffeine 32 mg) compared to Percodan ® only, and placebo in a crossover study with patients suffering from chronic pain. The combination had lower average results than the. Percodan® only for most analgesic parameters per hour in the last hours of the study. However, for the variables in summary, the combination did not show significant differences of either a placebo or Percodan®. A fixed combination of buprenorphine and naloxone was introduced in 1991 in New Zealand (Temgesic®Nx, Reckitt &Colman) for the treatment of pain. Fixed combination therapy comprising tilidine (50 mg) and naloxone (4 mg) has been available in Germany for the management of severe pain since 1978 (Valoron®N, Goedecke). The fundamental reason for the combination of these drugs is the effective relief of pain and the prevention of tilidine addiction through antagonisms induced by naloxone in the morphine receptor. U.S. Patent No. 3,773,955 (Pachter, et al.) Discloses orally effective analgesic compounds which in parenteral administration do not produce analgesia, euphoria, or physical dependence, and thus avoid parenteral abuse of analgesic agents. These compounds contain from about 0.1 mg to 10 mg of naloxone per oral analgesic dose. This reference had nothing to do with the oral abuse of opioids. In U.S. Patent No. 3,493,657 (Le enstein, et al.) Describe compounds comprising naloxone and morphine or oxymorphone, which were said to provide a strong analgesic effect without the occurrence of unwanted side effects such as hallucinations. U.S. Patent No. 4,457,933 (Gordon, et al.) Described a method to decrease both the oral and parenteral abuse potential of strong analgesic agents such as oxycodone, propoxyphene and pentazocine, by combining an analgesic dose of opioid with naloxone in a specific narrow range. Oxycodone-naloxone compounds having a percentage of 2.5-5: 1 parts by weight and pentazocine-naloxone compounds having a percentage of 16-50: 1 parts by weight were preferred. The dose of naloxone which was to be combined with the opioid was manifested in substantially eliminating the possibility of either oral or parenteral abuse of the opioid without substantially affecting the oral analgesic activity thereof. - U.S. Patent No. 4,582,835 (Lewis) describes a method of treating pain by administering an effective sublingual dose of buprenorphine with naloxone. Lewis describes the percentages of naloxone doses for buprenorphine from 1: 3 to 1: 1 for parenteral administration, and from 1: 2 to 2: 1 for sublingual administration. It has been widely recognized in the art that oral opioid forms are not only abused by the parenteral route, but also by the oral route when the patient or the addict is administered orally more than the oral dose prescribed during the oral route. any dosage interval. OBJECTIVES AND COMPENDIUM OF THE INVENTION It is an object of the invention to provide an oral dosage form of an opioid analgesic which is subject to less potential for abuse by the parenteral route of administration than by the commercially available prior dosage forms. It is further an object of the invention to provide a method of treating pain in human patients with an oral dosage form of an opioid analgesic while reducing the potential for parenteral abuse of the dosage form.

A further object of the invention is to provide a method of manufacturing an oral dosage form of an opioid analgesic so that it has less potential for parenteral and / or oral abuse. These and other objectives are achieved by means of the present invention, which is directed in part to a method of reducing the abuse potential of an oral dosage form of an opioid analgesic, comprising the combination of an effective amount of analgesic. of an opioid agonist together with an opioid antagonist within an oral dosage form which would require at least a two-step extraction process to be separated from the opioid agonist, the amount of the opioid antagonist included being sufficient to counteract the opioid effects if it is extracted together with the opioid agonist and administered parenterally. Preferably the combination of the opioid agonist and the opioid antagonist are only removable from the dosage form together, and subsequently must be separated from each other in a separate extraction step. For example, both the opioid agonist and the opioid antagonist may be soluble in acid, and must be separated using a solution with high pH. In a preferred embodiment, the opioid agonist is hydrocodone bitartrate and the opioid antagonist is naltrexone hydrochloride, wherein both hirdrocodone and naltrexone dissolve at a pH of less than 8 and about 80% of said hydracodone and about 10% of said naltrexone are extractable at a high pH, for example, substantially greater than pH 10, and preferably higher than pH 11. In another embodiment, the opioid agonist is hydromorphone hydrochloride and the opioid antagonist is naltrexone hydrochloride, or the Opioid agonist is oxycodone hydrochloride and the opioid antagonist is naltrexone hydrochloride; or the opioid agonist is morphine sulfate and the antagonist is naltrexone hydrochloride. In a further embodiment, the method further comprises incorporating into the dosage form an additional ingredient, which makes the separation of the opioid agonist from the opioid antagonist more difficult. Such additional ingredients include gelling agents, waxes, or other pharmaceutically acceptable excipients. In the further embodiments, the method further comprises incorporating within the preparation of the dosage form one or more processing steps, which further prevent separation of the opioid agonist from the opioid antagonist. In certain preferred embodiments of the method, the opioid is hydrocodone, hydromorphone, oxycodone, morphine or pharmaceutically acceptable salts thereof. In certain preferred embodiments of the method, the opioid agonist, and the opioid antagonist are combined in a percentage of opioid antagonist to opioid agonist (analgesic) which is effective analgesically when the combination is administered orally, but which is adverse in a physically dependent subject. In this way, the product of the combination (antagonist / agonist) could be essentially therapeutic to a population (patients with pain), whereas it is unacceptable (aversive) in a different population (for example physically dependent subjects) when administered orally. in the same dosage or in a higher dose than the commonly prescribed dosage, for example, approximately 2 to 3 times the commonly prescribed dose of the opioid. Therefore, the oral dosage form would have less potential for parenteral form as well as oral abuse. In such embodiments where the opioid is a hydrocodone and the antagonist is naltrexone, the percentage of naltrexone for hydrocodone is preferably 0.03-0.27: 1 by weight, and more preferably 0.05-0.20: 1 by weight. In such embodiments, wherein the opioid antagonist is naltrexone and the opioid agonist is hydromorphone, the percentage of naltrexone to the hydromorphphone is preferably from 0.148: 1 to approximately 1185: 1, and more preferably from approximately 0.222: 1 to approximately 0.889: 1. In such embodiments wherein the opioid antagonist is naltrexone and the opioid agonist is morphine, the percentage of naltrexone for morphine is preferably 0.018: 1 to 0.148: 1, and preferably 0.028: 1 to 0.111: 1. In such embodiments wherein the opioid antagonist is naltrexone and the opioid agonist is oxycodone, the percentage of naltrexone for oxycodone is preferably from 0.037: 1 to approximately 0.296: 1, and preferably from 0.056: 1 to 0.222: 1. . The dosage forms of the present invention may be liquids, tablets or multi-leaf formulas that utilize any pharmaceutically acceptable excipient known to those skilled in the art. However, it is preferred that the opioid agonist and the opioid antagonist be incorporated into the oral dosage form in a form that prevents easy separation of two drugs. In certain embodiments, the oral dosage forms of the present invention are sustained release forms. This can be achieved, for example through the incorporation of a sustained release carrier into a matrix containing the opioid agonist and an opioid antagonist.; or through a sustained release envelope of a matrix containing the opioid agonist and the opioid antagonist wherein the sustained release envelope contains at least a portion of the sustained release carrier included in the dosage form. In either case, it is preferred that the sustained release preparation be prepared in such a way that the opioid agonist or the opioid antagonist are combined in a matrix or dispersed together so as to compel the addict to use extraction methodology to separate these drugs. The present invention is also directed to a method of treating pain in human patients in a manner in which it reduces the possibility of oral abuse of opioid analgesics, comprises administering to a human patient an oral dosage form of the inventive combinations of the Opioid agonist or opioid antagonist which must be extracted at least two extraction steps separately. In certain embodiments, the opioid antagonist is included in an amount (i) which does not cause a reduction in the level of analgesia that occurs from the dosage form with oral administration at a non-therapeutic level and (ii) which provides at least a slightly negative "adverse" experience in physically dependent subjects (eg, abrupt withdrawal syndrome) when people try to take at least twice the commonly prescribed dose at once (and often 2 to 3) times that dose or more) as compared to a dose of the opioid without the opioid antagonist present. In certain preferred embodiments, the amount of naltrexone included in the oral dosage form is less positively enhancing (eg, less "like") to an addict not physically dependent on the opioid than a comparable oral dosage form without the included antagonist . Preferably, the formula provides effective analgesia when administered orally. In certain preferred embodiments, the method further comprises incorporating the opioid agonist and opioid antagonist into the dosage form that includes a sustained release carrier, either included in the matrix or as a sustained release envelope, so that the way that the oral dosage form can be administered twice a day or once a day. The pharmaceutical compounds which are used in the methods of the present invention may be in the form of tablets, troches, lozenges, aqueous or oily syrups, powders or dispersible granules, emulsions, soft or hard capsules, elixir syrups, microparticles (for