Opioidic agonistic/antagonistic combinations

Description of the invention

The invention relates to an oral dosage form comprising a combination of an orally effective analgesic dose of an opioid agonist and an opioid antagonist, the ratio of the opioid antagonist to the opioid agonist providing a combination product that is analgesically effective when the combination is administered orally to a non-physically dependent human subject, but which causes aversion in physically dependent human entities, at the same dose or at a dose higher than an analgesically effective dose when orally administered.

Opioids, also known as opioid agonists, are a group of drugs that exhibit opium or morphine-like properties. Opioids are primarily used as moderate to strong painkillers, but they also have many other pharmacological effects, including somnolence, respiratory depression, mood changes, and mental eclipse without loss of consciousness. Opioids act as agonists, interacting with stereospecific and saturable binding sites in the brain and other tissues. Endogenous opioid-like peptides are found especially in areas of the central nervous system that are believed to be associated with the perception of pain; with movement, mood and behavior, and with the regulation of neuroendocrine functions. Opium contains over twenty different alkaloids. Morphine, codeine and papaverine are included in this group.

By the mid-nineteenth century, the use of pure alkaloids, such as morphine, rather than unpurified opium had begun to spread in the medical world. Parenteral use of morphine tended to be more severe in the use of various addictive drugs. The problem of opioid addiction stimulated the search for strong painkillers that would be devoid of addiction properties. By 1967, researchers concluded that the complex interactions among morphine-like antagonists, and then called "mixed agonists-antagonists", could best be explained by assuming the existence of more than one type of receptor for opioids and related drugs. With the advent of new fully synthetic morphine-like drugs, the term "opioid" has generally been retained as a generic designation for all exogenous substances that stereospecifically bind to each of the several subtypes of opioid receptors and exhibit agonist activity.

The potential for development of tolerance and physical dependence with repeated opioid use is a hallmark of all opioid medications, and the potential for psychological dependence (i.e., dependence) is one of the major problems with opioid use in pain management, even though iatrogenic dependence is rare. Another major problem with opioid use is the taking of these drugs from pain patients for other (non-patient) entertainment purposes, such as drug addicts.

The totality of the abuse potential of opioids is not dictated by any single factor. Rather, there are a number of factors, including the ability of a drug to produce some kind of physical dependency, in which drug withdrawal causes a severe enough condition to induce drug-seeking behavior; the ability to inhibit withdrawal symptoms caused by withdrawal from other factors; the degree to which it induces euphoria similar to that caused by morphine and other opioids; the pattern of toxicity that occurs when dosing above the normal therapeutic range; and the physical characteristics of drugs such as water solubility. Such physical characteristics can determine whether a drug is likely to be addictive when administered parenterally.

In the United States, efforts to control drug users of addictive drugs include attempts to control drug availability by restricting the use of opioids for pain management in drug users. In practice, the physician is often faced with the choice of whether to administer a strong opioid analgesic even to people who seem predisposed to psychological dependence, i.e. drug dependence. In view of this problem, it is recommended that these patients should not be given opioids if another non-addictive drug suffices; and in addition, these patients should not be allowed to self-administer such drugs, and should be dispensed to them at a time in an amount sufficient only for a few days.

At least three basic patterns of opioid use and dependence have been identified. The first includes individuals who start using the drug in the context of a medical treatment and who receive an initial supply, e.g., from a physician. The second pattern begins with an experimental or "entertaining" drug use and progresses to more intensive use. Third

The formula includes users who start in one or the other of the above ways but later switch to oral opioids, such as methadone, obtained from structured drug addiction treatment programs.

Tolerance refers to the need to increase the dose of an opioid over a period of time in order to achieve the same level of anesthesia or euphoria, or to observe that repeated administration of the same dose results in a reduction of anesthesia, euphoria, or other opioid effects. It has been found that a particular degree of tolerance develops with respect to the opioid respiratory depressant, anesthetic, sedative, emetic and euphoric effects. However, the rate at which this tolerance can develop in either an addict or a patient in need of pain treatment depends on the regimen of use. The dose may need to be increased if the opioid is used frequently. Tolerance to all opioid effects does not develop equally or at the same rate, and even users who are highly tolerant to the respiratory depression effect still exhibit miosis and constipation. Opioid tolerance declines to a large extent once the symptoms of the withdrawal syndrome are over.

Physical dependence may develop with repeated administration or prolonged use of opioids. Physical dependence manifests progressively upon discontinuation of opioid use, or manifests in an accelerated manner (eg, within 20 minutes) following administration of a narcotic antagonist (referred to as "accelerated withdrawal). Depending on the drug on which dependence has arisen and the duration of use and dose, withdrawal symptoms vary with respect to type, duration and severity. The most common symptoms of withdrawal syndrome include anorexia, weight loss, pupil dilation, chills alternating with excessive sweating, stomach cramps, nausea, vomiting, muscle cramps, excessive irritability, lacrimation, runny nose, goose bumps and a rapid heart beat. Withdrawal syndrome usually starts 24-48 hours after the last dose and reaches maximum intensity around day three and may not improve by the end of week three.

Psychological dependence (or addiction) to opioids is characterized by drug-seeking behavior aimed at achieving euphoria and escaping, for example, psychosociological and economic pressure. The addict will continue to take opioids for non-medical purposes despite self-harm.

Pharmacologically, opioid antagonists usually block or reverse all the effects of opioid agonists. One use of opioid antagonists is one-day treatment with naltrexone to block euphoric effects that may otherwise be obtained by administering opioids to an addicted person. Low doses of opioid antagonists are used to determine whether individuals are physically dependent on opioids. Typically, opioid antagonists are used to reverse the effects of opioids in subjects who have overdosed on opioid agonist drugs.

There have previously been attempts in the art to control the abuse potential of opioid anesthetics. Typically, a particular dose of opioid anesthetic is more potent when administered parenterally as compared to the same dose administered orally. Thus, one common method of abuse in orally ingesting a drug is to extract the opioid from the dosage form, and then inject the opioid (using any "appropriate" injection vehicle) to get "high". Attempts to ameliorate abuse therefore revolve around the incorporation into an oral dosage form of an opioid antagonist which is not orally active but which essentially blocks the opioid's anesthetic effects if an attempt is made to dissolve the opioid and take it parenterally.

For example, a combination of pentazocine and naloxone in tablets available in the United States, commercially available as Talwin was used.^®Nx by Sanofi-Winthrop. Talwin^®Nx contains pentazocine hydrochloride equivalent to 50 mg of base and naloxone hydrochloride equivalent to 0.5 mg of base. Talwin^®Nx is indicated for the relief of moderate to severe pain. The amount of naloxone present in this combination has no effect when taken orally and will not interfere with the pharmacological action of pentazocine. However, this amount of naloxone given by injection is profoundly antagonistic to narcotic anesthetics. Thus, the inclusion of naloxone is intended to inhibit the form of misuse of oral pentazocine that occurs in dissolving and injecting the dosage form. Thus, this dosage has a lower potential for parenteral misuse than prior pentazo4 formulations

PL 193 273 B1 tin. However, it is still subject to patient misuse and abuse by the oral route, e.g., by a patient taking multiple doses at a time.

Sunshine et al., "Analgesic Efficacy of Pentazocine Versus a Pentazocine-Naloxone Combination Following Oral Administration", Clin, J. Pain, 1988: 4: 35-40, reported the effects of adding 0.5 mg naloxone on the anesthetic efficacy of 50 mg pentazocine. The combination was found to be significantly less effective than pentazocine in terms of the sum of the pain intensity difference (SPID), and in terms of pain relief and pain intensity difference (PID). the pain intensity difference) after four hours. For patients with a mean baseline pain relief, the combination provided significantly less pain relief than pentazocine in terms of SPID and relief and PID at 3 and 4 hours. In baseline severe pain patients, there was no significant difference between pentazocine and the combination of pentazocine and naloxone.

Wang et al., "Crossover and Parallel Study of Oral Analgesics", J.Clin. Pharmacol 1981; 21: 162-8, tested the combination of 0.25 mg naloxone and Percodan^® (composed of 4.5 mg oxycodone HCl, 0.28 mg oxycodone terephthalate, 224 mg aspirin, 160 mg phenacetin and 32 mg caffeine), compared to Percodan alone^®, and placebo in a crossover study of patients with chronic pain. The combination had lower average scores than Percodan alone^® for most of the hourly anesthetic parameters in the later hours of the experiment. However, in terms of sum variables, the combination showed no significant difference from placebo or Percodan^®.

A permanent combination of buprenorphine and naloxone for pain management was introduced in 1991 in New Zealand (Temgesic^®Nx, Reckitt & Colman).

A permanent combination therapy involving tilidine (50 mg) and naloxone (4 mg) has been available in Germany for the control of severe pain since 1878 (Valoron^®N, Goedecke). The rationale for combining these drugs is effective pain relief and prevention of tilidine dependence through naloxone-induced antagonism at the morphine receptor.

U.S. Patent No. 3,773,955 (Patcher et al.) Describes orally effective analgesic compositions which, when administered parenterally, do not cause anesthesia, euphoria, or physical dependence and thus prevent oral abuse of analgesic agents. Such compositions contain from about 0.1 mg to about 10 mg naloxone per oral analgesic dose. This reference did not include oral opioid abuse.

US Patent No. 3,493,657 (Lewenstein et al.) Describes compositions containing naloxone and morphine or oxymorphine, which compositions are believed to provide a strong analgesic effect without undesirable side effects such as hallucinations.

US Patent No. 4,457,933 (Gordon et al.) Describes a method of reducing both oral and parenteral abuse of potential painkillers such as oxycodone, propoxyphene and pentazocine by combining an opioid analgesic dose with naloxone in a specific, relatively narrow range. Oxycodone-naloxone compositions having a part by weight ratio of 2.5-5: 1 and pentazocin-naloxone compositions having a parts by weight ratio of 16-50: 1 have been preferred. The dose of naloxone to be combined with the opioid is determined to substantially eliminate the possibility of oral or parenteral abuse of the opioid without substantially affecting its oral analgesic activity.

US Patent No. 4,582,835 (Lewis) describes a method of treating pain by administering a sublingually effective dose of buprenorphine with naloxone. Lewis describes dosing ratios of naloxone to buprenorphine of 1: 3 to 1: 1 for parenteral administration and 1: 2 to 2: 1 for sublingual administration.

US Patent No. 5,512,578 describes a method for selectively potentiating the analgesic effect produced by administering a bi-modal opioid agonist. Thus, this specification relates to the combination of opioid agonists with opioid antagonists in amounts that presumably enhance the effect of opioid agonists rather than prevent oral abuse of opioid preparations. Importantly, if such negative effects are abolished, it encourages further use of this preparation and may cause even greater dependence on this preparation, thus promoting its abuse. The preparations disclosed in this specification abolish the effects of hyperactivity and physical dependence while enhancing the effects of opioid agonists, which does not suggest the potential for aversion in physically dependent subjects when administered at the same dose or at a dose higher than the therapeutically effective dose. Furthermore, this specification does not disclose the ratio of opioid antagonist to opioid agonist that provides a combined opioid antagonist / opioid agonist product that is analgesic when the combination is administered orally, but which causes aversion in physically dependent human subjects when the same is administered. a dose or a dose higher than the analgesic dose.

It has increasingly been found in the art that oral opioid formulations are not only abused by the parenteral route, but also by the oral route when a patient or addict administers himself orally more than the prescribed oral dose during each dosing period. There is therefore a need for a formulation for the treatment of pain that is orally administrable and that has a lower potential for oral abuse.

To the knowledge of the present inventors, the ratio of an opioid agonist to an opioid antagonist that is analgesically effective when the combination is orally administered, but which causes aversion in a physically dependent subject, is not known to date.

According to the invention, a new dosage form has been developed which is analgesically effective when the combination is administered orally to non-physically dependent human subjects, but which causes aversion, i.e. negative sensation, in physically dependent human subjects when orally administered the same dose or a dose higher than the analgesically effective dose thus preventing oral abuse. This form contains specific antagonist to agonist ratios that have not been previously disclosed or suggested in the art.

The invention relates to an oral dosage form comprising a combination of an orally effective analgesic dose of an opioid agonist and an opioid antagonist, the ratio of the opioid antagonist to the opioid agonist providing a combination product that is analgesically effective when the combination is administered orally to non-physically dependent human subjects, but which induces aversion. in physically dependent human entities, at the oral administration of the same dose or a dose higher than the analgesically effective dose characterized in that the opioid antagonist is naltrexone and the opioid agonist is selected from the group consisting of hydrocodone in a naltrexone: hydrocodone ratio of 0.03: 1 to 0.27: 1 , oxycodone in the naltrexone / oxycodone ratio from 0.037: 1 to 0.296: 1, codeine in the naltrexone / codeine ratio from 0.005: 1 to 0.044: 1, hydromorphone in the naltrexone / hydromorphone ratio from 0.148: 1 to 1.185: 1, levorphanol in the naltrexone / levorphanol ratio from 0.278: 1 to 2.222: 1, meperidine in the naltrexone / meperidine ratio from 0.0037: 1 to 0.0296: 1, methadone in the naltrexone / methadone ratio from 0.056: 1 to 0.444: 1 and morphine in a naltrexone / morphine ratio from 0.018: 1 to 0.148: 1.

