Pharmaceutical compositions

TECHNICAL FIELD [0002] This invention relates to a sequestering subunit comprising an antagonist and a blocking agent, and suitable compositions and methods of use, such as methods for preventing dependence on a therapeutic agent.

BACKGROUND OF THE INVENTION [0003] Opioids, also called opioid agonists, are a class of drugs that have opium-like or morphine-like properties. Opioids are used primarily as moderate to severe analgesics, but they also cause other pharmacological effects, including drowsiness, respiratory depression, mood changes, mental eclipse without causing loss of consciousness. Due to these other pharmacological actions, opioids have become subject to addiction and abuse. Therefore, the main problem associated with the use of opioids is to obtain these drugs from an illegal user, e.g. a drug addict.

[0004] Physical dependence may develop after repeated administration or longer opioid use. Physical dependence is revealed gradually after discontinuation of opioid use or occurs immediately (eg within a few minutes) after administration of a drug antagonist (referred to as "withdrawal symptoms"). Depending on the drug, followed by the addiction and the time of use and dose, withdrawal symptoms change in terms of quantity and type, duration and advancement. The most common symptoms of withdrawal syndrome include anorexia, weight loss, mydriasis, chills alternating with excessive sweating, abdominal cramps, nausea, vomiting, muscle cramps, excessive excitability, tearing, fluid flow, goose bumps and increased heart rate. Natural abstinence symptoms usually begin to appear 24-48 hours after the last dose, reach maximum intensity around the third day and may not decrease until the third week. The syndrome of withdrawal symptoms caused by the administration of the opioid antagonist varies in severity and duration depending on the dose and specific antagonist, but in general their duration varies from a few minutes to several hours.

[0005] The physiological dependence or dependence of opioids is characterized by the search for contact with an addictive substance and this behavior is directed towards the achievement of euphoria and escape, e.g. from psychosocean-economic pressures. A drug user will continue to take opioids for non-medical reasons and regardless of self-injury.

[0006] Although opioids, such as morphine, hydromorphone, hydrocodone and oxycodone, are effective in combating pain, there is an increase in their abuse by individuals who are psychologically addicted to opioids and who abuse opioids for non-therapeutic reasons. Previous studies with other opioids have shown that the addictive potential is reduced when opioids are administered in combination with a drug antagonist, especially in patients who are former drug users (Weinhold et al., Drug and Alcohol Dependence 30: 263-274 (1992); and Mendelson et al., Clin. Pharm. Ther. 60: 105-114 (1996)). However, such combinations do not contain an opioid antagonist which is in sequestered form. Contrary,

[0007] Previous attempts to control the addictive potential associated with opioid analgesics include, for example, a combination of pentazocine and naloxone tablets, available commercially in the United States as Talwin®Nx from Sanofi-Winthrop, Canterbury, Australia. Talwin® Nx contains pentazocine hydrochloride equivalent to 50 mg of the base and naloxone hydrochloride equivalent to 0.5 mg of base. Talwin ® Nx is indicated for moderate to severe pain relief. The amount of naloxone present in this combination has low activity on oral administration and minimally interferes with the pharmacological action of pentazocine. However, naloxone administered in this parenteral amount has a significant antagonistic effect to the narcotic analgesic. Thus, inclusion of naloxone is intended to limit the form of oral abuse of pentazocine, which occurs when the dosage form is solubilized and injected. Thus, such a parenteral dose has less potential for parenteral abuse than previous oral pentazocine formulations. However, such an oral dose is still a cause of abuse and addiction in the patient, especially in a patient taking multiple doses at once. In Germany, since 1978, combination therapy containing tilidine (50 mg) and naloxone (4 mg) (Valoron®N, Goedecke) is available for the treatment of severe pain. The rational combination of these drugs effectively removes pain and prevents tilidine from being compounded by naloxone antagonism to tilidine receptors. A complex combination of buprenorphine and naloxone for the treatment of pain (Terngesic®Nx,

[0008] International Patent Application No. PCT / US01 / 04346 (WO 01/58451) to Euroceltique, SA describes the use of a pharmaceutical composition that contains a substantially non-releasable opioid antagonist and a releasing opioid agonist as separate subunits that are combined in one a pharmaceutical dosage form, e.g. a tablet or capsule. However, because the agonist and antagonist are in separate subunits, they can be easily separated. Furthermore, when the agonist and antagonist are provided as separate subunits, the tablets are more difficult to manufacture due to the mechanical sensitivity of certain subunits containing a sequestering agent.

[0009] The advantages of non-addictive dosage forms are particularly important in the case of oral dosage forms of potent opioid agonists (e.g., morphine, hydromorphone, oxycodone or hydrocodone) who provide valuable analgesics but are susceptible to addiction. This is particularly true for opioid-based sustained release agonists that contain a high dose of the desired opioid agonist to be released over a period of time from each dosage unit. Drug abusers take such sustained-release products after crushing, grinding, extracting or other damage, and thus the entire contents of the dosage form becomes available for immediate absorption.

[0010] The non-additive, sustained release dosage forms have been described in the prior art (see, for example, U.S. Patent Application Publication Nos. 2003/0124185 and 2003/0044458). However, it is believed that due to the osmotic pressure accumulated in the core of the sequestered form, the substantial amounts of the opioid antagonist or other antagonist present in such sequestered forms are released over a period of time (generally less than 24 hours) because by this form into the core water permeates. A high osmotic pressure within the core of the sequestered form causes the opioid antagonist or other to be displaced from the sequestered form, which in turn causes its release from this form.

[0011] Due to the disadvantages of the sequestered forms known in the art, there remains a need for a sequestered form of an opioid antagonist or other antagonist from which substantially the antagonist is not released under osmotic pressure. The present invention provides such a sequestered form of an opioid antagonist or other antagonist. This and other objects and advantages of the present invention, as well as its additional features, will become apparent from the following description of the invention.

BRIEF SUMMARY OF THE INVENTION [0012] There is provided herein a pharmaceutical composition comprising an antagonist, agonist, seal coat and sequestering polymer, wherein all of these components, antagonist, agonist, seal coat and at least one sequestering polymer are contained in a single unit in which the sealing coating forms a layer that physically separates the antagonist and agonist. In one embodiment, a multilayer pharmaceutical composition comprising an agonist and antagonist is provided in which the agonist and antagonist in the intact form of the composition are not in contact with each other and from which the agonist is substantially released after administration and the antagonist is substantially sequestered. Methods of making such pharmaceutical compositions are also provided. In another implementation,

BRIEF DESCRIPTION OF THE DRAWINGS [0013]

Figure 1. Release of naltrexone (NT) from Eudragit® RS-coated pellets without SLS.

Figure 2. Effect of SLS levels in the coating of Eudragit® RS on the release of naltrexone (NT).

Figure 3. Effect of SLS levels in the Eudragit® RS coating on naltrexone (NT) release.

Figure 4. Effect of talc levels in the coating of Eudragit® RS on the release of naltrexone (NT).

Figure 5. Release profile of naltrexone depending on neutralization of Eudragit® RS at 26% (v / v) talc.

Figure 6. Release profile of naltrexone depending on the level of talc at 41% neutralization of Eudragit® RS.

Figure 7. Naltrexone plasma levels of the naltrexone solution (NTX).

Figure 8. Plasma 6-beta-naltrexol levels of the naltrexone solution (NTX).

Figure 9. Naltrexone plasma levels for PI-1460 and PI-1461.

Figure 10. Plasma 6-beta-naltrexol levels for PI-1460 and PI-1461.

Figure 11. Naltrexone plasma levels for PI-1462 and PO-1463.

Figure 12. Plasma 6-beta-naltrexol levels for PI-1462 and PI-1463.

Figure 13. Percent release of naltrexone (NT) for PI-1465 and PI-1466.

Figure 14. Naltrexone plasma levels for PI-1465 and PI-1466.

Figure 15. Plasma 6-beta-naltrexol levels for PI-1465 and PI-1466.

Figure 16. Naltrexone plasma levels for PI-1465 and PI-1466 (fasting and fed).

Figure 17. Plasma 6-beta-naltrexol levels for PI-1465 and PI-1466 (fasting and fed).

Figure 18. Naltrexone plasma levels for PI-1495 and PI-1496 (fasting and fed).

Figure 19. Plasma 6-beta-naltrexol levels for PI-1495 and PI-1496 (fasting and fed).

Figure 20. Naltrexone plasma levels for PI-1510 (fasting and fed).

Figure 21. Plasma 6-beta-naltrexol levels for PI-1510 (fasting and fed). Figure 22 A and B. An exemplary method of preparing a multilayer pharmaceutical composition naltrexone-morphine.

DETAILED DESCRIPTION OF THE INVENTION [0014] Provided herein are compositions and methods for administering to a mammal a plurality of active ingredients in a form and manner that minimizes the in vivo activity of one of these active agents over a second active agent. In certain embodiments, at least two active agents are formulated as part of the pharmaceutical compositions. The first of these active agents can provide therapeutic effects in vivo. The second active agent may be an antagonist to the first active agent and may be useful in preventing abuse of the composition. For example, when the first active agent is a drug, the second active agent may be a drug antagonist. The composition remains intact during normal use by patients and the antagonist is not released. However, due to the manipulation of the composition, the antagonist can be released, thereby preventing the intended effect of the drug. In some embodiments, both active agents are contained within a single entity, such as a bead, in the form of layers. The active agents can be formulated with a substantial impermeable barrier as, for example, in a controlled release composition, such that the release of the antagonist from the composition is minimized. In some embodiments, the antagonist is released in in vitro assays, but is substantially not released in vivo. In vitro and in vivo release of the active agent from the composition may be measured by any of several well-known methods. For example, in vivo release can be determined by measuring the levels of the active agent or its metabolites in the plasma (e.g., AUC, Cmax). thus preventing the intended effect of the drug. In some embodiments, both active agents are contained within a single entity, such as a bead, in the form of layers. The active agents can be formulated with a substantial impermeable barrier as, for example, in a controlled release composition, such that the release of the antagonist from the composition is minimized. In some embodiments, the antagonist is released in in vitro assays, but is substantially not released in vivo. In vitro and in vivo release of the active agent from the composition may be measured by any of several well-known methods. For example, in vivo release can be determined by measuring the levels of the active agent or its metabolites in the plasma (e.g., AUC, Cmax). thus preventing the intended effect of the drug. In some embodiments, both active agents are contained within a single entity, such as a bead, in the form of layers. The active agents can be formulated with a substantial impermeable barrier as, for example, in a controlled release composition, such that the release of the antagonist from the composition is minimized. In some embodiments, the antagonist is released in in vitro assays, but is substantially not released in vivo. In vitro and in vivo release of the active agent from the composition may be measured by any of several well-known methods. For example, in vivo release can be determined by measuring the levels of the active agent or its metabolites in the plasma (e.g., AUC, Cmax). both active agents are contained within a single entity, such as a bead, in the form of layers. The active agents can be formulated with a substantial impermeable barrier as, for example, in a controlled release composition, such that the release of the antagonist from the composition is minimized. In some embodiments, the antagonist is released in in vitro assays, but is substantially not released in vivo. In vitro and in vivo release of the active agent from the composition may be measured by any of several well-known methods. For example, in vivo release can be determined by measuring the levels of the active agent or its metabolites in the plasma (e.g., AUC, Cmax). both active agents are contained within a single entity, such as a bead, in the form of layers. The active agents can be formulated with a substantial impermeable barrier as, for example, in a controlled release composition, such that the release of the antagonist from the composition is minimized. In some embodiments, the antagonist is released in in vitro assays, but is substantially not released in vivo. In vitro and in vivo release of the active agent from the composition may be measured by any of several well-known methods. For example, in vivo release can be determined by measuring the levels of the active agent or its metabolites in the plasma (e.g., AUC, Cmax). in a controlled release composition, such that the release of the antagonist from the composition is minimized. In some embodiments, the antagonist is released in in vitro assays, but is substantially not released in vivo. In vitro and in vivo release of the active agent from the composition may be measured by any of several well-known methods. For example, in vivo release can be determined by measuring the levels of the active agent or its metabolites in the plasma (e.g., AUC, Cmax). in a controlled release composition, such that the release of the antagonist from the composition is minimized. In some embodiments, the antagonist is released in in vitro assays, but is substantially not released in vivo. In vitro and in vivo release of the active agent from the composition may be measured by any of several well-known methods. For example, in vivo release can be determined by measuring the levels of the active agent or its metabolites in the plasma (e.g., AUC, Cmax).

[0015] In one embodiment, the invention provides a sequestering subunit comprising an opioid antagonist and a blocking agent, wherein the blocking agent substantially prevents the release of the opioid antagonist from the sequestering subunit in the gastrointestinal tract for a period that is greater than 24 hours. This sequestering subunit is incorporated into a single pharmaceutical unit that also includes an opioid agonist. Thus, the pharmaceutical unit comprises a core portion in which the opioid antagonist is contained. Subsequently, a sealing coating is optionally applied to the antagonist. A composition comprising a pharmaceutically active agent is then applied to the sealing coating. Then, you can apply an additional layer containing the same or another blocking agent, in such a way that the opioid agonist releases over time in the digestive tract (i.e., controlled release). Thus, the opioid antagonist and opioid agonist are contained within one pharmaceutical unit, which is generally in the form of a bead.

[0016] As used herein, the term "sequestering subunit" refers to any means for introducing an antagonist and preventing or substantially preventing its release in the gastrointestinal tract when the subunit remains intact, i.e. not subjected to manipulation. The term "blocking agent" as used herein refers to means by which the sequestering subunit is capable of preventing the antagonist from essentially releasing. The blocking agent may be a sequestering polymer, for example as described in more detail below.

[0017] As used herein, the term "substantially prevents", "prevents" or any of the phrases derived therefrom means that the antagonist is substantially not released from the sequestering subunit in the gastrointestinal tract. By the term "substantially non-releasable" it is to be understood that the antagonist may be released in a small amount, but the amount released does not affect or significantly affect analgesic efficacy when the dosage form is intended to be administered to a host, e.g. a mammal (e.g., a human) , orally. As used herein, the terms "substantially prevent", "prevent", or any phrase derived therefrom, do not mean complete or 100% prevention. They refer to different degrees of prevention that can be considered by the specialist as potentially beneficial. In this sense, the blocking agent substantially prevents or prevents the release of the antagonist to the extent that at least 80% of the antagonist is protected against release in the gastrointestinal tract of the sequestering subunit for a time that is greater than 24 hours. Preferably, the blocking agent prevents the release of at least about 90% of the antagonist in the gastrointestinal tract of the sequestering subunit over a period that is greater than 24 hours. More preferably, the blocking agent prevents the release of at least about 95% of the antagonist from the sequestering subunit. Most preferably, the blocking agent prevents the release of at least about 99% of the antagonist from the sequestering subunit in the gastrointestinal tract for a time that is greater than 24 hours. wherein at least 80% of the antagonist is protected against release in the gastrointestinal tract of the sequestering subunit for a period that is greater than 24 hours. Preferably, the blocking agent prevents the release of at least about 90% of the antagonist in the gastrointestinal tract of the sequestering subunit over a period that is greater than 24 hours. More preferably, the blocking agent prevents the release of at least about 95% of the antagonist from the sequestering subunit. Most preferably, the blocking agent prevents the release of at least about 99% of the antagonist from the sequestering subunit in the gastrointestinal tract for a time that is greater than 24 hours. wherein at least 80% of the antagonist is protected against release in the gastrointestinal tract of the sequestering subunit for a period that is greater than 24 hours. Preferably, the blocking agent prevents the release of at least about 90% of the antagonist in the gastrointestinal tract of the sequestering subunit over a period that is greater than 24 hours. More preferably, the blocking agent prevents the release of at least about 95% of the antagonist from the sequestering subunit. Most preferably, the blocking agent prevents the release of at least about 99% of the antagonist from the sequestering subunit in the gastrointestinal tract for a time that is greater than 24 hours. the blocking agent prevents the release of at least about 90% of the antagonist in the gastrointestinal tract of the sequestering subunit for a period that is longer than 24 hours. More preferably, the blocking agent prevents the release of at least about 95% of the antagonist from the sequestering subunit. Most preferably, the blocking agent prevents the release of at least about 99% of the antagonist from the sequestering subunit in the gastrointestinal tract for a time that is greater than 24 hours. the blocking agent prevents the release of at least about 90% of the antagonist in the gastrointestinal tract of the sequestering subunit for a period that is longer than 24 hours. More preferably, the blocking agent prevents the release of at least about 95% of the antagonist from the sequestering subunit. Most preferably, the blocking agent prevents the release of at least about 99% of the antagonist from the sequestering subunit in the gastrointestinal tract for a time that is greater than 24 hours.

[0018] For the purposes of the present invention, the amount of the antagonist released after oral administration can be measured in vitro, in an release test, as described in United States

Pharmacopeia (USP26) in Chapter <711> Release. For example, release from a dosage unit at different times is measured using 900 ml of 0.1N HCl solution, apparatus 2 (paddle), 75 rpm at 37 ° C. Other methods for measuring the release of the antagonist from the sequestering subunit at a given time are known to those skilled in the art (see, e.g., USP26).

[0019] Without being bound by any particular theory, it is contemplated that the sequestering subunit of the invention is devoid of limitations associated with sequestered antagonist forms known in the art, because the sequestering subunit of the invention reduces the osmotic triggered release of the antagonist from the sequestering subunit. Furthermore, it is believed that, compared to the sequestered forms of the antagonist known in the art, the sequestering subunit of the present invention reduces the release of the antagonist over a longer time (e.g., greater than 24 hours). The fact that the sequestering subunit of the invention provides longer protection against the release of the antagonist is particularly important as withdrawal symptoms may arise after the time the therapeutic agent releases and acts. As is well known, the time of passage through the digestive tract in the patient varies significantly depending on the population. Thus, the remainder of the dosage form may persist in the gastrointestinal tract for more than 24 hours, and in some cases longer than 48 hours. Furthermore, as is well known, opioid analgesics cause a reduction in intestinal motility, thereby prolonging the passage time through the gastrointestinal tract. Recently, the Food and Drug Administration approved prolonged release forms that operate for 24 hours. For comparison, the sequestering subunit of the present invention provides protection against the release of the antagonist for a time that is greater than 24 hours, provided that it has not been manipulated. the remainder of the dosage form may persist in the gastrointestinal tract for more than 24 hours, and in some cases longer than 48 hours. Furthermore, as is well known, opioid analgesics cause a reduction in intestinal motility, thereby prolonging the passage time through the gastrointestinal tract. Recently, the Food and Drug Administration approved prolonged release forms that operate for 24 hours. For comparison, the sequestering subunit of the present invention provides protection against the release of the antagonist for a time that is greater than 24 hours, provided that it has not been manipulated. the remainder of the dosage form may persist in the gastrointestinal tract for more than 24 hours, and in some cases longer than 48 hours. Furthermore, as is well known, opioid analgesics cause a reduction in intestinal motility, thereby prolonging the passage time through the gastrointestinal tract. Recently, the Food and Drug Administration approved prolonged release forms that operate for 24 hours. For comparison, the sequestering subunit of the present invention provides protection against the release of the antagonist for a time that is greater than 24 hours, provided that it has not been manipulated. opioid analgesics cause a decrease in intestinal motility, thus prolonging the passage time through the gastrointestinal tract. Recently, the Food and Drug Administration approved prolonged release forms that operate for 24 hours. For comparison, the sequestering subunit of the present invention provides protection against the release of the antagonist for a time that is greater than 24 hours, provided that it has not been manipulated. opioid analgesics cause a decrease in intestinal motility, thus prolonging the passage time through the gastrointestinal tract. Recently, the Food and Drug Administration approved prolonged release forms that operate for 24 hours. For comparison, the sequestering subunit of the present invention provides protection against the release of the antagonist for a time that is greater than 24 hours, provided that it has not been manipulated.

[0020] The sequestering subunit of the invention is designed to substantially prevent the release of the antagonist when intact. By the term "intact" it should be understood that such a dosage form has not been subjected to any manipulations. The term "handling" includes all manipulations using any mechanical, thermal and / or chemical means that alter the physical properties of the dosage form. This manipulation can be, for example, crushing, shearing, grinding, chewing, dissolving in a solvent, heating (e.g., at a temperature higher than 45 ° C), or any combination of these activities. When the sequestering subunit of the invention is manipulated, the antagonist is immediately released from the subunit.

[0021] The term "subunit" includes a composition, a mixture, a particle, etc. which, when combined with another subunit, may be a dosage form (e.g., an oral dosage form). The subunit may be in the form of beads, pellets, granules, spheroids, etc., and may be combined with other the same or different subunits in the form of a capsule, tablet, etc., thereby obtaining a dosage form, e.g. an oral dosage form. The subunit may also be part of a larger, single unit, thereby forming part of the unit, such as a layer. For example, the subunit may be a core coated with an antagonist and a seal coat; this subunit may then be coated with additional compositions including a pharmaceutically active agent, such as an opioid agonist.

The term "antagonist therapeutic agent" means any drug or molecule, naturally occurring or synthetic, that binds to the same target molecule (e.g., a receptor) of a therapeutic agent without, however, causing a therapeutic, intercellular or in vivo response. In this context, the antagonist of the therapeutic agent binds to the receptor of the therapeutic agent, thereby preventing the agent from interfering with the receptor. In the case of opioids, the antagonist can prevent the achievement of intoxication in the host.

[0023] The antagonist can be any agent that abolishes the action of the therapeutic agent or causes an unpleasant or punishing stimulus or effect that prevents or avoids manipulation of the sequestering subunit or compositions comprising it. Preferably, the antagonist does not harm the host after administration or ingestion, but has properties that prevent its administration or ingestion, for example, by chewing and swallowing or by crushing and insufflation. The antagonist may have a strong or bad taste or smell, causing a burning or tingling sensation, lachrymatory reactions, nausea, vomiting, or other unpleasant or repulsive sensation, or, for example, coloration of the tissue. Preferably, the antagonist is selected from the group consisting of a therapeutic agent antagonist, a bittering agent, a dye, gelling agent and irritant. Examples of antagonists include capsaicin, a dye, bittering agents and vomiting agents. An antagonist may include one type of antagonist (e.g., capsaicin), multiple forms of one type of antagonist (e.g., capsaicin and analogs thereof) or combinations of different types of antagonists (e.g., one or more bittering agents and one or more gelling agents). Preferably, the amount of antagonist in the sequestering subunit of the invention is not toxic to the host. one or more bittering agents and one or more gelling agents). Preferably, the amount of antagonist in the sequestering subunit of the invention is not toxic to the host. one or more bittering agents and one or more gelling agents). Preferably, the amount of antagonist in the sequestering subunit of the invention is not toxic to the host.