example microcapsules , microspheres and the like), oral tablets, etc. The term "parenterally", as used in the present invention, includes subcutaneous, intravenous, intramuscular, intrasternal injection, or infusion techniques. The term "effective analgesia" is defined for the 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. It is recognized that the percentage of opioid antagonist to opioid agonist included in certain embodiments of the invention (eg, where the opioid antagonist is included in an amount (i) which does not cause a reduction in the level of analgesia produced from the oral dosage form with the dosage form with oral administration at a non-therapeutic level and (ii) which provides at least a slightly negative "adverse" experience in physically dependent persons when a large amount of the opioid, for example, approximately 2 or 3 times the common prescribed dosage, it is taken or administered orally to physically dependent persons) can decrease the analgesia of some way when the dosage form is orally administered as assessed by direct measurement in patients or by the use of one or more surrogate measures of opioid analgesic efficacy in human subjects such as a visual analogue scale ("VAS"). the acronym in English) for the "effect of the drug". The patient suffering from pain may or may not notice appreciably the difference between the formula administered according to such embodiment of the invention and a similar formula, which includes the same dose of the opioid agonist without the opioid antagonist, but will obtain an analgesic effect of the combination. Surrogate measures of opioid efficacy (analgesia) include sedation, respiratory rate and / or pupil size (via pupilometry), and visual analogue scale ("VAS") for the "effect of drugs". In such embodiments, the surrogate measurements are affected in a direction which indicates reduced opioid effect, as compared to the same dose of the opioid without the concomitant dose of the opioid antagonist. The pharmacodynamic effect (analgesia) of the formulas administered according to the invention can be described by, for example, results from an analgesic questionnaire reported by the patients on several occasions after the administration of the dosage form. In summary, measures of analgesia include the sum of the difference in pain intensity (SPID) and total pain relief (TOTPAR of acronym in English). The term "sustained release" is defined for the purposes of the present invention as the release of the drug (opioid analgesic) from the transdermal formula in a certain proportion that blood concentrations (levels) (eg, plasma) are maintained within the therapeutic range (above the minimum effective analgesic concentration or "MEAC" of the acronym in English) but below the toxic levels for a period of time indicative of a formula applied twice a day or once a day. For the purposes of the present invention, the term "opioid agonist" is interchangeable with the term "opioid" or "opioid analgesic" and will include the base of the opioid, pharmaceutically acceptable salts thereof, stereoisomers thereof, ethers and esters, agonists- combined antagonists, and partial agonists. For the purposes of the present invention, the term "opioid antagonist" will include the base, pharmaceutically acceptable salts thereof, stereoisomers, ethers and esters as well as mixtures thereof. DETAILED DESCRIPTION OF THE INVENTION It has been postulated that there are at least three subspecies of opioid receptors, designated mu, kappa and delta. Within this framework, the mu receptor is considered to be 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, iosis and sedation. The activation of the gamma receptors causes dysphoria and hallucinations, as well as respiratory and vasomotor simulating effects. A receptor other than the mu and gamma receptor designated in the "mouse vas deferens", Lord, et al. Nature, 1997, 267, 495-99. It is believed 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 type of receptor or another. These drugs have a superior effect. Such drugs include, nalorphine, propiram and buprenorphine. Other additional drugs act as competitive antagonists in the mu receptor and block the effects of drugs similar to morphine, by exerting agonist actions in the kappa and omega receptors. The term "agonist-antagonist" has been developed to describe said mechanism of actions. The concept of antagonism for opioid actions is considered complex. It has been discovered with the administration of opioid agonist-antagonists and partial agonists that tolerance develops for the agonist effects but not for the antagonistic effects of the drugs. Even after prolonged administration of high doses, the naloxone discontinuation is not characterized, by any recognizable withdrawal symptom, and the withdrawal of naltrexone, another relatively pure opioid antagonist, produces very few signs and symptoms. Nevertheless, after prolonged administration of high doses, the abrupt interruption of nalorphine or cyclozocine agonist-opioid antagonist causes a characteristic withdrawal syndrome that is similar for both drugs. Naloxone is an opioid antagonist which has almost no agonist effects. The subcutaneous dose of up to 12 mg of naloxone produces no discernible subjective effects, and 24 mg of naloxone causes only mild drowsiness. Small doses (0.4-0.8 mg) of naloxone given intramuscularly or intravenously in men quickly prevent or reverse the effects of the morphine-like opioid agonist. It has been reported that one mg of naloxone given intravenously completely blocks the effect of 25 mg of heroin. The effects of naloxone are shown in most cases immediately after intravenous administration. The drug is absorbed after oral administration, but it has been reported to be metabolized in an inactive form, rapidly in its first passage through the liver, so that it has been reported to be only one-fiftieth as potent as when administered parenterally. Oral dosing of more than one gram has been reported as almost completely metabolized in less than 24 hours. Other opioid antagonists, for example, cyclazocine and naltrexone, two of which have cyclopropylmethyl substitutes in nitrogen, retain much of their effectiveness through the oral route and their action durations are much longer, approaching more than 24 hours. hours after oral doses. A most preferred opioid antagonist is naltrexone. However, the oral equiantagonistic doses of other opioid antagonists, include but are not limited to, naloxone, nalmefene, cyclazocine, and levalorphan which may be used in accordance with the present invention. The relationship of said other antagonists to a particular opioid agonist can easily be determined without undue experimentation by one skilled in the art who wishes to use a different opioid antagonist than naltrexone, whose ratio of opioid agonists is exemplified and discussed in detail in the present. In those skilled in the art, they can determine such relationships of other antagonists with opioid agonists, for example, by directing the same or similar clinical studies set forth in the examples appended hereto. Therefore, combinations of opioid antagonists and opioid agonists which are administered orally in percentages that are equivalent to the ratio of, for example, naltrexone to hydrocodone set forth herein, are considered to be within the range of the present invention and within the range. of the appended claims. For example, in certain embodiments of the invention, naloxone is used as the opioid antagonist, the amount of naloxone included in the dosage form is large enough to provide an equiantagonistic effect as if naltrexone were included in the combination. In the treatment of patients who were previously addicted to opioids, naltrexone has been used in higher oral doses (more than 100 mg) to avoid the euphorigenic effects of opioid agonists. It has been reported that naltrexone exerts a very strong preferential blocking action against the mu receptor on the delta sites. Naltrexone is known as a synthetic congener of oxymorphone without opioid agonist properties, and it differs in the structure of oxymorphone by the replacement of the 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 have been evaluated in multiple animal and clinical studies. See, for example, Gonzales JP, et al. Naltrexone: a review of its pharmacokinetic and pharmacokinetic and efficacy-therapeutic properties in the management of opioid dependence. Drugs 1988; 35: 192-213, and incorporated herein by reference. After oral administration, naltrexone is rapidly absorbed (within one hour) and has a range of oral bioavailability of 5 to 40%. The protein bond of naltrexone is approximately 21% and the volume of distribution after the administration of a single dose is 16.1 L / kg. Naltrexone is commercially available in tablet form (Revia®, DuPont) for the treatment of alcohol dependence and for the blockade of exogenously administered opioids. See, for example, Revia (naltrexone hydrochloride tablets). Physician Reference 51st edition, Montvale, NJ. Medical Economics 1997; 51: 957-959. A dosage of 50 mg ReVia® blocks the pharmacological effects of 25 mg of heroin administered IV for up to 24 hours. It is known that when administered with morphine, heroin or other opioids and a chronic base, naltrexone blocks the development of physical dependence on opioids. It is considered that the method by which naltrexone blocks the effects of heroin is by competitive binding in opioid receptors. Naltrexone has been used to treat narcotic addiction by a complete blockade of the effects of opioids. It has been discovered that most of the successful use of naltrexone for a narcotic addiction is narcotic addicts of good prognosis, as part of a comprehensive occupational or rehabilitation program involving behavioral control or other methods to increase compliance. For the treatment of narcotic dependence with naltrexone, it is desired that the patient be free of opioids for at least 7-10 days. The initial dosage of naltrexone for such purposes has commonly been about 25 mg, and if no withdrawal signals occur, the dosage can be increased to 50 mg per day. A daily dosage of 50 mg is considered to produce an adequate clinical blockade of the opioid actions administered parenterally. Naltrexone has also been used for the treatment of alcoholism and in conjunction with psychotherapeutic and social methods. In the dosage forms and methods of the invention, the amount of naltrexone included is significantly lower than the doses previously available. This