Preferably, the amount of antagonist contained in the oral dosage form causes a feeling of aversion in the physical addict taking about 2-3 times the usual prescribed dose of opioid.

Preferably, the oral dosage form additionally comprises one or more inert pharmaceutically acceptable excipients.

Preferably, the oral dosage form further comprises a slow sustained release carrier such that the dosage form can be administered twice daily or once daily.

Preferably the oral dosage form further comprises a non-opioid drug selected from the group consisting of NSAID, COX-2 inhibitor, acetaminophen, aspirin, NMDA receptor antagonist, drug that blocks major intracellular NMDA receptor activation pathways, antitussive, expectorant, decongestant, antihistamine and mixtures thereof.

Preferably, in the oral dosage form, the opioid antagonist is naltrexone and the opioid agonist is selected from the group consisting of hydrocodone in a naltrexone: hydrocodone ratio from 0.05: 1 to 0.20: 1, oxycodone in a naltrexone / oxycodone ratio from 0.056: 1 to 0.222: 1, codeine in the naltrexone / codeine ratio from 0.0083: 1 to 0.033: 1, hydromorphone in the naltrexone / hydromorphone ratio from 0.222: 1 to 0.889: 1, levorphanol in the naltrexone / levorphanol ratio from 0.417: 1 to 1.667: 1, meperidine in a naltrexone / meperidine ratio from 0.0056: 1 to 0.022: 1, methadone in a naltrexone / methadone ratio from 0.083: 1 to 0.333: 1 and morphine in a naltrexone / morphine ratio from 0.028: 1 to 0.111: 1.

The oral dosage form of the present invention has a lower potential for abuse by the oral route than previously commercially available dosage forms, and provides therapeutic anesthesia while providing a negative "aversion-inducing" sensation when a physically addicted subject ingests or is administered a large amount of an opioid. e.g. about 2-3 times the usual prescribed dose.

The dosage form according to the invention finds use for therapeutic anesthesia in a manner that does not induce a positive amplification in a physically non-dependent subject, taking 6

Compared to the same amount of opioid in the absence of an antagonist, the amount of opioid is greater than the usually prescribed dose, e.g., about 2-3 times the usual prescribed dose.

The present invention is based on the unexpected finding that there is a ratio of opioid antagonist to opioid agonist (analgesic) that is effective in relieving pain when the combination is administered orally, but that is aversive in a physically addicted subject. According to the inventors' knowledge, it was not even considered by specialists such as addiction specialists, anesthesiologists or clinical pharmacologists. It is surprising that one combination product (combined antagonist / agonist) may generally have therapeutic effects in one population (pain patients), while for another population (e.g. physically dependent subjects) it is unacceptable (aversive) to the administration of this population. same dose or at higher doses than normally prescribed, e.g. 2-3 times the usual prescribed opioid dose.

The oral dosage form of the invention comprises an orally analgesically effective amount of an opioid agonist and an opioid antagonist in a ratio that maintains the analgesic efficacy of the opioid analgesic, but which may reduce the analgesic effect somewhat, as assessed by direct measurement in patients or by using one or more measurements. substitute for opioid (analgesic) efficacy in human subjects. Surrogate measures of opioid (analgesic) efficacy include sedation, respiration rate, and / or pupil size (via pupil measurement), and a visual analog scale ("VAS") for "drug effect". Such surrogate measures are taken in the direction that shows a reduced opioid effect as compared to the same opioid dose without the concomitant dose of the opioid antagonist.

In certain preferred embodiments, where the opioid is hydrocodone and the antagonist is naltrexone, the oral dosage form comprises hydrocodone in the form of its hydrogen tartrate salt and naltrexone in the form of its hydrochloride salt.

In certain preferred embodiments, where the opioid is hydrocodone and the antagonist is naltrexone, the ratio of naltrexone to hydrocodone is preferably from about 0.03-0.27: 1 by weight, and especially from about 0.05-0.20: 1 by weight. .

The oral dosage form of the invention finds use in preventing the oral abuse of an oral opioid formulation by a subject, the use comprising the preparation of an oral dosage form that comprises an orally effective analgesic amount of an opioid agonist and an opioid antagonist in a ratio that maintains the analgesic efficacy of the opioid agent. a pain reliever, but which may reduce the anesthesia somewhat as assessed by direct measurement in patients or by the use of one or more surrogate measurements of the opioid effect in human subjects. When the oral dosage form is taken by a physically dependent subject in a relatively high dose, e.g. about 2-3 times the normally prescribed dose, its use induces aversion in a physically dependent human subject and preferably does not induce opioid-like enhancement (taken alone) in a physically non-dependent human subject.

The oral dosage form of the invention also finds use in the treatment, comprising orally administering an orally effective amount of an opioid agonist, together with the opioid antagonist in a ratio that maintains the analgesic efficacy of the opioid analgesic but which may reduce anesthesia somewhat, when measured either directly in patients or by the use of one or more measurements of surrogate opioid effects in human patients.

The oral dosage form of the invention comprises a combination of an orally effective analgesic amount of an opioid agonist and an orally active opioid antagonist, wherein the opioid antagonist is present in an amount (i) which does not reduce the level of analgesia induced by the oral dosage form relative to the non-therapeutic level, and ( ii) which is at least slightly negative, "Aversion inducing" experience in physically dependent subjects (e.g. accelerated withdrawal syndrome) where subjects attempt to take at least twice the dose normally prescribed at a time (and often 2-3 times or more) compared to a comparable opioid dose with no antagonist present. Preferably, the amount of naltrexone contained in the oral dosage form produces less positive enhancement (e.g. is less "liked") in a physically non-addicted person than a comparable oral dosage form without the antagonist included. Preferably, the formulation provides effective oral analgesia.

PL 193 273 B1

For the purposes of the present invention, the phrase "which may reduce anesthesia somewhat, as assessed by direct measurement in patients or by using one or more surrogate measures of opioid analgesic efficacy in human patients" means that a patient with pain may or may not clearly notice the difference between the preparation administered according to the invention (i.e. an opioid agonist / antagonist combination) and a similar preparation, which contains the same dose of opioid agonist without the opioid antagonist, but will have an analgesic effect from this combination. The pharmacodynamic effect (anesthesia) of the administered preparations according to the invention can be described by means of e.g. the results of an anesthetic questionnaire filled in by the patients several times after administration of the dosage form. Summary measures of anesthesia include the sum of pain intensity difference (SPID) and total pain relief (TOTPAR).

In some preferred embodiments, the amount of opioid antagonist included in the dosage form may result in a clinically significant reduction in the level of analgesia induced by the dosage form after oral administration, e.g., as measured by surrogate measures such as a visual analogue scale ("VAS") or "effect". drug ". In other embodiments, the amount of opioid antagonist included in the dosage form may result in a noticeable reduction in the level of analgesia induced by the dosage form when administered orally, but does not reduce the level of analgesia provided to a subtherapeutic level.

Preferably, the amount of antagonist contained in the dosage form produces less positive enhancement (eg, less "liked") in a physically non-dependent subject than a comparable oral dosage form without the antagonist contained therein.

An oral opioid analgesic dosage form for the treatment of pain in human patients is prepared by a method that minimizes the likelihood of oral abuse of the dosage form, combining an orally analgesically effective amount of an opioid agonist with an opioid antagonist in a ratio that maintains the analgesic efficacy of the opioid analgesic, but which may slightly reduce anesthesia, by direct measurement in patients or by the use of one or more surrogate measures of anesthesia in human subjects. In some embodiments, the oral combination provides a clinically significant reduction in the level of analgesia induced by the oral dosage form (compared to the same dose of the opioid alone) and provides at least a slightly negative, "aversive" experience in a physically addicted subject ( e.g. sudden withdrawal syndrome) when subject is taking more than the usual prescribed or usual dose of opioid. The subject may be, for example, an addict who tries to get euphoric ("high") by taking more at a time (eg, 2-3 times more) than the usually prescribed dose. The amount of opioid antagonist contained in the dosage form may or may not result in a marked reduction in the level of anesthesia induced by the dosage form when administered orally, e.g. as measured by pharmacodynamic parameters such as the visual analogue scale ("VAS") for drug effect, but nonetheless preferably allows effective analgesia to be provided by the dosage form. In some preferred embodiments of the method, the dose of the opioid antagonist apparently affects the measure of the effect of opioid anesthesia. In some preferred embodiments, the amount of antagonist contained in the oral dosage form produces less positive enhancement (eg, is less "liked") by a physically non-dependent subject than a comparable oral dosage form without the antagonist included.

Oral pharmaceutical compositions containing a combination of drugs as described herein can be in the form of tablets, liquids, troches, lozenges, aqueous or oily suspensions, multiparticulates, including dispersible powders, granules, matrix spheroids or inert coated beads, emulsions. , hard or soft capsules, or syrups or elixirs, microparticles (e.g., microcapsules, microspheres, and the like), cheek tablets, etc. Dosage forms according to the present invention may contain all pharmaceutically acceptable excipients known to those skilled in the art. The dosage forms can additionally provide immediate release of the opioid agonist and the opioid antagonist. In certain preferred embodiments, the dosage forms provide sustained release of the opioid agonist, and provide some or all of the opioid antagonist dose in (i) immediate release, (ii) sustained release, or (iii) both immediate and sustained release. Such embodiments may additionally include an immediate release portion of the opioid agonist. Sustained release can be achieved according to formulations / production methods known to those skilled in the art of pharmaceutical formulations

For pharmaceutical purposes, e.g., by incorporating the sustained release carrier into a matrix containing an opioid agonist and an opioid antagonist; or by applying a sustained release matrix coating containing an opioid agonist and an opioid antagonist.

The invention may provide a safer product (e.g., less respiratory depression) as well as a slower rate of development of opioid tolerance and physical dependence.

In certain other preferred embodiments, the opioid contained in the dosage form is a different orally active opioid agonist than hydrocodone. The ratio of naltrexone contained in such formulations can be easily determined by a simple calculation taking into account the known equivalent anesthetic dosages of various opioid anesthetics compared to hydrocodone. The equivalent anesthetic dosing of opioid anesthetics is provided below, but on the other hand is known to those skilled in the art, for example, from the reading of Foley, K. "The Treatment of Cancer Pain;" N.Engl. J. Med. 1985; 313: 84-95, incorporated herein by reference. In still other aspects of this embodiment, naltrexone is replaced with various opioid antagonist compounds using equivalent antagonist doses thereof.

In some embodiments, the formulation comprises a combination of two opioid anesthetics. In additional embodiments, one or more opioid anesthetic agents are included, and an additional (non-opioid drug) is included in addition to the opioid antagonist. Such non-opioid drugs would provide additional anesthesia, and include e.g. aspirin, acetaminophen, non-steroidal anti-inflammatory drugs ("NSAIDs"), NMDA antagonists, and cyclooxygenase-II inhibitors ("COX-II inhibitors"). In still other embodiments, non-opioid drugs may be included that provide the desired effect other than analgesia, e.g., antitussive, expectorant, decongestant, antihistamine, and the like.

The term "parenteral" as used herein includes subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection, or infusion technique.

The term "effective analgesia" is defined for the purposes of the present invention as satisfactory pain reduction or elimination together with a tolerable level of side effects as determined by a human patient.

The term "delayed release" is defined for the purposes of the present invention as the release of a drug (opioid analgesic) from an oral preparation at a rate such that the concentration (level) in the blood (e.g., plasma) is kept within the therapeutic range (above the minimum effective anesthetic or analgesic concentration). "MEAC"), but below the toxic level, for the indicative period for "twice daily" or "once daily" formulation.

The term "steady state" refers to the time when the rate of elimination of a drug is the same as the rate at which the drug is absorbed by the body.

For the purposes of the present invention, the term "opioid agonist" is interchangeable with the term "opioid" or "opioid analgesic" and will include the opioid base, mixed agonist-antagonists, partial agonists, pharmaceutically acceptable salts thereof, stereoisomers, ethers and esters thereof, and mixtures.