[0024] In the case where the therapeutic agent is an opioid agonist, the antagonist is preferably an opioid antagonist such as naltrexone, naloxone, nalmefene, cyclazocin, levallorphan, their derivatives or complexes, their pharmaceutically acceptable salts and combinations thereof. More preferably, the opioid antagonist is naloxone or naltrexone. The term "opioid antagonist" includes one or more opioid antagonists, either alone or in combination, and further includes partial antagonists, pharmaceutically acceptable salts thereof, stereoisomers thereof, their ethers, esters and combinations thereof. Pharmaceutically acceptable salts include metal salts, such as sodium salts, potassium salts, cesium salts, and the like; alkaline earth metal salts, such as calcium salts, magnesium salt, and the like; salts of organic amines, such as triethylamine salts, pyridine salts, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N-dibenzylethylenediamine salt, and the like; salts of inorganic acids, such as hydrochloride, hydrobromide, sulfate, phosphate, etc .; salts of organic acids, such as formate, acetate, trifluoroacetate, maleate, tartrate, etc .; sulfonates, such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc .; amino acid salts, such as arginate, aspartate, glutamate, etc. In some embodiments, the amount of opioid antagonist may be from about 10 ng to about 275 mg. In a preferred embodiment, when the antagonist is naltrexone, preferably the intact dosage form releases less than 0.125 mg or less in 24 hours, wherein when the dosage form is crushed or chewed after 1 hour, 0 is released,

[0025] In a preferred embodiment, the opioid antagonist comprises naloxone. Naloxone is an opioid antagonist that is almost free of agonist activity. Subcutaneous doses of up to 12 mg of naloxone do not cause any discernible subjective effects, and 24 mg of naloxone cause only slight drowsiness. Low doses (0.4-0.8 mg) of naloxone, administered to a human intramuscularly or intravenously, prevent or quickly reverse the effects of a morphine-like agonist. It has been reported that intravenously 1 mg of naloxone completely blocks the effect of heroin 25 mg. Naloxone was observed almost immediately after intravenous administration. The drug is absorbed after oral administration, but is reported to rapidly metabolize to inactive form at the first passage through the liver, and therefore has a significantly lower potential than in the case of parenteral administration. It has been reported that oral doses above 1 g almost completely metabolize in less than 24 hours. It has been reported that 25% of sublingually administered naloxone is absorbed (Weinberg et al., Clin. Pharmacol. Ther. 44: 335-340 (1988)).

[0026] In another preferred embodiment, the opioid antagonist comprises naltrexone. For the treatment of opioid-addicted patients to prevent the euphoric effects of opioid agonists, naltrexone has been used in high oral doses (over 100 mg). Naltrexone has been reported to exert a strong blocking action primarily against the mu receptor compared to the delta regions. Naltrexone is known as the oxymorphone synthetic congener, which lacks the ability of an opioid agonist and differs in structure from oxymorphone by replacing the methyl group located on the oxymorphone nitrogen with the cyclopropylmethyl group.

β

The naltrexone hydrochloride salt is soluble in water up to about 100 mg / cm³. The pharmacokinetic and pharmacokinetic properties of naltrexone have been evaluated in many animal studies and in clinical trials. See, e.g., Gonzalez et al. Drugs 35: 192-213 (1988). After oral administration, naltrexone is absorbed rapidly (within 1 hour) and its oral bioavailability is in the range of 5-40%. The protein binding of naltrexone is approximately 21% and the volume of distribution after a single dose is 16.1 L / kg.

[0027] Naltrexone is commercially available in the form of tablets (Revia®, DuPont (Wilmington, Del.)) For the treatment of alcohol dependence and for blocking exogenously administered opioids. See, e.g., Revia (naltrexone hydrochloride tablets), Physician's Desk Reference, 51th Edition, Montvale, NJ; and Medical Economics 51: 957-959 (1997). The 50 mg dose of Revia® blocks the pharmacological action of 25 mg heroin IV in up to 24 hours. As is known, naltrexone, co-administered with morphine, heroin or other opioids chronically, blocks the development of physical dependence on opioids. It is believed that the mechanism by which naltrexone blocks the action of heroin is competitive binding to opioid receptors. Naltrexone has been used to treat drug addiction by completely blocking the effects of opioids. It was found that with the greatest success for the treatment of drug addiction, naltrexone is used by drug users with good prognosis, as part of a comprehensive occupational or rehabilitation program, including behavioral control and other methods of improving adaptability. In the treatment of drug addiction with naltrexone, it is desirable that the patient be free of opioids for at least 7-10 days. The initial dose of naltrexone for this purpose is typically about 25 mg, and when no withdrawal symptoms occur, the dose can be increased to 50 mg per day. It is believed that a suitable clinical block of action of parenterally administered opioids is obtained with a daily dose of 50 mg. Naltrexone was also used to treat alcoholism in combination with methods of social and psychological therapy.

[0028] The antagonist may also be a bittering agent. The term "bittering agent" as used herein refers to any agent that provides an unpleasant taste after inhalation and / or ingestion of a manipulated dosage form comprising a sequestering subunit. The introduction of the bittering agent causes that after taking the manipulated dosage form by inhalation or by oral administration, a bitter taste is obtained which, in some embodiments, destroys or interferes with the pleasure of achieving intoxication from the disrupted dosage form, which preferably prevents dependence on this form dosing.

[0029] Various bittering agents may be used, including, but not limited to, natural, artificial and synthetic fragrance oils and substances and / or flavor oils, oleoresins and extracts derived from plants, leaves, flowers, fruits, etc. , and their combinations. Non-limiting representative fragrance oils include spearmint oil, peppermint oil, eucalyptus oil, nutmeg oil, allspice, nutmeg peel, bitter almond oil, menthol, etc. Also useful are artificial, natural and synthetic flavors fruit, such as citrus oils, including lemon, orange, lime and grapefruit oils, fruit essences, etc. Other bittering agents include sucrose derivatives (e.g. sucrose octaacetate), chlorosucrose derivatives, quinine sulfate, etc. A preferred bittering agent for use in the invention is denatonium NF-anhydride benzoate sold under the name Bitrex ™ (Macfarlan Smith Limited, Edinburgh, UK). The bittering agent can be added to the formulation in an amount of less than about 50% by weight, preferably less than about 10% by weight, more preferably less than about 5% by weight, and most preferably in an amount in the range of about 0.1 to 1.0% by weight with respect to the dosage form, depending on the particular bittering agent (s) used.

[0030] Alternatively, the antagonist may be a dye. The term "dye" as used herein refers to any agent that in contact results in a color change in the tissue. In this context, when the sequestering subunit has been manipulated and its content inhaled, the dye will cause the nasal tissues and surrounding tissue to become colored. Dyes that bind strongly to subcutaneous tissue proteins and are well known in the art are preferred. Illustrative dyes useful in the present invention are, for example, dyes ranging from food colors to tattoo dyes. Food colors include, but are not limited to, FD & C Green # 3 green and FD & C Blue # 1 blue, as well as other FD & C or D & C dyes. Such food colors are available on the market from various companies,

[0031] Alternatively, the antagonist may also be an irritant. The term "irritant" as used herein includes a compound used to induce irritation, e.g., burning or uncomfortable sensation, to the abuser of taking the manipulated dosage form of the invention. The use of an irritant will discourage the abuser from manipulating the dosage form and then for inhaling, injecting or swallowing the manipulated dosage form. Preferably, the irritant is released when the dosage form is manipulated and, after inhalation, injection and / or ingestion of such a dosage form, causes the overactive effect of burning or irritation. Various irritants can be used, including, but not limited to, capsaicin, a capsaicin analog with capsaicin-like properties, etc. Some capsaicin analogs or derivatives include, for example, but are not limited to, resiniferatoxin, tinyatoxine, heptanoyl butylbutyl, heptanoylguacacylamide, other isobutyl amides or guaiacylamides, dihydrocapsaicin, homovanillin-octyl ester, nonanoylvalinoamide, or other compounds with a class known as vanilla. Resiniferatoxin is described, for example, in US Pat. Ser. Am. No. 5,290,816. In the Ser. Am. No. 4,812,446, capsaicin analogs and methods for their preparation are described. In addition, in the Ser. Am. No. 4,424,205, Newman's publication, Natural and Synthetic Pepper-Flavored Substances, was published, published in 1954, which lists a list of irritating analogues similar to capsaicin. In the publication of Ton et al, British Journal of Pharmacology 10: 175-182 (1955) discusses the pharmacological effect of capsaicin and its analogues. When an irritant (e.g., capsaicin) is introduced into the dosage form, it causes the abuser to feel burning or discomfort, which discourages him from inhaling, injecting or receiving the manipulated dosage form orally, and preferably prevents abuse of this form. Suitable capsaicin compositions include capsaicin (trans-8-methyl-Nwaniline-6-nothingamide) or analogs thereof at a concentration ranging from about 0.00125% to 50% by weight, preferably in the range of from about 1% to about 7.5% by weight, and most preferably in the range of about 1% to about 5% by weight. When an irritant (e.g., capsaicin) is introduced into the dosage form, it causes the abuser to feel burning or discomfort, which discourages him from inhaling, injecting or receiving the manipulated dosage form orally, and preferably prevents abuse of this form. Suitable capsaicin compositions include capsaicin (trans-8-methyl-Nwaniline-6-nothingamide) or analogs thereof at a concentration ranging from about 0.00125% to 50% by weight, preferably in the range of from about 1% to about 7.5% by weight, and most preferably in the range of about 1% to about 5% by weight. When an irritant (e.g., capsaicin) is introduced into the dosage form, it causes the abuser to feel burning or discomfort, which discourages him from inhaling, injecting or receiving the manipulated dosage form orally, and preferably prevents abuse of this form. Suitable capsaicin compositions include capsaicin (trans-8-methyl-Nwaniline-6-nothingamide) or analogs thereof at a concentration ranging from about 0.00125% to 50% by weight, preferably in the range of from about 1% to about 7.5% by weight, and most preferably in the range of about 1% to about 5% by weight.

[0032] The antagonist can also be a gelling agent. As used herein, the term "gelling agent" refers to any agent that provides a manipulated dosage form gel-like properties that slow the absorption of the therapeutic agent that is formulated with the sequestering subunit, such that the host has a lower chance of rapidly achieving the state of intoxication. In certain preferred embodiments, when the dosage form has been manipulated by exposing it to a small amount (e.g., less than about 10 mL) of an aqueous liquid (e.g., water), it will be unsuitable for injection and / or inhalation. After the addition of the aqueous liquid, the treated dosage form preferably becomes thick and viscous, making it unsuitable for injection. For the purposes of the invention, the term " after administration to the nostrils, the gelling agent may become gel-like due to moisture in mucous membranes. It also makes such a formulation arouse aversion before being taken into the nose, because the gel sticks to the nostrils and reduces the absorption of the addictive substance. Various gelling agents may be used, including, without limitation, sugars or alcohols derived from sugars, such as mannitol, sorbitol, etc., starches and starch derivatives, cellulose derivatives, such as microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose, attapulgites, bentonites, dextrins, alginates, carrageenan, gum tragacanth, arabic resin, guar gum, xanthan gum, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, carbomers and carbopols, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, surfactants, mixed surfactant / wetting agent, emulsifiers, other polymeric substances, and mixtures thereof; etc. In certain preferred embodiments, the gelling agent is a xanthan gum. In other preferred embodiments, the gelling agent of the invention is pectin. Pectin or pectin substances useful in this invention include not only purified or isolated pectinates, but also raw natural pectin sources, such as apples, citrus or sugar beet pectin which, if necessary, have been esterified or de-esterified, e.g. with alkaline substances or enzymes. preferably, the pectins used in the invention are derived from citrus fruits such as lime, lemon, grapefruit and orange. The incorporation of the gelling agent into the dosage form preferably gives gelatin-like properties in this form, which nuisances or hinders the pleasure of achieving a rapid intoxication due to the gel-like consistency of the manipulated dosage form in contact with the mucosa, and which in certain embodiments prevents addiction from this dosage form due to reduced absorption, e.g. through the nostrils. The gelling agent can be added to the formulation at a ratio of gelling agent to opioid agonist of from about 1:40 to about 40: 1 by weight, preferably from about 1: 1 to about 30: 1 by weight, more preferably from about 2: 1 to about 10 : 1 with respect to the weight of the opioid agonist. In certain other embodiments, after being subjected to manipulation by dissolving in an aqueous liquid (in an amount of about 0.5 to about 10 ml, and preferably 1 to about 5 ml), the dosage form forms a viscous gel with a viscosity of at least about 10 cP. More preferably, the mixture produced has a viscosity of at least about 60 cP.

[0033] A "blocking agent" prevents or substantially prevents the release of an antagonist in the gastrointestinal tract for a time that is greater than 24 hours, e.g., in the range of

24 to 25 hours, 30 hours, 35 hours, 40 hours, 45 hours, 48 ​​hours, 50 hours, 55 hours, 60 hours, 65 hours, 70 hours, 72 hours, 75 hours, 80 hours, 85 hours, 90 hours, 95 hours or 100 hours; etc. Preferably, the time during which the release of the antagonist in the gastrointestinal tract is prevented or substantially prevented is at least about 48 hours. More preferably, the blocking agent prevents or substantially prevents release over a period of at least about 72 hours. [0034] The blocking agent in the sequestering subunit of the present invention may be a system comprising a first substance that is impermeable to the antagonist and core. The term "antagonist-impermeable substance" means any substance that is substantially impermeable to the antagonist, yes, that the antagonist is substantially not released from the sequestering subunit. As used herein, the term "substantially impermeable" does not necessarily mean total or 100% impermeability. Various degrees of impermeability are possible, of which the specialist will be able to select those potentially beneficial. In this context, the antagonist-resistant substance substantially prevents or prevents the release of the antagonist to the extent that at least about 80% of the antagonist is protected by release in the gastrointestinal tract of the sequestering subunit for a period that is greater than 24 hours. Preferably, the antagonist-preventive substance prevents the release of at least about 90% of the antagonist from the sequestering subunit in the gastrointestinal tract for a period that is greater than 24 hours. More preferably, the antagonist-impermeable substance prevents the release of at least 95% of the antagonist from the sequestering subunit. Most preferably, the antagonist-preventive substance prevents the release of at least about 99% of the antagonist from the sequestering subunit in the gastrointestinal tract for a time that is greater than 24 hours. The antagonist-preventive substance prevents or substantially prevents the release of the antagonist in the gastrointestinal tract for a time that is greater than 24 hours and is preferably at least about 48 hours. More preferably, the antagonist-impermeable substance prevents or substantially prevents the release of the adjuvant from the sequestering subunit for a time of at least about 72 hours. an antagonist-resistant substance prevents the release of at least 95% of the antagonist from the sequestering subunit. Most preferably, the antagonist-preventive substance prevents the release of at least about 99% of the antagonist from the sequestering subunit in the gastrointestinal tract for a time that is greater than 24 hours. The antagonist-preventive substance prevents or substantially prevents the release of the antagonist in the gastrointestinal tract for a time that is greater than 24 hours and is preferably at least about 48 hours. More preferably, the antagonist-impermeable substance prevents or substantially prevents the release of the adjuvant from the sequestering subunit for a time of at least about 72 hours. an antagonist-resistant substance prevents the release of at least 95% of the antagonist from the sequestering subunit. Most preferably, the antagonist-preventive substance prevents the release of at least about 99% of the antagonist from the sequestering subunit in the gastrointestinal tract for a time that is greater than 24 hours. The antagonist-preventive substance prevents or substantially prevents the release of the antagonist in the gastrointestinal tract for a time that is greater than 24 hours and is preferably at least about 48 hours. More preferably, the antagonist-impermeable substance prevents or substantially prevents the release of the adjuvant from the sequestering subunit for a time of at least about 72 hours.

[0035] Preferably, the first impermeable substance antagonist comprises a hydrophobic substance such that the antagonist is not released or substantially not released during passage through the gastrointestinal tract when it is intended to be orally administered and not manipulated. Hydrophobic substances suitable for use in the invention are described and discussed below. The hydrophobic substance is preferably a pharmaceutically acceptable hydrophobic substance. [0036] Also preferably, the first antagonist-impervious substance comprises a polymer insoluble in the gastrointestinal tract. It will be obvious to a person skilled in the art that a polymer that is insoluble in the gastrointestinal tract will prevent the release of the antagonist from the sequestering subunit upon its reception. The polymer may be a cellulose or an acrylic polymer. Preferably the cellulose is selected from the group consisting of ethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate and combinations thereof. Ethylcellulose includes, for example, ethylcellulose with an ethoxy group content of from about 44 to about 55%. The ethylcellulose may be used in the form of an aqueous dispersion, an alcoholic solution or a solution in other suitable solvents. The cellulose may have a degree of substitution (DS) in the anhydroglucose unit ranging from above zero to and including 3. The term "degree of substitution" means the average number of hydroxyl groups in the cellulose polymer anhydroglucose unit which has been replaced with a substituting group.

More specifically, the celluloses include cellulose propionate of DS of 1.8 and having a propyl content of 39.2 to 45 and a hydroxyl content of 2.8 to 5.4%; cellulose acetate butyrate having a DS of 1.8, an acetyl content of 13 to 15% and a butyryl content of 34 to 39%; cellulose acetate butyrate with an acetyl content of 2 to 29%, with a butyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7%; cellulose triacylate with DS from 2.9 to 3, such as cellulose triacetate, cellulose trivalerate, cellulose tralaurate, cellulose tripalmitate, cellulose trisuccinate and cellulose triacetate; cellulose diacrylates with DS from 2.2 to 2.6, such as cellulose disuccinate, cellulose dipalmitate, cellulose diacetate, cellulose dipentanoate and cellulose co-esters, such as cellulose acetate butyrate, cellulose acetate octanoate, and cellulose acetate propionate. Additional cellulosic polymers that can be used to form the sequestering subunit include cellulose acetate dimethyl acetaldehyde, cellulose acetate ethyl cellulamate, cellulose acetate methylcarbamate, and cellulose acetate-dimethylaminocellulose acetate.

[0038] The acrylic polymer is preferably selected from the group consisting of methacrylic polymers and copolymers of acrylic acid and methacrylic acid, copolymers of methyl methacrylate, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly (acrylic acid), poly (methacrylic acid), methacrylic acid-alkylamide copolymer, poly (methyl methacrylate), polymethacrylate, poly (methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic acid anhydride), glycidyl methacrylate copolymers, and combinations thereof. The acrylic polymer useful in the production of the sequestering subunit of the invention includes acrylic resins comprising copolymers synthesized from acrylic and methacrylic acid esters (e.g., a lower alkyl acrylic acid ester and a lower alkyl methacrylic acid copolymer) containing from about 0, 02 to about 0.03 moles of the tri (lower alkyl) ammonium group per mole of acrylic and methacrylic monomer used. An example of a suitable acrylic resin is the NF21 ammonium methacrylate copolymer, a polymer manufactured by Rohm Pharma GmbH, Darmstadt, Germany and sold under the trade name Eudragit®. Eudragit® is a water soluble copolymer of ethyl acrylate (EA), methyl methacrylate (MM) and trimethylammonium methyl methacrylate (TAM), in which the molar ratio of TAM to the other components (EA and MM) is 1:40. Acrylic resins, such as Eudragit®, can be used in the form of an aqueous dispersion or as a solution in suitable solvents. Preferred acrylic polymers include copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups,

[0039] In another preferred embodiment, the antagonist-impermeable material is selected from the group consisting of polylactic acid, a polyglycolic acid, polylactic acid copolymer and poly glycolic acid, and combinations thereof. In certain other embodiments, the hydrophobic substance includes a biodegradable polymer comprising poly (lactic acid / glycolic acid) ("PLGA"), polylactide, polyglycolide, polyanhydride, polyorthoester, polycaprolactones, polyphosphazenes, polysaccharides, protein polymers, polyesters, polydioxanone, polygluconate, polyacid copolymers. lactic polyethylene oxide, poly (hydroxybutyrate), polyphosphate or combinations thereof. Preferably, the biodegradable polymer comprises poly (lactic acid / glycolic acid), a copolymer of lactic acid and glycolic acid with a molecular weight of about 2,000 to about 500,000 daltons.

[0040] Poly (lactic acid / glycolic acid) can be prepared by the methods described in US Pat. Ser. Am. Ref. No. 4,293,539 (Ludwig et al.), Which is hereby incorporated by reference. Briefly, according to the Ludwig method, the copolymer is prepared by condensation of lactic acid and glycolic acid in the presence of a readily removable polymerization catalyst (e.g., a strong ion exchange resin such as Dowex HCR-W2H). The amount of catalyst is not critical for polymerization, but is generally from about 0.01 to about 20 parts by weight with respect to the total weight of the combined lactic acid and glycolic acid. The polymerization reaction can be carried out in the absence of solvents at a temperature of about 100 ° C to about 250 ° C, for about 48 to about 96 hours, preferably under reduced pressure, to facilitate removal of water and by-products.

[0041] Suitable plasticizers for use in the sequestering subunit include, for example, acetyltriethyl citrate, acetyltributyl citrate, triethyl citrate, diethyl phthalate, dibutyl phthalate (DBP), acetyl tri- N-butyl citrate (ATBC) or dibutyl sebacate, which can be mixed with polymer. Other additives, such as coloring agents, may also be used to form the sequestering subunit of the present invention.

[0042] In some embodiments, additives may be added to improve the sequestering properties of the sequestering subunit to the composition. As described below, to obtain a better increase or delay in the sequestration of the agent contained in the subunit, the ratio of additives or components can be modified. To alter the release of the antagonist, especially when a water-soluble core (i.e., a sugar spheres) is used, various amounts of a functional additive (e.g., a charge neutralizing additive) may be included. For example, it has been shown that the incorporation of a small amount of a charge neutralizing additive relative to a sequestering polymer based on weight by weight may result in reduced release of the antagonist.

[0043] In some embodiments, the function of the charge neutralizing additive may be surfactant. In some embodiments, such neutralization can reduce swelling of the sequestering polymer by hydrating the positively charged groups contained therein. For the production of the sequestering subunit, it is also possible to use surfactants (ionic or non-ionic). Preferably, the surfactant is ionic. Suitable examples of such agents include, for example, alkylaryl sulfonates, alcohol sulfates, sulfosuccinates, sulfoamino succinates, sarcosinates or tartrates and others. Other examples include, but are not limited to, castor oil ethoxylate, benzalkonium chloride, polyglycolized glycerides, acetylated monoglycerides, fatty acid esters and sorbitan, poloxamers, polyethoxylated fatty acid esters, polyethoxylated derivatives, monoglycerides or their ethoxylated derivatives, diglycerides or their polyethoxylated derivatives, sodium docusate, sodium lauryl sulfate, sodium dioctylsulfosuccinate, sodium lauryl sarcosinate and sodium methyl cocoyl taurate, magnesium lauryl sulfate, triethanolamine, cetrimide, sucrose laurate and other sucrose esters, esters glucose (dextrose), simethicone, ocoxinol, sodium dioctylsulfosuccinate, polyglycolized glycerides, sodium dodecylbenzenesulfonate, sodium dialkylsulfosuccinate, fatty alcohols such as lauryl alcohol, cetyl and stearic alcohol, glyceryl esters, cholic acid or its derivatives, lecithins and phospholipids. These agents are typically referred to as ionic (i.e., anionic or cationic) or non-ionic. In some realizations,

Effect of Anionic Surfactants on the Release of Chlorpheniramine Maleate From an Inert, Heterogeneous Matrix. Drug Development and Industrial Pharmacy 18 (2) (1992): 175186. Rao, et al. "Effect of Sodium Lauryl Sulfate on the Rifampicin from Guar Gum Matrix." Indian Journal of Pharmaceutical Science (2000): 404-406; Knop, et al Influence of surfactants of quaternary acrylic polymers. STP Pharma Sciences, Vol. 7, No. 6, (1997) 507-512). Other suitable agents are known in the art.