is in part because the use of naltrexone is different in the present invention: the aim is not to block the opioid effects, but rather to provide a negative "adverse" experience when a large amount of the combination product is taken, for example. example, approximately 2 to 3 times the common prescribed dose or is administered to a physically dependent person. Then, for example, in the formulas of the present invention in which the opioid is a hitarocodone bitartrate 15 mg, the amount of naltrexone hydrochloride included in the formula is 0.5 mg to about 4 mg, and preferably 0.75 mg a approximately 3 mg naltrexone per 15 mg hydrocodone. Opioid analgesics which are of great utility in the present invention include all opioid agonists or combined agonists-antagonists, partial agonists, including but not limited to alfentanil, allylprodine, alphaprodin, anileridin, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocin, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimetheptanol, dimethyl thiambutene, dioxafethyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambenne, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydroromorphone, hydroxypetidine, isomethadone , ketobemidone, levorphanol, levofenacil-morfan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, mirofin, narcein, nicomorphine, norlevorphanol, normetadone, nalorphine, nalbufen, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, fenadoxone, fenomorfan, phenazocine, phenoperidine, piminodine, piritramide, profeptazine, promedol, properidin, propoxyphene, sufentanil, tilidine, tramadol, combinations of any of the foregoing, salts of any of the foregoing and the like. In certain preferred embodiments, the opioid or analgesic agonist is selected from a group consisting of hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone, or salts thereof, or mixtures thereof. In certain preferred embodiments, the opioid agonist is hydrocodone. The equianalgesic doses of these opioids, compared to a dose of 15 mg of hydrocodone are set forth in Table 1 below: Table 1: Eq ianalgesic doses of Opioid Opioids Calculated dose (mg) Oxycodone 13.5 Codeine 90.0 Hydrocodone 15.0 Hydromorphone 3.375 Levorphanol Meperidine 135.0 Methadone 9.0 Morphine 27.0 Based on the preferred ratio of naltrexone in an amount of about 0.5 to about 4 mg per 15 mg of hydrocodone, the appropriate percentage of naltrexone for 1 mg of each opioid is set forth in the Table Table 2: Weight Percentage of Naltrexone by Opioid Dosing Opioid Percentage of Naltrexone Weight by 1 mg of Opioid Oxycodone 0.037 to 0.296 Codeine 0.005 to 0.044 Hydrocodone 0.033 to 0.267 Hydromorphone 0.148 to 1.185 Levorphanol 0.278 to 2.222 Meperidine 0.0037 to 0.0296 Methadone 0.056 to 0.444 Morphine 0.018 to 0.148 Based on the most preferred percentage of about 0.75 to 3 mg of naltrexone per 15 mg of hydrocodone, of naltrexone, the approximate percentage of naltrexone for 1 mg of each opioid is stated in Table 3: Table 3: Naltrexone Weight Percentage by Opioid Dosing Opioid Percentage of Naltrexone Weight Oxycodone 0.056 to 0.222 Codeine 0.0083 to 0.033 Hydrocodone 0.050 to 0.200 Although hydrocodone is effective in pain management, there has been no incr in its abuse by people who are psychologically dependent on opioids or who misuse opioids for non-therapeutic rns. Previous experience with other opioids has shown a potential for decrd abuse when opioids are administered in combination with a narcotic antagonist especially in patients who are exadicts. einhold LL, at al. Buprenorphine Alone and in Combination with Naltrexone in Non Dependent Humans, Drug Dependence and Alcohol 1992; 30: 263-274; Mendelson J., et. Al., Interactions of Buprenorphine and Naloxone in Narcotics Dependent Wills, Clin Pharm Ther 1996; 60: 105-114; two of which are incorporated herein by reference. Hydrocodone is a semisynthetic narcotic analgesic and an antitussive with actions of the central nervous system and multiple gastrointestinal. Chemically, hydrocodone is 4,5-epoxy-3-methoxy-17-ethylmorphinan-6-one, and is also known as dihydrocodeinon. Like other opioids, hydrocodone can be a habit of formation and can lead to drug dependence of the morphine type. In excess, doses of hydrocodone, like any other opium derivative, would reduce respiration. Oral hydrocodone is also available in Europe (Belgium, Germany, Greece, Italy, Luxembourg, Norway and Switzerland) as an antitussive agent. A parenteral formula is also found in Germany as an antitussive agent. For use as an analgesic, hydrocodone bitartrate is commercially available in the United States only as a fixed combination with non-narcotic drugs (ie, ibuprofen, acetaminophen, aspirin, etc.) for pain relief ranging from moderate to severe. A common dosage form of hydrocodone is a combination. with acetaminophen, and is commercially available, for example, as Lortab® in the United States from UCB Pharma, Inc. as tablets of 2.5 / 500 mg, 5/500 mg, 7.5 / 500 mg and 10/500 mg of hydrocodone / acetaminophen. The tablets are also available in a percentage of 7.5 mg of hydrocodone bifartrate and 650 mg of acetaminophen; and 7.5 mg of hydrocodone bitartrate and 750 mg of acetaminophen. Hydrocodone in combination with aspirin is administered in oral dosage form to adults usually one to two tablets every 4 to 6 hours as needed to alleviate it. pain. The tablet form is 5 mg of hydrocodone bitartrate and 224 mg of aspirin with 32 mg of caffeine; or 5 mg of hydrocodone bitartrate and 500 mg of aspirin. A relatively new formula comprises' the hydrocodone and ibuprofen bitrartrate. Vicoprofen®, which is commercially available in the United States from Knoll Laboratories, is a tablet that contains 7.5 mg of hydrocodone bitrartrate and 200 mg of ibuprofen. The present invention is contemplated to encompass such formulas, with the inclusion of the orally active opioid antagonist within the inventive amounts set forth herein. The abuse potential of opioid analgesics such as hydrocodone is surprisingly reduced by the inventive combinations of the present invention. More particularly it has been found that it is possible to combine in an oral simple dosage form an opioid analgesic together with a small amount of opioid antagonist, to achieve a product which still provides analgesia but which substantially denies the possibility of a physically dependent human being continuing abusing the drug by taking more than one tablet at a time, for example, 2-3 times more than the commonly prescribed dose. The oral dosage forms of the invention comprise a therapeutically effective amount orally of an opioid agonist together with an opioid antagonist such as naltrexone in an amount (i) which does not cause a reduction in the level of analgesia that occurs of the dosage form with oral administration at a non-therapeutic level and (ii) which provides for at l a slightly negative "adverse" experience in physically dependent humans, for example, physically dependent addicts (eg, abrupt withdrawal syndrome) when taking more than the prescribed doses at the same time. Preferably the amount of the antagonist included in the oral dosage form is (iii) less positive reinforcement (for example, less "like") by a non-physically dependent human, for example, opioid addict, than a comparable oral dosage form without the included antagonist. The amount of antagonist which is very useful to achieve the parameters (i) - (iii) established in the previous paragraph can be determined at least in part, for example, through the use of "surrogate" tests such as VAS scale (where the person graduates their perception of the effect of the dosage form) and / or by means of a measurement such as the size of the pupil (measured by pupilometry). Said measurements allow a person skilled in the art to determine the dose of the relative antagonist with the dose of the agonist, which causes a decrease in the narcotic effects of the agonist. Subsequently, a person skilled in the art can terminate the level of the opioid antagonist which causes adverse effects in physically dependent persons as well as the level of opioid antagonist which minimizes "like results" or the opioid reinforcing properties in dependent addicts not physically. Once these levels of opioid antagonist are determined, then it is possible to determine the range of antagonistic doses at or below the level which would be very useful to achieve the parameters (i) - (iii) established in the previous paragraph. The combination of the opioid agonist and the opioid antagonist can be employed in additional combinations with conventional excipients, i.e., pharmaceutically acceptable organic inorganic carriers or carriers suitable for oral administration, known in the art. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, saline solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelato, carbohydrates, such as lactose, amylose or starch, magnesium talc stearate , silicic acid, viscous paraffin, perfume oil, monoglycerides- and diglycerides of fatty acid, fatty acid esters of pentaerythritol, hydroxymethylcellulose, polyvinylpyrrolidone, etc. the pharmaceutical preparations can be sterilized if it is desired to combine them with auxiliary oils, for example lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, colorants, flavors and / or aromatic substances and the like. These can also be combined when desired with other active agents, for example other analgesic agents. For oral administration, particularly suitable are tablets, dragees, liquids, drops, suppositories or capsules, pills and gel capsules. The compounds intended for oral use can be prepared by any method known in the art and such compounds can contain one or more agents selected from the group consisting of pharmaceutically inert non-toxic excipients which are suitable for the manufacture of tablets. Such excipients include, for example, an inert diluent such as lactose; granulating and disintegrating agents such as corn starch; binding agents, such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncovered or they may be covered by techniques known for elegance or to release the delay of the active ingredients. Formulas for oral use may also be presented as hard gelatin capsules wherein the active ingredient is combined with an inert diluent. The aqueous suspensions contain the above-identified combination of drugs and the mixture has one or more suitable excipients, suspending agents, for example pharmaceutically acceptable synthetic gums such as hydroxypropylmethylcellulose or natural gums. Oily suspensions can be formulated