Brief description of the drawings

Figure 1 shows the naltrexone "drug effect" antagonism on hydrocodone-induced VAS (visual analogue scale) for example 1;

Figure 2 shows the antagonism of naltrexone against hydrocodone-induced pupillary constriction, for example 1;

Figure 3 shows the mean "drug effect" VAS score over time for each treatment of Example 2;

Figure 4 shows the mean "drug effect" pupil diameters over time for each of the treatments of Example 2;

Figures 5 and 6 show the corresponding mean maximum "drug effect" VAS score (± 95% CI) and mean minimum pupil diameter (± 95% CI) relative to the log of each naltrexone dose of Example 2;

Figure 7 illustrates the subject's ability to sense the effects of hydrocodone in the presence of varying amounts of naltrexone from Example 3;

Figures 7B and 7C illustrate the subject's favorable or unfavorable subjective experiences with hydrocodone in the presence of varying amounts of naltrexone for Example 3, respectively;

Figure 8A illustrates the withdrawal subject's perception to the effects of hydrocodone in the presence of varying amounts of naltrexone, for example 3;

PL 193 273 B1

Figure 8B illustrates the subjective experiences of illness perception by the subject in the presence of varying amounts of naltrexone, for example 3;

Figure 9A illustrates the effect of hydrocodone on pupil size in the presence of varying amounts of naltrexone in Example 3;

Figure 9B illustrates the apparent extent of withdrawal from the effect of hydrocodone in the presence of varying amounts of naltrexone in Example 3, from an observer's perspective;

Figures 10A-C show the areas under the curves in Figures 7A-C, collected during the 6 hour observation period as a function of naltrexone dose, and the 95% confidence level for the naltrexone placebo response (30 mg hydrocodone, 0 mg naltrexone); and

Figures 11A-C show the areas under the curves in Figures 8A-C and Figure 9A, collected over time over the 6 hour observation period as a function of naltrexone dose, and the 95% confidence level for the naltrexone placebo response (30 mg hydrocodone, 0 mg naltrexone).

It has been assumed that there are three subgenera of opioid receptors designated mu, kappa and delta. In this frame, the mu receptor is believed to be associated with the induction of supracranial anesthesia, respiratory depression, euphoria, and physical dependence. The kappa receptor is believed to be associated with the induction of spinal anesthesia, miosis and sedation. Activation of gamma receptors causes mood disturbances and hallucinations, as well as respiratory and vasomotor effects. The receptor is distinct from the mu receptor and designated gamma has been described in the mouse vas deferens, Lord et al., Nature, 1977, 267, 495-99. Opioid agonists are believed to exert their agonist activity primarily through the mu receptor and to a lesser extent through the kappa receptor. There are several drugs that appear to act as partial agonists at one receptor type or the other. Such drugs have a maximum effect. Such drugs include nalorphine, propiram, and buprenorphine. Still other drugs act as competitive antagonists at the mu receptor and block the effects of morphine-like drugs by exerting an agonist effect on the kappa and omega receptors. The term "agonist-antagonist" has been phrased to describe such a mechanism of action. The concept of opioid antagonism is believed to be complex.

With administration of opioid agonist-antagonists and partial agonists, it has been found that tolerance develops to the agonist effect but not to the antagonistic effect of the drugs. Even after prolonged administration of high doses, discontinuation of naloxone administration is not associated with any noticeable withdrawal syndrome, and discontinuation of naltrexone, the other relatively pure opioid antagonist, produces very few signs and symptoms. However, after prolonged administration of high doses, abrupt discontinuation of the administration of the opioid agonist nalorphine or cyclazocine produces a characteristic withdrawal syndrome which is similar for both drugs.

Naloxone is an opioid antagonist which has almost no agonist effect. Subcutaneous doses of up to 12 mg of naloxone have no discernible subjective effects and 24 mg of naloxone causes only slight drowsiness. Low doses (0.4-0.8 mg) of naloxone administered intramuscularly or intravenously to man will prevent or immediately reverse the effect of morphine-like opioid agonists. One mg of naloxone intravenously has been reported to completely block the effect of 25 mg of heroin. The effect of naloxone is seen almost immediately after intravenous administration. The drug is absorbed orally, but is reported to be metabolized rapidly into its inactive form at its first passage through the liver, so that only one fifty as reported is as potent as when administered parenterally. An oral dose of more than 1 g has been reported to be almost completely metabolized in less than 24 hours.

Other opioid antagonists, e.g. cyclazocin and naltrexone, both of which have cyclopropylmethyl substitutions on the nitrogen atom, retain most of their efficacy when administered orally, and their duration of action is much longer, up to 24 hours after an oral dose. The most preferred opioid antagonist is naltrexone. However, in accordance with the present invention, equivalent oral antagonist doses of other opioid antagonists may be used, including but not limited to naloxone, nalmefene, cyclazocin, and levalorphan. The ratio of such other antagonists to the particular opioid agonist can be readily determined by one of skill in the art who wishes to employ an opioid antagonist other than naltrexone without undue experimentation, the ratio of opioid agonists being exemplified and discussed in detail herein. Such a ratio of other antagonists to opioid agonists can be determined by those skilled in the art, e.g., by carrying out the same or similar studies

The clinical examples provided herein. Thus, combinations of opioid antagonists / opioid agonists that are administered orally in ratios that are equivalent to the ratio of e.g. naltrexone to hydrocodone provided herein are considered to fall within the scope of the present invention and within the scope of the appended claims. For example, in some embodiments of the invention, naloxone may be used as the opioid antagonist, and the amount of naloxone included in the dosage form should be large enough to provide an equivalent antagonistic effect as if naltrexone were included in the combination.

High doses of oral naltrexone (over 100 mg) have been used in the treatment of patients previously dependent on opioids to prevent euphoria from opioid agonists. Naltrexone has been reported to exert a strong preferential blocking effect on mu sites over delta. It is known that naltrexone is a synthetic compound related to oxymorphone, without opioid agonist properties, and differs in structure from oxymorphone in the replacement of the methyl group on the oxymorone nitrogen with a cyclopropylmethyl group. Naltrexone hydrochloride salt is soluble in water up to about 100 mg / cc. The pharmacodynamic and pharmacokinetic properties of naltrexone have been evaluated in multiple animal studies and clinical trials. See, e.g. Gonzales JP, et al., Naltrexone: A review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Efficacy in the Management of Opioid Dependence. Drugs 1988; 35: 192-213, incorporated herein by reference. Following oral administration, naltrexone is rapidly absorbed (within 1 hour) and shows an oral bioavailability ranging from 5-40%. The protein binding of naltrexone is approximately 21% and the volume of distribution after 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 blocking exogenously administered opioids. See, e.g., Revia (naltrexone hydrochloride tablets), Physician's Desk Reference 51st Edition, Montvale, NJ. "Medical Ecnomics" 1997; 51: 957-959. Revia 50 mg dose^® blocks the pharmacological effect of 25 mg of intravenous heroin for up to 24 hours.

It is known that, when administered chronically with morphine, heroin or other opioids, naltrexone blocks the development of physical dependence on opioids. The way naltrexone blocks the effects of heroin is believed to be through competitive binding at opioid receptors. Naltrexone has been used to treat drug addiction by completely blocking the effects of opioids. The use of naltrexone for drug addiction in drug addicts with a good prognosis has been found most satisfactory as part of a comprehensive occupational or rehabilitation program that includes behavioral control or other methods of adherence. Regarding the treatment of drug dependence with naltrexone, it is desirable that the patient be opioid-free for at least 7-10 days. The starting dosage of naltrexone for this purpose is usually about 25 mg, and if there are no signs of withdrawal, the dosage may be increased to 50 mg per day. A daily dosage of 50 mg is considered to be adequate to clinically block the effects of parenteral opioids. Naltrexone is also used to treat alcoholism as an aid to social and psychotherapeutic approaches.

In the dosage forms of the invention, the amount of naltrexone contained is much less than dosages previously available on the market. This is partly because the use of naltrexone in the dosage forms of the invention has a different purpose, namely the goal is not to block the effects of opioids but rather to induce negative feelings of "aversion" when a physically addicted subject takes or is given a large amount of the product combined, e.g. approximately 2-3 times more than the usual prescribed dose.

Thus, for example, in formulations comprising the oral dosage form of the invention, wherein the opioid is 15 mg of hydrocodone acid tartrate, the amount of naltrexone hydrochloride contained in the formulation is from about 0.5 mg to about 0.4 mg, and preferably from about 0.5 mg to about 0.4 mg. about 0.75 mg to about 3 mg of naltrexone per 15 mg of hydrocodone.

Opioid analgesics that are useful in the present invention include all opioid agonists or mixed agonists / antagonists, partial agonists, including, but not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, besithramide, buprenorphine, butenitazorphine, clonitine, , deomorphine, dextromoramide, deocin, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimefeptanol, dimethylthiambutene, dioxafetyl butyrate, dipipanone, eptazocin, etohepPL 193 273 B1 thazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadophenone, metaphe- dimonophen, ketanophenol, meta-methyl-phenytoin , morphine, myrophin, narcein, nicomorphine, norleworphanol, normethadone, nalorphine, nalbufene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, fenadoxone, phenomorphan, fenazocin, phenoperidine, piminodine, pyramidal, propeptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, mixtures thereof, salts and the like.

In certain preferred embodiments, the opioid agonists or analgesics may be selected from the group consisting of hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone, or salts thereof, or mixtures thereof. In some preferred embodiments, the opioid agonist is hydrocodone. The equivalent analgesic doses of these opioids, compared to a 15 mg dose of hydrocodone, are given in Table 1 below:

Table 1:

Equivalent doses of opioids

<td>Opioid</td><td>Calculated dose (mg)</td>

<td>Oxycodone</td><td> 13,5</td>

<td>Codeine</td><td> 90,0</td>

<td>Hydrocodone</td><td> 15,0</td>

<td>Hydromorphone</td><td> 3,375</td>

<td>Levophanol</td><td> 1,8</td>

<td>Meperidine</td><td> 135,0</td>

<td>Methadone</td><td> 9,0</td>

<td>Morphine</td><td> 27,0</td>

Based on the recommended naltrexone ratio of about 0.5 to about 4 mg per 15 mg hydrocodone, the approximate ratio of naltrexone to 1 mg of each opioid is given in Table 2:

Table 2:

Weight ratio of naltrexone to opioid dose

<td>Opioid</td><td>The weight ratio of naltrexone to 1 mg of opioid</td>

<td>Oxycodone</td><td>0.037 to 0.296</td>

<td>Codeine</td><td>0.005 to 0.044</td>

<td>Hydrocodone</td><td>0.033 to 0.267</td>

<td>Hydromorphone</td><td>0.148 to 1.185</td>

<td>Levorphanol</td><td>0.278 to 2.222</td>

<td>Meperidine</td><td>0.0037 to 0.0296</td>

<td>Methadone</td><td>0.056 to 0.444</td>

<td>Morphine</td><td>0.018 to 0.148</td>

Based on the more recommended ratio of about 0.75 mg to about 3 mg naltrexone per 15 mg naltrexone hydrocodone, the approximate ratio of naltrexone to 1 mg of each opioid is given in Table 3:

PL 193 273 B1

Table 3:

The ratio of naltrexone to opioid dose

<td>Opioid</td><td>Naltrexone weight ratio</td>

<td>Oxycodone</td><td>0.056 to 0.222</td>

<td>Codeine</td><td>0.0083 to 0.033</td>

<td>Hydrocodone</td><td>0.050 to 0.200</td>

<td>Hydromorphone</td><td>0.222 to 0.889</td>

<td>Levorphanol</td><td>0.417 to 1.667</td>

<td>Meperidine</td><td>0.0056 to 0.022</td>

<td>Methadone</td><td>0.083 to 0.333</td>

<td>Morphine</td><td>0.028 to 0.111</td>

Although hydrocodone is effective for pain control, there has been an increase in its abuse by people who are psychologically addicted to opioids or who take opioids for non-therapeutic reasons. Previous experience with other opioids has shown a reduced abuse potential when opioids are administered in combination with a narcotic antagonist, especially in patients who have been addicted. Weinhold LL et al., Buprenorphine Alone and in Combination with Naltrexone in Non-Dependent Humans, Drug and Alcohol Dependence 1992; 30: 263-274; Mendelson J., et al., Buprenorphine and Naloxone Interactions in OpiateDependent Volunteers, Clin Pharm Ther 1996; 60: 105-114, which is hereby incorporated by reference.

Hydrocodone is a semi-synthetic narcotic anesthetic and antitussive with multiple effects on the central nervous and digestive systems. Chemically, hydrocodone is 4,5-epoxy-3-methoxy-17-methylmorphinan-6-one and is also known as dihydrocodeinone. Like other opioids, hydrocodone can cause habituation and drug dependence of the morphine type. In excessive doses, hydrocodone, like other opium derivatives, inhibits respiration.

Oral hydrocodone is also available in Europe (Belgium, Germany, Greece, Italy, Luxembourg, Norway and Switzerland) as an antitussive agent. A parenteral preparation is also available in Germany as an antitussive. For use as an analgesic, hydrocodone bitartrate is commercially available in the United States only as a permanent combination with non-opiate drugs (i.e., ibuprofen, acetaminophen, aspirin, etc.) for the management of moderate to moderate pain.