[0044] As discussed herein, SLS is particularly useful in combination with Eudragit RS, when the sequestering subunit is formed on a sugar sponge substrate. The introduction of SLS at a level of less than about 6.3% by weight with respect to the sequestering polymer (i.e., Eudragit RS) can provide antacid (theoretically 20% and 41% neutralization, respectively) and thus can significantly slow down the release of the encapsulated active agent ( i.e., antagonist, naltrexone). The introduction of SLS at a level higher than about 6.3% relative to the sequestering polymer is likely to increase the release of the antagonist from the sequestering subunit. When SLS is used in combination with Eudragit® RS, preferably SLS is present at a level of about 1%, 2%, 3%, 4% or 5%, and generally below 6% with respect to the weight of the sequestering polymer (i.e. Eudragit® RS). In preferred embodiments, the SLS may be present at about 1.6% or about 3.3% relative to the sequestering polymer. As discussed above, many agents (i.e., surfactants) can be used in place of SLS in the compositions disclosed herein. [0045] Other useful agents include agents that can physically block the migration of the antagonist from the subunit and / or increase the hydrophobicity of the barrier. One example of such an agent is talc, which is commonly used in pharmaceutical compositions (Pawar et al. Agglomeration of Ibuprofen With Talk by Novel Crystallo-Co-Agglomeration Technique. AAPS PharmSciTech. 2004; 5 (4): article 55). As shown in the Examples, talc is particularly useful when the sequestering subunit is formed on the sugar spindle core. Various forms of talc may be used, provided that they do not adversely affect the performance of the composition. Most of the talc comes from the transformation of dolomite (CaMg (CO3) 2 or magnesite (MgO) in the presence of excess dissolved silica (SiO2), or from the transformation of serpentine or quartzite.

Talc may include minerals such as tremolite (CaMg3 (SiO3) 4); serpentine (3MgO ^ 2SiO ^ 2H₂O), antofilite (Mg₇^ (OH)₂^ (Si₄ABOUT₁₁)₂), magnesite, mica, chlorite, dolomite, calcite form of calcium carbonate (CaCO3), iron oxide, carbon, quartz and / or manganese oxide. In the compositions described herein, the presence of such impurities may be acceptable, provided that the talc function is maintained. Talcum with USP quality is a preferred talc. As mentioned above, the function of talc is to increase the hydrophobicity and thus the functionality of the sequestering polymer. Many substitutes for talc can be used in the compositions described herein, which will be apparent to those skilled in the art.

[0046] It has been found that the ratio of talc to sequestering polymer can result in a dramatic difference in the functionality of the composition described herein. For example, in the Examples described below, it has been shown that the ratio of talc to sequestering polymer (w / w) is important in compositions that prevent the release of naltrexone therefrom. It has been shown that the introduction of an approximately equivalent amount (in weight ratio) of talc and Eudragit® RS results in a very low release profile of naltrexone. In contrast, significantly lower or higher, or both lower (69% w / w) and higher (151% w / w) talc: Eudragit® RS ratios cause increased release of naltrexone. Thus, when talc and Eudragit® RS are used, preferably talc is present in a ratio of about 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120% or 125 % wt./wind. with reference to Eudragit® RS. As described above, the most preferred ratio for other additives or components will vary and can be determined using standard experimental procedures.

[0047] In some embodiments, when a water-soluble core is used, it may be useful to incorporate factors that can affect the osmotic pressure of the composition (i.e., the osmotic pressure adjusting agent) (see, generally, WO 2005/046561 A2 and WO 2005/046649 A2 regarding Eudramode®). This agent is preferably used in the Eudragit® RS / talc layer described above. In a pharmaceutical unit comprising a sequestering subunit coated with an active agent (e.g., a controlled release agonist formulation), the osmotic pressure adjusting agent is preferably located immediately below the layer with the active agent. Suitable osmotic pressure regulating agents may include, for example, hydroxypropyl methylcellulose (HPMC) or chloride ions (i.e., NaCl), or a combination of HPMC and chloride ions (i.e., NaCl). Other ions that may be useful include bromide or iodide. The combination of sodium chloride and HPMC can be prepared in water or, for example, in a mixture of ethanol and water. HPMC is widely used in pharmaceutical compositions (see, e.g., US Patent Nos. 7,226,620 and 7,229,982). In some embodiments, the HPMC may have a molecular weight ranging from about 10,000 to about 1,500,000, and typically from about 5,000 to about 10,000 (low molecular weight HPMC). The specific gravity of HPMCs is generally from about 1.19 to about 1.31, the average specific gravity is about 1.26 and the viscosity is in the range of about 3600 to 5600. HPMC may be a water-soluble synthetic polymer. Examples of suitable, available on the market, hydroxypropyl methylcellulose polymers include Methocel K100 LV and Methocel K4M (Dow). Other HPMC additives are known in the art and may also be suitable for the preparation of the compositions described herein. As shown in the Examples, the introduction of NaCl (along with HPMC) has been found to have a positive effect on sequestration of naltrexone by Eudragit® RS. In some embodiments, preferably the charge neutralizing additive (i.e., NaCl) is contained in an amount of less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% by weight based on the sequestering polymer. In other preferred embodiments, the charge neutralizing additive is present in an amount of about 4% by weight with respect to the sequestering polymer. Other HPMC additives are known in the art and may also be suitable for the preparation of the compositions described herein. As shown in the Examples, the introduction of NaCl (along with HPMC) has been found to have a positive effect on sequestration of naltrexone by Eudragit® RS. In some embodiments, preferably the charge neutralizing additive (i.e., NaCl) is contained in an amount of less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% by weight based on the sequestering polymer. In other preferred embodiments, the charge neutralizing additive is present in an amount of about 4% by weight with respect to the sequestering polymer. Other HPMC additives are known in the art and may also be suitable for the preparation of the compositions described herein. As shown in the Examples, the introduction of NaCl (along with HPMC) has been found to have a positive effect on sequestration of naltrexone by Eudragit® RS. In some embodiments, preferably the charge neutralizing additive (i.e., NaCl) is contained in an amount of less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% by weight based on the sequestering polymer. In other preferred embodiments, the charge neutralizing additive is present in an amount of about 4% by weight with respect to the sequestering polymer. NaCl) is included in an amount of less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% by weight with respect to the sequestering polymer. In other preferred embodiments, the charge neutralizing additive is present in an amount of about 4% by weight with respect to the sequestering polymer. NaCl) is included in an amount of less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% by weight with respect to the sequestering polymer. In other preferred embodiments, the charge neutralizing additive is present in an amount of about 4% by weight with respect to the sequestering polymer.

[0048] Thus, in one embodiment, a sequestering subunit coated on a sugar bead substrate, including a sequestering polymer (i.e., Eudragit® RS) is provided in combination with several optimization factors, including sodium lauryl sulfate (SLS) as charge neutralizer to reduce membrane swelling due to hydration of positively charged groups in the polymer; talc to form a solid impermeable barrier to the transport of naltrexone across the membrane and as a hydrophobicity-enhancing agent; and chloride ion (such as NaCl) as an osmotic pressure reducing agent. It has been found that the amount of each of these additional components in the ratio of sequestering polymer is important for the function of the sequestering subunit: For example, in the Examples a sequestering subunit comprising a sequestering polymer and optimization factors is described: SLS in an amount of less than 6%, preferably 1-4%, and still more preferably 1.6% or 3.3% in weight ratio with respect to Eudragit RS; talc in an amount of approximately the equivalent amount of Eudragit® RS (weight ratio); and NaCl present in an amount of about 4% by weight to Eudragit® RS.

[0049] Methods of making any of the sequestering subunits of the invention are known in the art. See, for example, Remington: The Science and Practice of Pharmacy, Alfonso R. Genaro (Eds.), 20th Edition, and Example 2 below. The sequestering subunits can be prepared by any suitable method, for example, by obtaining beads, pellets, granules, spheroids, etc. Spheroids or beads coated with the active ingredient can be prepared, for example, by dissolving the active ingredient in water and then by spraying the solution on the substrate, for example, nu par 18/20 beads, using a Wurster insert. Prior to coating the beads, additional components are optionally also added to help in binding the active ingredient to the substrates, and / or coloring the solution, etc. The resulting substrate-actin system may optionally be coated with a barrier substance that separates the therapeutically active agent from the next coating of the substance, e.g. a release retardant or sequestering material. Preferably, the barrier substance is a hydroxypropyl methylcellulose containing substance. However, another film-forming material known in the art may also be used. Preferably, the barrier substance does not affect the release rate of the final product. However, another film-forming material known in the art may also be used. Preferably, the barrier substance does not affect the release rate of the final product. However, another film-forming material known in the art may also be used. Preferably, the barrier substance does not affect the release rate of the final product.

[0050] Pellets containing the active ingredient may be prepared, for example, by a melt palletization technique. In a typical such technique, the active ingredient in a finely divided form is combined with the binder (also in the form of particles) and optionally with other inert ingredients, and then the mixture is palletized, e.g. by mechanical treatment of the mixture in a high shear mixer to obtain pellets ( e.g., pellets, granules, spheroids, pearls, etc., collectively referred to herein as "pellets"). Then, the pellets can be sieved to obtain pellets of the desired size. The binder is preferably in particulate form and has a melting point above about 40 ° C. Suitable binders include, for example, hydrogenated castor oil, hydrogenated vegetable oil, other hydrogenated fats,

[0051] In order to change the thickness of the extruded strands, it is also possible to adjust the diameter of the extrusion gap or the exit aperture. Furthermore, the exit aperture of the extruder does not have to be round; it can be oblong, rectangular, etc. The outgoing bands can be reduced to particles using a hot cutting ball, guillotine, etc.

[0052] The melt-extruded multiparticulate system may be, for example, in the form of granules, beads, pellets, etc., depending on the outlet opening in the extruder. The terms "melt-extruded (i)", "melt-extruded multiparticle system (s)" and "extruded particles" are used interchangeably herein and include many subunits, preferably in a similar size and / or shape range. The extruded multi-particles preferably have a length ranging from about 0.1 to about 12 mm and a diameter ranging from about 0.1 to about 5 mm. Furthermore, the multi-particles extruded on the melting path can have any geometric shape in the range of the given size. Alternatively,

[0053] The substrate may also be made by a pelletizing technique. In general, melt granulation techniques involve melting a typically hydrophobic solid, e.g. a wax, and incorporating an active ingredient therein. In order to obtain a sustained release dosage form, it may be necessary to incorporate an additional hydrophobic substance.

[0054] The coating composition may be applied to the substrate by spraying it on the substrate using any spray device. For example, a fluidized-bed Wurster system can be used in which a stream of air flowing from the bottom fluidizes the coated substance and has a drying effect; when an insoluble coating polymer is sprayed onto it. The thickness of the coating will depend on the properties of the particular coating composition and can be determined by routine experimentation.

[0055] Any method for producing a subunit may be used. For example, a pellet subunit or the like may be prepared by co-extruding a substance comprising an opioid agonist and a substance comprising an opioid antagonist and / or an antagonist in a sequestered form. Optionally, the opioid agonist composition may cover, for example as a surface layer, a substance comprising an antagonist and / or antagonist in a sequestered form. A bead, for example, can be prepared by coating a substrate comprising an opioid antagonist and / or an antagonist in a sequestered form with an opioid agonist containing solution.

[0056] The sequestering subunits of the invention are particularly suitable for use in compositions comprising a sequestering subunit and a therapeutic agent in a form that can be released. In this regard, the invention also provides a composition comprising any of the sequestering subunits of the invention and a therapeutic agent in a releasable form. The term "release form" includes forms with immediate release, moderate release and sustained release. The therapeutic agent can be formulated so as to ensure its immediate release. In preferred embodiments, the composition provides sustained release of a therapeutic agent.

[0057] The therapeutic agent applied to the sequestering subunit may be any drug. In the compositions of the present invention, the therapeutic agent can be any medical agent used to treat a condition or disease, a pharmaceutically acceptable salt thereof, or an analog of such an agent or a salt thereof. The therapeutic agent may be, for example, a painkiller (e.g., an opioid agonist, aspirin, acetaminophen, non-steroidal anti-inflammatory drugs ("NSAIDs"), N-methyl-Dasparagin receptor antagonists ("NMDA"), cyclooxygenase-II inhibitors (COX inhibitors) -II ") and glycine receptor antagonists, anti-bacterial agent, antiviral agent, antimicrobial agent, anti-infective agent, chemotherapeutic agent, immunosuppressive agent, antitussive agent, expectorant, an anti-oedematous agent, antihistamines, an anti-oedematous agent, antihistamines, etc. Preferably, the therapeutic agent is an addict (physically and / or psychologically) after repeated use, which generally leads to its abuse. In this context, the therapeutic agent can be any opioid agonist as discussed herein.

[0058] The therapeutic agent may be an opioid agonist. As used herein, the term "opioid" includes a drug, hormone or other chemical or biological substance, natural or synthetic, having a sedative, narcotic or other effect similar to opium-containing agents or its natural or synthetic derivatives.

The term "opioid agonist," sometimes used interchangeably herein with the terms "opioid" and "opioid analgesic" includes one or more opioid agonists, alone or in combination, and further includes an opioid base, mixed or combined agonist-antagonists, partial agonists, their pharmaceutically acceptable salts, their stereoisomers, their ethers, esters and combinations thereof.

phenpridine, piminodine, pyrithamide, propeptase, promedol, propidin, propiram, propoxyphene, sufentanil, tramadol, tilidine, derivatives or complexes, pharmaceutically acceptable salts thereof and combinations thereof. Preferably, the opioid agonist is selected from the group consisting of hydrocodone, hydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, derivatives or complexes, pharmaceutically acceptable salts thereof and combinations thereof. Most preferably, the opioid agonist is morphine, hydromorphone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, derivatives or complexes, pharmaceutically acceptable salts thereof and combinations thereof. Most preferably, the opioid agonist is morphine, hydromorphone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, derivatives or complexes, pharmaceutically acceptable salts thereof and combinations thereof. Most preferably, the opioid agonist is morphine, hydromorphone,oxycodone or hydrocodone. In a preferred embodiment, the opioid agonist is oxycodone or hydrocodone and is present in the dosage form in an amount of about 15 to about 45 mg, and the opioid antagonist is naltrexone, which is present in the dosage form in an amount of about 0.5 to about 5 mg.

[0060] In Table 1 below, the quasi-analgesic doses of these opioids are compared to the 15 mg dose of hydrocodone:

Table I

Ecuviaalic doses of opioids

<td>opioid</td><td>calculated</td>

<td></td><td>(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>levorphanol</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>

Dose [0061] Hydrocodone is a semi-synthetic narcotic analgesic and antitussive with a variety of effects on the nervous system and on the gastrointestinal tract.

Chemically, hydrocodone is 4,5-epoxy-3-methoxy-17-methylmorphinan-6-one and is also known as dihydrocodeinone. Like other opioids, hydrocodone can be addictive and can cause dependence on morphine-like medicines. Like other opium derivatives, excessive doses of hydrocodone cause respiratory depression.

[0062] Oral hydrocodone is also available in Europe (e.g., Belgium, Germany,

Greece, Italy, Luxembourg, Norway and Switzerland) as an antitussive agent. In Germany, a parenteral formulation is also available as an antitussive. For use as a painkiller hydrocodone hydrogen tartrate is widely available in the United States, but only as a fixed combination with non-opiate drugs (e.g., ibuprofen, acetaminophen, aspirin, etc.) and is intended for moderate to moderately severe pain relief.

[0063] A typical dosage form of hydrocodone is a combination with acetaminophen and is available, for example, as Lortab® in the United States from UCB Pharma, Inc. (Brussels, Belgium), in tablets with a content of 2.5 / 500 mg, 5/500 mg, 7.5 / 500 mg and 10/500 mg hydrocodone / acetaminophen. These tablets are also available in relation

7.5 mg hydrocodone bitartrate and 650 mg acetaminophen and 7.5 mg hydrocodone bitartrate 750 mg acetaminophen. For the relief of pain, hydrocodone, in combination with aspirin, is given to adults in an oral dosage form, generally in an amount of 1-2 tablets every 4-6 hours. The tablets are also in a form containing 5 mg hydrocodone bitartrate and 224 mg aspirin with 32 mg caffeine; or 5 mg hydrocodone tartrate and 500 mg aspirin. Another formulation includes hydrocodone bitartrate and ibuprofen. Vicoprofen®, commercially available in the US from Knoll Laboratories (Mount Olive, NJ) is a tablet containing 7.5 mg of hydrocodone hydrogen tartrate and 200 mg of ibuprofen. The scope of the invention includes all such formulations including the opioid antagonist and / or antagonist in the sequestered form as part of the subunit containing the opioid agonist.

[0064] Oxycodone, chemically known as 4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one, is an opioid agonist whose main therapeutic activity is analgesia. Other therapeutic effects of oxycodone include reduction of anxiety, euphoria and relaxation. The exact mechanism of its analgesic effect is unknown, but specific CNS opioid receptors have been identified in the brain and spinal cord for endogenous compounds with opioid-like activity that play a role in the analgesic effect of this drug. Oxycodone is commercially available in the United States, e.g., as Oksycotin® from Purdue Pharma LP (Stamford, Conn.), In the form of controlled-release tablets for oral administration containing 10 mg, 20 mg, 40 mg or 80 mg oxycodone hydrochloride and as OxyY ™, also from Purdue Pharma LP in the form of immediate-release capsules containing 5 mg of oxycodone hydrochloride. The scope of the invention includes all such formulations including the opioid antagonist and / or antagonist in the sequestered form as part of the subunit containing the opioid agonist.

[0065] Oral hydromorphone is commercially available in the United States, e.g. as Dilaudid® from Abbott Laboratories (Chicago, Ill.). Oral morphine is commercially available in the United States, e.g. as Kadian® from Faulding Laboratories (Piscataway, NJ).

[0066] Examples of NSAIDs include ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxoprofen, suprofen, aminoprofen, thiaprofenic acid, fluprofen, bukloxynic acid, indometacin, sulindac, tolmetin, zomepirac, thiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxspinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, etc. Useful doses of these drugs are well known.

[0067] Examples of NMDA receptor active drugs include morphinans such as dexotromethorphan or dexophorate, ketamine, d-methadone and their pharmaceutically acceptable salts, and include drugs that block the main intracellular effect of NMDA receptor activation, e.g. a ganglioside such as ( 6-aminohexyl) -5-chloro-1naftalenosulfonamid. These drugs inhibit the development of tolerance and / or dependence on addictive drugs, e.g. narcotic analgesics, such as morphine, codeine, etc., as stated in US Pat. Ser. Am. Nos. 5,321,012 and 5,556,838 (both to Mayer et al.), Which are incorporated herein by reference, and in accordance with U.S. Pat. Ser. Am. No. 5,502,058 (Mayer et al.), Introduced herein by reference, are intended for the treatment of chronic pain. As described in the patents to Mayer et al., The NMDA agonist may be administered alone or in combination with a local anesthetic agent, such as lidocaine. [0068] COX-2 inhibitors have been described in the prior art and many chemical compounds are known that cause inhibition of cyclooxygenase-2. COX-2 inhibitors are described, for example, in US Pat. Ser. Am. No. 5,616,601; 5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,475,995; 5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,409,944 and 5,130,311, each of which is incorporated herein by reference. Some preferred COX-2 inhibitors include celecoxib (SC-58635), DUP697, flosulide (CGP-28238), meloxicam, 6-methoxy-2-naphthylacetic acid (6-NMA), MK-966 (also known as Vioxx), nabumeton (prodrug for 6-MNA), nimesulide, NS-398, SC-5766, SC-58215, T-614, or combinations thereof. It has been found that in combination with an opioid analgesic COX-2 inhibitors are therapeutically effective at doses ranging from about 0.005 mg to about 140 mg per kilogram of body weight per day. Alternatively, the COX-2 inhibitor may be administered in combination with an opioid analgesic at a dose of from about 0.25 mg to about 7 g per patient per day. [0069] In U.S. Pat. Ser. Am. No. 5,514,680 (Weber et al.), Incorporated herein by reference, describes the treatment of chronic pain with glycine receptor antagonists, and such drugs have been identified. The COX-2 inhibitor may be administered in combination with an opioid analgesic at a dose of from about 0.25 mg to about 7 g per patient per day. [0069] In U.S. Pat. Ser. Am. No. 5,514,680 (Weber et al.), Incorporated herein by reference, describes the treatment of chronic pain with glycine receptor antagonists, and such drugs have been identified. The COX-2 inhibitor may be administered in combination with an opioid analgesic at a dose of from about 0.25 mg to about 7 g per patient per day. [0069] In U.S. Pat. Ser. Am. No. 5,514,680 (Weber et al.), Incorporated herein by reference, describes the treatment of chronic pain with glycine receptor antagonists, and such drugs have been identified.

[0070] In embodiments wherein the opioid agonist comprises hydrocodone, sustained release oral dosage forms may contain analgesic doses of from about 8 mg to about 50 mg of hydrocodone per dosage unit. In sustained release oral dosage forms in which the therapeutically active opioid is hydromorphone, it is present in the form of hydromorphone hydrochloride in an amount from about 2 mg to about 64 mg. In another embodiment, the opioid agonist is morphine and the sustained release oral dosage forms of the invention are contained in an amount of about 2.5 mg to about 800 mg of morphine by weight. In yet another embodiment, the opioid agonist is oxycodone and the sustained release oral dosage forms comprise from about 2.5 to about 800 mg of oxycodone. In certain preferred embodiments, Sustained release oral dosage forms include from about 20 mg to about 30 mg of oxycodone. Controlled release oxycodone formulations are known in the art. The following documents describe various controlled release oxycodone formulations suitable for use in the invention described herein, and methods of making the same: Ser. Am. No. 5,266,331; 5,549,912; 5,508,042 and 5,656,295, incorporated herein by reference. The opioid agonist may be tramadol and the sustained release oral dosage forms may contain from about 25 to 800 mg of tramadol per dosage unit. The following documents describe various controlled release oxycodone formulations suitable for use in the invention described herein, and methods of making the same: Ser. Am. No. 5,266,331; 5,549,912; 5,508,042 and 5,656,295, incorporated herein by reference. The opioid agonist may be tramadol and the sustained release oral dosage forms may contain from about 25 to 800 mg of tramadol per dosage unit. The following documents describe various controlled release oxycodone formulations suitable for use in the invention described herein, and methods of making the same: Ser. Am. No. 5,266,331; 5,549,912; 5,508,042 and 5,656,295, incorporated herein by reference. The opioid agonist may be tramadol and the sustained release oral dosage forms may contain from about 25 to 800 mg of tramadol per dosage unit.

[0071] The therapeutic agent in the sustained release form is preferably a therapeutic agent particle that is combined with a release retardant or with sequestering material. The release retardant or sequestering material is preferably a substance that allows release of the therapeutic agent to a degree that is supported in an aqueous medium. The release or sequestering retardant can be selectively selected so that, in combination with the other properties described herein, the desired release rate is obtained in vitro.