by suspending the aforementioned combination of drugs in a vegetable oil or mineral oil. The oily suspensions may contain a thickening agent such as beeswax or cetyl alcohol. Syrup, elixir, or similar can be used where a sweetening vehicle is used. Injectable suspensions may also be prepared, in which case suitable liquid carriers, suspending agents and the like may be employed. The method of treatment and pharmaceutical formulas of the present invention may further include one or more drugs in addition to the opioid analgesics and opioid antagonists, whose additional drugs may or may not act synergistically with the present. Therefore, in certain embodiments, a combination of two opioid analgesics may be included in the formula, in addition to the opioid antagonist. For example, the dosage form may include two opioid analgesics having different properties, such as half-life, solubility, potency and a combination of any of the foregoing. In the additional embodiment, one or more opioid analgesics are included and an additional opioid drug is also included, in addition to opioid antagonist. Such non-opioid drugs would preferably provide additional analgesia and would influence, for example, aspirin; acetaminophen; non-spheroidal anti-inflammatory drugs ("NSAIDS"), for example, ibuprofen, ketoprofen, etc .; N-methyl-D-aspartate (NMDA) receptor antagonists, for example, a morphine such as dextromethorphan or dextorphan, or ketamine; cyclooxygenase-ll inhibitors ("COX-II inhibitors"); and / or glycine receptor antagonists. In certain preferred embodiments of the present invention, the invention allows for the use of lower doses of opioid analgesics by virtue of the inclusion of an additional non-opioid agonist, such as an NSAID or a COX-2 inhibitor. By using smaller amounts of one or both drugs, side effects associated with effective pain management in humans are reduced. Suitable non-spheroidal anti-inflammatory agents, including ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprefen, flubufen, ketoprofen, indoprofen, prioprofen, carprofen, oaxiprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid , indomethacin, sulindac, tolmetin, zomepirac, thiopinac, zidomethacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, and the like. The very useful doses of these drugs is well known to those skilled in the art. N-methyl-D-aspartate (NMDA) receptor antagonists are well known in the art, and comprise, for example, morphins such as dextromethorphan or dextorphan, ketamine, d-methadone or pharmaceutically acceptable salts thereof. For the purposes of the present invention the term "NMDA antagonist" is also considered to comprise drugs that block a greater intracellular consequence of NMDA receptor activation such as a gangliosity such as GMi or GTi such as a phenothiazine such as trifluoperazine or a naphthalenesulfonamide as N- (6-aminotexyl) -5-chloro-1-naphthalenesulfonamide. It establishes that these drugs inhibit the development of tolerance for and / or dependence on addictive drugs, for example narcotic analgesics such as morphine, codeine, etc., in U.S. Patent Nos. 5,321,012 and 5,556,838 (both by Mayer. , et al.), and to treat chronic pain in US Pat. No. 5,502,058 (Mayer, et al.), of which all are incorporated by reference. The NMDA antagonist may be included on its own, or in combination with a local anesthetic such as lidocaine, as described in these patents of Mayer et al. The treatment of chronic pain by the use of the glycine receptor antagonist and the identification of such drugs are described in U.S. Patent No. 5,514,680 (Wuber, et al.), By means of which incorporated by reference. COX-2 inhibitors have been reported in the art and many chemical structures are known to produce cyclooxygenase-2 inhibition. COX-2 inhibitors are described, for example, in U.S. Patent No. 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 of which are hereby incorporated by reference. Preferred COX-2 inhibitors include celecoxib (SC-58635), DUP-697, flosulide (CGP-28238), meloxicam, 6-methoxy-2 naphthyl acetic acid (6-MNA), MK-966, nabumetone (prodrug for 6-) MNA), nimesulide, NS-398, SC-5766, SC-58215, T-614; or combinations thereof. The dosage levels of the COX-2 inhibitor in the order of about 0.005 mg to about 140 mg per kilogram of body weight per day therapeutically effective in combination with an opioid analgesic. Alternately, approximately 0.25 mg to 7 mg per patient per day of COX-2 inhibitor is administered in combination with an opioid analgesic. In a further embodiment, a non-opioid drug can be included which provides a desired effect in addition to analgesia, for example antitussive drugs, expectorants, decongestants, antihistamines, local anesthetics and the like. An oral dosage form according to the invention can provide, for example, granules, spheroids, beads, tablets (hereinafter referred to as "multiparticulates"). An amount of the multiparticulates which is effective to provide the desired dose of opioids over time, may be placed in a capsule or may be incorporated into any other suitable oral solid form. Alternatively, alternately, the oral dosage form may be in the form of a tablet. CONTROLLED RELEASE DOSAGE FORM The combination of opioid agonist with opioid antagonist can be formulated as a controlled or sustained release oral formula in any suitable tablet, coated tablet or multiparticulate formula known to those skilled in the art. The sustained release dosage form may optionally include a sustained release carrier which is incorporated into a matrix together with the opioid agonist and the opioid antagonist, or it may be applied as a sustained release coating. In embodiments in which the opioid analgesic comprises hydrocodone, sustained release oral dosage forms may include analgesic doses of about 8 mg to 50 mg of hydrocodone per unit dose. In oral sustained release dosage forms wherein the hydromorphon is the therapeutically active opioid, it is included in an amount ranging from an amount of 2 mg to about 64 mg of hydromorphonate hydrochloride. In another embodiment, the opioid analgesic comprises morphine, and sustained release oral dosage forms of the present invention include from about 2.5 mg to 800 mg morphine by weight. In another embodiment, the opioid analgesic comprises oxycodone and sustained release oral dosage forms include from about 2.5 mg to about 800 mg oxycodone.

Controlled release In another embodiment, the opioid analgesic comprises oxycodone and sustained release oral dosage forms include from about 2.5 mg to 800 mg oxycodone. The opioid analgesic may comprise scavenger and sustained release oral dosage forms may include from 25 mg to 800 mg of Cramadol per unit dose. The dosage form may contain more than one opioid analgesic to provide a substantially equivalent therapeutic effect. Alternatively, the dosage form may contain equivalent molar 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 such particles that contain or comprise active ingredient, wherein the particles have a diameter of about 0.1 mm to 2.5 mm, preferably 0.5 mm to 2 mm The particles are preferably film coated with a material that allows the release of the combination of opioid agonist and opioid antagonist in a sustained ratio in an aqueous medium. The film coating is chosen to achieve, in combination with other established properties, a desired in-vitro release rate. The sustained release coating formulations of the present invention should be capable of producing a strong and continuous film which is smooth and elegant, capable of supporting pigments and other coating additives, non-toxic inert and lacking in viscosity. In certain areas of embodiment, the particles comprise normal release matrices containing the opioid analgesic with the opioid antagonist. PROTECTIVE LAYERS The dosage forms of the present invention may optionally be covered with one or more materials suitable for the regulation of the release or for the protection of the formula. In one embodiment, the protective layers are provided to allow either pH-dependent or pH-independent release, for example when exposed to a gastrointestinal fluid. A pH-dependent protective layer serves to release the opioid in the desired areas of the gastrointestinal tract (GI), for example the stomach or small intestine, so that the absorption profile is provided which is capable of providing at least eight hours and preferably about twelve hours to about twenty-four hours of analgesic to a patient. When a pH-independent protective layer is desired, the protective layer is designed to achieve optimal release without considering changes in pH in the environmental fluid, for example, the gastrointestinal tract. It is also possible to formulate compounds which release a part of the dose in a desired area of the gastrointestinal tract, for example, the stomach and release the remainder of the dose in another area of the gastrointestinal tract such as the small intestine. The formulas according to the invention using pH-dependent protective layers to obtain formulas, can also impart a repeated action effect whereby the unprotected drug is covered with the enteric layer and is released into the stomach, while the remainder, Protected by the enteric layer, it is also released downwards into the grasto-intestinal tract. The protective layers which are pH dependent may be used according to the present invention, these include shellac, cellulose, acetate phthalate (CAP), polyvinyl phthalate (PVAP), hydroxypropylmethylcellulose phthalate and methacrylic acid ester copolymers, zein, and the like. In certain preferred embodiments, on substrate (eg, pearl with tablet center, matrix particle) they contain the opioid analgesic (with or without the COX-2 inhibitor) is covered with a hydrophobic material selected from (i) an alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof. The protective layer can be applied in the form of an organic or aqueous solution or dispersion. The protective layer can be applied to obtain a weight gain of about 2 to 25% of the substrate to obtain a desired sustained release profile. Protective layers deriving from aqueous dispersions are described, for example in detail in U.S. Patent Nos. 5,273,760 and 5,286,493, transferred to the assignee of the present invention and are hereby incorporated by reference. Other examples of sustained release formulas and protective layers which may be used in accordance with the present invention include U.S. Patent No. 5,324,351; 5,356,467 and 5,472,712, hereby incorporated by reference in their entirety.