A common dosage form for hydrocodone is in combination with acetaminophen and is commercially available e.g. as Lortab^® in the US 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. Tablets are also available in a ratio of 7.5 mg hydrocodone bitartrate and 650 mg acetaminophen, and 7.5 mg hydrocodone bitartrate and 750 mg acetaminophen. Hydrocodone in combination with aspirin is administered in an oral dosage form to adults, generally 1-2 tablets every 4-6 hours as needed to reduce pain. Tablet form means 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 formulation includes hydrocodone and ibuprofen bitartrate. Vicoprofen^®, commercially available in the US from Knoll Laboratories, is a tablet containing 7.5 mg hydrocodone bitartrate and 200 mg ibuprofen. All such preparations, including orally active opioid antagonists, may be contained in the oral dosage form of the invention in the amounts specified in accordance with the invention.

The abuse potential of opioid analgesics such as hydrocodone is surprisingly inhibited by oral dosage forms including the combinations of the invention. More specifically, it has been found possible to combine in a single dosage form an opioid analgesic together with a small amount of an opioid antagonist to obtain a product that still provides analgesia but which essentially rules out the possibility that a physically dependent human subject will continue to abuse the drug by taking more than one tablets at a time, e.g. 2-3 times the usual prescribed dose.

PL 193 273 B1

The oral dosage forms of the invention comprise an orally effective amount of an opioid agonist, together with an opioid antagonist such as naltrexone in an amount (i) that does not reduce the level of analgesia induced by the oral dosage form to a non-therapeutic level, and (ii) that provides at least slightly negative "aversive" feeling in physically dependent human subjects (e.g. accelerated withdrawal syndrome), when taking more than the usual prescribed dose at a time. Preferably, the amount of antagonist included in the oral dosage form (iii) is less positive for (eg, less "liked") a physically non-dependent human subject, eg, an opioid dependent, than a comparable dosage form without the antagonist included.

The amount of antagonist that is useful in deriving the parameters (i) - (iii) given in the preceding paragraphs can be determined at least in part, e.g. by using "surrogate" tests such as the VAS scale (where the subject grades his perception of the effect of the dosage form) and / or by measurement such as pupil size (measured by pupillometry). Such measurements allow one of skill in the art to determine the dose of the antagonist relative to the dose of the agonist which reduces the effect of the opiate agonist. Thereafter, one skilled in the art can determine the level of the opioid antagonist that induces aversion in physical addicts, as well as the level of the opioid antagonist that minimizes the "craving scale" or opioid enhancing properties in the physically non-addicted. Once this opioid level has been determined, it is further possible to define a dosage range of the antagonist at or below that level that would be useful in achieving the parameters (i) - (iii) given in the previous paragraph.

The combination of the opioid agonist and the opioid antagonist can be used in admixture with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances 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, gelatin, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, paraffin viscous, perfume oil, monoglycerides of fatty acid and diglycerides, pentaerythritol fatty acid esters, hydroxymethyl cellulose, polyvinylpyrrolidone, etc. The pharmaceutical preparations can be sterilized and, if necessary, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts of buffers for influencing the osmotic pressure, coloring, flavoring and / or aromatic substances and the like. They can also be combined, if desired, with other active agents, e.g. other analgesics. For oral administration, tablets, dragées, liquids, drops, suppositories or capsules, caplets and gelatine capsules are particularly suitable. Compositions intended for oral use may be prepared according to any method known in the art, and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically toxic excipients which are suitable for the manufacture of tablets. Such excipients include e.g. an inert diluent such as lactose; granulating and disintegrating agents such as corn starch; binding agents such as starch; and lubricants such as magnesium stearate. The tablets may be uncoated or may be coated by known techniques for an attractive appearance or to delay the release of the active ingredients. Preparations for oral use can also be in the form of hard gelatin capsules with the active ingredient mixed with an inert diluent.

Aqueous suspensions may contain the above-specified combination of drugs, and this mixture may contain one or more excipients suitable as suspending agents, for example, pharmaceutically acceptable synthetic gums such as hydroxypropyl methylcellulose or natural gums. Oily suspensions may be prepared by suspending the above-defined drug combinations in a vegetable oil or a mineral oil. The oily suspensions may contain a thickening agent, such as beeswax or cetyl alcohol. Syrups, elixir or the like may be used, in which a sweetening medium is used. Injectable suspensions may also be prepared, using suitable liquid vehicles, suspending agents and the like, to be used.

The oral dosage forms of the invention may additionally contain one or more drugs in addition to the opioid analgesic and the opioid antagonist, which additional drug (s) may or may not act synergistically therewith. Thus, in some embodiments in the oral dosage form, there may be a combination of two opioid anesthetic agents in addition to the opioid antagonist. For example, a dosage form may contain two opioid analgesics having different properties such as half-life, solubility, potency, and

Actions, and combinations thereof. In still other embodiments, one or more opioid analgesics may be included in the oral dosage form of the invention, and in addition a non-opioid drug in addition to the opioid antagonist. Such non-opioid drugs would preferably provide additional anesthesia, and include, for example, aspirin; acetaminophen; non-steroidal anti-inflammatory drugs ("NSAIDs"), e.g. ibuprofen, ketoprofen, etc .; N-methyl-D-aspartate receptor antagonists, e.g. morphinan such as dextromorphan or dextrorphan, or ketamine; cyclooxygenase-II inhibitors ("COX-II inhibitors"); and / or glycine receptor antagonists.

In certain preferred embodiments of the present invention, lower doses of the opioid analgesic may be used due to the inclusion of an additional non-opioid agonist such as an NSAID or a COX-2 inhibitor. By using lower amounts of either or both drugs, the side effects associated with effective pain management in humans are reduced.

Suitable non-steroidal anti-inflammatory agents include ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxapindosine, pramoprofen, muroprofen, trioxaprofen acid, aminoprofen, suprofen, trioxaprofen acid, aminoprofen, suprofen, trioxaprofen, , tolmetin, zomepirac, thiopinac, zidomethacin, acemetacin, fentiazac, clindac, oxspinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam and the like. The useful dosages of these drugs are well known to those skilled in the art.

N-methyl-D-aspartate (NMDA) receptor antagonists are well known in the art and include, for example, morphinans such as dextromorphan or dextrorphan, ketamine, d-methadone or pharmaceutically acceptable salts thereof. For the purposes of the present invention, the term "NMDA antagonists" also includes drugs that block the major intracellular NMDA receptor activation pathway, e.g. ganglioside such as GM1 or GT1b, a phenothiazine such as trifluoperazine or naphthalenesulfonamide such as N- (6-aminotexyl) -5-chloro-1-naphthalenesulfonamide. These drugs are intended to inhibit the development of tolerance and / or dependence on narcotic drugs, e.g. narcotic analgesics such as morphine, codeine, etc. in U.S. Patent Nos. 5,321,012 and 5,556,838 (both Mayer et al.), And for the treatment of chronic ego pain in US patents No. 5,502,058 to mayer et al., which is hereby incorporated by reference. NMDA antagonists can be present alone or in combination with a local anesthetic such as lidocaine as described in these patents by Mayer et al.

Treatment of chronic pain by the use of glycine receptor antagonists and the identification of such drugs is described in US Patent No. 5,514,680 (Weber et al.), Incorporated herein by reference.

COX-2 inhibitors have been reported in the art and many chemical structures are known to cause inhibition of cyclooxygenase-2. COX-2 inhibitors have been described, e.g., in US Patent Nos. 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 which are hereby incorporated by reference. Some recommended COX-2 inhibitors include celecoxib (SC-58635), DUP-697, flosulide (CGP-28236), meloxicam, 6-methoxy-2-naphthylacetic acid (6-MNA), MK-966, nabumetone (prodrug for 6 -MNA), nimesulide, NS-398, SC-5766, SC-58215, T-614; or combinations of them. Dosage levels of a CPX-2 inhibitor of the order of from about 0.005 mg to about 140 mg per kilogram of body weight per day are therapeutically effective in combination with an opioid analgesic. Optionally, about 0.25 mg to about 7 g of a COX-2 inhibitor can be administered to the patient per day in combination with an opioid analgesic.

In still other embodiments, a non-opioid drug may be included that provides a desired effect other than analgesia, e.g., an antitussive, an expectorant, a decongestant, an antihistamine, a local anesthetic, and the like.

The oral dosage form of the invention may be in the form of, for example, granules, spheroids, beads, pellets (hereinafter collectively referred to as multiparticulates). An amount of the multiparticulate effective to provide the desired opioid dose over time may be encapsulated or incorporated into any suitable oral solid form. Optionally, the oral dosage form may be a tablet.

Controlled Release Dosage Forms

The opioid agonist / opioid antagonist combinations can be formulated as a controlled release or delayed release oral formulation into any tablet, coated tablet or multiparticulate formulation known to those skilled in the art. The delayed release dosage form can optionally include a delayed release carrier that is incorporated into a matrix together with the opioid agonist and opioid antagonist, or it can be used in the form of a delayed release coating.

In embodiments where the opioid analgesic comprises hydrocodone, the delayed release oral dosage forms may contain analgesic doses from about 8 mg to about 50 mg hydrocodone per dosage unit. In delayed release oral dosage forms, when the therapeutically active opioid is hydromorphone, it is present in an amount from about 2 mg to about 64 mg hydromorphone hydrochloride. In another embodiment, the opioid analgesic may include morphine and the delayed release oral dosage forms of the present invention contain from about 2.5 mg to about 800 mg of morphine by weight. In yet another embodiment, the opioid analgesic may include oxycodone and the delayed release oral dosage forms contain from about 2.5 mg to about 800 mg of oxycodone. The opioid analgesic may include tramadol and delayed release oral dosage forms may contain from about 25 mg to 800 mg of tramadol per dosage unit. The dosage form may contain more than one opioid analgesic to provide a substantially equivalent therapeutic effect. Optionally, the dosage form may contain molar equivalent amounts of other opioid salts useful in the present invention.

In one preferred embodiment of the present invention, the delayed release oral dosage form may comprise such particles containing or including an active ingredient, the particles having a diameter ranging from about 0.1 mm to about 2.5 mm. preferably from about 0.5mm to about 2mm.

The particles are preferably film coated with a material which allows the opioid agonist / opioid antagonist combination to be slowly released in an aqueous medium. The membrane coating is selected to achieve, in combination with other determined properties, the desired in vitro release rate. Slow release coated formulations should be capable of producing a strong, uninterrupted film that is smooth and good looking, able to hold pigments and other coating additives, non-toxic, inert and non-sticky.

In some embodiments, the particles can comprise normal release matrices containing the opioid analgesic with the opioid antagonist.

Halo

The dosage forms of the present invention may optionally be coated with one or more materials suitable to control release or to protect the formulation. For this purpose, release coatings may be used depending on the pH or independently of the pH, e.g. when exposed to digestive juices. The pH-dependent coatings serve to release the opioid in the desired areas of the GI tract, e.g. stomach or small intestine such that an absorption profile is present to provide the patient with at least eight hours, and preferably about twelve hours to about twenty-four hours, pain relief. If a pH-independent coating is required, the coating is designed to achieve optimal release regardless of pH changes in the environmental fluid, e.g., the gastrointestinal tract. It is also possible to formulate compositions that release the remainder of the dose in another area of ​​the gastrointestinal tract, such as the small intestine.

In formulations using pH dependent coatings, the unprotected drug is coated onto the enteric coating to obtain formulations that may also provide a repeated action, whereby it is released in the stomach, while the remainder being protected by the enteric coating. is further released in the digestive tract. The pH-dependent coatings that can be used in accordance with the present invention include shellac, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose phthalates and methacrylic acid ester copolymers, zein and the like.

In certain preferred embodiments, a substrate (e.g., tablet core bead, matrix particle) containing an opioid analgesic (with or without a COX-2 inhibitor) may be coated with a hydrophobic material selected from (i) alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof. The coatings can be used in the form of an organic or aqueous solution or dispersion. The coating is applied until there is a weight gain of from about 2 to about 25% of the substrate to obtain the desired release profile. Coatings derived from aqueous dispersions are described, for example, in detail

No. 5,273,760 and 5,286,493, incorporated herein by reference.

Other examples of sustained release formulations and coatings that can be used in accordance with the present invention are disclosed in US Patent Nos. 5,324,351; 5,356,467; and 5,472,712, incorporated herein in its entirety by reference.

Alkyl cellulose polymers

Cellulosic materials and polymers, including alkyl celluloses, provide hydrophobic materials very suitable for coating the beads described above. For example, ethyl cellulose is one of the preferred alkylcellulose polymers, although one skilled in the art will appreciate that other cellulose and / or alkylcellulose polymers can readily be used, individually or in any combination, as all or part of the hydrophobic shell described above.