[0072] In a preferred embodiment, the oral dosage form of the invention may be formulated so as to obtain a prolonged duration of the therapeutic effect, which allows administration of one dose per day. In general, the release retardant or sequestering material is used to achieve a longer duration of the therapeutic effect. Preferably, one daily dose is provided by the dosage forms and methods described in US Patent Application Ser. Am. Nos. (Unknown) to Boehm, under the title "Sustained-Release Opioid Formulations and Method of Use"

effected on September 22, 2003 and introduced herein by reference.

[0073] Preferred release retarders or sequestrants include acrylic polymers, alkylcelluloses, shellac, zein, hydrogenated vegetable oil, hydrogenated castor oil, and combinations thereof. In certain preferred embodiments, the release or sequestering material is a pharmaceutically acceptable acrylic polymer, comprising a copolymer of acrylic acid and methacrylic acid, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly (acrylic acid), poly (methacrylic acid), methacrylic acid alkylamide copolymer, poly (methyl methacrylate), poly (methacrylic acid) anhydride, methyl methacrylate, polymethacrylate, poly (methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer and glycidyl methacrylate copolymers. In certain preferred embodiments, the acrylic polymer comprises one or more ammonium methacrylate copolymers. Ammonium methacrylate copolymers are well known in the art and are described in NF21, 21 edition of the National Formulary, published by the United States Pharmacopeial Convention Inc. (Rockville, Md.) As fully polymerized copolymers of acrylic acid esters and methacrylic acid esters with a low content of quaternary ammonium groups. In other preferred embodiments, the release retardant or sequestering material is an alkylcellulose substance, such as ethylcellulose. It will be apparent to those skilled in the art that other cellulosic polymers, including other alkylcellulose polymers, may be used instead of some or all of ethylcellulose. the acrylic polymer comprises one or more ammonium methacrylate copolymers. Ammonium methacrylate copolymers are well known in the art and are described in NF21, 21 edition of the National Formulary, published by the United States Pharmacopeial Convention Inc. (Rockville, Md.) As fully polymerized copolymers of acrylic acid esters and methacrylic acid esters with a low content of quaternary ammonium groups. In other preferred embodiments, the release retardant or sequestering material is an alkylcellulose substance, such as ethylcellulose. It will be apparent to those skilled in the art that other cellulosic polymers, including other alkylcellulose polymers, may be used instead of some or all of ethylcellulose. the acrylic polymer comprises one or more ammonium methacrylate copolymers. Ammonium methacrylate copolymers are well known in the art and are described in NF21, 21 edition of the National Formulary, published by the United States Pharmacopeial Convention Inc. (Rockville, Md.) As fully polymerized copolymers of acrylic acid esters and methacrylic acid esters with a low content of quaternary ammonium groups. In other preferred embodiments, the release retardant or sequestering material is an alkylcellulose substance, such as ethylcellulose. It will be apparent to those skilled in the art that other cellulosic polymers, including other alkylcellulose polymers, may be used instead of some or all of ethylcellulose. Ammonium methacrylate copolymers are well known in the art and are described in NF21, 21 edition of the National Formulary, published by the United States Pharmacopeial Convention Inc. (Rockville, Md.) As fully polymerized copolymers of acrylic acid esters and methacrylic acid esters with a low content of quaternary ammonium groups. In other preferred embodiments, the release retardant or sequestering material is an alkylcellulose substance, such as ethylcellulose. It will be apparent to those skilled in the art that other cellulosic polymers, including other alkylcellulose polymers, may be used instead of some or all of ethylcellulose. Ammonium methacrylate copolymers are well known in the art and are described in NF21, 21 edition of the National Formulary, published by the United States Pharmacopeial Convention Inc. (Rockville, Md.) As fully polymerized copolymers of acrylic acid esters and methacrylic acid esters with a low content of quaternary ammonium groups. In other preferred embodiments, the release retardant or sequestering material is an alkylcellulose substance, such as ethylcellulose. It will be apparent to those skilled in the art that other cellulosic polymers, including other alkylcellulose polymers, may be used instead of some or all of ethylcellulose. ) as fully polymerized copolymers of acrylic acid esters and methacrylic acid esters with a low content of quaternary ammonium groups. In other preferred embodiments, the release retardant or sequestering material is an alkylcellulose substance, such as ethylcellulose. It will be apparent to those skilled in the art that other cellulosic polymers, including other alkylcellulose polymers, may be used instead of some or all of ethylcellulose. ) as fully polymerized copolymers of acrylic acid esters and methacrylic acid esters with a low content of quaternary ammonium groups. In other preferred embodiments, the release retardant or sequestering material is an alkylcellulose substance, such as ethylcellulose. It will be apparent to those skilled in the art that other cellulosic polymers, including other alkylcellulose polymers, may be used instead of some or all of ethylcellulose.

[0074] Release modifying agents that affect the release properties of the release-retarding or sequestering substances may also be used. In a preferred embodiment, the release modifying agent acts as a blowing agent. The blowing agent may be organic or inorganic and includes substances that can be dissolved, extracted or leached from the coating in the environment of use. The blowing agent may comprise one or more hydrophilic polymers, such as hydroxypropyl methylcellulose. In certain preferred embodiments, the release modifying agent is selected from hydroxypropylmethylcellulose, lactose, metal stearates, and combinations thereof.

[0075] The release-retarding or sequestering material may also include an erosion-promoting agent, such as starch and gums; a release modifier, useful for the production of a microporous film in a use environment, such as polycarbonates consisting of linear polyesters of carbonic acid in which carbonate groups are present in the polymer chain; and / or a semipermeable polymer.

[0076] The release-retarding or sequestering material may also include outlet elements including at least one passageway, aperture, etc. The passageway may be formed by the methods as disclosed in U.S. Ser.

Am. No. 3,845,770; 3,916,889; 4,063,064 and 4,088,864, incorporated herein by reference. The corridor can have any shape, such as round, rectangular, square, elliptical, irregular, etc.

[0077] In some embodiments, the therapeutic agent in a sustained release form may comprise a plurality of substrates comprising the active ingredient, which substrates are coated with a delayed release coating comprising a release retardant or sequestering material.

[0078] The sustained release formulations of the invention can be prepared in combination with any multiparticulate system, such as beads, ion exchange resin beads, spheroids, microspheres, beads, pellets, granules, and other multiparticulates, thereby obtaining the desired therapeutic agent with sustained release . The multiparticulate system may be contained in a capsule or other suitable utility dosage form.

[0079] In certain preferred embodiments, more than one multiparticulate system may be used, each of which has different properties, such as dependence of release from pH, release time in various media (e.g., acidic, alkaline, simulated intestinal fluid), in vivo release. , size and composition.

[0080] In order to obtain a sustained release of the therapeutic agent in a manner that will provide a therapeutic effect over a prolonged period of time, the therapeutic agent may be coated with a release retardant or sequestering material in an amount at which the weight gain will be from about 2 to about 30%, although the coating may be larger or smaller depending, among other things, on the physical properties of the particular therapeutic agent used and the desired release rate. In addition, more than one release retardant or sequestering material may be used in the coating as well as various other pharmaceutical excipients.

[0081] Solvents typically used for the release retardant or sequestering material include pharmaceutically acceptable solvents such as water, methanol, ethanol, methylene chloride, and combinations thereof.

[0082] In some embodiments of the invention, the release-retarding or sequestering material is in the form of a coating comprising an aqueous dispersion of the hydrophobic polymer. The physical properties of the layer can be further improved by incorporating an effective amount of a plasticizer into the aqueous dispersion of the hydrophobic polymer. For example, because the ethylcellulose has a relatively high glass transition temperature and does not form flexible layers under normal coating conditions, it is necessary to impart plasticity to ethylcellulose before using it as a coating substance. In general, the amount of plasticizer incorporated into the solution depends on the concentration of the film-forming material, e.g. it is most often from about 1 to about 50% by weight of the film-forming substance. However,

[0083] Examples of plasticizers for ethylcellulose and other celluloses include dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and triacetin, although other plasticisers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) can be used. A plasticizer that is not washed into the aqueous phase, such as DBS, is preferred.

[0084] Examples of plasticizers for acrylic polymers include citric acid esters, such as NF21 trimethyl citrate, tributyl citrate, dibutyl phthalate (DBP), acetyl tri- N-butyl citrate (ATBC), as well as 1,2-propylene glycol, polyethylene glycols, propylene glycol, diethyl phthalate, castor oil and triacetin, although other plasticisers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) can be used.

[0085] The sustained release drug profile of the formulations of the invention (in vivo or in vitro) can be altered, for example, by using more than one release retardant or sequestering substance, by varying the thickness of the release retardant or sequestering substance, by varying the specific application used a release retardant or sequestering substance, by changing the relative amount of a release retardant or sequestering material, by changing the method in which the plasticizer is added (e.g., when the extended release coating is formed from an aqueous dispersion of the hydrophobic polymer) by changing the amount of plasticizer in in relation to the retardant or by the addition of additional ingredients or excipients and by a change in the manufacturing method; e.t.c.

[0086] In some other embodiments, sustained-release multi-particle matrices may be used in an oral dosage form. In some embodiments, the sustained release matrix includes a hydrophilic and / or hydrophobic polymer, such as resins, cellulose ethers, acrylic resins, or proteinaceous materials. Of these polymers, cellulose ethers, in particular hydroxyalkylcelluloses and carboxyalkylcelluloses, are preferred. The oral dosage form may contain from about 1% to about 80% (by weight) of at least one hydrophilic or hydrophobic polymer.

[0087] The hydrophobic substance is preferably selected from the group consisting of alkylcellulose, polymers and copolymers of acrylic acid and methacrylic acid, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil or mixtures thereof. Preferably, the hydrophobic substance is a pharmaceutically acceptable acrylic polymer comprising copolymers of acrylic acid and methacrylic acid, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly (acrylic acid), poly (methacrylic acid), methacrylic acid copolymer and alkylamines, poly (methyl methacrylate), poly (anhydride) poly (methacrylic acid), polymethacrylate, polyacrylamide, poly (methacrylic acid anhydride) and glycidyl methacrylate copolymers. In other projects,

[0088] Preferred hydrophobic substances are insoluble in water with more or less pronounced hydrophobic tendencies. Preferably, the hydrophobic material has a melting point ranging from about 30 ° C to about 200 ° C, more preferably from about 45 ° C to about 90 ° C. The hydrophobic substance may comprise neutral or synthetic waxes, fatty alcohols (such as lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol or preferably cetostearyl alcohol), fatty acid, including fatty acid esters, fatty acid glycerides (mono-, di- and triglycerides), hydrogenated fats, hydrocarbons, ordinary waxes, stearic acid, stearyl alcohol and hydrophobic and hydrophilic substances containing a hydrocarbon chain. Suitable waxes include beeswax, glycol wax, castor wax,

[0089] Preferably, a combination of two or more hydrophobic substances is present in the matrix formulations. When an additional hydrophobic substance is incorporated, it is preferably a natural or synthetic wax, a fatty acid, a fatty alcohol or mixtures thereof. Examples include beeswax, carnauba wax, stearic acid and stearyl alcohol.

[0090] In other embodiments, the sustained release matrix comprises bioavailable, long-chain (e.g., C8-C50, and preferably C12-C40), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, fatty acid glycerine esters, mineral oils and vegetable and waxes. Hydrocarbons having a melting point in the range of about 25 ° C to about 90 ° C are preferred. Of these long-chain hydrocarbons, fatty (aliphatic) alcohols are preferred.

The oral dosage form may contain up to about 60% (by weight) of at least one available long-chain hydrocarbon. In addition, the sustained release matrix can contain up to 60% (by weight) of at least one polyalkylene glycol.

[0091] In a preferred embodiment, the matrix comprises at least one water-soluble hydroxyalyl cellulose, at least one C12-C36, preferably C14-C22, an aliphatic alcohol and, optionally, at least one polyalkylene glycol. The at least one hydroxyalkyl cellulose is preferably a hydroxy (C1-C6) alkyl cellulose, such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose and, preferably, hydroxyethyl cellulose. The amount of at least one hydroxyalkyl cellulose in the oral dosage form will depend, among other things, on the prescribed rate of opioid release. The amount of the at least one aliphatic alcohol in the oral dosage form of the present invention will depend on the precise rate of desired opioid release. However, this amount will also depend on

[0092] In some embodiments, together with the active ingredient, a sterophilizing agent can be spheroniZed to form spheroids. Examples of such factors are microcrystalline cellulose and undetectable hydrated lactose. In addition (or alternatively), the spheroids may comprise a water-insoluble polymer, preferably an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer, or ethylcellulose. In such embodiments, the sustained release coating generally includes a water insoluble substance, such as (a) a wax, alone or in admixture with a fatty alcohol, or (b) shellac or zein.

[0093] A sustained release unit may be produced by any suitable method. For example, a plasticized aqueous dispersion of a release retardant or sequestering substance may be applied to the subunit containing an opioid agonist. The aqueous dispersion of the release retardant or sequestering material is preferably used in an amount sufficient to achieve the predetermined sustained release of the opioid agonist when the coated substrate is exposed to an aqueous solution, e.g., gastric fluid, taking into account the physical properties of the given opioid agonist, the method of incorporating the plasticizer , etc. Alternatively, after coating with a release retardant or sequestering material, a further top coat of a film forming agent, such as Opadry (Colorcon,

[0094] The subunit may be cured to obtain a constant rate of release of the therapeutic agent. In embodiments where an acrylic coating is used, the stabilized product is preferably obtained by subjecting the subunit to oven cure at a temperature above the glass transition temperature of the plasticized acrylic polymer for the required time. The optimal temperature and time for a particular formulation can be determined by routine experiments.

[0095] Once prepared, the subunit may be linked to at least one additional subunit and, optionally, other excipients or drugs, to form an oral dosage form. In addition to the above ingredients, the delayed release matrix may also contain appropriate amounts of other substances, e.g. diluents, lubricants, binders, granulating substances, coloring agents; flavors and lubricants that are typical in the pharmaceutical field.

[0096] Optionally and preferably, the mechanical strength of each of the sequestering subunits described herein is the same as the strength of the therapeutic agent in a releasable form. Thus, manipulating the composition of the invention in such a way as to obtain a therapeutic agent will destroy the sequestering subunit and then the antagonist will be released and mixed with the therapeutic agent. Consequently, the antagonist can not be separated from the therapeutic agent, and the therapeutic agent can not be administered in the absence of the antagonist. Methods for testing the mechanical strength of the sequestering subunit and the therapeutic agent are known in the art.

[0097] The composition of the invention may be in any suitable dosage form or formulation (see, e.g., Pharmaceutics and Pharmacy Practice, JB Lippincott Company, Philadelphia, Pa., Banker and Chalmers, pp. 238-250 (1982)). Pharmaceutically acceptable salts of antagonist or agonists as discussed herein include metal salts such as sodium salt, potassium salt, cesium salt, etc., alkaline earth metal salts such as calcium salt, magnesium salt, and the like; organic amine salts, such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, and the like; salts of inorganic acids, such as hydrochloride, hydrobromide, sulfate, phosphate, etc .; salts of organic acids, such as formate, acetate, trifluoroacetate, maleate, tartrate, etc .; sulfonates, such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc .; amino acid salts such as arginate, aspartate, glutamate, etc. Formulations suitable for oral administration may include (a) liquid solutions, such as an effective amount of an inhibitor dissolved in a diluent, such as water, saline, or orange juice; (b) capsules, sachets, tablets, troches and troches, each containing a predetermined quantity of the active ingredient, in the form of solids or granules; (c) powders; (d) suspensions in a suitable liquid; and (e) suitable emulsions. Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol and polyethylene alcohols, with or without the addition of a pharmaceutically acceptable surfactant. Capsules may be ordinary hard shell capsules or a soft gelatin shell containing, for example, surfactants, lubricants and inert fillers, such as lactose, sucrose, calcium phosphate and corn starch. The tablets may include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, gum arabic, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearate calcium, zinc stearate, stearic acid and other auxiliary substances, coloring substances, diluents, buffering agents, disintegrating agents, wetting agents, preservatives, flavoring and pharmacological substances compatible auxiliary substances. The pellets may comprise the active ingredient in a flavoring, generally sucrose and gum arabic or gum tragacanth, and may also contain the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, etc. comprising, in addition to the active ingredient, excipients that are well known in the art.

[0098] It will be evident to a person skilled in the art that the compositions of the invention may be modified in a variety of ways to increase the therapeutic effectiveness of the composition as a result of such modification. For example, the therapeutic agent or sequestering subunit may be coupled to the target residue either directly or indirectly via a linker. Methods for conjugating therapeutic agents or sequestering subunits to target residues are known in the art. See, for example, Wadwa et al., J. Drug Targeting 3: 111 (1995), and U.S. Pat. Ser.

Am. Ref No. 5,087,616. As used herein, the term "target residue" refers to any molecule or agent that specifically recognizes and binds to a cell surface receptor such that the target residue directly delivers a therapeutic agent or sequestering subunit to a population of cells on which the receptor is expressed. . Target residues include, but are not limited to, antibodies or fragments thereof, peptides, hormones, growth factors, cytokines, and any other naturally or abnormally occurring ligands that bind to cell surface receptors. The term "linker" as used herein refers to any agent or molecule that links a therapeutic agent or sequestering subunit to a target moiety. It will be obvious to a person skilled in the art that

[0099] The compositions of the present invention are preferably in an oral dosage form. The term "oral dosage form" includes a dosage unit comprising subunits and being indicated or intended for oral administration. Preferably, the composition comprises a sequestering subunit coated with the therapeutic agent in a releasable form, thereby forming a composite subunit comprising a sequestering subunit and a therapeutic agent. Thus, the invention further provides capsules suitable for oral administration, comprising a plurality of such composite subunits.

[0100] Alternatively, the oral dosage form may comprise any of the sequestering subunits of the invention in combination with a therapeutic subunit, wherein the therapeutic subunit comprises a therapeutic agent in a releasable form. In this aspect, the invention provides capsules suitable for oral administration, comprising a plurality of sequestering subunits of the invention and a variety of therapeutic subunits each comprising a therapeutic agent in a releasable form.

[0101] The invention further provides tablets comprising a sequestering subunit of the invention and a therapeutic agent in a releasable form. For example, the invention provides a tablet suitable for oral administration, comprising a first layer comprising any of the sequestering subunits of the invention and a second layer comprising the therapeutic agent in a releasable form, wherein the first layer is coated with a second layer. The first layer may comprise a plurality of sequestering subunits. Alternatively, the first layer may be or may consist of a single sequestering subunit. The therapeutic agent in a releasable form may be in the form of a subunit of a therapeutic agent, and the second layer may comprise a plurality of therapeutic subunits. Alternatively,

[0102] When the blocking agent is a system comprising a first antagonist and core impermeable substance, the sequestering subunit may be in one of several different forms. For example, the system may further comprise a second antagonist-impermeable substance, in which case the sequestering moiety comprises an antagonist, a first antagonist-impermeable material, a second antagonist-impermeable substance, and a core. In this case, the core is coated with a first antagonist-impermeable material, which in turn is coated with an antagonist which, in turn, is coated with a second antagonist-impermeable material. The first antagonist-impermeable substance and the second antagonist-resistant substance substantially prevent the release of the antagonist from the sequestering subunit in the gastrointestinal tract over time that is greater than 24 hours. In some cases, it is preferred that the first antagonist-impermeable substance is the same as the second impermeable substance of the antagonist bottom. In other cases, the first antagonist-impermeable substance is different from the second antagonist-impermeable substance. One skilled in the art will easily determine whether the first and second antagonist-impermeable substances should be the same or different. Factors that affect the decision,

[0103] Alternatively, the antagonist may be introduced into the core and the core is coated with the first antagonist-impermeable material. In this case, the invention provides a sequestering subunit comprising an antagonist, a core, and a first antagonist-impermeable material, wherein the antagonist is introduced into the core and the core is coated with a first antagonist-impermeable material that substantially prevents the release of the antagonist from the sequestering subunit in the gastrointestinal tract. for a period that is longer than 24 hours. As used herein, the term &amp; quot; introduced &amp; quot; and derivatives thereof, includes any method of introducing, e.g., a homogeneous dispersion of an antagonist through a core,

[0104] In another alternative embodiment, the core comprises a water-insoluble substance and is coated with an antagonist which, in turn, is coated with a first antagonist-impermeable material. In this case, the invention further provides a sequestering subunit comprising an antagonist, a first antagonist-impermeable substance, and a core that is a water-insoluble substance, wherein the core is coated with an antagonist which, in turn, is coated with a first antagonist-impermeable substance; substantially prevents the release of the antagonist from the sequestering subunit in the gastrointestinal tract over time that is greater than 24 hours. The term "water-insoluble substance" as used herein means any substance, which is essentially insoluble in water. The term "substantially insoluble in water" does not necessarily refer to total or 100% insolubility in water. There are various degrees of water insolubility among which a person skilled in the art can easily determine which one is potentially beneficial. Preferred water-insoluble substances include, for example, microcrystalline cellulose, calcium salt and wax. Calcium salts include, but are not limited to, calcium phosphate (e.g. hydroxyapatite, apatite, etc.), calcium carbonate, calcium sulfate, calcium stearate, etc. Waxes include, for example, carbauba wax, beeswax, petroleum wax, candelilla wax, e.t.c. There are various degrees of water insolubility among which a person skilled in the art can easily determine which one is potentially beneficial. Preferred water-insoluble substances include, for example, microcrystalline cellulose, calcium salt and wax. Calcium salts include, but are not limited to, calcium phosphate (e.g. hydroxyapatite, apatite, etc.), calcium carbonate, calcium sulfate, calcium stearate, etc. Waxes include, for example, carbauba wax, beeswax, petroleum wax, candelilla wax, e.t.c. There are various degrees of water insolubility among which a person skilled in the art can easily determine which one is potentially beneficial. Preferred water-insoluble substances include, for example, microcrystalline cellulose, calcium salt and wax. Calcium salts include, but are not limited to, calcium phosphate (e.g. hydroxyapatite, apatite, etc.), calcium carbonate, calcium sulfate, calcium stearate, etc. Waxes include, for example, carbauba wax, beeswax, petroleum wax, candelilla wax, e.t.c.

[0105] In one embodiment, the sequestering subunit comprises an antagonist and a seal coating that forms a layer that physically separates the antagonist in the sequestering subunit from the agonist that is located on the sequestering unit. In one embodiment, the seal coat comprises one or more osmotic pressure regulating agents, a charge neutralizing additive, a hydrophobicity enhancing additive of the sequestering polymer and a first sequestering polymer (each of which is described above). In such embodiments, preferably the osmotic pressure adjusting agent, the charge neutralizing additive and / or the additive increasing the hydrophobicity of the sequestering polymer, respectively, are present relative to the first sequestering polymer in a proportion such as wherein no more than 10% of the antagonist is released from the intact dosage form. When the opioid antagonist is used in the sequestering subunit and the intact dosage form is included in the opioid agonist, preferably the ratio of the osmotic pressure adjusting agent, the charge neutralization additive and / or the hydrophobicity additive of the sequestering polymer, respectively, when present, with respect to the first sequestering polymer is that the physiological effect of the opioid agonist is not reduced when the composition is in intact dosage form or when it is normally taken by the patient. The release may be determined as described above using the USP paddle method (optionally using a surfactant-containing buffer, such as Triton X100) or by plasma measurement after administration to a patient after a meal or fasting. In one embodiment, the plasma levels of naltrexone are determined; in others, naltrexone 6-beta levels in plasma are measured. One can use standard tests to determine the effect of the antagonist on agonist function (i.e., reduce pain).