Alkylcellulose Polymers Cellulosic materials and polymers, including alkylcelluloses, provide very suitable hydrophobic materials for coating the beads according to the present invention simply by way of example, a preferred alkyl cellulosic polymer is ethylcellulose, although the artisan would appreciate that other polymers of Cellulose or alkylcellulose can be used easily, either singly or in combination, in its entirety or part of the hydrophobic protective layer according to the invention.

A commercially available aqueous dispersion of ethylcellulose is Aquacoat® (FMC Corp., Philadelphia, Pennsylvania, USA) Aquacoat® is prepared by dissolving ethylcellulase in water immiscible organic solvent and then emulsifying it in water in the presence of a surfactant and a stabilizer . After homogenization to generate submicron droplets, the organic solvent is evaporated under vacuum to form a pseudo latex. The plasticizer is not incorporated in the pseudo latex during the elaboration phase. Therefore, before using it as a protective layer, it is necessary to intimately mix the Aquacoat® with a suitable plasticizer before using it.

Another aqueous dispersion of the ethylcellulose is commercially available as Surelease® (Colorcon, Inc., West Point, Pennsylvania, U. A.). This product is prepared by incorporating the plasticizer in the dispersion during the manufacturing process. A heated melted substance of a polymer, plasticizer (dibutyl sebacanth), and stabilizer (oleic acid) is prepared as a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion which can be applied directly to the substrates Acrylic Polymers In other preferred embodiments of the present invention, the hydrophobic material comprising the controlled release protective layer, is a pharmaceutically accepted acrylic polymer which includes but is not limited to acrylic acid and methacrylic acid copolymers, copolymers of methyl methacrylate, ethoxyethyl methacrylates, cyanoethyl methacrylates, poly (acrylic acid), poly (methacrylic acid), alkylamido copolymer of methacrylic acid, poly (methyl methacrylate) polymethacrylate, poly (methyl methacrylate) polyacrylamide copolymer methacrylate aminoalkyl, poly (methacrylate) methacrylic acid anhydride) and glycidyl methacrylate copolymers. In certain preferred embodiments, the acrylic polymer is composed of one or more ammonium methacrylate copolymers. Ammonium methacrylate copolymers are very well known in the art, and are described in NF XVII as fully polymerized copolymers of methacrylic acid esters and acrylic acid with low content of quaternary ammonium groups. In order to obtain a desirable dissolution profile, it may be necessary to incorporate two or more ammonium methacrylate copolymers having different physical properties, such as molar percentages different from the quaternary ammonium groups to neutral (meth) acrylic esters. Certain methacrylic acid ester type polymers are very useful for the preparation of pH dependent protective layers which can be used according to the present invention. For example, there is a family of copolymers synthesized from diethylaminoethyl methacrylate and other neutral methacrylic esters, also known as methacrylic acid copolymers or polymeric methacrylates, commercially available as Eudragit® from Rohm Tech, Inc. There are various types of Eudragit® for example, Eudragit® E is an example of a methacrylic acid copolymer which bulges or dissolves in acidic media. Eudragit®L is a copolymer of methacrylic acid which does not thicken approximately pH >5.7 and is soluble at approximately pH > 6. Eudragit® S does not increase by approximately pH > 6.5 and is soluble in about pH > 7. Eudragrit® RL and Eudragrit® RS are swollen in water and the amount of water absorbed by these polymers is pH-dependent. However, the dosage forms covered with Eudragit® RL and RS are pH-independent. In certain preferred embodiments the acrylic protective layer comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the tradenames Eudragit® RL30D and Eudragit® Rs30D, respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylic esters with low content of quaternary ammonium groups, the molar percentage of the ammonium groups for neutral (meth) acrylic esters are 1:20 in Eudragit® RL30d and 1: 40 in Eudragit®RS30D. The average molecular weight is about 150,000. The designation of codes RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents. The mixtures of Eudragit® RL / R7S are insoluble in water and digestive fluids. However, the protective layers formed therefrom can be thickened and are permeable in aqueous solutions and digestive fluids. The Eudragit® RL / RS dispersions of the present invention can be combined together in any desired percentage to finally obtain a sustained release formula having a desired dissolution profile. The desired sustained release formulas can be obtained, for example, from a protective retardant layer derived from 100% Eudragit®RL, 50% Eudragit® and 50% Eudragit® RS and 10% Eudragit® RL: Eudragit® 90 % RS. Of course a person skilled in the art will recognize that other acrylic polymers can also be used such as for example Eudragit® L. Plasticizers In the embodiments of the present invention wherein the protective cover comprises an aqueous dispersion of a hydrophobic material, the inclusion of an effective amount of a plasticizer in the aqueous dispersion of the hydrophobic material will further improve the physical properties of the sustained release protective coating. For example, because ethylcellulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, it is preferred to incorporate a plasticizer into a protective ethylcellulose layer containing a sustained release protective layer before use. the same, as a coating material. Generally, the amount of plasticizer -included in a coating solution, is based on the concentration of the film former, for example more often from about 1 to 50% by weight of the film former. However, the concentration of the plasticizer can only be determined adequately after a careful experiment 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, although it is possible that other water-insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, resin oil, etc.) can be used in this case. Triethyl citrate is a plasticizer that is especially preferred for the aqueous dispersions of the ethyl cellulose 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 which have proven to be suitable for improving the elasticity of films formed from acrylic films such as Eudragit® RL / RS lacquer solutions, include polyethylene glycols, propylene glycol, diethyl phthalate, resinous oil and triacetin. Triethyl citrate is a plasticizer that is especially preferred for the aqueous dispersions of the ethyl cellulose of the present invention. It has further been observed that the addition of a small amount of talc reduces the tendency of the aqueous dispersion to stick during processing and acts as a polishing agent. PROCESSES FOR THE PREPARATION OF COVERED PEARLS When a hydrophobic material is used to cover inert pharmaceutical beads such as beads a pariel 18/20, a plurality of the resulting solid controlled release beads can subsequently be placed in a gelatin capsule in a sufficient quantity to provide an effective controlled release dose When hydrophobic material is used to cover inert pharmaceutical beads such as nu-pariel 18/20 beads, a plurality of resulting solid controlled release beads can subsequently be co-dried in a gelatin capsule in a sufficient amount to provide an effective controlled release dose when ingested and when contacted by an environmental fluid, for example gastric fluid or dissolution media. The controlled release pearl formulas of the present invention slowly release the active agent therapeutically, for example when ingested and exposed to gastric fluids, and then to intestinal fluids. The controlled release profile of the formulas of the invention can be altered, for example by varying the amount of the overlayer with the hydrophobic material alternating the manner in which the plasticizer is added to the hydrophobic material by varying the amount of plasticizer relative to the hydrophobic material , through the inclusion of additional ingredients or excipients, altering the manufacturing method, etc. The dissolution profile of the last product can also be seen by modifying, for example, by increasing or decreasing the thickness of the retarding layer.