One of the commercially available aqueous dispersions of ethyl cellulose is Aquacoat^® (FMC Corp., Philadelphia, Pennsylvania, USA). Aquacoat^® is prepared by dissolving ethyl cellulose in a water-immiscible organic solvent and then emulsifying it in water in the presence of a surfactant and stabilizer. After homogenization to generate submicron droplets, the organic solvent is evaporated under reduced pressure to form a pseudolatex. The softener is not incorporated into the pseudolatex during the production phase. So it is necessary to mix Aquacoat separately before using it as a coating^® with a suitable softener before use.

Another aqueous dispersion of ethyl cellulose is commercially available as Surelease^® (Colorcon, Inc., West Point, Pennsylvania, USA). This product is made by incorporating a softening agent into the dispersion during the manufacturing process. A hot melt of a polymer, a softening agent (dibutyl sebacate), and a stabilizer (oleic acid) are prepared as a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion that can be applied directly to substrates.

Acrylic polymers

In other preferred embodiments of the present invention, the hydrophobic material, including controlled release coatings, can be a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, poly (acrylic acid). , poly (methacrylic acid), methacrylic acid alkylamide copolymer, polymethacrylate, poly (methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic acid anhydride), and glycidyl methacrylate copolymers.

In certain preferred embodiments, the acrylic polymer may be composed of one or more ammonium methacrylate copolymers. Ammonium methacrylate copolymers are well known in the art and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.

In order to obtain the desired dissolution profile, it may be necessary to incorporate two or more ammonium methacrylate copolymers having different physical properties, such as different molar ratios of quaternary ammonium groups to neutral (meth) acrylic esters.

Certain methacrylic acid ester polymers are useful in the preparation of pH dependent coatings that can be used in the oral dosage forms of 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 copolymer or polymeric methacrylates, commercially available as Eudragit® from Rohm Tech, Inc. There are several different types of Eudragit^®. For example, Eudragit^® E is an example of a methacrylic acid copolymer that swells and dissolves in an acidic environment. Eudragit^® L is a methacrylic acid copolymer that does not swell to a pH of about <5.7 and is soluble at a pH of about> 6. Eudragit^® S does not swell at about pH <6.5 and is soluble at about pH> 7. Eudragit^® RL and Eudragit^® S swell in water and the amount of water absorbed by these polymers is pH dependent, however Eudragit coated dosage forms^® RL and RS are not pH dependent.

In some preferred embodiments, the acrylic coatings may comprise a mixture of two acrylic resins available from Rohm Pharma under the trade names Eudragit, respectively.^® RL30D and Eudragit^® RS30D. Eudragit^® RL30D and Eudragit^® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of the ammonium groups to the remaining neutral (meth) acrylic esters being

PL 193 273 B1

1:20 for Eudragit^® RL30D and 1:40 for Eudragit^® RS30D. The average molecular weight is about 150,000. The code designations RL (high permeability) and RS (low permeability) refer to the permeation properties of these agents. Eudragit mixtures^®RL / RS are insoluble in water and digestive juices. However, the shells formed therefrom expand and are permeable in aqueous solutions and digestive fluids.

Eudragit dispersions^® The RL / RS can be mixed together at any desired ratio to ultimately obtain a delayed release formulation having the desired dissolution profile. The desired delayed release formulations can be obtained e.g. from retard coatings derived from 100% Eudragit^®RL, 50% Eudragit^®RL and 50% Eudragit^®RS and 10% Eudragit^®RL: Eudragit^®90% RS. Of course, the skilled person will appreciate that other acrylic polymers can also be used, such as, for example, Eudragit^®L.

Softeners

In embodiments of the present invention wherein the coatings comprise an aqueous dispersion of a hydrophobic material, the inclusion of an effective amount of a softening agent in the aqueous dispersion of the hydrophobic material will further improve the physical properties of the sustained-release coating. For example, because ethyl cellulose has a relatively high glass transition temperature and does not form elastic films under normal coating conditions, it is preferable to incorporate a softening agent into an ethyl cellulose coating containing a delayed release coating before using it as a coating material. Generally, the amount of softening agent present in the coating solution is based on the film-forming agent, e.g. most commonly from about 1 to about 50 weight percent of the film-forming agent. However, the concentration of the softener can only be accurately determined after careful research with the particular coating solution and method of application.

Examples of suitable softeners for ethyl cellulose include water-insoluble softeners such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin, although other water-insoluble softeners (such as acetylated monoglycerides, esters, castor oil, etc.). Triethyl citrate is a particularly preferred emollient for aqueous dispersions of ethyl cellulose.

Examples of suitable softeners for acrylic polymers include, but are not limited to, citric acid esters such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and optionally 1,2-propylene glycol. Other emollients which have proved suitable to enhance the elasticity of the acrylic film, such as Eudragit lacquer solutions^® RL / RS, include polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, and triacetin. Triethyl citrate is a particularly preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.

It has also been found that the addition of a small amount of talc reduces the tendency of the aqueous dispersion to stick during processing and acts as a smoothing agent.

Methods of producing coated beads

When using a hydrophobic material to coat inert pharmaceutical beads, such as nu pariel 18/20 beads, many of the resultant controlled release solid beads can then be filled into a gelatin capsule, in an amount sufficient to provide an effective controlled release dose when withdrawn and contacted. digestive fluid, such as gastric fluid or the dissolution medium.

Controlled release bead formulations slowly release the therapeutically active agent, e.g., upon uptake and exposure to gastric fluids and then to intestinal fluids. The controlled release profile of the formulations of the invention can be varied, e.g. by changing the amount of the top shell of hydrophobic material, by changing the method of adding plasticizer to the hydrophobic material, by changing the amount of plasticizer relative to the hydrophobic material, by adding additional ingredients or excipients, by changing the production method, etc. The dissolution profile of the final product can also be modified e.g. by increasing or decreasing the thickness of the retard shell.

Spheroids or beads coated with a therapeutically active agent are prepared, e.g., by dissolving the therapeutically active agent in water and then dispensing the solution onto a substrate, e.g. nu pariel 18/20 beads, using a Wurster insert. Optionally, additional ingredients are also added prior to coating the beads to aid in binding the opioid to the beads, and / or to color the solution, etc. (e.g., Opadry^®, commercially available from Colorcon, Inc.). For example, for a solution you can

To add a product that contains hydroxypropyl methylcellulose, etc., with or without a coloring agent (e.g. Opadry^®, commercially available from Colorcon, Inc.) and mix the solution (e.g., for about 1 hour) before applying it to the beads. The resulting coated substrate, in this example beads, may then optionally be coated a second time with a barrier agent to separate the therapeutically active ingredient from the controlled-release hydrophobic coating. An example of a suitable barrier agent is one that contains hydroxypropyl methylcellulose. However, any film-forming agent known in the art may be used. It is recommended that the barrier agent should not affect the dissolution rate of the final product.

The spheres can then be coated again with an aqueous dispersion of the hydrophobic material. The aqueous dispersion of the hydrophobic material preferably further comprises an effective amount of a softening agent, e.g., triethyl citrate. Preformulated aqueous dispersions of ethyl cellulose, such as Aquacoat, can be used^® or Surelease^®. If Surelease is used^®it is not necessary to separately add a softener. Optionally, preformulated aqueous dispersions of acrylic polymers such as Eudragit can be used^®.

The coating solutions may advantageously contain, in addition to the film-forming agent, softening agent, and solvent system (i.e., water), a colorant to provide good appearance and product distinction. The colorant may be added to the solution of the therapeutically active ingredient in place of or in addition to the aqueous dispersion of the hydrophobic material, for example, the colorant may be added to the Aquacoat.^® by using an alcohol or propylene glycol based dispersion, ground aluminum flakes, and an opacifier such as titanium dioxide, by adding a coloring agent to a water-soluble polymer solution, and then applying low shear to the Aquacoat softener^®. Optionally, any suitable method may be used to provide color to the formulations so formed. Suitable ingredients for providing color to the formulations when using aqueous dispersions of an acrylic polymer include titanium dioxide and color pigments such as iron oxide pigments. The incorporation of pigments may, however, increase the retarding effect of the shell.

The softened hydrophobic material can be applied to a substrate containing the therapeutically active ingredient by spraying using any suitable device known in the art. In a preferred method, a Wurster fluidized bed system can be used in which air from a nozzle, injected from the bottom, fluidizes the core material and causes drying during coating of the acrylic polymer shell. Preferably, a sufficient amount of hydrophobic material is applied to obtain a predetermined controlled release of said therapeutically active ingredient when the coated substrate is exposed to aqueous solutions, e.g. gastric fluids, taking into account the physical characteristics of the therapeutically active ingredient, method of incorporation of the softening agent, etc. After coating with a hydrophobic material, the spheres are optionally coated with an additional coating of a film-forming agent, such as Opadry.^®. If the latter coating is applied, it is to substantially reduce the agglomeration of the beads. The release of a therapeutically active ingredient from a controlled-release formulation may be further influenced, i.e., the desired rate, by the addition of one or more release-modifying agents, or by providing one or more transit sites in the coating. The ratio of hydrophobic material to water-soluble material is determined, among other factors, by the release rate and the solubility characteristics of the selected materials.

The release modifying agents that act as pore formers can be organic or inorganic, and include materials that can be dissolved, extracted, or leached from the shell in the environment of use. Pore ​​formers can include one or more hydrophilic materials such as hydroxypropyl methylcellulose.

Sustained-release coatings may also include erosion promoters such as starches and gums.

Sustained-release coatings may also include materials useful in making microporous films in the environment of use, such as polycarbonates, which are composed of linear polyhydric acid polyesters in which carbonate groups are repeated throughout the polymer chain.

The release modifying agent may also include a semipermeable polymer.

In some preferred embodiments, the release modifying agent may be selected from hydroxypropyl methylcellulose, lactose, metal stearates, and mixtures thereof.

PL 193 273 B1

Sustained release envelopes may include drop means including at least one passage, aperture or other. The transitions may be created by such a method as that disclosed in US Patent Nos. 3,845,770; 3,916,889; 4,063,064 and 4,088,864 (which are hereby incorporated by reference). The transition can be of any shape, such as round, triangular, square, elliptical, irregular, etc.

Matrix ball preparations

In other embodiments of the present invention, the controlled release formulation may be obtained using a matrix with a controlled release coating as set forth above. The present invention may also employ controlled release matrices that achieve opioid in vitro dissolution factors within the recommended ranges, and that release opioids in a pH-dependent or pH-independent manner. Suitable materials for incorporation into the controlled release matrix will depend on the method used in forming the matrix.

For example, the matrix may include in addition to the opioid analgesic and (optionally) COX-2:

- hydrophilic and / or hydrophobic materials such as gums, cellulose ethers, acrylic resins, protein-derived materials; This list is not intended to be exhaustive, and any pharmaceutically acceptable hydrophobic or hydrophilic material that is capable of causing controlled release of the active ingredient and that melts (or softens to the extent necessary for extrusion) can be used in the present invention.

- edible long-chain (C8-C50, especially C12-C40), substituted or unsubstituted hydrocarbons such as fatty acids, fatty alcohols, glyceryl esters or fatty acids, mineral and vegetable oils and waxes, and stearyl alcohol; and polyalkylene glycols.

Of these polymers, acrylic polymers are preferred, especially Eudragit^®RSPO - cellulose ethers, especially hydroxyalkyl celluloses and carboxyalkyl celluloses. Oral dosage forms may contain between 1% and 80% (by weight) of at least one hydrophilic or hydrophobic material.

When the hydrophobic material is a hydrocarbon, the hydrocarbon preferably has a melting point of between 25 ° and 90 ° C. For long chain hydrocarbon materials, fatty (aliphatic) alcohols are recommended. Oral dosage forms may contain up to 60% (by weight) of at least one edible long chain hydrocarbon.

Preferably, the oral dosage form contains up to 60% (by weight) of at least one polyalkylene glycol.

The hydrophobic material is preferably selected from the group consisting of alkyl celluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil or mixtures thereof. In certain preferred embodiments of the present invention, the hydrophobic material can be a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate, ethoxyethyl methacrylate copolymers, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly (acrylic acid) acrylate copolymer. , poly (methacrylic acid), methacrylic acid and alkylamine copolymer, poly (methyl methacrylate), poly (methacrylic acid) (anhydride), polymethacrylate, polyacrylamide, poly (methacrylic acid anhydride) and glycidyl methacrylate copolymers. In other embodiments, the hydrophobic material can be selected from materials such as hydroxyalkyl celluloses such as hydroxypropyl methyl cellulose, and mixtures thereof.