[0106] The sequestering subunit of the invention may comprise a blocking agent that is a loop to which an antagonist is attached. The term "loop" as used herein refers to any means by which the antagonist is bound or attached to the interior of the sequestering subunit, such that it is not released if the subunit is not manipulated. In this case, a loop-antagonist complex is formed. This complex is coated with a loop impermeable substance, and the release of the antagonist from the subunit is substantially prevented in this way. The term "loop impermeable substance" as used herein refers to any substance that substantially protects or protects the loop from penetration of the substance. The loop is preferably an ion exchange resin bead.

[0107] The invention further provides a tablet suitable for oral administration, comprising a single layer comprising a therapeutic agent in a releasable form and a plurality of any sequestering subunits of the invention dispersed within this reactive drug layer within this releasable form. The invention also provides a tablet wherein the therapeutic agent in a releasable form is in the form of a therapeutic unit subunit, and the tablet comprises at least a substantially homogeneous mixture of multiple sequestering subunits and a plurality of subunits comprising a therapeutic agent.

[0108] In preferred embodiments, oral dosage forms are prepared in such a way as to include an effective amount of multi-particulate extrudates encapsulated inside the capsule. For example, many extruded multi-particles can be placed in a gelatin capsule in an amount sufficient to ensure effective release of the dose after ingestion and after contact with the gastric fluid.

[0109] In another preferred embodiment, the subunits, e.g. in the form of multiparticulates, can be compressed into oral tablets using a conventional tabletting machine and standard techniques. Techniques and compositions for making tablets (compressed and extruded), capsules (hard and soft gelatin) and pills are also described in Remington's Pharmaceutical Sciences, (publisher of Aurther Osol.), 1553-1593 (1980), incorporated herein by reference. Excipients in the tablet formulation may include, for example, an inert diluent, such as lactose, granulating and disintegrating agents, such as corn starch, binders such as starch, and lubricants, such as magnesium stearate. In yet another preferred embodiment, the subunits are added during the extrusion process and the extruded product can be shaped into tablets as described in US Patent No. 4,879,267. Ser. Am. No. 4,957,681 (Klimesch et al.) Incorporated herein by reference.

[0110] Alternatively, melt-extruded multiparticulates or prolonged-release tablets can be coated, or a gelatin capsule can be coated with a sustained release coating such as the sustained release coatings described herein. Such coatings are particularly useful when the subunit comprises an opioid agonist in a releasable form, but not in a sustained release form. The coatings preferably include a hydrophobic material in an amount sufficient to provide a weight gain of about 2 to about 30%, although the top layer may be larger depending, among other things, on the physical properties of the particular opioid analgesic used and the desired release rate.

[0111] The melt-extrudable dosage forms can further comprise combinations of multi-particulate extrudates containing one or more therapeutic agents prior to encapsulation. In addition, the dosage forms can also include a quantity of an immediate release therapeutic agent to provide a rapid therapeutic effect. The immediate release therapeutic can be introduced, or it can be coated with the surface of the subunits, after the preparation of the dosage forms (e.g., in a controlled release coating or in a matrix). In order to obtain the desired effect, the dosage forms may also comprise a combination of controlled release beads and a microparticulate matrix.

[0112] Sustained-release formulations preferably release the therapeutic agent slowly, for example, when ingested and exposed to gastric fluids, and then to intestinal fluids. The sustained release profile of the melt-extruded formulations can be altered, for example, by varying the amount of retardants, e.g. a hydrophobic substance, by varying the amount of plasticizer relative to the hydrophobic substance, by adding additional ingredients or excipients, by changing the manufacturing method, etc. .

[0113] In other embodiments, the melt-extruded substance is prepared without introducing subunits, which are then added to the extruded product. Such formulations may include subunits and other drugs mixed together with the extruded matrix substance, and then the mixture is tableted and a slow release of the therapeutic agent or other drugs is obtained. Such formulations are particularly advantageous, for example when the therapeutically active agent introduced into the formulation is sensitive to the temperatures necessary to soften the hydrophobic substance and / or the retardant.

[0114] In certain embodiments, the release of the antagonist from the sequestering subunit or composition is expressed with respect to the release ratio obtained after manipulation, e.g. by crushing or chewing, relative to the amount released from the intact formulation. Thus, this ratio is expressed as Crushed: All, and preferably in the numerical range of at least about 4: 1 or above (e.g. release from crushed within 1 hour / release from intact within 24 hours). In certain embodiments, the ratio of therapeutic agent and antagonist present in the sequestering subunit is about 1: 1 to about 50: 1 by weight, and preferably about 1: 1 to about 20: 1 by weight, or 15: 1 to about 30: 1 by weight. The weight ratio of the therapeutic agent to the antagonist refers to the weight of the active ingredients. So, for example, the weight of the therapeutic agent does not include the weight of the coating, matrix or other components that give the antagonist the sequestered form, or other possible excipients associated with the antagonist particles. In certain preferred embodiments, the ratio is about 1: 1 to about 10: 1 by weight. Since in some embodiments the antagonist is in a sequestered form, the amount of such antagonist in the dosage form may vary within a wider range than in the combination of a therapeutic agent / antagonist dosage form in which both of these components are available for release following administration because the proper effect of such formulation is not is dependent on differences in metabolism or hepatic clearance. For safety reasons, the amount of antagonist present in a substantially non-releasable form is selected such that

[0115] Thus, in some embodiments, a pharmaceutical composition is provided including an antagonist in direct contact with a seal coating, an agonist in direct contact with a seal coating and with a sequestering polymer, but not with an antagonist, wherein the antagonist and agonist are present in a single multi-layered pharmaceutical unit. In other embodiments, pharmaceutical compositions are provided comprising a pharmaceutical dosage unit, substantially consisting of a multi-layer of beads comprising an antagonist and an agonist that are not in direct contact with each other. In yet other embodiments, a pharmaceutical composition is provided comprising a plurality of pharmaceutically active units, each unit containing an antagonist, an agonist, a seal coating, and a sequestering polymer, wherein the antagonist and agonist are not in direct contact with each other. In yet other embodiments, pharmaceutical compositions comprising a pharmaceutically inert carrier substance, such as a sugar globule, an antagonist in direct contact with a carrier substance, a sealing coating in direct contact with an antagonist and an agonist, and a sequestering polymer in direct contact with an agonist are provided. In preferred embodiments, multi-layer pharmaceutical compositions are provided, including agonist and antagonist in separate layers of the composition, wherein at least 90-95% of the antagonist is sequestered for at least 24 hours after administration to a human. In a particularly preferred embodiment, there is provided a pharmaceutical composition comprising naltrexone in the sequestering subunit and morphine in contact with said subunit, but not with naltrexone, whereby after administration of the composition to man within 24 hours, substantially all of the morphine of the composition is released but less than 5-10% of naltrexone from the composition. Methods of preparing pharmaceutical compositions are also provided, for example, by attaching an antagonist to a pharmaceutically inert carrier substance, coating the antagonist with a seal coating that includes a sequestering polymer, coating the sealing coating with an agonist, and coating the agonist with a release retardant or sequestering material. In another embodiment, a method is provided for measuring the amount of an antagonist or derivative thereof in a biological sample, wherein the antagonist or derivative is released from the pharmaceutical composition in vivo, which method comprises a USP paddle method at 37 ° C, 100 rpm,

[0116] A particularly preferred embodiment is the multi-layered pharmaceutical formulation described in the Examples, which is a multi-layered dosage unit of naltrexone / morphine in a form not susceptible to abuse. Naltrexone is contained in a sequestering subunit comprising a seal coating containing Eudragit® RS and optimization factors, SLS, talc and chloride ions, which together prevent the release of naltrexone upon hydration. A layer containing morphine is applied to the sequestering subunit, which is released under hydration in a pH 7.5 buffer; however, under these conditions, naltrexone remains within the sequestering subunit. When the entity is modified, for example, by crushing, the sequestering subunit is also broken, which releases morphine and naltrexone.

[0117] Thus, the compositions are particularly suitable for use in preventing abuse of a therapeutic agent. In this context, the invention also provides a method for preventing abuse of a therapeutic agent by a human. The method includes introducing a therapeutic agent into any of the compositions of the invention. After administration of the composition to the patient, the antagonist is substantially prevented from being released in the gastrointestinal tract for a period that is greater than 24 hours. However, when the patient manipulates the compositions, the sequestering subunit, which is not mechanically resistant, will fail and thus allow the release of the antagonist. Since the mechanical strength of the sequestering subunit is the same as the strength of the therapeutic agent in a releasable form,

[0118] The invention and many of its advantages will become clearer on the basis of the following examples, which are provided for illustrative purposes.

EXAMPLES [0119] The production methods and experiments described herein have actually been carried out. However, in some cases, the present tense was used.

Example 1

Evaluation of the formulation

A. Exclusion of the charge neutralization additive (SLS) [0120]

<td></td><td colspan="2">RB 380-56</td>

<td></td><td>I'm playing for the party</td><td>Percent</td>

<td>Sugar balls coated with a sealing coat</td><td></td><td></td>

<td>Sugar balls</td><td>577.9</td><td>51.8</td>

<td>Ethylcellulose N50</td><td>46.2</td><td>4.1</td>

<td>Talc</td><td>123.3</td><td>11.1</td>

<td>Sebibutanate</td><td>4.6</td><td>0.4</td>

<td colspan="3"></td>

<td>Naltrexone cores</td><td></td><td></td>

<td>Sugar balls coated sealing coating</td><td>(752.0)</td><td>(&lt;7.4)</td>

<td>Naltrexone HCl</td><td>27.2</td><td>2.4</td>

<td>Klucel LF</td><td>5.2</td><td>0.5</td>

<td>Talc</td><td>12.8</td><td>1.1</td>

<td>Ascorbic acid</td><td>2.8</td><td>0.3</td>

<td></td><td></td><td></td>

<td>Naltrexone pellets</td><td></td><td></td>

<td>Naltrexone cores</td><td>(800.0)</td><td>(71.7)</td>

<td>Eudragit RS</td><td>150.0</td><td>13.5</td>

<td>Sodium lauryl sulphate</td><td>0.0</td><td>0.0</td>

<td>Talc</td><td>150.0</td><td>13.5</td>

<td>Sebibutanate</td><td>15.0</td><td>1.3</td>

<td>Together</td><td>1115.0</td><td>100.0</td>

Manufacturing method:

[0121]

1. Ethylcellulose and dibutyl sebacate were dissolved in ethanol and talc dispersed in the solution.

2. Dispersion from point 1 was sprayed onto sugar balls in a Wurster apparatus and sugar spheres coated with a seal coat were obtained.

3. Klucel LF and ascorbic acid were dissolved in 20:80 water and ethanol. A dispersion of naltrexone HCl and talc was prepared in the solution.

4. The naltrexone dispersion from point 3 in the Wurster apparatus was sprayed onto the sugar spheres overcoated with a stain coating from point 2 and the naltrexone cores were obtained.

5. Eudragit RS and dibutyl sebacate were dissolved in ethanol and talc dispersion was prepared in solution.

6. Dispersion from point 5 was sprayed onto naltrexone cores from step 4 using Wurster apparatus and received naltrexone pellets.

7. The pellets were dried at 50 ° C for 48 hours.

8. The obtained pellets had a coating with Eudragit RS, 47 μm thick.

Results for drug release [0122] Release conditions: USP vane method at 37 ° C and 100 rpm, 1 hour in 500 ml of 0.1N HCl, and then 72 hours in 500 ml of 0.05M phosphate buffer pH 7.5.

[0123] Conclusions: The results are shown in Figure 1. Exclusion of SLS from naltrexone pellet coating (Eudragit RS) results in rapid release of naltrexone and releases over 90% within 24 hours.

B. Different amounts of SLS (coating with Eudragit RS 53 μm thick) [0124]

<td>Lot number</td><td colspan="2">RB 358-88</td><td colspan="2">RB 358-73</td><td colspan="2">RB 358-83</td>

<td></td><td>I'm playing on party</td><td>Percent</td><td>I'm playing on party</td><td>Percent</td><td>I'm playing on party</td><td>Percent</td>

<td>Sugar balls coated shell sealing</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Sugar balls</td><td>646.1</td><td>50.1</td><td>646.1</td><td>50.0</td><td>646.1</td><td>49.8</td>

<td>Ethylcellulose N50</td><td>48.5</td><td>3.8</td><td>48.5</td><td>3.7</td><td>48.5</td><td>3.7</td>

<td>Talc</td><td>126.0</td><td>9.8</td><td>126.0</td><td>9.7</td><td>126.0</td><td>9.7</td>

<td>sebacate dibutyl</td><td>4.9</td><td>0.4</td><td>4.9</td><td>0.4</td><td>4.9</td><td>0.4</td>

<td>stearate magnesium</td><td>19.4</td><td>1.5</td><td>19.4</td><td>1.5</td><td>19.4</td><td>1.5</td>

<td>lauryl sodium</td><td>1.9</td><td>0.2</td><td>1.9</td><td>0.1</td><td>1.9</td><td>0.1</td>

<td>cores naltrexone</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Sugar balls coated shell sealing</td><td>(846.7)</td><td>(65.6)</td><td>(846.7)</td><td>(65.6)</td><td>(846.7)</td><td>(65.2)</td>

<td>Naltrexone HCl</td><td>29.5</td><td>2.3</td><td>29.5</td><td>2.3</td><td>29.5</td><td>2.3</td>

<td>Klucel LF</td><td>5.9</td><td>0.5</td><td>5.9</td><td>0.5</td><td>5.9</td><td>0.5</td>

<td>Talc</td><td>17.8</td><td>1.4</td><td>17.8</td><td>1.4</td><td>17.8</td><td>1.4</td>

<td>pellets naltrexone</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>cores naltrexone</td><td>(900.0)</td><td>(69.7)</td><td>(900.0)</td><td>(69.6)</td><td>(900.0)</td><td>(69.3)</td>

<td>Eudragit RS</td><td>184.6</td><td>14.3</td><td>184.3</td><td>14.3</td><td>183.7</td><td>14.2</td>

<td>lauryl sodium</td><td>3.0</td><td>0.23</td><td>6.1</td><td>0.47</td><td>12.3</td><td>0.95</td>

<td>Talc</td><td>184.6</td><td>14.3</td><td>184.3</td><td>14.3</td><td>183.7</td><td>14.2</td>

<td>sebacate</td><td>18.5</td><td>1.4</td><td>18.4</td><td>1.4</td><td>18.4</td><td>1.4</td>

<td>dibutyl</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Together</td><td>1290.7</td><td>100.0</td><td>1293.2</td><td>100.0</td><td>1298.1</td><td>100.0</td>

Manufacturing method:

[0125]

1. Ethylcellulose, sodium lauryl sulfate and dibutyl sebacate were dissolved in ethanol, and then a dispersion of talc and magnesium stearate was prepared in solution.

2. In the Wurster apparatus, the dispersion from point 1 was sprayed onto sugar spheres and sugar spheres coated with a sealing coating were obtained.

3. Klucel LF was dissolved in a 20:80 mixture of water and ethanol. A dispersion of naltrexone HCl and talc was then made in the solution.

4. In the Wurster apparatus, the naltrexone dispersion from point 3 was sprayed onto the sugar-coated sugar spheres from point 2 to obtain the naltrexone cores.

5. Eudragit RS, sodium lauryl sulfate and dibutyl sebacate were dissolved in ethanol and dispersed in a talc solution.

6. In the Wurster apparatus, the dispersion from 5 was sprayed onto naltrexone cores from step 4 to obtain naltrexone pellets.

7. The pellets were dried at 50 ° C for 13-16.5 hours.

8. The pellets produced had a coating of 51-53 μm Eudragit RS.

Results for drug release [0126] Release conditions: USP vane method at 37 ° C and 100 rpm, 72 hours in 500 ml of 0.05 M phosphate buffer pH 7.5.

[0127] Conclusions: The results are shown in Figure 2. Addition of a small amount of SLS (1.6% wt / wt Eudragit RS) results in a change in neutralization of Eudragit RS (theoretically 20% neutralization) and significantly slows the release of naltrexone. Further addition of SLS (3.2% w / w Eudragit RS) leads to a greater neutralization of the Eudragit RS charge (theoretically 41% neutralization) and dramatically slows the release of naltrexone. However, even higher amounts of SLS (6.3% w / w Eudragit RS) result in greater release of naltrexone, probably due to the plasticizing effect of SLS.

3. Different levels of SLS (coating with Eudragit RS with a thickness of 65 μm) [0128]

<td>Lot number</td><td colspan="2">RB 358-88A</td><td colspan="2">RB 358-73A</td><td colspan="2">RB 358-83A</td>

<td></td><td>I'm playing on party</td><td>Percent</td><td>I'm playing on party</td><td>Percent</td><td>I'm playing on party</td><td>Percent</td>

<td>Sugar balls coated shell sealing</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Sugar balls</td><td>646.1</td><td>45.5</td><td>646.1</td><td>45.4</td><td>646.1</td><td>45.1</td>

<td>Ethylcellulose N50</td><td>48.5</td><td>3.4</td><td>48.5</td><td>3.4</td><td>48.5</td><td>3.4</td>

<td>Talc</td><td>126.0</td><td>8.9</td><td>126.0</td><td>8.8</td><td>126.0</td><td>8.8</td>

<td>sebacate dibutyl</td><td>4.9</td><td>0.3</td><td>4.9</td><td>0.3</td><td>4.9</td><td>0.3</td>

<td>stearate magnesium</td><td>19.4</td><td>1.4</td><td>19.4</td><td>1.4</td><td>19.4</td><td>1.4</td>

<td>lauryl sodium</td><td>1.9</td><td>0.1</td><td>1.9</td><td>0.1</td><td>1.9</td><td>0.1</td>

<td>cores naltrexone</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Sugar balls coated shell sealing</td><td>(846.7)</td><td>(59.6)</td><td>(846.7)</td><td>(59.6)</td><td>(846.7)</td><td>(59.1)</td>

<td>Naltrexone HCl</td><td>29.5</td><td>2.1</td><td>29.5</td><td>2.1</td><td>29.5</td><td>2.1</td>

<td>Klucel LF</td><td>5.9</td><td>0.4</td><td>5.9</td><td>0.4</td><td>5.9</td><td>0.4</td>

<td>Talc</td><td>17.8</td><td>1.3</td><td>17.8</td><td>1.2</td><td>17.8</td><td>1.2</td>

<td>pellets naltrexone</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>cores naltrexone</td><td>(900.0)</td><td>(63.4)</td><td>(900.0)</td><td>(63.2)</td><td>(900.0)</td><td>(62.8)</td>

<td>Eudragit RS</td><td>245.8</td><td>17.3</td><td>245.8</td><td>17.3</td><td>245.8</td><td>17.2</td>

<td>lauryl sodium</td><td>4.0</td><td>0, 3</td><td>8.2</td><td>0.6</td><td>16.4</td><td>1.1</td>

<td>Talc</td><td>245.8</td><td>17.3</td><td>245.8</td><td>17.3</td><td>245.8</td><td>17.2</td>

<td>sebacate dibutyl</td><td>24.6</td><td>1.7</td><td>24.6</td><td>1.7</td><td>24.6</td><td>1.7</td>

<td>Together</td><td>1420.2</td><td>100.0</td><td>1424.4</td><td>100.0</td><td>1432.6</td><td>100.0</td>

Production method [0129]

1. Ethylcellulose, sodium lauryl sulfate and dibutyl sebacate were dissolved in ethanol; the dispersion of talc and magnesium stearate was then prepared in solution.

2. In the Wurster apparatus, the dispersion from point 1 was sprayed onto sugar spheres and sugar spheres coated with a sealing coating were obtained.

3. Klucel LF was dissolved in a 20:80 mixture of water and ethanol; then naltrexone HCl and talc were dispersed in the solution.

4. In the Wurster apparatus, the naltrexone dispersion from point 3 was sprayed onto the sugar-coated sugar spheres from point 2 to obtain the naltrexone cores.

5. Eudragit RS, sodium lauryl sulfate and dibutyl sebacate were dissolved in ethanol;

the talc was then dispersed in the solution.

6. In the Wurster apparatus, the dispersion from 5 was sprayed onto naltrexone cores from step 4 to obtain naltrexone pellets.

7. The pellets were dried at 50 ° C for 13-16.5 hours.

8. The pellets produced had a coating of Eudragit RS, 63-67 μm thick.

Results for drug release [0130] Release conditions: USP vane method at 37 ° C and 100 rpm, 72 hours in 500 ml of 0.05 M phosphate buffer pH 7.5.

[0131] Conclusions: The results are shown in Figure 3. As described above, this is the optimal ratio of SLS to Eudragsi t RS.

B. Talc content relative to Eudragit RS polymer [0132]

<td>Lot number</td><td colspan="2">RB 358-93</td><td colspan="2">RB 358-73A</td><td colspan="2">RB 358-78</td>

<td></td><td>I'm playing on party</td><td>Percent</td><td>I'm playing on party</td><td>Percent</td><td>I'm playing on party</td><td>Percent</td>

<td>Sugar balls coated shell sealing</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Sugar balls</td><td>646.1</td><td>46.5</td><td>646.1</td><td>45.4</td><td>646.1</td><td>43.9</td>

<td>Ethylcellulose N50</td><td>48.5</td><td>3.5</td><td>48.5</td><td>3.4</td><td>48.5</td><td>3.3</td>

<td>Talc</td><td>126.0</td><td>9.1</td><td>126.0</td><td>8.8</td><td>126.0</td><td>8.6</td>

<td>sebacate dibutyl</td><td>4.9</td><td>0.4</td><td>4.9</td><td>0.3</td><td>4.9</td><td>0.3</td>

<td>stearate magnesium</td><td>19.4</td><td>1.4</td><td>19.4</td><td>1.4</td><td>19.4</td><td>1.3</td>

<td>lauryl sodium</td><td>1.9</td><td>0.1</td><td>1.9</td><td>0.1</td><td>1.9</td><td>0.1</td>

<td>cores naltrexone</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Sugar balls coated shell sealing</td><td>(846.7)</td><td>(61.0)</td><td>(846.7)</td><td>(59.4)</td><td>(846.7)</td><td>(57.5)</td>

<td>Naltrexone HCl</td><td>29.5</td><td>2.1</td><td>29.5</td><td>2.1</td><td>29.5</td><td>2.0</td>

<td>Klucel LF</td><td>5.9</td><td>0.4</td><td>5.9</td><td>0.4</td><td>5.9</td><td>0.4</td>

<td>Talc</td><td>17.8</td><td>1.3</td><td>17.8</td><td>1.2</td><td>17.8</td><td>1.2</td>

<td>pellets naltrexone</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>cores naltrexone</td><td>(900.0)</td><td>(64.8)</td><td>(900.0)</td><td>(63.2)</td><td>(900.0)</td><td>(61.1)</td>

<td>Eudragit RS</td><td>266.5</td><td>19.2</td><td>245.8</td><td>17.3</td><td>216.7</td><td>14.7</td>

<td>lauryl sodium</td><td>8.8</td><td>0.6</td><td>8.2</td><td>0.6</td><td>7.2</td><td>0.5</td>

<td>Talc</td><td>186.2</td><td>13.4</td><td>245.8</td><td>17.3</td><td>326.3</td><td>22.2</td>

<td>sebacate dibutyl</td><td>26.6</td><td>1.9</td><td>24.6</td><td>1.7</td><td>21.7</td><td>1.5</td>

<td>Together</td><td>1388.1</td><td>100.0</td><td>1424.4</td><td>100.0</td><td>1471.9</td><td>100.0</td>

Production method [0133]

1. Ethylcellulose, sodium lauryl sulfate and dibutyl sebacate were dissolved in ethanol and then a dispersion of talc and magnesium stearate was made in the solution.