Spheroids or beads coated with a therapeutically active agent are prepared, for example by dissolving the active therapeutically, in water and then spraying the solution onto a substrate, for example, nu-pariel 18/20 beads, using a Wuster insert. Optionally, additional ingredients are also added prior to coating the beads to assist in the binding of the opioid to the beads and / or to color the solution etc. For example, a product that includes hydroxypropylmethylcellulose, with or without a dye (for example Opadry, commercially available from Colorcon, Inc.) can be added to the solution and the solution mixed (for example for about one hour) before application thereof. the pearls. The resulting coated substrate, in these beads of the example, can then be optionally coated with a barrier agent to remove the therapeutically active agent from the hydrophobic release protective layer. An example of a suitable barrier agent is one comprising hydroxylpropylmethylcellulose. However, any film former known in the art can be used preferring that the barrier agent does not affect the dissolution percentage 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 further includes an effective amount of plasticizer as for example, triethyl citrate. Preformulated aqueous dispersions of ethylcellulose, such as Aquacoat or Surelease, can be used. If Sureales is used, it is not necessary to add a plasticizer separately. 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 solvent system (ie water), a colorant to provide elegance and distinction of the product. The color can be added to the solution of the active agent therapeutically instead of or in addition to the aqueous dispersion of the hydrophobic material. For example, color can be added to the Aquacoat (R) through the use of alcohol or propylene glycol based on color dispersions, laminated aluminum lacquers and opacifiers such as titanium dioxide, adding color with deviation to the soluble polymer solution in water and then using low deflection for the Aquacoat, plasticized. Alternatively, any suitable method can be used to provide color to the formulas of the present invention. Suitable ingredients for providing color to the formula when using an aqueous dispersion of an acrylic polymer, include titanium dioxide and color pigments, such as iron oxide pigments. The incorporation of pigments, however, can increase the retarding effect of the protective layer. The plasticized hydrophobic material can be applied to the substrate comprising the therapeutically active agent by "spraying using any suitable spray equipment known in the art." In a preferred method, a Wurster fluidized bed system is used in which a jet of air, injected from below fluidizes the core material and effect drying while the protective layer of the acrylic polymer is sprayed in. A sufficient quantity of the hydrophobic material to obtain a release predetermined control of said active agent therapeutically when the coated substrate is exposed to the aqueous solutions by Gastric fluid example, is preferably applied, taking into account "the physical characteristics of the active agent therapeutically when the covered substrate is exposed to aqueous solutions, for example gastric fluid, is preferably applied, taking into account the physical characteristics of the therapeutic active agent the form of incorporation of the plasticizer, etc. After covering with the hydrophobic material, an additional overcoat of a film former such as Opadry is optionally applied to the beads. This overburden is provided if so provided, to substantially reduce the agglomeration of the beads.

The release of the therapeutically active agent from the controlled release formula of the present invention can be further influenced, ie adjusted to a desired percentage, by the addition of one or more release modifying agents, or by providing one or more passages through the protective layer. The percentage of the hydrophobic material for the 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, extracted or filtered from the protective layer in the environment of use. The pore formers may comprise one or more hydrophilic materials such as hydroxypropylmethylcellulose. The sustained release protective layers of the present invention also include erosion promoters such as starches and gums. The sustained release protective layers of the present invention may also include materials useful for making micropore laminae in the environment of use, such as polycarbonates which are formed from linear polyesters of carbonic acid in which the 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 hydroxypropylmetalcellulose, lactose, metal stearates, and mixtures of any of the foregoing. The sustained release protective layers of the present invention may also include exit means comprising at least one passage, orifice or the like. The passage may be formed by such methods as those disclosed in U.S. Patent No. 3,845,770; 3,916,889; 4,063,064; and 4,088,864 (all of which are hereby incorporated by reference). The passage can have any shape such as round, triangular, square, elliptical, irregular, etc. AGGLOMERATED PEAR FORMULAS In other embodiments of the present invention, the controlled release formula is achieved by means of a binder having a controlled release protective layer as set forth above. The present invention may also utilize a liberated release binder that allows percentages of in-vitro dissolution of the opioid within the preferred ranges and that releases the opioid. opioid in the pH-dependent or pH-independent form. The materials suitable for inclusion in a controlled release binder will depend on the method used to form the binder. For example, a binder in addition to the opioid analgesic and (optionally) COX-2 may include: Hydrophilic and / or hydrophobic materials, such as gums, cellulose esters, acrylic resins, protein derived materials; The list is not intended to be exclusive, and any pharmaceutically acceptable hydrophobic material or hydrophilic material which is capable of imparting controlled release of the active agent and which melts (or softens to the extent necessary to be extruded) may be used in accordance with the present invention. . The long chain (Cg-C5Q 'especially C? _2-C4o) substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters or fatty acids, mineral and vegetable oils and waxes, sterile alcohol; polyalkylene glycols. These polymers, acrylic polymers, especially Eudragit RSIPO, cellulose esters, especially hydroxyalkylcelluloses and carboxyalkylcelluloses, are the most 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 a hydrocarbon, the hydrocarbon preferably has a melting point between 25 and 90 ° C. From long-chain hydrocarbon materials, the fatty alcohols (aliphatic) sonios that are preferred. The oral dosage form may contain up to 60% (by weight) of at least one long chain, digestible 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 a group consisting of alkyl celluloses, polymers of acrylic and methacrylic acids as well as copolymers, shellac, zein, hydrogenated resin oil, hydrogenated vegetable oil or combinations 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 acid and methacrylic acid, methyl methacrylate, methyl methacrylate copolymers, ethoxy methacrylates, ethyl, cyanoethyl methacrylate, copolymer of methacrylate aminoalkyl poly (acrylic acid) poly (methacrylic acid), alkylamino copolymer of methacrylic acid, poly (methyl methacrylate), poly (methacrylic acid) (anhydride) polymethacrylate, polyacrylamido, poly (anhydride) methacrylic acid) and copolymers of glycrylic methacrylate. In other embodiments, the hydrophobic material is selected from materials such as hydroxyalkylcelluloses such as hydroxypropylmethylcellulose and mixtures of the foregoing. Preferred hydrophobic materials are insoluble in water with more or less pronounced hydrophobic and / or hydrophilic tendencies, preferably the hydrophobic materials used in the invention have a melting point of from 30 to approximately 200 ° C, preferably approximately 45 ° at 90"C. Specifically, the hydrophobic material may comprise natural or synthetic waxes, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or preferably ketostearyl alcohol), fatty acids including, but not limited to fatty acid esters, fatty acid glycerides (mono, - di, -and triglycerides), hydrogenated fatty acids, hydrocarbons, normal waxes, stearic acid, stearyl alcohol and hydrophobic and hydrophilic materials that have major hydrocarbon elements. Suitable waxes include, for example, beeswax, glycol wax, resin wax and carnauba wax. For the purposes of the present invention, a wax-like substance is defined as any material which is normally solid at room temperature and which has a melting point of about 30 to 100 'C. Suitable hydrophobic materials which may be used in accordance with the present invention include long chain (Cg-C5Qi especially C? 2-c4?) substituted or unsubstituted hydrocarbons such as fatty acids, fatty alcohols, glyceryl esters or fatty acids, mineral and vegetable oils as well as natural and synthetic waxes. The hydrocarbons that have a melting point between 25 and 90 'C are the most preferred. The hydrocarbons that have a melting of between 25 and 90 'C are the most preferred. Of the long chain hydrocarbon materials, the fatty alcohols (aliphatic) are those that are preferred in certain embodiments. The oral dosage form can have up to 60% (by weight) of at least one long-chain, digestible hydrocarbon. Preferably, a combination of two or more hydrophobic materials is included in the binder formulas. If an additional hydrophilic material is included, it is preferably selected from natural and synthetic waxes, fatty acids, fatty alcohols and combinations thereof. Examples include beeswaxes, carnauba wax, stearic acid and stearyl alcohol. This list does not pretend to be exclusive. A particular suitable binder comprises at least one water-soluble hydroxyalkyl cellulose, at least one C.sub.2 -C.sub.3 g aliphatic alcohol, preferably C.sub.4 -C.sub.22 and optionally at least one polyalkylene glycol. The cellulose of at least one hydroxyalkyl is preferably a hydroxy (C-Cg alkyl) alkyl cellulose, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and especially hydroxyethylcellulose. The amount of cellulose of at least one hydroxyalkyl in the present oral dosage form will be determined, inter alia, by the precise percentage of opioid release required. In at least one aliphatic alcohol it can be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol. However, in preferred embodiments particularly of the present dosage form, the alcohol of at least one aliphatic element is cetyl alcohol or keto stearyl alcohol. The amount of alcohol of at least one aliphatic element in the present oral dosage form will be determined, as above, by the precise percentage of opioid release required. This will also depend on