The preferred hydrophobic materials are water-insoluble with a more or less pronounced hydrophilic and / or hydrophobic tendency. Preferably, the hydrophobic materials useful in the invention have a melting point of from about 30 ° to about 200 ° C, preferably from about 45 ° to about 90 ° C. Specifically, the hydrophobic material can include natural or synthetic waxes, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl, or preferably cetostearyl alcohol), fatty acids including but not limited to fatty acid esters, fatty acid glycerides (mono-, di- and triglycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol, and hydrophobic and hydrophilic materials having a hydrocarbon backbone. Suitable waxes include, for example, beeswax, glycolic wax, castor wax, and carnauba wax. For the purposes of the present invention, a wax-like is defined as any material that is normally solid at room temperature and has a melting point of from about 30 ° to about 100 ° C.

Suitable hydrophobic materials that can be used in accordance with the present invention include edible long chain (C8-C50, especially C12-C40), substituted or unsubstituted

Hydrocarbons such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils, and natural and synthetic waxes. Hydrocarbons with a melting point between 25 ° and 90 ° C are recommended. Of the long chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred in some embodiments. Oral dosage forms may contain up to 60% (by weight) of at least one edible long chain hydrocarbon.

Advantageously, a combination of two or more hydrophobic materials may be included in the matrix formulations. If additional hydrophobic material is included, it is preferably selected from natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof. Examples include beeswax, carnauba wax, stearic acid, and stearyl alcohol. This list is not exhaustive.

One particular suitable matrix comprises at least one water-soluble hydroxyalkyl cellulose, at least one C12-C36, preferably C14-C22 aliphatic alcohol, and optionally, at least one polyalkylene glycol. The at least one hydroxyalkyl cellulose is preferably hydroxy (C1 to C6) alkyl cellulose, such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, in particular hydroxyethyl cellulose. The amount of at least one hydroxyalkyl cellulose in the present oral dosage form will be determined, inter alia, by the exact rate of opioid release desired. The at least one aliphatic alcohol can be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol. However, in particularly preferred embodiments of the present oral dosage form, the at least one aliphatic alcohol is cetyl alcohol or cetostearyl alcohol. The amount of at least one aliphatic alcohol in the present oral dosage form as above will be determined by the exact rate of opioid release desired. It will also depend on whether or not at least one polyalkylene glycol is present in the oral dosage form. In the absence of at least one polyalkylene glycol, the oral dosage form preferably contains between 20% and 50% (by weight) of at least one aliphatic alcohol. If at least one polyalkylene glycol is present in the oral dosage form, then the combined weight of the at least one aliphatic alcohol and the at least one polyalkylene glycol is preferably between 20% and 50% (by weight) of the total dose.

In one embodiment, the ratio of, e.g., the at least one hydroxyalkyl cellulose or acrylic resin, to the at least one aliphatic alcohol / polyalkylene glycol determines, to a reasonable extent, the opioid release rate from the formulation. A ratio of at least one hydroxyalkyl cellulose to at least one aliphatic alcohol / polyalkylene glycol of between 1: 2 and 1: 4 is particularly preferred, with a ratio of between 1: 3 and 1: 4 being particularly preferred.

The at least one polyalkylene glycol can be, for example, polypropylene glycol or, preferably, polyethylene glycol. A preferred number of average molecular weight of the at least one polyalkylene glycol is between 1,000 and 15,000, especially between 1,500 and 12,000.

Another suitable controlled release matrix would include alkyl cellulose (especially ethyl cellulose), a C12 to C36 aliphatic alcohol and, optionally, a polyalkylene glycol.

In another preferred embodiment, the matrix may include a pharmaceutically acceptable combination of at least two hydrophobic materials.

In addition to the above ingredients, the controlled release matrix may also contain appropriate amounts of other materials, e.g. diluents, lubricants, binders, granulation aids, colorants, flavors, glidants common in pharmaceutical art.

Methods of producing beads on a matrix matrix

Any method of preparing a matrix formulation known to those skilled in the art can be used to facilitate the preparation of a solid controlled release oral dosage form according to this invention. For example, the introduction into the matrix can be achieved e.g. by (a) forming granules containing at least one water-soluble hydroxyalkyl cellulose and an opioid or opioid salt; (b) mixing the hydroxyalkyl cellulose containing granules with at least one C12-C36 aliphatic alcohol; and (c) optionally, compressing and shaping the granules. Preferably, the granules may be formed by wet granulating the hydroxyalkyl cellulose / opioid with water. In a particularly preferred embodiment of this method, the amount of water added during the wet granulation step may be preferably between 1.5 and 5 times, in particular between 1.75 and 3.5 times the dry weight of the opioid.

In still other alternative embodiments, a spheronizing agent may be spheronized with the active ingredient to form spheroids. Microcrystalline cellulose is recommended.

PL 193 273 B1

A suitable microcrystalline cellulose is e.g. the material sold as Avicel PH 101 (Trademark of FMC Corporation). In such embodiments, the spheroids may also contain a binder when the active ingredient and the spheronizing agent are added. Suitable binders, such as water-soluble low viscosity polymers, will be well known to those skilled in the pharmaceutical art. However, water-soluble hydroxyalkyl cellulose with lower alkyl groups, such as hydroxypropyl cellulose, is preferred. Additionally (or alternatively), the spheroids may contain a water-insoluble polymer, particularly an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer, or ethyl cellulose. In such embodiments, the sustained release coating will generally comprise a hydrophobic material such as (a) a wax, either alone or in admixture with a fatty alcohol; or (b) shellac or zein.

Die for embossing

Slow release matrices can also be made by melt granulation or melt extrusion techniques. Generally, melt granulation techniques involve melting a normally solid hydrophobic material, e.g., a wax, and incorporating a powdered drug therein. To obtain a delayed release dosage form, it may be necessary to incorporate an additional hydrophobic substance, e.g. ethyl cellulose or a water-insoluble acrylic polymer to a molten wax hydrophobic material. Examples of slow release formulations made by melt granulation techniques are disclosed in US Patent No. 4,861,598, which is hereby incorporated by reference.

The additional hydrophobic material may include one or more water-insoluble wax-like thermoplastics which can be mixed with one or more wax-like thermoplastic materials that are less hydrophobic than the one or more insoluble wax-like substances. In order to achieve sustained release, the individual wax-like substances in the formulation should be substantially non-degradable and insoluble in the gastrointestinal fluids during the initial release phases. Useful insoluble wax-like substances can be those whose water solubility is less than about 1: 5000 (by weight).

In addition to the above ingredients, the sustained release matrix may also contain suitable amounts of other materials, e.g., diluents, lubricants, binders, granulating aids, coloring, flavoring and glidants common in pharmaceutical art. The amounts of these additional materials will be sufficient to provide the desired effect for the desired formulation.

In addition to the above ingredients, the delayed release matrix containing the melt extruded multiparticulates may also include appropriate amounts of other materials, e.g. up to 50% by weight of the granulate, if required.

Specific examples of pharmaceutically acceptable carriers and excipients that can be used in the preparation of oral dosage forms are described in the Handbook of Pharmaceuticals Excipients, American Pharmaceutical Assotiation (1986), which is hereby incorporated by reference.

Multiparticulates for melt extrusion

The preparation of a suitable melt extrusion matrix may, for example, involve the steps of mixing the opioid analgesic together with at least one hydrophobic material and preferably an additional hydrophobic material to obtain a homogeneous mixture. The homogeneous mixture is then heated to a temperature sufficient to at least soften the mixture sufficiently to extrude it. The resulting homogeneous mixture is then extruded to form strands. The extruded material is preferably cooled and cut into multiparticulates by any method known in the art. The strands are cooled and cut into multiparticulates. Thereafter, the multiparticulates are divided into unit doses. The extruded material preferably has a diameter of from about 0.1 to about 5 mm and provides slow release of the therapeutically active ingredient over a period of time of from about 8 to about 24 hours.

An optional method of producing the melt-extruded material may include directly metering the hydrophobic material, therapeutically active ingredient, and optional binder into the extruder; heating the homogeneous mixture; extruding a homogeneous mixture to form a strand; cooling the strand containing the homogeneous mixture; cutting the thread on

Particles having a size from about 0.1 mm to about 12 mm; and dividing said particles into unit doses. A relatively continuous manufacturing process takes place in this aspect of the invention.

The diameter of the extruder bore or exit port can also be adjusted to vary the thickness of the extruded strands. Moreover, the exit part of the extruder need not be round; it can be elongated, rectangular, etc. The strands coming out can be reduced to particles using a wire cutter, guillotine, etc.

The melt-extruded multiparticulate system can be, for example, in the form of granules, spheroids or pellets, depending on the exit port of the extruder. For the purposes of the present invention, the terms "melt-extruded multiparticulate (s)" and "melt-extruded multiparticulate system (s)" and "melt-extruded particles" shall refer to a plurality of units, preferably in a range of similar size and / or shape and containing one or more active agents and one or more excipients, preferably containing a hydrophobic material as described herein. In this regard, the melt-extruded multiparticulates will have a size ranging from about 0.1 to about 12 mm in length and will have a diameter of from about 0.1 to about 5 mm. In addition, it should be understood that the melt-extruded multiparticulates can be of any geometric shape within this size range. Optionally, the extrudate can simply be cut to the desired length and divided into unit doses of the therapeutically active ingredient without the need for a spheronization step.

In one preferred embodiment, oral dosage forms can be prepared so that within the capsule it will contain an effective amount of melt-extruded multiparticulates. For example, a plurality of melt-extruded multiparticulates may be placed in a gelatin capsule, in an amount sufficient to provide an effective delayed dose upon aspiration and contact with gastric fluid.

In another preferred embodiment, an appropriate amount of the extruded multiparticulate material is tabletted into an oral tablet using a conventional tableting machine using standard techniques. Techniques and compositions for making tablets (compressed or molded), gelatin capsules (hard and soft), and pills are also described in Remington's Pharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 91980), which is hereby incorporated by reference. .

In yet another preferred embodiment, the extrudate can be shaped into tablets as set forth in US Patent No. 4,957,681 (Klimesch et al.), Described in further detail above and hereby incorporated by reference.

Optionally, the sustained release melt extruded multiparticulate systems or tablets may be coated with either a gelatin capsule, or may be further coated with a sustained release coating such as the sustained release coatings described above. Such coatings preferably include a sufficient amount of hydrophobic material to achieve a weight gain level of from about 2 to about 30 percent, although the second coating may be more dependent upon, among other things, the physical properties of the particular opioid analgesic used and the desired release rate. .

The melt-extruded unit dosage forms may further comprise a combination of the melt-extruded multiparticulates containing one or more of the therapeutically active agents disclosed above, prior to encapsulation. In addition, unit dosage forms can also include an amount of an instantaneous therapeutically active agent for immediate therapeutic effect. The immediately released therapeutically active agent can be incorporated, e.g. as discrete pellets in a gelatin capsule, or may be coated onto the surface of the multiparticulate after the dosage form is formed (e.g., a controlled release coating or a matrix matrix). The dosage forms of the present invention may also contain a combination of controlled release beads and matrix multiparticulates to achieve the desired effect.

Sustained-release preparations preferably release the therapeutically active agent slowly, e.g., after ingestion and exposure to gastric fluids and then intestinal fluids. The sustained release profile of melt-extruded formulations can be varied, e.g. by changing the amount of the retarder, i.e., the hydrophobic material, by changing the amount of the softening agent relative to the hydrophobic material, by adding additional ingredients or excipients, by changing the production method, etc.

PL 193 273 B1

In other embodiments of the invention, the melt extrudate may be produced without incorporating a therapeutically active ingredient which is then added to the extrudate. Such formulations typically will have the therapeutically active agent mixed with the extruded matrix material and the mixture then compressed to provide a slow release formulation. Such preparations may be advantageous, e.g. where the therapeutically active agent contained in the formulation is sensitive to the temperatures needed to soften the hydrophobic material and / or the retard material.

Various aspects of the present invention are illustrated by the following examples.

To the knowledge of the present inventors, no direct comparison of the competitive properties of a naltrexone antagonist after co-administration with various opioid agonists has been previously performed. However, dose-ranging studies have been performed to evaluate the properties of the opioid antagonist in subjects receiving either heroin or morphine challenges. Overall, pretreatment with naltrexone 50 mg 24 hours prior to 25 mg intravenous heroin challenge completely blocked or attenuated the effect of the opioid agonist. See Gonzales JP, Brodgen RN. "Naltrexone: A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic efficacy in the Management of Opioid Dependence" Drugs 1988; 35: 192-213; Resnick RR, Valavka J, Freeman AM, Thomas M. "Studies of EN-169A (Naltrexone): A New Narcotic Antagonist" Am. J. Psychiatry 1974; 131: 646-650, which is hereby incorporated by reference.