2. In the Wurster apparatus, the dispersion from point 1 was sprayed onto sugar spheres and sugar spheres coated with a sealing coating were obtained.

3. Klucel LF was dissolved in a 20:80 mixture of water and ethanol. A dispersion of naltrexone HCl and talc was prepared in the solution.

4. In the Wurster apparatus, the naltrexone dispersion from point 3 was sprayed onto the sugar-coated sugar spheres from point 2 to obtain the naltrexone cores.

5. Eudragit RS, sodium lauryl sulfate and dibutyl sebacate were dissolved in ethanol and talc dispersion was prepared in solution.

6. In the Wurster apparatus, the dispersion from 5 was sprayed onto naltrexone cores from step 4 to obtain naltrexone pellets.

7. The pellets were dried at 50 ° C for 13-16.5 hours.

8. The pellets produced had a coating of Eudragit RS, 63-67 μm thick.

Results for drug release [0134] Release conditions: USP vane method at 37 ° C and 100 rpm, 72 hours in 500 ml of 0.05 M phosphate buffer pH 7.5.

[0135] Conclusions: The results are shown in Figure 4 and indicate that this is the optimal ratio of talc to Eudragit RS (approximately 1: 1). Talc increases the hydrophobicity of the coating with Eudragit RS, but also reduces the integrity of the layer in high quantities. Figure 5 shows the transition point for the behavior of the layer. Figure 6 shows that there is a separate optimum for the ratio between layer permeability and talc content when using a sugar spar core.

C. Effect of the osmotic pressure of reducing agents on the topcoat layer of Eudragit RS [0136]

<td></td><td colspan="4">Percent</td>

<td>Serial number</td><td>RB 362-28</td><td>RB 362-48</td><td>RB 362-67</td><td>RB 362-65</td>

<td>Naltrexone cores</td><td></td><td></td><td></td><td></td>

<td>Naltrexone HCl</td><td>1.01</td><td>0.93</td><td>0.89</td><td>1.00</td>

<td>Sugar (# 20-25 mesh)</td><td>24,48</td><td>20.59</td><td>19,80</td><td>22.15</td>

<td>HPC (Klucel LF)</td><td>0.22</td><td>0.19</td><td></td><td></td>

<td>HPMC, 3 cps</td><td></td><td></td><td>0.18</td><td>0.20</td>

<td>Citric acid</td><td></td><td></td><td>0,004</td><td>0,004</td>

<td>Ascorbic acid</td><td></td><td></td><td>0,004</td><td>0,004</td>

<td>BHA</td><td></td><td></td><td>0,004</td><td>0,004</td>

<td>Talc</td><td>0.66</td><td>0.56</td><td>0.54</td><td>0.60</td>

<td>Naltrexone pellets</td><td></td><td></td><td></td><td></td>

<td>Naltrexone cores</td><td>(26.47)</td><td>(22.26)</td><td>(21,41)</td><td>(23.95)</td>

<td>Eudragit RS PO</td><td>10.64</td><td>8.95</td><td>8.62</td><td>9.64</td>

<td>SLS</td><td>0.36</td><td>0.30</td><td>0.29</td><td>0.33</td>

<td>DBS</td><td>1.06</td><td>0.89</td><td>0.85</td><td>0.95</td>

<td>Talc</td><td>10.89</td><td>9.16</td><td>8.62</td><td>9.64</td>

<td>Naltrexonmorphine cores</td><td></td><td></td><td></td><td></td>

<td>Naltrexone pellets</td><td>(49.41)</td><td>(41.55)</td><td>(39.78)</td><td>(44.50)</td>

<td>Morphine sulphate</td><td>26.05</td><td>21.70</td><td>21.70</td><td>24.76</td>

<td>Powdered sugar</td><td></td><td>13.66</td><td>9.32</td><td></td>

<td>Sodium chloride</td><td></td><td></td><td>6.43</td><td>7.01</td>

<td>HPMC, 3 cps</td><td>2.32</td><td>3.46</td><td>3.13</td><td>4.10</td>

<td>Naltrexonmorphine pellets</td><td></td><td></td><td></td><td></td>

<td>Naltrexonmorphine cores</td><td>(77.78)</td><td>(80.37)</td><td>(80.37)</td><td>(80.37)</td>

<td>Ethylcellulose N50</td><td>7.48</td><td>7.07</td><td>7.07</td><td>7.07</td>

<td>PEG 6000</td><td>3.59</td><td>2.88</td><td>2.81</td><td>2.62</td>

<td>Eudragit L 100-55</td><td>2.10</td><td>1.70</td><td>1.77</td><td>1.96</td>

<td>DEP</td><td>1.65</td><td>1.44</td><td>1.44</td><td>1.44</td>

<td>Talc</td><td>7.41</td><td>6.54</td><td>6.54</td><td>6.54</td>

<td>Together</td><td>100.00</td><td>100.00</td><td>100.00</td><td>100.00</td>

Manufacturing method:

[0137]

1. Klucel LF or HPMC (with or without citric acid, ascorbic acid and butylated hydroxyanisole) was dissolved in a 20:80 mixture of water and ethanol; and a dispersion of naltrexone HCl and talc was prepared in the solution.

2. In the Wurster apparatus, the naltrexone dispersion from point 1 was sprayed onto sugar spheres and naltrexone cores were obtained.

3. Eudragit RS, sodium lauryl sulfate and dibutyl sebacate were dissolved in ethanol and talc dispersion was prepared in solution.

4. In the Wurster apparatus, the dispersion from point 3 was sprayed onto naltrexone cores from point 2 and naltrexone pellets were obtained.

5. Naltrexone pellets were dried at 50 ° C for 12 hours (RB 362-28 and

RB 362-48) or for 65 hours (RB 362-67 and RB 362-65).

6. The obtained pellets had a coating of Eudragit RS with a thickness of 85-90 μm.

7. Sodium chloride and hypromellose are dissolved in water.

8. HPMC was dissolved in water or in a mixture of ethanol and water.

9. Sodium chloride was dissolved in the HPMC solution from point 8.

10. The powdered sugar was dissolved in the HPMC solution from point 8.

11. Morphine sulphate was dispersed in the HPMC solution from point 8.

12.

a. For RB 362-28, the naltrexone pellets from point 5 were sprayed in the rotor with the solution from 8, followed by the dispersion from 11, and the naltrexone-morphine cores were obtained.

b. For RB 362-48, the naltrexone pellets from point 5 were sprayed in the rotor with the solution from 8, followed by the dispersion from 10, the solution from 8 and the dispersion from 11 and the naltrexone-morphine cores were obtained.

c. For RB 362-67, the naltrexone pellets from point 5 were sprayed in the rotor with the solution from 9, followed by the dispersion from 10, then the solution from 8 and the dispersion from 11, and the naltrexone-morphine cores were obtained.

d. For RB 362-65, the naltrexone pellets from point 5 were sprayed in the rotor with the solution from step 9, followed by the solution from step 8, followed by the dispersion from step 11 to obtain the naltrexone-morphine cores.

13. Ethylcellulose, PEG 6000, Eudragit L100-55 and diethyl phthalate were dissolved in ethanol and talc dispersion was prepared in this solution.

14. Dispersion from point 13 was sprayed onto naltrexone-morphine cores from point 12 to obtain naltrexone-morphine pellets.

Results for drug release:

[0138] Release conditions: USP vane method at 37 ° C and 100 rpm, 72 hours in 500 ml of 0.05M phosphate buffer pH 7.5; or USP paddle method at 37 ° C and 100 rpm, 1 hour in 0.1 N HCl, and then 72 hours in 0.05 M phosphate buffer at pH 7.5

Results:

[0139]

<td>Serial number</td><td colspan="2">% of released NT at the end of release</td>

<td rowspan="2">RB 362-28</td><td>Naltrexone pellets</td><td>2</td>

<td>Naltrexone-morphine pellets</td><td>7.9</td>

<td rowspan="2">RB 362-48</td><td>Naltrexone pellets</td><td>2</td>

<td>Naltrexone-morphine pellets</td><td>68.5</td>

<td rowspan="2">RB 362-67</td><td>Naltrexone pellets</td><td>0</td>

<td>Naltrexone-morphine pellets</td><td>25</td>

<td rowspan="2">RB 362-65</td><td>Naltrexone pellets</td><td>0.2</td>

<td>Naltrexone-morphine pellets</td><td>1.4</td>

[0140] Conclusions: Sugar has a deleterious effect on the release of NT. After applying NaCl / HPMC, the desired NT release profile is obtained.

II. Evidence of the correctness of the test, 16 mg of naltrexone HCl (20-727-1N) [0141]

<td></td><td colspan="2">PI-1460</td><td colspan="2">PI-1461</td>

<td></td><td>mg / unit</td><td>Percent</td><td>mg / unit</td><td>Percent</td>

<td>Naltrexone HCl</td><td>8</td><td>2.23</td><td>8</td><td>2.07</td>

<td>Sugar balls (# 20-25 mesh)</td><td>177.9</td><td>49.6</td><td></td><td></td>

<td>Celines (# 20-25 mesh)</td><td></td><td></td><td>228.3</td><td>59.1</td>

<td>HPC (Klucel LF)</td><td>1.6</td><td>0.4</td><td>1.6</td><td>0.4</td>

<td>Talc</td><td>4.8</td><td>1.3</td><td>4.8</td><td>1.2</td>

<td>Eudragit RS PO</td><td>77.3</td><td>21.5</td><td>66.2</td><td>17.2</td>

<td>SLS</td><td>2.6</td><td>0.7</td><td>2.3</td><td>0.6</td>

<td>DBS</td><td>7.7</td><td>2.1</td><td>6.6</td><td>1.7</td>

<td>Talc</td><td>79.1</td><td>22.0</td><td>68.2</td><td>17.7</td>

<td>Together</td><td>359</td><td>100.0</td><td>386</td><td>100.0</td>

A. Method of production [0142]

1. Klucel LF was dissolved in a 20:80 mixture of water and ethanol. A dispersion of talc and naltrexone HCl was prepared in the solution.

2. In the Wurster apparatus, the dispersion from step 1 was sprayed onto sugar spheres (for PI-1460) or celette (for PI-1461) and naltrexone cores were obtained.

3. Eudragit RS, sodium lauryl sulfate and dibutyl sebacate were diluted in ethanol. A dispersion of talc was prepared in the solution.

4. In the Wurster apparatus, the dispersion from point 3 was sprayed onto naltrexone cores from point 2 and naltrexone pellets were obtained.

5. Naltrexone pellets were dried in an oven at 50 ° C for 12 hours.

6. The obtained pellets had a 90 μm thick Eudragit RS coating (for PI-1460) and 60 μm for PI-1461.

7. The pellets were filled in capsules.

B. In-vitro drug release [0143]

Method - USP vane method at 37 ° C and 100 rpm; 1.5 hours in 0.1 N HCl, then 72 hours in 0.05 M phosphate buffer at pH

7.5

Results - Percentage of released NT at 73 hours for PI-1460 = 2%

Percent of released NT at 73 hours for PI-1461 = 0%

C. In vivo bioassays [0144] An open-label, two-period, pilot study was conducted with a single dose on 26 healthy fasting patients:

Period 1: Oral liquid containing 16 mg of naltrexone (N = 26)

Period 2: 2 PI-1460 capsules (N = 13) or PI-1461 (N = 13) [0145] Blood samples were taken prior to dosing and between 0.5 to 72 hours after the dose and naltrexone and 6-beta levels were tested. -altrexol in plasma. The limit of quantification was 20.0 pg / ml for naltrexone and 0.250 pg / ml for 6-beta-naltrexol. The results are shown in Figures 7-10.

Summary of pharmacokinetic results [0146]

<td></td><td colspan="3">6-beta-naltrexol</td><td colspan="3">naltrexone</td>

<td></td><td>Solution NTX</td><td>2 capsules PI-1460</td><td>2 capsules PI-1461</td><td>Solution NTX</td><td>2 capsules PI-1460</td><td>2 capsules PI-1461</td>

<td>Tmax (hours)</td><td>0.75</td><td>43.02</td><td>32.01</td><td>0.75</td><td>24.38 (N = 4)</td><td>23.21 (N = 10)</td>

<td>Cmax (pg / ml)</td><td>24600</td><td>298</td><td>834</td><td>2950</td><td>22.4 (N = 11)</td><td>60.7</td>

<td></td><td colspan="3">6-beta-naltrexol</td><td colspan="3">naltrexone</td>

<td></td><td>Solution NTX</td><td>2 capsules PI-1460</td><td>2 capsules PI-1461</td><td>Solution NTX</td><td>2 capsules PI-1460</td><td>2 capsules PI-1461</td>

<td>AUClast (Pg * hr. / Ml)</td><td>205800</td><td>10460</td><td>32530</td><td>8925</td><td>200.2 (N = 11)</td><td>1258</td>

<td>AUClinf (pg * hr. / Ml)</td><td>212700</td><td></td><td></td><td>9569 (N = 23)</td><td></td><td></td>

<td colspan="7">The relative bioavailability of the oral solution:</td>

<td>Ratio of Cmax Ratio (Capsule / solution)</td><td></td><td>1.21%</td><td>3.39%</td><td></td><td>0.76%</td><td>2.06%</td>

<td>AUClast ratio (capsule/ solution)</td><td></td><td>5.08%</td><td>15.80%</td><td></td><td>2.24%</td><td>14.08%</td>

<td colspan="7">N = 26 for the solution, unless otherwise indicated, N = 12 for PI-1460 or PI-1461, unless otherwise indicated</td>

D. Application [0147]

1. Plasma 6-beta-naltrexol levels are a more accurate bioavailability index than NT levels in plasma due to their higher plasma levels and greater analytical sensitivity.

2. When the AUClast ratio of capsules to 6-beta-naltrexol solution was used as an indicator of cumulative NT release in vivo, significant sequestration of naltrexone was observed during up to 72 hours under fasting conditions. When celites were used as the core grains, three times higher NT release was observed in vivo than in the case of sugar. However, NT pellets that use celtics have an RS coating less thick than sugar (60 Pm compared to 90 Pm) because at 60 Pm thickness NT pellet cellets have a much better release profile in vitro than NT sugar pellets at 90 Pm.

III. Optimization study # 1, morphine sulphate and naltrexone 60 mg / 2.4 mg (ALPHKNT-002) [0148]

<td rowspan="2"></td><td colspan="3">PI-1462</td><td colspan="2">PI-1463</td>

<td>mg / unit</td><td colspan="2">Percent</td><td>mg / unit</td><td>Percent</td>

<td colspan="6">Naltrexone cores</td>

<td>Naltrexone HCl</td><td>2.4</td><td colspan="2">0.96</td><td>2.4</td><td>0.94</td>

<td>Celines (# 20-25 mesh)</td><td>67.1</td><td colspan="2">26.8</td><td>59.8</td><td>23.4</td>

<td>HPC (Klucel LF)</td><td>0.5</td><td colspan="2">0.2</td><td>0.5</td><td>0.2</td>

<td>Citric acid</td><td>0.01</td><td colspan="2">0.0040</td><td>0.01</td><td>0,004</td>

<td>Ascorbic acid</td><td>0.01</td><td colspan="2">0.0040</td><td>0.01</td><td>0,004</td>

<td>BHA</td><td>0.01</td><td colspan="2">0.0040</td><td>0.01</td><td>0,004</td>

<td>Talc</td><td>1.38</td><td colspan="2">0.6</td><td>1.57</td><td>0.6</td>

<td>Subtotal</td><td>71.4</td><td colspan="2">28.5</td><td>64.3</td><td>25.1</td>

<td colspan="6">Naltrexone pellets</td>

<td>Naltrexone cores</td><td>(71.4)</td><td colspan="2">(28.5)</td><td>(64.3)</td><td>(25.1)</td>

<td>Eudragit RS PO</td><td>19.5</td><td colspan="2">7.8</td><td>26</td><td>10.2</td>

<td>SLS</td><td>0.7</td><td colspan="2">0.3</td><td>0.9</td><td>0.4</td>

<td>DBS</td><td>2</td><td colspan="2">0.8</td><td>2.6</td><td>1.0</td>

<td>Talc</td><td>20</td><td colspan="2">8.0</td><td>26.6</td><td>10.4</td>

<td>Subtotal</td><td>113.6</td><td colspan="2">45.4</td><td>120.4</td><td>47.1</td>

<td colspan="6">Naltrexone-morphine cores</td>

<td>Naltrexone pellets</td><td colspan="2">(113.6)</td><td>(45.4)</td><td>(120.4)</td><td>(47.1)</td>

<td>Morphine sulphate</td><td colspan="2">58.7</td><td>23.5</td><td>56.3</td><td>22.0</td>

<td>Sodium chloride</td><td colspan="2">16.6</td><td>6.6</td><td>16.6</td><td>6.5</td>

<td>HPMC, 3 cps</td><td colspan="2">13.6</td><td>5.4</td><td>13.5</td><td>5.3</td>

<td>Subtotal</td><td colspan="2">202.5</td><td>80.9</td><td>206.8</td><td>80.8</td>

<td colspan="5">Naltrexone-morphine pellets</td>

<td>Naltrexone-morphine cores</td><td>(202.5)</td><td>(80.9)</td><td>(206.8)</td><td>(80.8)</td>

<td>Ethylcellulose N50</td><td>16</td><td>6.4</td><td>16.4</td><td>6.4</td>

<td>PEG 6000</td><td>7.4</td><td>3.0</td><td>7.6</td><td>3.0</td>

<td>Eudragit L100-55</td><td>3.5</td><td>1.4</td><td>3.6</td><td>1.4</td>

<td>DEP</td><td>3.3</td><td>1.3</td><td>3.4</td><td>1.3</td>

<td>Talc</td><td>17.5</td><td>7.0</td><td>18</td><td>7.0</td>

<td>Together</td><td>250.2</td><td>100.0</td><td>255.8</td><td>100.0</td>

A. Method of production [0149]

1. Klucel LF, citric acid, ascorbic acid and butylated hydroxyanisole were dissolved in a 20:80 mixture of water and ethanol. A dispersion of naltrexone HCl and talc was prepared in the solution.

2. In the Wurster apparatus the dispersion from point 1 was sprayed onto the celettes and naltrexone cores were obtained.

3. Eudragit RS, sodium lauryl sulfate and dibutyl sebacate were dissolved in ethanol. A dispersion of talc was prepared in this solution.

4. In the Wurster apparatus, the dispersion from point 3 was sprayed onto naltrexone cores from point 2 and naltrexone pellets were obtained.

5. Naltrexone pellets were dried at 50 ° C for 48 hours.

6. The obtained pellets had a 60 μm thick Eudragit RS coating for PI1462 and 90 μm for PI-1463.

7. Sodium chloride and hypromellose are dissolved in water.

8. Hypromellose was dissolved in a 10:90 mixture of water and ethanol. Morphine sulphate was dispersed in this solution.

9. The solution from point 7, followed by the dispersion from point 8, was sprayed onto the naltrexone pellet from point 5 to obtain the naltrexone-morphine cores.

10. Ethylcellulose, PEG 6000, Eudragit L100-55 and diethylphthalate were dissolved in ethanol. A dispersion of talc was prepared in this solution.

11. Dispersion from point 10 was sprayed onto naltrexone-morphine cores from point 9 to obtain naltrexone-morphine pellets.

12. These pellets were filled in capsules.

B. In-vitro drug release [0150]

Way

- USP vane method at 37 ° C and 100 rpm.

- 1 hour 0.1N HCl, then 72 hours in 0.05M phosphate buffer pH 7.5 [0151] Results

- Percentage of NT released in 73 hours for PI-1462 = 0%

- Percentage of NT released in 73 hours for PI-1463 = 0%

C. In vivo study [0152] One-dose open-label, single-dose study was conducted in which two groups of eight patients were administered one dose of PI-1462 or PI-1463 on an empty stomach. Blood samples were collected before the dose and 0.5 to 168 hours after the dose. The limits of quantification were 4.00 pg / ml for naltrexone and 0.250 pg / ml for 6-betanaltrexol. The data is shown in Figures 11-12.

2. Summary of pharmacodynamic parameters [0153]

<td></td><td colspan="2">6-beta-naltrexol</td><td colspan="2">naltrexone</td>

<td></td><td>PI-1462</td><td>PI-1463</td><td>PI-1462</td><td>PI-1463</td>

<td>Tmax (hours)</td><td>49.52</td><td>40.53</td><td>42.03</td><td>37.75 (N = 3)</td>

<td>Cmax (pg / mL)</td><td>349</td><td>285</td><td>25.3</td><td>35.5</td>

<td>AUClast (pg * hour / ml)</td><td>16850</td><td>11130</td><td>705.1</td><td>835.0</td>

<td>AUCoo (pg * hour / mL)</td><td>17040</td><td>11170</td><td>1057 (N = 4)</td><td>1711 (N = 3)</td>

<td>T1 / 2 (hours)</td><td>18.18</td><td>14.49</td><td>14.15 (N = 4)</td><td>8.89 (N = 3)</td>

<td colspan="4">Relative bioavailability of oral solution (adjusted dose)</td><td></td>

<td>The Cmax ratio (Test / Solution)</td><td>9.46%</td><td>7.72%</td><td>5.71%</td><td>8.02%</td>

<td>AUClast ratio (Test / Solution)</td><td>54.58%</td><td>36.05%</td><td>52.67%</td><td>62.37%</td>

<td>The AUCoo ratio (Test / Solution)</td><td>53.41%</td><td>35.01%</td><td>78.95%</td><td>119.2%</td>

<td colspan="5">N = 8, unless otherwise indicated</td>

3. Application [0154]

a. Plasma 6-beta-naltrexol levels are a more consistent indicator of bioavailability than naltrexone.

b. Significant release in vivo was observed in both formulations as indicated by relative bioavailability based on AUCro ratios. With a 90 μm coating, less release is observed than at 60 μm. From the comparison of PI-1463 (Opt # 1) and

PI-1461 (POC), it appears that the morphine / NaCl / Kadian ER coating on the top of naltrexone pellets causes more than a triple increase in NT release.

c. After a 7-day trial, 6-beta-naltrexol returns to baseline.

d. When a conventional buffer system is used, there is no clear correlation with NT release in vitro / in vivo. At the end of 72 hours, NT showed 0% release in vitro, but in vivo data showed significant NT release.