whether at least one glycolpolyalkylene is present in or in the absence of the oral dosage form. In the absence of at least one glycol polyalkylene, the oral dosage form preferably contains between 20% and 50% (by weight) of at least one aliphatic alcohol. When at least one polyalkylene glycol is present in the oral dosage form, then the combined weight of at least one aliphatic alcohol and at least one polyalkylene glycol preferably constitutes between 20% and 50% (by weight) of the dosage total. In one embodiment, the proportion of, for example, at least one hydroxyalkyl cellulose or acrylic resin for at least one aliphatic alcohol / polyalkylene glycol, determines to a considerable degree, the release rate of the opioid of the formula. A proportion of at least one hydroxyalkyl cellulose for at least one aliphatic alcohol / polyalkylene glycol of between 1: 2 and 1: 4 is the most preferred, with a ratio between 1: 3 and 1: 4 which is the which is particularly preferred. The glycol of at least one polyalkylene can be, for example, polypropylene glycol or the one which is preferred, glycol polyethylene The number average molecular weight of at least one polyalkylene glycol which is preferred is between 1,000 and 15,000 especially between 1,500 and 12,000 Another suitable controlled release agglomerate comprises an alkylcellulose (especially ethylcellulose) an aliphatic alcohol Ci2-C36 and optionally a polyalkylene glycol In another preferred embodiment the binder includes a pharmaceutically acceptable combination of at least two hydrophobic materials. of the above ingredients, a controlled release binder may also contain suitable amounts of other materials, for example, diluents, lubricants, binders, granulating acids, colorants, flavors and glidants that are conventional in the pharmaceutical art. PROCESSES FOR PREPARING PEARLS WITH BASE AGLOMERANTE For the To facilitate the preparation of an oral, controlled release, solid dosage form according to this invention, any method for preparing a binder formula known to those skilled in the art can be used. For example, incorporation into the binder can be effected, for example, by opening (a) to form granules comprising at least one hydroxyalkyl cellulose soluble in water and opioid or an opioid salt; (b) mixing the hydroxyalkyl cellulose containing granules with at least one C 2 ~ c 36 Y (c) aliphatic alcohol optionally, by compressing and forming the granules. Preferably, the granules are formed by wet granulation of the hydroxy-alkyl cellulose / 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 3.75 times, the dry weight of the opioid. Still in alternate embodiments, a spheronizing agent together with an active ingredient can be spheronized to form spheroids. The preferred microcrystalline cellulose is for example the material sold Avicel PH 101 (Trade Mark, FMC Corporation). In such embodiments, in addition to the active ingredient and the spheronizing agent, the spheroids may also contain a binder. Suitable binders such as low viscosity and water soluble polymers will be well known to those skilled in the pharmaceutical art. However, alkyl, water-soluble lower hydroxy cellulose such as hydroxypropyl cellulose are preferred. Additionally (or alternatively) the spheroids may contain a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer or ethylcellulose. In such embodiments, the sustained release protective layer will generally include a hydrophobic material such as (a) a wax either alone or in a mixture with fatty alcohol; or (b) shellac or zein. FUSION EXTRUSION AGLOMERANT Sustained-release binders can also be prepared by melt-granulation or extrusion-melt techniques. Generally, melt granulation techniques involve fusing a normally solid hydrophobic material, for example, a wax and incorporating a sprayed drug into it. To obtain a sustained release dosage form, it is necessary to incorporate an additional hydrophobic substance, for example ethylcellulose or a water-insoluble acrylic polymer, into a hydrophobic melted wax material. Examples of sustained release formulas prepared by melt granulation techniques are found in U.S. Patent No. 4,861,598, which were assigned to the assignee of the present invention and which are hereby incorporated by reference into its entirety The additional hydrophobic material may comprise one or more water-insoluble wax-like thermoplastic substances, possibly mixed with one or more wax-like thermoplastic substances that are less hydrophobic than that or more water-insoluble wax-like substances. To achieve constant release, the individual wax-like substances in the formula should be substantially non-degradable and insoluble in gastrointestinal fluids during the initial release phases. Water-insoluble wax-like substances that are very useful can be those with a solubility in water that is less than about I: 5,000 (w / w). In addition to the aforementioned ingredients, a sustained release binder may also contain suitable amounts of other materials such as diluents, lubricants, binders, granulating acids, colorants, flavors and glidants which are conventional in the pharmaceutical art. The amounts of these additional materials will be sufficient to provide the desired effect for the desired formula. In addition to the additional ingredients, a sustained release binder incorporating melt extruded multiparticulates may also contain suitable amounts of other materials, for example, diluents, lubricants, binders, granulating acids, colorants, flavors and glidants that are conventional in the pharmaceutical art. in amounts up to about 50% per -weight of the particulate if desired. Specific examples of pharmaceutically acceptable carriers and excipients that can be used to formulate oral dosage forms are described in the American Pharmaceutical Association (1986) Pharmaceutical excipients brochure, incorporated by reference herein. Fusion Extruded Multiparticulates The preparation of an extruded binder by suitable melting according to the present invention can, for example, include the steps of mixing the opioid analgesic 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 eliminate it. The resulting homogeneous mixture is then removed to form filaments. The extruded product is preferably cooled and cut into multiparticulates by means already known in the art. The filaments are cooled and cut into multiparticulates. The multiparticulates are subsequently divided into unit doses. The extruded product preferably has a diameter of about .01 to 5 mm and provides sustained release of the active agent therapeutically for a period of time from 8 to about 24 hrs. An optional process for preparing the melt extrusions of the present invention includes measuring directly in an extruder, a hydrophobic material, a therapeutically active agent, and an optional binder; heat the homogeneous mixture; eliminate the homogeneous mixture to form the filaments; cool the filaments containing the homogeneous mixture; cutting the filaments into particles having a size of approximately 0.1 mm to 12 mm; and dividing said particles unit doses. In this aspect of the invention, a relatively continuous manufacturing process is carried out.

The diameter of the extruder opening or outlet port can also be adjusted by varying the thickness of the extruded filaments. In addition, the outlet port of the extruder does not need to be round; it can be oblong, rectangular, etc. ~~ Existing filaments can be reduced to particles using a hot wire cutter, guillotine, etc.

The melt extruded multiparticulate system may be, for example, in the form of granules, spheroids, or tablets depending on the exit orifice of the extruder. For purposes of the present invention, the terms "multiparticulate (s) extruded by melting" and "multiparticulate system extruded by melting" and "melt extruded particles" will refer to a plurality of units, preferably within a range of similar size and / or form and containing one or more active agents and one or more excipients preferably including a hydrophobic material as described herein. In this aspect, the multiparticulates extruded by fusion will be of a range of approximately 0.1 to 12 mm in length and will have a diameter of approximately 0.1 to 5 mm. It is further understood that the melt extruded multiparticulates can be of any geometric shape within this size range. Alternatively, the extruded product can be simply cut to the desired length and divided into unit doses of the therapeutically active agent if the need for a spheronization step. In a preferred embodiment, the oral dosage forms are prepared to include an effective amount of multiparticulates extruded by fusion within a capsule. For example, as a plurality of melt extruded multiparticulates can be placed in a gelatin capsule in an amount sufficient to provide an effective sustained release dose when ingested and in contact with gastric fluid. In another preferred embodiment, a suitable amount comes into contact with the gastric fluid. In another preferred embodiment, a suitable amount of the multiparticulate extrudate is compressed into an oral tablet, using conventional tabletting equipment using standard techniques. The techniques and compositions for tabletting (compressed and molded), capsules (hard and soft gelatin) and pills are also described in Remington Pharmaceutical Sciences (Arthur Osol Editor), 1553-1593 (1980), incorporated by reference herein. In another preferred embodiment, the extruded product may be in the form of tablets as set forth in U.S. Patent No. 4,957,681 (Klimesh, et. Al.), "Described in additional detail above and incorporated by the present by reference Optionally, the multiparticulate systems extruded by sustained release fusion or tablets may be covered, or the gelatin capsule may be further coated with a sustained release protective layer such as the sustained release layers described above. protective agents preferably include a sufficient amount of hydrophobic material to obtain a weight gain level of 2 to about 30%, although the overlayer may be higher depending on the physical properties of the particular opioid analgesic compound used and the percentage of desired release, between Other things: Dosage forms of units extruded by f Use of the present invention may further include combinations of melt extruded multiparticulates containing one or more therapeutically active agents previously disclosed before being encapsulated. In addition, the unit dosage forms may also include an amount of an immediate release therapeutically active agent for an immediate therapeutic effect. The therapeutically active agent of immediate release can be incorporated as separate tablets into a gelatin capsule or can be coated on the surface of the multiparticulates after the preparation of the dosage forms (eg) controlled release or protective layer binder base. The unit dosage forms of the present invention may also contain a combination of controlled release beads and multiparticulate binders to achieve a desired effect. The sustained release formulas of the present invention slowly release the active agent therapeutically, for example, when ingested or exposed to gastric fluids, and then to intestinal fluids. The sustained release profile of the melt extruded formulas of the invention can be altered as for example by varying the amount of retarder, ie hydrophobic material, * by varying the amount of the plasticizer relative to the hydrophobic material, by including additional ingredients or excipients , altering the manufacturing method. In other embodiments of the invention, the melt extrudate is prepared without the inclusion of the therapeutically active agent which is subsequently added to the extrudate. Said formulas will commonly have the therapeutically mixed active agent together with the extruded binder material, and then the mixture will be prepared into tablets to provide a slow release formula. Such formulas may have advantages such as when the therapeutically active agent included in the formula is sensitive to temperatures necessary to soften the hydrophobic material and / or retarding material. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples illustrate various aspects of the present invention. These will not be construed to limit the claims in any way whatsoever. EXAMPLE I The separability of naltrexone hydrochloride from hydrocodone bitartrate is examined using an extraction procedure similar to that of drug addicts. Inspection of the structures and consideration of the pKa '(Figure I) will suggest that the two compounds are soluble in acid. However, naltrexo.na would also be very soluble at high pH with a minimum solubility between high pH with a minimum solubility between pH 8.4 and 10.3. It serves us more to test the hypothesis that the compounds can be extracted from a tablet in acid and then the hydrocodone could be precipitated by the high pH. Because hydrocodone controlled release tablets (HYCR) and naltrexone tablets were not available for this study, simulated samples were prepared by adding known amounts of pharmaceutical substances of hydrocodone bitartrate and naltrexone hydrochloride to HYCR tablets AcroContin 15mg of placebo ("Acrocontin" refers to a controlled release base comprising an ammonium methacrylate polymer, together with a aliphatic alcohol, as described in the example of U.S. Patent No. 4,861,598, incorporated herein by reference). Different solvents of varying pH were used to extract the hydrocodone bitartrate and / or naltrexone hydrochloride at concentrations of 4 tablets / 25 ml (section 2.1) and 5 tablets (section 2.2) of the solvent. Recovery is quantified by using HPLC. 2.1 Extraction in concentrations of 4 tablets in 25 ml of Solvent. 2.1.1 Approximately 60 mg of hydrocodone bitartrate, 25mg of naltrexone hydrochloride and 400 mg of HYCR, Acrocontin 15mg placebo tablets (equivalent to 4 tablets) were added to a 25ml volumetric fl ow. Approximately 15ml of water was added to the volumetric flask and the solution was sonicated ("sonicate") for 10 minutes. The solution was diluted to one volume with water and mixed well. This was the sample booking solution. Thirteen sample reserve solutions were prepared in this way. 2.1.2 The pH of the solutions was adjusted with glacial acetic acid or 0.2N NaOH at pH 2.0, 4.0, 5.1, 6.0, 6.5, 7.0, 7.4, 8.0, 8.5, 9.0, and 10.0. However, in the preparation of the pH 1.1 solution, hydrochloric acid was used. Then he followed step 2.1.4. 2.1.3 Step 2.1.1 of the procedure was repeated to prepare sample reserve solutions in ethanol, methanol, and acetone instead of water. 2.1.4 Each solution was filtered using a 5ml disposable syringe and a Millex-HV.45 um filter unit. 1.0 ml of the clear filtrate was measured with a pipette in a 25mm volumetric flask, diluted to volume with water and mixed well. The sample solutions were then injected into the HPLC system and the results are presented in Table 1. 2.2 Extraction in Concentrations of 5 Tablets in 5ml of solvent. 2.2.1 Approximately 75 mg of hydrocodone bitartrate and 32 mg of naltrexone hydrochloride were added to a scintillation bottle which contained 465 mg of HYCR, 15 mg AcroContin placebo tablets (equivalent to 5 tablets). 5.0 ml of water was added to the scintillation bottle and the solutions were sonicated for 10 minutes. This was the sample booking solution. 2.2.2 The pH of the solution was adjusted with 50% w / w NaOH to pH 7.1. After the solution settled for one hour, all the solution was filtered using a 5 ml disposable syringe and a Millex-HV 0.45 um filter unit. 1.0 ml of this clear filtrate was pipetted into a 25 mm volumetric flask, diluted to volume with water and mixed well. This was the sample buffer solution of pH 7.1. 2.2.3 Steps 2.2.1 and 2.2.2 of the procedure were repeated to prepare the sample solutions at pH 8.0, 9.0, 10.0, 11.0, 12.0 and 12.7. The sample solutions are injected into the HPLC system and the results are shown in Table 2. 3. Results The results are presented in Table 1 and 2. In Table 2, it is noted that both hydrocodone and naltrexone were dissolved completely in all solvents except acetone. In Table 2 it is noted that the amount of naltrexone retained in the solution decreased to pH 8 and increased again to pH 10 and the hydrocodone retained in the solution decreased to a higher pH. Table 1. Simulated stratability of naltrexone hydrochloride of hydrocodone bitartrate CR Acrocontin tablets of 15 mg in concentrations of 4 tablets in 25 ml of solvent.

Table 2. Simulated Stratability of Naltrexone Hydrochloride of Hydrocodone Bitartrate Cr, AcroContin tablets of 15 mg in concentration of 5 tablets in 5 ml. of solvent.

Figure 1 provides structures and pKa values of hydrocodone and naltrexone base. 4. - Conclusions In table 1, it can be observed that the concentrations of hydrocodone and naltrexone were very low in 25 ml of solvents and they dissolved almost completely in varied pH as well as in ethanol and methanol. In acetone, hydrocodone and naltrexone are less soluble and poor recoveries were obtained. In Table 2, the results can be explained by examining the pKa of the pharmaceutical substances. The pKa values of naltrexone hydrochloride which were obtained in PRC, Yonkers are 8.4 (in the amino functional group) and 10.3 (in the functional group phenol) and the pKa value of the hydrocodone bistartrate (in the amino functional group) is 9.2. The chemical structures and pKa values of the base hydrocodone and naltrexone are shown in figure 1. For naltrexone hydrochloride: When the pH reaches 8.4, naltrexone is converted to the free base form and starts to precipitate out of the solution and when the pH reaches 10.3, the phenolic functional group OH is deionized and the compound is dissolved again in the solution. For hydrocodone bitartrate: Hydrocodone becomes a free base at pH greater than 9.2 and starts to precipitate out of the solution. Table 1 shows that about 80% of the hydrocodone bitartrate and 10% naltrexone hydrochloride can be removed from the tablets at the higher pH. This procedure probably would not be so easy on the street. Both the strong acid and the strong base would require additional crushing and filtration steps. In addition, the recovered hydrocodone is impregnated with strong caustic, any attempt to clean the caustic would result in a loss of hydrocodone. However, it is advisable to note that in this wet recovery experiment no drug was incorporated into the tablet binder through the manufacturing process (hot wax). It is more likely that from a real tablet the recoveries would be worse. In addition, the addition of a gelling agent or other excipient would make this more difficult. EXAMPLE 2 The extractability of naltrexone hydrochloride (1.5 mg) hydromorphone hydrochloride (15 mg) is studied in a concentration of 5 tablets / 5 ml of solvent, using the same techniques established in example 1. The results are given in the table 3 that appears below: TABLE 3 EXAMPLE 3 The extractability of naltrexone hydrochloride (1.5 mg) of oxycodone hydrochloride (15 mg) in a concentration of 5 tablets / 5 ml of solvent is studied, using the same techniques established in example 1. The results are given in the table 4 that appears below: TABLE 4 While the invention has been described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art would appreciate that obvious modifications can be made to the present without departing from the spirit and range of the invention. Said variations are contemplated to be within the range of the appended claims.

Claims (10)

1. A method for reducing the abuse potential of an oral dosage form of an opioid analgesic, comprising: combining an analgesically effective amount of an active opioid agonist together with an opioid antagonist in an oral dosage form, said agonist combination opioid and opioid antagonist are extracted only from the dosage form together, and in a two step extraction process, it is required to separate to separate the opioid antagonist from the opioid agonist, the amount of the opioid antagonist included being sufficient to counteract the opioid effects if it is extracted together from the oral dosage form with the opioid agonist and administered parenterally. The method of claim 1, wherein said combination of the opioid agonist and the required opioid antagonist are extracted only from the dosage form together, and subsequently must be separated from each other in a separate extraction step. 3. The method of claim 2 wherein both the opioid agonist and the opioid antagonist are soluble in acid, and must be separated using a solution with high pH. The method of claim 3, wherein the opioid agonist is hydrocodone bitartrate and the opioid antagonist is naltrexone hydrochloride, wherein both hydrocodone and naltrexone dissolve at a pH of less than 8 and about 80% of hydrocodone and approximately 10% of the naltroxone is extracted at a higher pH. The method of claim 1 wherein the opioid agonist is hydromorphone hydrochloride and the opioid antagonist is naltrexone hydrochloride. The method of claim 1 wherein the opioid agonist is oxycodone hydrochloride and the opioid antagonist is naltrexone hydrochloride. The method of claim 1 wherein the opioid agonist is morphine sulfate and the opioid antagonist is naltrexone hydrochloride. 8. The method of claim 3 further comprises incorporating within the dosage form an additional ingredient which makes separation of the opioid agonist from the opioid antagonist more difficult. The method of claim 8 wherein said additional ingredient is selected from the group consisting of gelling agents, waxes and mixtures thereof. 10. The method of claim 8 further comprises incorporating in the preparation of the dosage form one or more processing steps which would further prevent separation of the opioid agonist from the opioid antagonist.