Example 1

In Example 1, a randomized, single-blind, placebo-controlled, single dose, four-way, alternating study was conducted that assessed whether 6.4 mg naltrexone oral solution blocked the properties of the opioid agonist hydrocodone 15 mg in normal patients. , healthy, female six volunteers. The study population included only women as previous observations showed that women have an increased sensitivity to the effects of an opioid agonist compared to men. Four treatments were used: HYIR / APAP (2 tablets of hydrocodone 7.5 mg and acetaminophen 750 mg, Vicodin ES^®) and naltrexone oral solution 3.2 mg; HYIR / APAP (2 x 7.5 mg) and naltrexone oral solution 6.4 mg; comparator HYIR tablets (2 x 750 mg Trilisate tablets^®) and naltrexone oral solution (placebo); and HYIR / APAP (2 Vicodin ES^®) and naltrexone oral solution (placebo). All treatments were starved. There was a 48 hour washout period between doses between doses prior to administration of any other drugs. Subjects were randomly assigned to four treatment schedules in four treatment groups. Subjects checked into the test room the evening before the first dose, and remained there until the end of the 24 hour evaluation period following the last dose. Safety measures consisted of descriptions of adverse events, vital signs, abnormal laboratory values, abnormal physical examination, and ECG results. Pharmacodynamic parameters (pupil size and modified specific drug effect questionnaire) were also assessed.

Test Treatments

The four treatments were as follows:

Hydrocodone immediate-release tablets (2 x 7.5 mg) and naltrexone oral solution 3.2 mg.

Hydrocodone immediate-release tablets (2 x 7.5 mg) and naltrexone oral solution

6.4 mg.

Hydrocodone immediate-release comparator tablets and naltrexone oral solution placebo.

Placebo hydrocodone immediate-release tablets (2 x 7.5 mg) and placebo naltrexone oral solution.

Test products

Products evaluated in this study included Vicodin ES^® (hydrocodone acid tartrate

7.5 mg and 750 mg acetaminophen, Knoll Pharmaceuticals), Trilisate^® (750 mg choline magnesium trisalicinate, Purdue Frederick), which served as comparators, and naltrexone powder. Vicodin ES^®was chosen as an active treatment because the acetaminophen part of this product has no effect as expected on the central nervous system or pupil measurements. Trilisat was chosen to be used as a "comparison" because its physical appearance is similar to Vicodin ES^® and it has no effect on the central nervous system or pupil measurements. A naltrexone powder formulation was chosen rather than a marketed tablet formulation (Revia^® 50 mg, DuPont) to improve overall accuracy24

In the preparation of an oral solution. On site, the pharmacist reconstituted the oral solution from the naltrexone powder in a sterile environment, using appropriate pharmaceutical techniques. Naltrexone powder (Mallinckrodt Chemical) was used to prepare the naltrexone solution. The individual naltrexone stock solutions were prepared using a modification of the method proposed by Tsang and Holtsman. Tsang BK, Holtsman R. "Room Temperature Stability of Liquid Naltrexone" Anesthesiology 1995; 83: AS64 is hereby incorporated by reference. Just before (&lt;60 minutes) each dosing period, naltrexone stock solution was prepared by weighing out 32 mg and 64 mg of naltrexone powder. Each of these portions was dissolved in 50 ml of distilled water and 50 ml of simple syrup, NF to a final volume of 100 ml. The concentration of the final solutions was 0.32 mg / ml (32 mg / 100 ml) and 0.64 mg / ml (64 mg / 100 ml), respectively. These concentrations allowed the same volume (10 ml) of naltrexone oral solution to be administered during each dosing period. Placebo of naltrexone oral solution is prepared in the same vehicle as the active solution. The bitter center, Bitterguard powder (denatonium benzoate, NF) was added to provide a taste similar to the active solution.

Pharmacodynamic measurements

a. Pupil size - measured by pupillometry.

Pupil diameter measurements were taken with a 75mm Polaroid CU-5 camera with an integrated electronic ring flash, using a 12 film pack with Polacolor ER 669 immediate development. This method has been accepted as a safe and accurate method of examining the pupils and it is widely believed that it is second only to the infrared television pupillometry technique (a more universal and sophisticated method, but also much more expensive and inconvenient). The Polaroid CU-5 method is considered accurate to 0.1 millimeters. See Czarnecki JS, Pilley SF, Thompson HS. "The Use of Photography in the Clinical Evaluation of Unequal Pupils". Canada. J. Ophtal. 1979; 14: 297-302; which is hereby incorporated by reference.

Pupil diameters were measured as follows: The camera was modified by covering the two small sections of the flashlight ring at 3 and 9 o'clock so that the reflection at the corners of the flash did not obscure the horizontal rim of the pupil. The camera was centered in front of the subject's face using a 3 inch (4.5 cm) frame against the lateral rims of the eye socket and uppermost eyes (minimizing looking up). Subject was asked to look just above the camera and stop at a non-accommodative target in the distance, thereby minimizing near reflection. A picture was taken when the volunteer gazed into the distance. All photos were taken under constant ambient light. The pupil latency was such that the flash did not affect the pupil diameter. Tonic constriction of the pupil after a flash occurs but is of short duration; therefore it does not interfere with the measurements necessary for the experiment. See Smith SA, Dewhist RR. "A Single Diagnostic Test for Pupillary Abnormality in Diabetic Neuropathy." Diabetitic Medicine 1988; 3: 38-41; which is hereby incorporated by reference. Developing the photo for the recommended length of time (approximately one (1) minute, varying with the ambient temperature) results in a one-to-one photo of the center of the volunteer's face, with the pupils at the top of the photo. The horizontal ¼ circle diameter is then measured using a simple magnifier with embedded mesh, calibrated to 0.1 millimeter. Only the left eye is used to measure the pupil effect at each time period specified in the protocol.

b. Modified Specific Drug Effect Questionnaire.

The questionnaire is a modification of the 22-item questionnaire used by Jasinski and Preston. Look, Jasinski DR. "Assessment of the Abuse Potential of Morphine-Like Drugs (human methods)." In: Drug Addiction I (Martin WR publisher), 1997: 197-258. Springer-Verlag, New York; Preson KL, Jasinski DR, Testa M. "Abuse Potential and Pharmacological Comparison of Tramadol and Morphine." Drug and Alcohol Dependence 1991; 27: 7-17; which is hereby incorporated by reference. The present questionnaire consisted of 10 items assessed by the subject 10 minutes prior to blood sampling. The items describe the signs of opioid agonist drug effects and were as follows: Questions to the subject: 1) do you feel any effect of the drug? 2) is your skin itchy? 3) are you relaxed? 4) are you feeling sleepy? 5) are you feeling drunk? 6) are you feeling nervous? 7) are you feeling full of energy? 8) do you feel the need to talk? 9) do you feel that your stomach is sick? 10) are you feeling dizzy? The subject then rated the position by placing a vertical marker along a 100mm visual analog scale (VAS) followed by "not at all" at one end and "very tight" at the other end.

PL 193 273 B1

Left eye pupil size was measured at baseline (30 minutes before dosing) and at 0.5, 1, 2, 4, 6, 9, and 12 hours post-dose, and the subject rated drug effects as measured on a visual analog scale for Modified Specific Drug Effect Questionnaire (“MSDEQ”) at baseline and at 0.5, 1, 2, 4, 6, 9 and 12 hours post-dose.

Separate plots for the eleven responses (MSDEQ questions and pupil diameter measurements) versus naltrexone dose were visually and statistically tested to determine the nominally effective naltrexone dose in combination with the hydrocodone dose used in the study.

The adverse events reported were those commonly associated with the administration of opioid analgesics and the majority were classified as "mild". There were no serious adverse events or deaths, and no patient discontinued the study due to adverse events.

The results are shown in Figures 1 and 2.

Figure 1 shows the naltrexone "drug effect" antagonism on hydrocodone-induced VAS (visual analogue scale). This corresponds to the first question of the modified drug specific effect questionnaire, which was "do you feel any drug effect?" The results suggest that there is a dose-response effect for naltrexone; increasing the dose of naltrexone decreased the "drug effect" of hydrocodone VAS. The 6.4 mg naltrexone dose antagonized the effects of the 15 mg dose of hydrocodone to a greater extent than the 3.2 mg naltrexone dose. The opioid effect of hydrocodone was not completely blocked by the 6.4 mg dose of naltrexone. Figure 2 shows the antagonism of naltrexone to hydrocodone-induced pupillary constriction. These results also suggest a dose-response effect for naltrexone; increasing the dose of naltrexone resulted in less constriction of the pupil in the subject that had received 15 mg of hydrocodone. The 6.4 mg naltrexone dose antagonized hydrocodone-induced pupil constriction to a greater extent than the 3.2 mg naltrexone dose. Pupillary constriction by hydrocodone was completely blocked by a 6.4 mg dose of naltrexone. The smallest pupillary constriction occurred in the placebo group. The hydrocodone plus naltrexone placebo group experienced the greatest pupillary constriction and thus, had the lowest pupillary diameter measurements.

Example 2

Example 2 conducted ten-period, randomized, alternating, single-blind, studies evaluating the ratio of oral naltrexone to oral hydrocodone that would nominally minimize the effect of an opioid agonist in normal, healthy female volunteers. Twenty-one subjects participated in the study and 16 completed the study. The ten treatments included HYIR / APAP (2 hydrocodone 7.5 tablets and 750 mg acetaminophen per tablet, Vicodin ES^®) with the following doses of naltrexone oral solution: 0.4 mg / 10 ml, 0.8 mg / 10 ml,

1.6 mg / 10 ml, 3.2 mg / 10 ml, 4.8 mg / 10 ml, 6.4 mg / 10 ml, 9.6 mg / 10 ml, 12.8 mg / 10 ml and oral placebo naltrexone solution as well as the immediate-release hydrocodone comparator tablets (2 x 750 mg tablets of Trilisat^®) with placebo naltrexone oral solution. All treatments were given under fasting conditions. There was a 48 hour washout period between doses between doses prior to administration of subsequent drugs. Subjects were randomly assigned to ten treatment schedules in ten treatment groups. The subjects reported to the testing room on the evening before the first dose, and remained there until the end of the 24 hour evaluation period following the last dose administration. Safety measures consisted of descriptions of adverse events, vital signs, abnormal laboratory values, abnormal physical examination, and ECG results. Plasma levels of hydrocodone, naltrexone and 6-e-naltrexone were obtained, and pharmacokinetic values ​​were calculated and analyzed. Pharmacokinetic parameters (pupil size and modified specific drug effect questionnaire) were also assessed.

Dosing mode

The dosing regimen was as follows:

Hydrocodone immediate-release comparator (placebo) tablets were administered with 10 ml of naltrexone oral solution (placebo) at approximately 08:00, on dosing days, for periods 1 to 10 following an 8-hour fast. Fasting continued for an additional four (4) hours post-dose;

Hydrocodone immediate release tablets (2 x 7.5 mg) were administered with 10 ml of naltrexone oral solution (placebo) at approximately 08:00 on dosing days for periods 1 to 10 following an 8-hour fast. Fasting continued for an additional four (4) hours post-dose;

Hydrocodone immediate release tablets (2 x 7.5 mg) were administered from 10 ml of naltrexone oral solution (0.4 mg) at approximately 08:00 on dosing days for periods 1 to 10 following an 8-hour fast. Fasting continued for an additional four (4) hours post-dose;

PL 193 273 B1

Hydrocodone immediate release tablets (2 x 7.5 mg) were administered from 10 ml of naltrexone oral solution (0.8 mg) at approximately 08:00 on dosing days for periods 1 to 10 following an 8-hour fast. Fasting continued for an additional four (4) hours post-dose;

Hydrocodone immediate release tablets (2 x 7.5 mg) were administered from 10 ml of naltrexone oral solution (1.6 mg) at approximately 08:00 on dosing days for periods 1 to 10 following an 8-hour fast. Fasting continued for an additional four (4) hours post-dose;

Hydrocodone immediate release tablets (2 x 7.5 mg) were administered with 10 ml of naltrexone oral solution (3.2 mg) at approximately 08:00 on dosing days for periods 1 to 10 following an 8-hour fast. Fasting continued for an additional four (4) hours post-dose;

Hydrocodone immediate release tablets (2 x 7.5 mg) were administered from 10 ml of naltrexone oral solution (4.8 mg) at approximately 08:00 on dosing days for periods 1 to 10 following an 8-hour fast. Fasting continued for an additional four (4) hours post-dose;

Hydrocodone immediate release tablets (2 x 7.5 mg) were administered from 10 ml of naltrexone oral solution (6.4 mg) at approximately 08:00 on dosing days for periods 1 to 10 following an 8-hour fast. Fasting continued for an additional four (4) hours post-dose;

Hydrocodone immediate release tablets (2 x 7.5 mg) were administered from 10 ml of naltrexone oral solution (9.6 mg) at approximately 08:00 on dosing days for periods 1 to 10 following an 8-hour fast. Fasting continued for an additional four (4) hours post-dose;

Hydrocodone immediate release tablets (2 x 7.5 mg) were administered from 10 ml of naltrexone oral solution (12.8 mg) at approximately 08:00 on dosing days for periods 1 to 10 following an 8-hour fast. Fasting continued for an additional four (4) hours post-dose.