IV. Optimization studies # 2 and # 3, morphine sulphate and naltrexone HCl 60mg / 2.4mg (20-778-1N and 20-779-1N) [0155]

<td rowspan="2"></td><td>PI-1465</td><td></td><td>PI-1466</td><td></td>

<td>mg / unit</td><td>Percent</td><td>mg / unit</td><td>Percent</td>

<td colspan="3">Sugar balls coated with a sealing coat</td><td colspan="2" rowspan="2"></td>

<td colspan="3"></td>

<td>Sugar balls (# 20-25 mesh)</td><td>52.1</td><td>16.0</td><td>53.1</td><td>14.6</td>

<td rowspan="2"></td><td>PI-1465</td><td></td><td>PI-1466</td><td></td>

<td>mg / unit</td><td>Percent</td><td>mg / unit</td><td>Percent</td>

<td colspan="3">Sugar balls coated with a sealing coat</td><td colspan="2" rowspan="2"></td>

<td colspan="3"></td>

<td>Ethylcellulose N50</td><td>3.9</td><td>1.2</td><td>3.98</td><td>1.1</td>

<td>Magnesium stearate</td><td>1.6</td><td>0.5</td><td>1.6</td><td>0.4</td>

<td>Sebibutanate</td><td>0.4</td><td>0.1</td><td>0.4</td><td>0.1</td>

<td>Talc</td><td>10</td><td>3.1</td><td>10.27</td><td>2.8</td>

<td>Subtotal</td><td>68.0</td><td>20.9</td><td>69.4</td><td>19.0</td>

<td colspan="5">Naltrexone cores</td>

<td>Sealed sugar balls</td><td>(68.0)</td><td>(20.9)</td><td>(69.4)</td><td>(19.0)</td>

<td>Naltrexone HCl</td><td>2.4</td><td>0.74</td><td>2.4</td><td>0.66</td>

<td>HPC (Klucel LF)</td><td>0.5</td><td>0.2</td><td>0.5</td><td>0.1</td>

<td>Citric acid</td><td>0.01</td><td>0.0031</td><td>0.01</td><td>0.0027</td>

<td>Ascorbic acid</td><td>0.01</td><td>0.0031</td><td>0.01</td><td>0.0027</td>

<td>Butylated hydroxyanisole</td><td>0.01</td><td>0.0031</td><td>0.01</td><td>0.0027</td>

<td>Talc</td><td>1.4</td><td>0.4</td><td>1.43</td><td>0.4</td>

<td>Subtotal</td><td>72.3</td><td>22.3</td><td>73.7</td><td>20.2</td>

<td colspan="5">Naltrexone pellets</td>

<td>Naltrexone cores</td><td>(144.7)</td><td>(44.5)</td><td>(147.4)</td><td>(40.4)</td>

<td>Eudragit RS PO</td><td>25.4</td><td>7.8</td><td>38.7</td><td>10.6</td>

<td>Sodium lauryl sulphate</td><td>0.9</td><td>0.3</td><td>1.31</td><td>0.4</td>

<td>Sebibutanate</td><td>2.53</td><td>0.8</td><td>3.87</td><td>1.1</td>

<td>Talc</td><td>26</td><td>8.0</td><td>38.7</td><td>10.6</td>

<td>Subtotal</td><td>199.5</td><td>61.4</td><td>230, 0</td><td>63.1</td>

<td colspan="5">Naltrexone-morphine cores</td>

<td>Naltrexone pellets</td><td>(199.5)</td><td>(61-4)</td><td>(230.0)</td><td>(63.1)</td>

<td>Morphine sulphate</td><td>59.3</td><td>18.2</td><td>59.5</td><td>16.3</td>

<td colspan="5">Naltrexone pellets</td>

<td>Sodium chloride</td><td>17.5</td><td>5.4</td><td>20.1</td><td>5.5</td>

<td>Hypromellose 2910, 3 cps</td><td>14.2</td><td>4.4</td><td>15.1</td><td>4.1</td>

<td>Subtotal</td><td>290.5</td><td>89.4</td><td>324.7</td><td>89.0</td>

<td colspan="5">Naltrexone-morphine pellets</td>

<td>Naltrexone-morphine cores</td><td>(290.5)</td><td>(89.4)</td><td>(324.7)</td><td>(89.0)</td>

<td>Ethylcellulose N50</td><td>11.51</td><td>3.5</td><td>13.1</td><td>3.6</td>

<td>Polyethylene glycol 6000</td><td>5.3</td><td>1.6</td><td>6.1</td><td>1.7</td>

<td>Eudragit L100-55</td><td>2.1</td><td>0.6</td><td>2.85</td><td>0.8</td>

<td>Diethyl phthalate</td><td>2.4</td><td>0.7</td><td>2.8</td><td>0.8</td>

<td>Talc</td><td>13.23</td><td>4.1</td><td>15.2</td><td>4.2</td>

<td>Together</td><td>325.0</td><td>100.0</td><td>364.8</td><td>100.0</td>

A. Method of production [0156]

1. Ethylcellulose and dibutyl sebacate were dissolved in ethanol, and then a dispersion of talc and magnesium stearate was made in the solution.

2. In the Wurster apparatus, the dispersion from point 1 was sprayed onto the sugar spheres and sugar spheres were coated with a sealing coating (thickness of the seal coating 25 μm).

3. Klucel LF, citric acid, ascorbic acid and butylated hydroxyanisole were dissolved in a 20:80 mixture of water and ethanol. Naltrexone HCl and talc were dispersed in this solution.

4. In the Wurster apparatus, the dispersion from point 3 was sprayed on the sugar-coated sugar beads and the naltrexone cores were obtained.

5. Eudragit RS, sodium lauryl sulfate and dibutyl sebacate were dissolved in ethanol. Talc was dispersed in the solution.

6. In the Wurster apparatus, the dispersion from 5 was sprayed onto naltrexone cores from step 4 to obtain naltrexone pellets.

7. Naltrexone pellets were dried at 50 ° C for 48 hours.

8. The obtained pellets had a 90 μm thick Eudragit RS coating for PI-1465 and 120 μm for PI-1466.

9. Sodium chloride and hypromellose are dissolved in water.

10. Hypromellose was dissolved in a 10:90 mixture of water and ethanol. The solution was dispersed with morphine sulphate.

11. The solution from 9 and then the dispersion from 10 was sprayed onto the naltrexone pellet from point 7 to obtain the naltrexone-morphine cores.

12. Ethylcellulose, PEG 6000, Eudragit L100-55 and diethylphthalate were dissolved in ethanol. Talc was dispersed in the solution.

13. Dispersion from point 12 was sprayed onto naltrexone-morphine cores from point 11 to obtain naltrexone-morphine pellets.

14. The pellets were filled into capsules.

B. In-vitro drug release [0157]

1. Way

- USP vane method at 37 ° C and 100 rpm.

- 1 hour in 0.1N HCl, then 72 hours in 0.05M phosphate buffer at pH 7.5

Results

- Percentage of NT released in 73 hours for PI-1465 = 1%

- Percentage of NT released in 73 hours for PI-1466 = 0%

2. Way

- USP vane method at 37 ° C and 100 rpm.

- 72 hours in 0.2% Triton X-100 / 0.2% sodium acetate / 0.002N HCl, pH 5.5

- The data is shown in Figure 13.

C. In-vivo Study # 1 [0158] An open, single-dose, single-dose study was conducted in which two groups of eight patients received one bolus of PI-1465 or PI-1466. Blood samples were collected prior to the dose administration and 0.5 to 168 hours after the dose. The limits of quantification were 4.00 pg / ml for naltrexone and 0.250 pg / ml for 6-betanaltrexol. The data is shown in Figures 14-15.

2. Summary of pharmacokinetic parameters [0159]

<td></td><td colspan="2">6-beta-naltrexol</td><td colspan="2">naltrexone</td>

<td></td><td>PI-1465</td><td>PI-1466</td><td>PI-1465</td><td>PI-1466</td>

<td>Tmax (hr)</td><td>58.51</td><td>79,50</td><td>50.30 (N = 7)</td><td>45.17 (N = 3)</td>

<td>Cmax (pg / mL)</td><td>1060</td><td>72.6</td><td>139.3</td><td>46.2</td>

<td>AUClast (pg * hours / mL)</td><td>54693</td><td>23473</td><td>3713</td><td>744</td>

<td>AUCoo (pg * hours / mL)</td><td>56260</td><td>23940</td><td>7213 (N = 4)</td><td>5943 (N = 2)</td>

<td>T1 / 2 (hours)</td><td>20.90</td><td>15.09</td><td>16.47 (N = 4)</td><td>34.10 (N = 2)</td>

<td colspan="4">Relative bioavailability for an oral solution (adjusted dose)</td><td></td>

<td>Cmax ratio (test / solution)</td><td>4.31%</td><td>1.97%</td><td>4.72%</td><td>1.57%</td>

<td>The ratio of AUC_forestt (test / solution)</td><td>26.58%</td><td>11.41%</td><td>41.60%</td><td>8.34%</td>

<td>AUCro ratio (test / solution)</td><td>26.45%</td><td>11.26%</td><td>75.38%</td><td>62.11%</td>

<td colspan="5">N = 8, unless otherwise indicated</td>

3. Applications [0160]

a. The presence of a surfactant in the release medium (the second method of in vitro drug release) provides better in vitro-in-vivo release of the release than in the buffer alone (the first in-vitro drug release method).

b. Kadian NT pellets (additionally NaCl / morphine / Kadian ER coating on top of naltrexone pellets) showed higher release of naltrexone in vivo than naltrexone pellets alone. PI-1465 with a sealing coat and naltrexone pellets with a coating of the same thickness as for PI-1460 with POC, without a sealing coat (90 μm), showed more than 5-times the release of naltrexone. Even after the coating thickness of the naltrexone pellets was increased to 120 μm (PI-1466), the release of naltrexone was still observed twice.

D. In-vivo Study # 2 [0161] An open, single-dose, single-dose study was conducted in which four groups of four healthy subjects received one dose of PI-1465 or PI1466 after fasting or after a meal. Blood samples were collected before the dose and 0.5 to 168 hours after the dose. The limits of quantification were 4.00 pg / ml for naltrexone and 0.250 pg / ml for 6-beta-naltrexol. The data is shown in Figures 1617.

1. Summary of pharmacokinetic parameters

a. Naltrexone [0162]

<td></td><td colspan="2">PI-1465</td><td colspan="2">PI-1466</td>

<td></td><td>Fast</td><td>Fed</td><td>Fast</td><td>Fed</td>

<td>Tmax (hours)</td><td>72.00</td><td>26.67 (N = 3)</td><td>60.00 (N = 2)</td><td>32.00 (N = 3)</td>

<td>Cmax (pg / mL)</td><td>107.3</td><td>279.3</td><td>35.73</td><td>262</td>

<td>AUClast (pg * h / mL)</td><td>2825</td><td>4135</td><td>1319</td><td>4611</td>

<td>AUCoo (pg * hours / mL)</td><td>3593 (N = 1)</td><td>6787 (N = 2)</td><td>3651 (N = 2)</td><td>-</td>

<td>T1 / 2 (hours).</td><td>15.26 (N = 1)</td><td>20.98 (N = 2)</td><td>24.75 (N = 2)</td><td>-</td>

<td colspan="5">Relative bioavailability for an oral solution (adjusted dose)</td>

<td>Cmax ratio (Test / solution)</td><td>3.64%</td><td>9.47%</td><td>1.21%</td><td>8.89%</td>

<td>AUClast ratio (Test / solution)</td><td>31.65%</td><td>46.33%</td><td>14.78%</td><td>51.66%</td>

<td>AUCro ratio (Test / Solution)</td><td>37.55%</td><td>70.93%</td><td>38.15%</td><td>-</td>

<td colspan="5">N = 4, unless otherwise indicated</td>

b. 6-beta-naltrexol levels [0163]

<td></td><td colspan="2">PI-1465</td><td colspan="2">PI-1466</td>

<td></td><td>On an empty stomach</td><td>After meal</td><td>On an empty stomach</td><td>After meal</td>

<td>Tmax (hours)</td><td>69,00</td><td>29.00</td><td>69,00</td><td>36,00</td>

<td>Cmax (pg / mL)</td><td>1280</td><td>3787</td><td>873</td><td>2680</td>

<td>AUClast (pg * h / mL)</td><td>53307</td><td>120400</td><td>47140</td><td>78533</td>

<td>AUCro (pg * hours / mL)</td><td>53547</td><td>122533</td><td>47920</td><td>78867</td>

<td>T1 / 2 (hours)</td><td>19,21</td><td>18.17</td><td>20.69</td><td>20.19</td>

<td colspan="3">Relative bioavailability for an oral solution</td><td></td><td></td>

<td>Cmax ratio (Test / solution)</td><td>5.20%</td><td>15.39%</td><td>3.55%</td><td>10.89%</td>

<td>AUClast ratio (Test / solution)</td><td>25.90%</td><td>58.50%</td><td>22.91%</td><td>38.16%</td>

<td>The AUCro ratio (Test / solution)</td><td>25.17%</td><td>57.61%</td><td>22.53%</td><td>37.08%</td>

<td colspan="5">N = 4, unless otherwise indicated</td>

2. Conclusion [0164]

a. A significant effect of the meal was observed, after which the dead time was shortened and the release of NT was increased. After the meal, a two-fold increase in NT release for PI-1465 and 1.5-fold for PI-1466 was observed.

b. There was also some variability in the group of patients. For comparison, at PI-1466 in both in-vivo studies, # 1 and # 2, although the same product was used, a double difference in AUC was observed. In the case of PI-1465, the AUC was similar in both studies.

V. Optimization study # 4, morphine sulphate and naltrexone HCl 60mg / 4.8 mg (20-7801N) [0165]

<td rowspan="2"></td><td colspan="2">PI-1495</td><td colspan="2">PI-1496</td>

<td>mg / unit</td><td>Percent</td><td>mg / unit</td><td>Percent</td>

<td colspan="3">Sugar balls coated with a sealing coat</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td>

<td>Sugar balls (# 20-25 mesh)</td><td>37.2</td><td>11.7</td><td>37.1</td><td>11.9</td>

<td>Ethylcellulose N50</td><td>6.2</td><td>1.9</td><td>6.2</td><td>2.0</td>

<td>Magnesium stearate</td><td>2.5</td><td>0.8</td><td>2.5</td><td>0.8</td>

<td>DBS</td><td>0.6</td><td>0.2</td><td>0.6</td><td>0.2</td>

<td>Talc</td><td>15.5</td><td>4.9</td><td>15.5</td><td>5.0</td>

<td>Subtotal</td><td>62.0</td><td>19.4</td><td>61.9</td><td>19.9</td>

<td colspan="5">Naltrexone cores</td>

<td>Sealed balls sugar</td><td>(62.0)</td><td>(19.4)</td><td>(61.9)</td><td>(19.4)</td>

<td>Naltrexone HCl</td><td>4.8</td><td>1.50</td><td>4.8</td><td>1.54</td>

<td>HPC (Klucel LF)</td><td>0.9</td><td>0.3</td><td>0.9</td><td>0.3</td>

<td>Ascorbic acid</td><td>0.5</td><td>0.2</td><td>0.5</td><td>0.2</td>

<td>Talc</td><td>2.27</td><td>0.7</td><td>2.24</td><td>0.7</td>

<td>Subtotal</td><td>70.5</td><td>22.1</td><td>70.3</td><td>22.6</td>

<td colspan="5">Naltrexone pellets</td>

<td>Naltrexone cores</td><td>(70.5)</td><td>(22.1)</td><td>(70.3)</td><td>(22.6)</td>

<td>Eudragit RS PO</td><td>53.3</td><td>16.7</td><td>53.3</td><td>17.1</td>

<td>SLS</td><td>1.8</td><td>0.6</td><td>1.8</td><td>0.6</td>

<td>DBS</td><td>5.36</td><td>1.7</td><td>5.36</td><td>1.7</td>

<td>Talc</td><td>52.1</td><td>16.3</td><td>52.1</td><td>16.8</td>

<td>Subtotal</td><td>183.0</td><td>57.4</td><td>182.9</td><td>58.8</td>

<td colspan="5">Naltrexone-morphine cores</td>

<td>Naltrexone pellets</td><td>(183.0)</td><td>(57.4)</td><td>(182.9)</td><td>(58.8)</td>

<td>Morphine sulphate</td><td>59.9</td><td>18.8</td><td>59.7</td><td>19.2</td>

<td>Sodium chloride</td><td>11.2</td><td>3.5</td><td></td><td></td>

<td>HPC (Klucel LF)</td><td>7.3</td><td>2.3</td><td>4.75</td><td>1.5</td>

<td>HPMC, 3 cps</td><td></td><td></td><td>7.6</td><td>2.4</td>

<td>Subtotal</td><td>261.4</td><td>82.0</td><td>255.0</td><td>82.0</td>

<td colspan="2">Naltrexone-morphine cores</td><td></td><td></td><td></td>

<td>Naltrexonmorphine cores</td><td>(261.4)</td><td>(82.0)</td><td>(255.0)</td><td>(82.0)</td>

<td>Ethylcellulose N50</td><td>19.81</td><td>6.2</td><td>19.31</td><td>6.2</td>

<td>PEG 6000</td><td>9.16</td><td>2.9</td><td>8.9</td><td>2.9</td>

<td>Eudragit L100-55</td><td>4.3</td><td>1.3</td><td>4.2</td><td>1.4</td>

<td>DEP</td><td>4.12</td><td>1.3</td><td>4</td><td>1.3</td>

<td>Talc</td><td>20.13</td><td>6.3</td><td>19.62</td><td>6.3</td>

<td>Together</td><td>319.0</td><td>100.0</td><td>311.0</td><td>100.0</td>

A. Production method [0166]

1. Ethylcellulose and dibutyl sebacate were dissolved in ethanol, followed by dispersion of talc and magnesium stearate in solution.

2. In the Wurster apparatus, the dispersion from point 1 was sprayed onto the sugar spheres and sugar spheres were coated with a sealing coating (thickness of the sealing film 50 μm).

3. Klucel LF and ascorbic acid were dissolved in a 20:80 mixture of water and ethanol. Naltrexone HCl and talc were dispersed in the solution.

4. In the Wurster apparatus, the dispersion from point 3 was sprayed onto the sugar-coated sugar beads from point 2 and the naltrexone cores were obtained.

5. Eudragit RS, sodium lauryl sulfate and dibutyl sebacate were dissolved in ethanol. Talc was dispersed in the solution.

6. In the Wurster apparatus, the dispersion from 5 was sprayed onto naltrexone cores from step 4 to obtain naltrexone pellets.

7. Naltrexone pellets were dried at 50 ° C for 48 hours.

8. The obtained pellets had a coating with Eudragit RS 150 μm thick for PI-1495 and for PI-1496.

9. (Only for PI-1496) Sodium chloride and hypromellose are dissolved in water.

10. Hypromellose was dissolved in a 10:90 mixture of water and ethanol. The solution was dispersed with morphine sulphate.

11. (Only for PI-1495). The solution from 9, followed by the dispersion from 10, was sprayed onto the naltrexone pellet from point 7 to obtain the naltrexone-morphine cores.

12. (Only for PI-1496). Dispersion from point 10 was sprayed onto the naltrexone pellet from point 7 to obtain naltrexone-morphine cores.

13. Ethylcellulose, PEG 6000, Eudragit L100-55 and diethylphthalate were dissolved in ethanol. Talc was dispersed in the solution.

14. Dispersion from point 12 was sprayed onto naltrexone-morphine cores from point 11 or from point 12 to obtain naltrexone-morphine pellets.

15. The pellets were filled into capsules.

B. In-vitro drug release [0167]

1. Way

- USP vane method at 37 ° C and 100 rpm.

- 1 hour in 0.1N HCl, then 72 hours in 0.05M phosphate buffer at pH 7.5

Results

- Percentage of NT released at 73 hours for PI-1495 = 0%

- Percentage of NT released in 73 hours for PI-1496 = 0%

2. Way

- USP vane method at 37 ° C and 100 rpm.

- 72 hours in 0.2% Triton X-100 / 0.2% sodium acetate / 0.002N HCl, pH 5.5

Results

- Percentage of NT released at 73 hours for PI-1495 = 0%

- Percentage of NT released in 73 hours for PI-1496 = 0%

C. In-vivo study [0168] Open-label, single-dose, bipartite studies were conducted in which two groups of eight patients were given one dose of PI-1495 or PI-1496. Each patient received the treatment sequence assigned to him according to the fasting and non-fasting randomization scheme. Blood samples were collected before the dose and 0.5 to 168 hours after the dose. The limits of quantification were 4.00 pg / ml for naltrexone and 0.250 pg / ml for 6-beta-naltrexol. The data is shown in Figures 18-19.

2. Summary of pharmacokinetic parameters

a. Naltrexone [0169]

<td></td><td colspan="2">PI-1495</td><td colspan="2">PI-1496</td>

<td></td><td>On an empty stomach</td><td>After meal</td><td>On an empty stomach</td><td>After meal</td>

<td>Tmax (hours)</td><td>54,00 (N = 2)</td><td>14.34 (N = 3)</td><td>55.20 (N = 5)</td><td>41.60 (N = 5)</td>

<td>Cmax (pg / mL)</td><td>8.53</td><td>6.32 (N = 7)</td><td>24.23 (N = 7)</td><td>45.67 (N = 7)</td>

<td>AUClast (pg * h / mL)</td><td>100.8</td><td>75.9 (N = 7)</td><td>500.6 (N = 7)</td><td>1265 (N = 7)</td>

<td>AUCro (pg * hours / mL)</td><td>-</td><td>-</td><td>2105.3 (N = 2)</td><td>3737 (N = 2)</td>

<td>T1 / 2 (hours)</td><td>-</td><td>-</td><td>44.56 (N = 2)</td><td>33.17 (N = 2)</td>

<td colspan="5">Relative bioavailability for an oral solution (adjusted dose)</td>

<td>Cmax ratio (Test / solution)</td><td>0.29%</td><td>0.21%</td><td>0.82%</td><td>1.55%</td>

<td>AUClast ratio (Test / solution)</td><td>1.13%</td><td>0.85%</td><td>5.61%</td><td>14.17%</td>

<td>AUCro ratio (Test / Solution)</td><td>-</td><td>-</td><td>22.0%</td><td>39.1%</td>

<td colspan="5">N = 8, unless otherwise indicated</td>

b. 6-beta-naltrexol levels [0170]

<td></td><td colspan="2">PI-1495</td><td colspan="2">PI-1496</td>

<td></td><td>On an empty stomach</td><td>After meal</td><td>On an empty stomach</td><td>After meal</td>

<td>Tmax (hours)</td><td>69,00</td><td>41.44 (N = 7)</td><td>70.51</td><td>67.63</td>

<td></td><td colspan="2">PI-1495</td><td colspan="2">PI-1496</td>

<td></td><td>On an empty stomach</td><td>After meal</td><td>On an empty stomach</td><td>After meal</td>

<td>Cmax (pg / mL)</td><td>116.3</td><td>151.7 (N = 7)</td><td>303.3</td><td>656.7</td>

<td>AUClast (pg * h / mL)</td><td>5043</td><td>7332 (N-7)</td><td>14653</td><td>27503</td>

<td>AUCro (pg * hours / mL)</td><td>5607</td><td>8449 (N = 6)</td><td>14930</td><td>27827</td>

<td>T1 / 2 (hours)</td><td>20.97</td><td>16.69 (N = 7)</td><td>16.29</td><td>22,59</td>

<td colspan="5"></td>

<td colspan="5">Relative bioavailability for an oral solution (adjusted dose)</td>

<td>Cmax ratio (Test / solution)</td><td>0.47%</td><td>0.62%</td><td>1.23%</td><td>2.67%</td>

<td>The ratio of AUC_last (Test / solution)</td><td>2.45%</td><td>3.45%</td><td>7.12%</td><td>13.36%</td>

<td>AUCro ratio (Test / Solution)</td><td>2.64%</td><td>3.97%</td><td>7.02%</td><td>13.08%</td>

<td colspan="5">N = 8, unless otherwise indicated</td>

3. Application [0171]

a. Kadian NT pellets with naltrexone pellets with a 150 μm coating have a comparable release of naltrexone, such as NT pellets with a 90 μm coating. This comparable NT release can also be attributed to the presence of a 50 μm sealing coating on sugar spheres that is used in Kadian NT pellets.

b. In both states, fasting (&gt; 97%) and after a meal (&gt; 96%), significant NT sequestration was observed.

c. According to in vitro results, Kadian NT pellets containing sodium chloride directly above the naltrexone pellet coating (PI-1495) showed half the release of naltrexone, compared to Kadian NT pellets without sodium chloride (PI-1496).

d. The impact of food was again observed. Dead time was significantly reduced.