The subjects were fasted for 8 hours prior to dosing and fasted for 4 hours after each dose administration of the prescribed drug on each dosing day. A baseline blood sample (for hydrocodone, naltrexone, and plasma 6-β-naltrexone) was collected (within 30 minutes) (0 hour) and sampled at 0.5, 1, 2, 4, 6 and 9 hours prior to the initial dose administration. after dose. All samples were collected within ± 2 minutes of the specified time. Pharmacodynamic parameter measurements were performed for the baseline blood sample (within 30 minutes prior to dosing) and for the 0.5 hour, 1 hour, 2 hour, 4 hour, 6 hour, and 9 hour post-dose sample.

Immediately after each dosing period, 8 individual naltrexone stock solutions were prepared by weighing out 4, 8, 16, 32, 48, 64, 96, and 128 mg of naltrexone powder. Each of these portions was dissolved in 50 ml of distilled water and 50 ml of simple syrup. The final solution was 100 ml in volume and its concentration was 0.04; 0.08; 0.16; 0.32; 0.48; 0.96 and 1.28 mg / ml. These concentrations allowed the same volume (10 ml) of naltrexone solution to be administered during each dosing period. A naltrexone placebo solution was prepared in the same vehicles as the active solution. The bitter agent, Bitterguard Powder (denatonium benzoate) was added to provide a taste similar to the active solution.

Pharmacodynamic measurements

The pharmacodynamic measurements for Example 2 were obtained according to the procedures set forth for Example 1 above.

The mean "drug effect" VAS score and pupil diameter versus time for each treatment are shown in Figures 3 and 4, respectively. Generally, single dose administration of immediate release hydrocodone / acetaminophen ("HYIR / APAP") with escalating doses naltrexone (range 0 mg -12.8 mg) resulted in a complete reduction in the VAS score for "drug effect" and a reduction in pupillary constriction. Figures 5 and 6 show the corresponding mean maximum "drug effect" VAS score (± 95% CI) and mean minimum pupil diameter (± 95% CI) versus log for each of the naltrexone doses. Both figures suggest a dose-response relationship with pupil effect, showing a greater dose-response relationship as compared to VAS response for "drug effect".

The results suggest that even with the introduction of 0.4 mg naltrexone, there was a reduction in the pharmacological effect of the hydrocodone dose. About 0.4 mg of naltrexone minimally antagonized the 15 mg dose of hydrocodone. Doses above 0.4 mg naltrexone increasingly reduced the effect of the hydrocodone dose.

The adverse events reported were those commonly associated with the administration of opioid analgesics and were mostly classified as "mild". A total of five (5/21) subjects discontinued the study. Three subjects discontinued due to adverse events. Two of these subjects experienced adverse events which they classified as not very serious.

PL 193 273 B1

One subject developed anemia that was classified as severe and required iron therapy. The other two subjects discontinued the study because their doctors discovered information in their medical history that prevented them from participating in the study. There were no fatalities in this study.

Overall, administration of a single dose of 15 mg hydrocodone in an immediate release tablet, with increasing doses of naltrexone oral solution (range 0 mg - 12.8 mg) resulted in a complete reduction in the "drug effect" VAS score and an increase in pupil diameter.

Example 3

Example 3 shows the results of a study evaluating abrupt withdrawal in morphine-dependent volunteers receiving immediate release hydrocodone tablets and naltrexone oral solution. The study was a single-blind, single-dose, placebo-controlled escalating naltrexone study in subjects physically dependent on opioids. Subjects (5) were opioid dependent as determined by Narkan challenge, addiction severity index scores, physical examination, observation, and urine screening results, and did not currently expect treatment for their addiction. To assess abrupt withdrawal following the co-administration of immediate-release hydrocodone and naltrexone, a 30 mg immediate-release hydrocodone dose was selected to simulate the dose level used by subjects who abuse hydrocodone. It was also a dose that is considered to be equivalent to analgesic to other commonly used opioids in opioid naïve patients. The relative analgesic potency of hydrocodone is considered to be similar to oxycodone and about twice that of oral morphine.

Test treatment

The treatment was as follows:

Immediate-release tablets hydrocodone / acetaminophen (HYIR / APAP) 30 mg (Lortab^®3 x 10 mg) and increasing doses of naltrexone oral solution 0, 0.25 mg, 0.5 mg, 1.0 mg and 2.0 mg. Immediate-release tablets hydrocodone / acetaminophen (HYIR / APAP) 30 mg (Lortab^® 3 x 10 mg) and naltrexone oral solution placebo. An oral naltrexone solution and a placebo solution were prepared according to Examples 1-2.

The subjects were stabilized for 5 days by administering 15 mg morphine sulfate intramuscularly at regular intervals: 6 and 10 am and 4 and 10 pm daily. Fifteen mg of morphine sulfate intramuscularly is equivalent to 30 mg of oral hydrocodone. The study medication was administered after stabilization at 10 AM on the study medication dosing days, and observations were made for the next six hours. After six hours, if no accelerated withdrawal was observed, the intramuscular administration of 15 mg morphine sulfate was resumed with the dose at 4 p.m. The subjects were stabilized 48 hours prior to the next study drug administration. After each treatment (1-4), if no abrupt discontinuation was observed, the subject received the study drugs from the next treatment in the following increasing order:

Treatment # 1: HYIR / APAP tablets 30 mg (Lortab^® 3 x 10 mg) administered with placebo naltrexone oral solution (10 ml), at approximately 10:00 on the dosing day, after an 8-hour fast. Fasting continued for an additional four (4) hours post-dose.

Treatment # 2: HYIR / APAP tablets 30 mg (Lortab^® 3 x 10 mg) administered with 0.25 mg naltrexone oral solution (10 ml), at approximately 10:00 on the dosing day, after an 8-hour fast. Fasting continued for an additional four (4) hours post-dose.

Treatment # 3: HYIR / APAP tablets 30 mg (Lortab^® 3 x 10 mg) administered with 0.5 mg naltrexone oral solution (10 ml), at approximately 10:00 on the dosing day, after an 8-hour fast. Fasting continued for an additional four (4) hours post-dose.

Treatment # 4: HYIR / APAP tablets 30 mg (Lortab^® 3 x 10 mg) administered with 1.0 mg naltrexone oral solution (10 ml), at approximately 10:00 on the dosing day, after an 8-hour fast. Fasting continued for an additional four (4) hours post-dose.

Treatment # 5: HYIR / APAP tablets 30 mg (Lortab^® 3 x 10 mg) administered with 2.0 mg naltrexone oral solution (10 ml), at approximately 10:00 on the dosing day, after an 8-hour fast. Fasting continued for an additional four (4) hours post-dose.

Blood samples were collected 0.5 hours pre-dose and 0.5, 1, 2, 4, and 6 hours post-dose. Pupil diameter measurements were obtained using a Pupilscan pupillometer and recorded in millimeters against the nearest millimeter. Each test period was followed by 48 hour periods of clearing prior medications prior to administering more. Four entities completed the research,

One entity has ceased. The effect of naltrexone was mild abstinence (withdrawal symptoms) at 1 and 2 mg.

The protocol was changed and twelve study subjects participated in a protocol that was identical to the study outlined above except for the increased naltrexone ratio. The naltrexone doses in the revised protocol were 0, 1, 2, 4, and 8 mg. Eight test subjects completed the study, while four were discontinued.

Vital signs for each subject were monitored and subjects were monitored for signs and symptoms of opioid withdrawal. Withdrawal symptoms included shortness of breath or runny nose, watery eyes, yawning, sweating, tremors, vomiting, hair-raising, mydriasis, irritability, and restlessness. Withdrawal symptoms include sensation of temperature changes, joint, bone or muscle pain, stomach cramps, chills, nausea, and the subject's description of the symptoms listed above.

To provide a measure of the subjective perception of the drug combination, subjects replied to the questionnaire during the study period. Responses to the questions were graded on the visual analog scale described in Example 1. The subjective experiences that were assessed were as follows: I like / dislike the drug, the ability to be aware of the effect of the drug, sweating, restlessness, chills, wet eyes, goosebumps, stomach pain, nasal congestion, sleepiness, cold, heat, muscle pain, tension or flaccidity, confusion, fear, irritability, talkativeness, withdrawal, feeling sick. Subjects were also observed for the following symptoms: yawning, scratching, relaxation, nasal congestion, irritability, and withdrawal. In addition, blood pressure, pulse, respiratory rate, pupil size and body temperature were monitored.

Data from five entities are presented below. Figures 7A-C illustrate the mean scores for subjective perception of hydrocodone effects from the questionnaires, plotted as a function of time post-administration and as a function of naltrexone dose. Figure 7A illustrates the subject's ability to experience the effects of hydrocodone in the presence of varying amounts of naltrexone. Figures 7B and 7C illustrate the subjects' favorable or unfavorable subjective experiences of hydrocodone in the presence of varying amounts of naltrexone, respectively.

Figures 8A and B illustrate the mean scores for subjective perception of the effects of hydrocodone, plotted as a function of time after administration and as a function of naltrexone dose. Figure 8A illustrates the perception of the withdrawal subject to the effects of hydrocodone in the presence of varying amounts of naltrexone. Figure 8B illustrates the subjective experience of disease in the presence of varying amounts of naltrexone. Figure 9A illustrates the effect of hydrocodone on pupil size in the presence of varying amounts of naltrexone. Figure 9B illustrates the apparent extent of withdrawal from the effects of hydrocodone in the presence of varying amounts of naltrexone, from an observer's perspective.

Figures 10A-C show the areas under the curves shown in Figures 7A-C, collected during the 6 hour observation period as a function of naltrexone dose, and the 95% confidence level for the naltrexone placebo response (30 mg hydrocodone, 0 mg naltrexone). Figure 10A illustrates that up to 8 mg of naltrexone does not abolish the subject's ability to feel the effects of hydrocodone: the experimentally determined AUC (0 to 6 hours) observed for each naltrexone dose is fully within 95% confidence limits for the naltrexone placebo response. Figure 10B illustrates the AUC (0 to 6 hours) for the subject's favorable subjective experience of hydrocodone as a function of naltrexone dose. Figure 10B illustrates that the subjective benefit is reduced with> 1 mg naltrexone, i.e. the experimentally determined AUC (0 to 6 hours) decreased below the 95% confidence limits for the naltrexone placebo at about 1 mg naltrexone. Figure 10C illustrates that the adverse subjective experience increases with> 1 mg naltrexone, i.e. the experimentally determined AUC (0 to 6 hours) increased above the 95% confidence limits for naltrexone placebo at about 1 mg naltrexone.

Figures 11A-C show the areas under the curves shown in Figures 8A-B and Fig. 9A, collected over the 6 hour observation period, as a function of naltrexone dose, and 95% confidence levels for the naltrexone placebo response (30 mg hydrocodone, 0 mg naltrexone). ). Figure 11A illustrates the AUC (0 to 6 hours) for subjective withdrawal perception in the presence of varying amounts of naltrexone. Figure 11A shows that naltrexone doses greater than about 0.75 mg cause a subjective perception of disease: the experimentally determined AUC (0 to 6 hours) observed in Figure 8A for each naltrexone dose increases the greater than 95% confidence limits for the naltrexone placebo response at approximately 0.75 mg naltrexone. Figure 11B illustrates the AUC (0 to 6 hours) for the subject's perception of disease in the presence of declining amounts of naltrexone. Figure 11B shows that naltrexone doses greater than about 0.75 mg cause subjective disease sensation: experimentally determined AUC (0 to 6 hours)

As observed in Figure 8B for each naltrexone dose, the confidence limits for the naltrexone placebo response were increased over 95% at about 0.75 mg naltrexone. Figure 11C illustrates the AUC (0 to 6 hours) for the experimentally determined change in pupil size as a function of naltrexone dose. Figure 11C shows that up to an 8 mg dose of naltrexone does not abolish the pupillary effect of hydrocodone: the experimentally determined AUC (0 to 6 hours) observed in Fig. 9A for each naltrexone dose is fully within 95% confidence limits for the naltrexone placebo response.

A clinical study shows that hydrocodone in combination with naltrexone takes effect in about &lt;0.5 hours, reaches a maximum effect in 0.5 to 1 hour and diminishes significantly within 3 to 4 hours. A flat dose response curve was observed. The addition of naltrexone decreased the pleasant subjective feeling of hydrocodone, increased the subjective feeling of aversion to hydrocodone, and increased the subjective feeling of illness and hydrocodone withdrawal. These feelings evoke a clear aversion.