VI. Optimization study # 5, morphine sulphate and naltrexone HCl 60mg / 2.4 mg (20903-AU) [0172]

<td rowspan="2"></td><td colspan="2">PI-1510</td>

<td>mg / unit</td><td>Percent</td>

<td>Sealed sugar balls</td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td>Sugar balls (# 25-30 mesh)</td><td>39.9</td><td>12.2</td>

<td>Ethylcellulose N50</td><td>6.5</td><td>2.0</td>

<td>Magnesium stearate</td><td>2.6</td><td>0.8</td>

<td>DBS</td><td>0.7</td><td>0.2</td>

<td>Talc</td><td>16.7</td><td>5.1</td>

<td>Subtotal</td><td>66.4</td><td>20.3</td>

<td>Naltrexone cores</td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td>Sealed sugar balls</td><td>(66.4)</td><td>(20.3)</td>

<td>Naltrexone HCl</td><td rowspan="2">2.4</td><td rowspan="2">0.73</td>

<td></td>

<td>HPC (Klucel LF)</td><td>0.5</td><td>0.1</td>

<td>Ascorbic acid</td><td>0.2</td><td>0.1</td>

<td>Talc</td><td>1.1</td><td>0.4</td>

<td>Subtotal</td><td>70.6</td><td>21.6</td>

<td>Naltrexone pellets</td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td>Naltrexone cores</td><td>(70.6)</td><td>(21.6)</td>

<td>Eudragit RS PO</td><td>53.0</td><td>16.2</td>

<td>SLS</td><td>1.8</td><td>0.6</td>

<td>DBS</td><td>5.3</td><td>1.6</td>

<td>Talc</td><td>53.0</td><td>16.2</td>

<td>Subtotal</td><td>183.7</td><td>56.2</td>

<td>Naltrexone-morphine cores</td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td>Naltrexone pellets</td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td>Naltrexone pellets</td><td>(183.7)</td><td>(56.2)</td>

<td>Morphine sulphate</td><td>60.1</td><td>18.4</td>

<td>Sodium chloride</td><td>12.5</td><td>3.8</td>

<td>HPC (Klucel LF)</td><td>6.2</td><td>1.9</td>

<td>Subtotal</td><td>262.4</td><td>80.2</td>

<td>Naltrexone-morphine pellets</td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td>Naltrexone-morphine cores</td><td>(262.4)</td><td>(80.2)</td>

<td>Ethylcellulose N50</td><td>22.9</td><td>7.0</td>

<td>PEG 6000</td><td>10.6</td><td>3.2</td>

<td>Eudragit L100-55</td><td>5.0</td><td>1.5</td>

<td>DEP</td><td>4.7</td><td>1.5</td>

<td>Talc</td><td>21.5</td><td>6.6</td>

<td>Together</td><td>327.1</td><td>100.0</td>

B. Production method [0173]

1. Ethylcellulose and dibutyl sebacate were dissolved in ethanol, then a dispersion of talc and magnesium stearate was made in the solution.

2. In the Wurster apparatus, the dispersion from point 1 was sprayed onto the sugar spheres and sugar spheres were coated with a sealing coating (thickness of the sealing film 50 μm).

3. Klucel LF and ascorbic acid were dissolved in a 20:80 mixture of water and ethanol. Naltrexone HCl and talc were dispersed in the solution.

4. In the Wurster apparatus, the dispersion from point 3 was sprayed on the sugar-coated sugar beads and the naltrexone cores were obtained.

5. Eudragit RS, sodium lauryl sulfate and dibutyl sebacate were dissolved in ethanol. Talc was dispersed in the solution.

6. In the Wurster apparatus, the dispersion from 5 was sprayed onto naltrexone cores from step 4 to obtain naltrexone pellets.

7. Naltrexone pellets were dried at 50 ° C for 48 hours.

8. The obtained pellets had a coating of Eudragit RS with a thickness of 150 μm.

9. Sodium chloride and hypromellose are dissolved in water.

10. Hypromellose was dissolved in a 10:90 mixture of water and ethanol. The solution was dispersed with morphine sulphate.

11. The solution from 9 and then the dispersion from 10 was sprayed onto the naltrexone pellet from point 7 to obtain the naltrexone-morphine cores.

12. Ethylcellulose, PEG 6000, Eudragit L100-55 and diethylphthalate were dissolved in ethanol. Talc was dispersed in the solution.

13. Dispersion from point 12 was sprayed onto naltrexone-morphine cores from step 11 or 12 to obtain naltrexone-morphine pellets.

14. The pellets were filled into capsules.

B. In-vitro drug release [0174]

1. Way

- USP vane method at 37 ° C and 100 rpm.

- 1 hour in 0.1N HCl, then 72 hours in 0.05M phosphate buffer at pH 7.5

Results

- Percentage of NT released in 73 hours = 0%

2. Way

- USP vane method at 37 ° C and 100 rpm.

- 72 hours in 0.2% Triton X-100 / 0.2% sodium acetate / 0.002N HCl, pH 5.5

Results

- Percentage of NT released in 73 hours = 0%

C. In-vivo study [0175] Open-label, single-dose, bipartite studies were conducted in which eight patients were administered one bolus of PI-1510 on an empty or fed meal during Study Period 1 and alternately fasted or fed during Study Period 2. Blood Samples were taken before the dose and 0.5 to 168 hours after the dose. The limits of quantification were 4.00 pg / ml for naltrexone and 0.250 pg / ml for 6-betanaltrexol. The data is shown in Figures 20 and 21.

2. Summary of pharmacokinetic parameters

a. 6-beta-naltrexol levels [0176]

<td></td><td colspan="2">PI-1510</td>

<td></td><td>On an empty stomach</td><td>After meal</td>

<td>Tmax (hours)</td><td>45,00 (N = 6)</td><td>57,29 (N = 7)</td>

<td>Cmax (pg / mL)</td><td>16.1</td><td>25.0</td>

<td>AUClast (pg * hours / mL)</td><td>609.2</td><td>1057</td>

<td>AUCro (pg * hours / mL)</td><td>1233</td><td>1431 (N = 6)</td>

<td>T1 / 2 (hours)</td><td>17.36</td><td>17.48 (N = 6)</td>

<td colspan="3">Relative bioavailability for an oral solution (adjusted dose)</td>

<td>Cmax ratio (Test / solution)</td><td>0.44%</td><td>0.68%</td>

<td>The ratio of AUC_last (Test / solution)</td><td>1.97%</td><td>3.42%</td>

<td>AUCro ratio (Test / Solution)</td><td>3.86%</td><td>4.49%</td>

<td colspan="3">N = 8, unless otherwise indicated</td>

3. Application [0177]

a. PI-1510 and PI-1495 are comparable. The reduction of naltrexone load in pellets (from 1.5% in PI-1495 to 0.7% in PI-1510) does not seem to affect the release of NT.

b. Fast sequestration of NT was observed both on an empty stomach (&gt; 96%) and after a meal (&gt; 95%).

c. The observed effect of the meal was small with respect to the total release of NT. However, the dead time was significantly shortened in the presence of food. There were also patients with multiple release peaks.

VII. Summary of NT release in all in vivo studies [0178]

BA (Cmax) = Relative bioavailability based on Cmax = ratio of the dose adjusted for Cmax (NT / KNT pellets) to Cmax (NT solution)

BA (AUC last) = Relative availability based on AUC last = ratio of the adjusted dose for AUC last (NT / KNT pellets) to AU

BA (AUC inf) = Relative availability based on AUC inf = adjusted dose ratio for AUC inf (NT / KNT pellets)

Total cumulative NT release in vivo can be extrapolated from BA (AUC inf) from 6-beta-naltrexone plasma levels

<td></td><td>BA (Cmax) (%)</td><td>BA (AUC last) (%)</td><td>BA (AUC inf) (%)</td>

<td></td><td></td><td></td><td></td>

<td>POC</td><td></td><td></td><td></td>

<td>PI-1460 on an empty stomach</td><td></td><td></td><td></td>

<td>Average ± SD</td><td>1.2 ± 0.9</td><td>5.1 ± 3.1</td><td></td>

<td>Range</td><td>0.32 - 2.99</td><td>1.92 - 10.65</td><td></td>

<td></td><td></td><td></td><td></td>

<td>PI-1461 on an empty stomach</td><td></td><td></td><td></td>

<td>Average ± SD</td><td>3.1 ± 2.4</td><td>15.8 ± 11.9</td><td></td>

<td>Range</td><td>0.7 - 10.3</td><td>2.8 - 49.2</td><td></td>

<td></td><td></td><td></td><td></td>

<td>OPTIMIZATION # 1</td><td></td><td></td><td></td>

<td>PI-1462 on an empty stomach</td><td></td><td></td><td></td>

<td>Average ± SD</td><td>9.5 ± 2.8</td><td>54.6 + 21.0</td><td>53.4 ± 20.6</td>

<td>Range</td><td>5.7 - 13.0</td><td>26.3 - 86.3</td><td>25.6 - 84.4</td>

<td></td><td></td><td></td><td></td>

<td>PI-1463 on an empty stomach</td><td></td><td></td><td></td>

<td>Average ± SD</td><td>7.7 ± 3.7</td><td>36.1 ± 18.2</td><td>35.0 ± 17.7</td>

<td>Range</td><td>0.8 - 12.4</td><td>3.9 - 59.2</td><td>3.8 - 57.3</td>

<td></td><td></td><td></td><td></td>

<td>OPTIMIZATION # _2 and # 3</td><td></td><td></td><td></td>

<td>PI-1465</td><td></td><td></td><td></td>

<td>On an empty stomach 1</td><td></td><td></td><td></td>

<td>Average ± SD</td><td>4.3 ± 6.2</td><td>26.6 ± 35.4</td><td>26.4 ± 35.0</td>

<td>Range</td><td>0.1-18.6</td><td>0.1-111.6</td><td>0.1 - 110.5</td>

<td></td><td></td><td></td><td></td>

<td>Fasting 2</td><td></td><td></td><td></td>

<td>Average ± SD</td><td>5.2 ± 3.9</td><td>25.9 ± 15.7</td><td>25.2 ± 15.2</td>

<td>Range</td><td>1.8 - 10.5</td><td>9.6 - 41.5</td><td>9.4 - 40.2</td>

<td></td><td></td><td></td><td></td>

<td>After meal</td><td></td><td></td><td></td>

<td>Average ± SD</td><td>15.4 ± 12.5</td><td>58.5 ± 34.6</td><td>57.6 ± 34.4</td>

<td>Range</td><td>1.4 - 31.2</td><td>11.9 - 90.6</td><td>11.5 - 90.6</td>

<td></td><td></td><td></td><td></td>

<td>PI-1466</td><td></td><td></td><td></td>

<td>On an empty stomach 1</td><td></td><td></td><td></td>

<td>Average ± SD</td><td>2.0 ± 2.3</td><td>11.4 ± 11.8</td><td>11.3 ± 11.4</td>

<td>Range</td><td>0.2 - 5.9</td><td>1.1-30.0</td><td>11.1 - 29.1</td>

<td></td><td></td><td></td><td></td>

<td>Fasting 2</td><td></td><td></td><td></td>

<td>Average ± SD</td><td>3.6 ± 3.9</td><td>22.9 - 25.6</td><td>22.5 ± 24.9</td>

<td>Range</td><td>0.5 - 8.6</td><td>1.8 - 57.4</td><td>1.8 - 56.1</td>

<td></td><td></td><td></td><td></td>

<td>After meal</td><td></td><td></td><td></td>

<td>Average ± SD</td><td>10.9 ± 12.7</td><td>38.2 ± 40.0</td><td>37.1 ± 38.9</td>

<td>Range</td><td>0.3 - 28.5</td><td>1.7 - 90.3</td><td>1.6 - 87.7</td>

<td></td><td></td><td></td><td></td>

<td>OPTIMIZATION # 4</td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td>PI-1495</td><td></td><td></td><td></td>

<td>On an empty stomach</td><td></td><td></td><td></td>

<td>Average ± SD</td><td>0.5 ± 0.5</td><td>2.5 ± 2.3</td><td>2.6 ± 2.4</td>

<td>Range</td><td>0.1 - 1.4</td><td>5.9 - 0.3</td><td>0.3 - 5.7</td>

<td></td><td></td><td></td><td></td>

<td>After meal</td><td></td><td></td><td></td>

<td>Average ± SD</td><td>3.0 ± 6.7</td><td>10.2 ± 19.4</td><td>11.3 ± 20.0</td>

<td>Range</td><td>0.1-19.4</td><td>0.2 - 57.0</td><td>0.2 - 55.4</td>

<td></td><td></td><td></td><td></td>

<td>After a meal (Patient 1)</td><td></td><td></td><td></td>

<td>Average ± SD</td><td>0.6 ± 0.9</td><td>3.6 ± 4.9</td><td>4.0 ± 5.0</td>

<td>Range</td><td>0.1 - 2.5</td><td>0.2 - 13.8</td><td>0.2 - 13.4</td>

<td></td><td></td><td></td><td></td>

<td>PI-1496</td><td></td><td></td><td></td>

<td>On an empty stomach</td><td></td><td></td><td></td>

<td>Average ± SD</td><td>1.2 ± 0.9</td><td>7.1 ± 4.6</td><td>7.0 ± 4.6</td>

<td>Range</td><td>0.1-2.7</td><td>0.6 - 14.2</td><td>0.6 - 14.5</td>

<td>After meal</td><td></td><td></td><td></td>

<td>Average ± SD</td><td>2.7 ± 2.9</td><td>13.4 ± 12.6</td><td>13.1 ± 12.3</td>

<td>Range</td><td>0.1-7.6</td><td>0.1 - 31.6</td><td>0.4 - 30.7</td>

<td></td><td></td><td></td><td></td>

<td>OPTIMIZATION # 5</td><td></td><td></td><td></td>

<td>PI-1510</td><td></td><td></td><td></td>

<td>On an empty stomach</td><td></td><td></td><td></td>

<td>Average</td><td>0.4</td><td>2.0</td><td>3.9</td>

<td></td><td></td><td></td><td></td>

<td>After meal</td><td></td><td></td><td></td>

<td>Average</td><td>0.7</td><td>3.4</td><td>4.5</td>

[0179] Although the present invention has been described with reference to preferred embodiments, it should be understood that changes and modifications will be apparent to those skilled in the art.

Thus, as intended, the appended claims include all such equivalent changes that fall within the scope of the claimed invention.

Paragraphs according to the invention [0180]

A multilayered pharmaceutical composition comprising an agonist and an antagonist in which the agonist and antagonist in the intact composition form are not in contact with one another, and wherein, when administered to a human, the agonist is substantially released and the antagonist is substantially sequestered.

2. The pharmaceutical composition according to paragraph 1, wherein the agonist and antagonist are separated from each other by a sealing coating comprising a sequestering polymer.

3. The pharmaceutical composition according to paragraph 2, wherein the seal coat comprises an additive increasing the hydrophobicity of the sequestering polymer.

4. The pharmaceutical composition according to paragraph 2, wherein the seal coat further comprises a charge neutralizing additive.

5. The pharmaceutical composition according to paragraph 1, wherein the agonist and antagonist are separated from each other by means of a sealing coating comprising a sequestering polymer, an additive increasing the hydrophobicity of the sequestering polymer, and a charge neutralizing additive.

6. The pharmaceutical composition according to any of paragraphs 2-5, wherein the sequestering polymer is Eudragit^® RS.

7. A pharmaceutical composition according to paragraphs 3, 5 or 6, wherein the addition increasing the hydrophobicity of the sequestering polymer is talc.

8. The pharmaceutical composition according to paragraphs 4, 5 or 6, wherein the antacid additive is sodium lauryl sulphate.

9. A pharmaceutical composition according to any of paragraphs 1-8, wherein the composition comprises at least a first layer comprising an agonist and a second layer including its antagonist and wherein the first and second layers are physically separated from each other by a third layer.

A pharmaceutical composition according to paragraph 9, wherein the first layer is external to the second layer.

11. The pharmaceutical composition according to paragraph 9 or 10, wherein the third layer comprises at least one sequestering polymer and optionally comprises a hydrophobicity enhancing additive sequester, charge neutralizing additive, or both, and a weight / weight ratio of the hydrophobicity additive of the sequestering polymer or additive. the neutralizing charge to the sequestering polymer in the third layer is such that no more than 10% of the antagonist is released from the composition as determined using the USP paddle method at 37 ° C, 100 rpm, with incubation in the buffer containing the surfactant.

12. The pharmaceutical composition according to paragraph 9 or 10, wherein the third layer comprises at least one sequestering polymer and optionally comprises a hydrophobicity enhancing additive sequester, charge neutralizing additive, or both, a weight / weight ratio of the hydrophobicity additive of the sequestering polymer or antacid. the charge for the sequestering polymer in the third layer is such that no more than about 10% of the antagonist is released from the composition in vivo after administration to the patient.

13. A pharmaceutical composition according to paragraph 9 or 10, wherein the third layer comprises at least one sequestering polymer and optionally comprises a hydrophobicity enhancing additive sequester, charge neutralizing additive, or both, a weight / weight ratio of the hydrophobicity additive of the sequestering polymer or neutralizing additive. the charge for the sequestering polymer in the third layer is such that no more than about 10% of the antagonist is released from the composition in vivo after administration to the patient, as determined by measuring 6-beta-naltrexol plasma levels.

14. A pharmaceutical composition according to any paragraph 9 or 10, wherein the third layer comprises at least one sequestering polymer and optionally comprises a hydrophobicity enhancing additive of the sequestering polymer, a charge neutralizing additive, or both, a weight / weight ratio of the hydrophobicity additive of the sequestering polymer or additive. the neutralizing charge to the sequestering polymer in the third layer is such that no more than about 10% of the antagonist is released from the composition in vivo after administration to the subject after a meal.

15. A pharmaceutical composition according to any of paragraphs 9-14, wherein the third layer comprises a sequestering polymer and a charge neutralizing additive present in an amount of less than about 4% by weight relative to the sequestering polymer.

16. A pharmaceutical composition according to any of paragraphs 9-15, wherein the third layer comprises a sequestering polymer and an additive increasing the hydrophobicity of the sequestering polymer present in a weight ratio of about 1: 1 with respect to the sequestering polymer.

17. A pharmaceutical composition according to any of paragraphs 9-16, wherein the third layer comprises a sequestering polymer, a charge neutralizing additive and a hydrophobicity enhancing additive for the sequestering polymer, wherein the charge neutralizing additive is present in an amount of less than about 4% by weight relative to the sequestering polymer. and the addition increasing the hydrophobicity of the sequestering polymer is present in a weight ratio of about 1: 1 with respect to the sequestering polymer.

18. A pharmaceutical composition according to any of paragraphs 9-17, wherein the third layer comprises a neutralizing additive sodium lauryl sulphate in an amount of less than about 4% by weight based on the first sequestering polymer.

19. A pharmaceutical composition according to any of paragraphs 9-18, wherein the third layer comprises a hydrophilicity additive of talc sequestering polymer in a weight ratio of about 1: 1 with respect to the sequestering polymer.

20. A pharmaceutical composition according to any of paragraphs 9-19, further comprising an osmotic pressure regulating agent in the first layer.

21. A pharmaceutical composition according to paragraph 20, wherein the osmotic pressure regulating agent is sodium chloride.

22. A pharmaceutical composition according to any of paragraphs 1-21, further comprising a sustained release carrier that imparts sustained release properties to the agonist.

23. A pharmaceutical composition according to paragraph 22, wherein the sustained release carrier is Eudragit L100-55.

24. A pharmaceutical composition comprising an antagonist in direct contact with a seal coating, an agonist in direct contact with the seal coating and with a sequestering polymer, but not with an antagonist, wherein the antagonist and agonist are present in a single multilayer pharmaceutical unit.

25. A pharmaceutical composition comprising a pharmaceutical dosage unit essentially composed of a multi-layer bead comprising an antagonist and an agonist that are not in direct contact with each other.

26. A pharmaceutical composition comprising a plurality of pharmaceutically active units, each unit containing an antagonist, an agonist, a seal coat and a sequestering polymer, wherein the antagonist and agonist are not in direct contact with each other.

27. A pharmaceutical composition comprising a pharmaceutically inert carrier substance, an antagonist in direct contact with a carrier substance, a seal coating in direct contact with an antagonist and an agonist, and a sequestering polymer in direct contact with an agonist.

28. A pharmaceutical composition comprising an agonist-associated fixation antagonist such that the physical disruption of the intact dosage form causes the antagonist and agonist to mix together.

29. A pharmaceutical composition according to any of paragraphs 2-24 and 26, wherein the charge neutralizing additive is in admixture with a sequestering polymer in an amount sufficient to reduce the amount of antagonist released from the in vivo composition.

30. A pharmaceutical composition according to paragraph 29, wherein the neutralizing additive is sodium lauryl sulphate.

31. The pharmaceutical composition according to paragraph 31, wherein the amount of charge neutralizing additive relative to the amount of weight sequestering polymer is about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5 %, about 4%, about 4.5%, about 5%, about 5.5%, about 1-2%, about 2-3%, about 3-4% or about 4-5%.

32. The pharmaceutical composition of paragraph 31, wherein the amount of the charge neutralizing additive relative to the amount of the sequestering polymer is about 1 to about 3%.

33. The pharmaceutical composition of paragraph 31, wherein the amount of charge neutralizing additive relative to the amount of sequestering polymer is about 3.2%.

34. The pharmaceutical composition of paragraph 31, wherein the amount of charge neutralizing additive relative to the amount of sequestering polymer is about 3.4%.

35. A pharmaceutical composition according to any of paragraphs 1-34, further comprising the addition increasing the hydrophobicity of the sequestering polymer in an amount sufficient to reduce the amount of antagonist released from the in vivo composition.

36. The pharmaceutical composition of paragraph 35, wherein the hydrophobicity enhancing additive of the sequestering polymer is present in an amount greater than about 66% and less than about 150% of the amount of weight sequestering polymer.

37. The pharmaceutical composition according to paragraph 35, wherein the hydrophobicity enhancing additive of the sequestering polymer is present in an amount approximately equal to the sequestering polymer.

38. The pharmaceutical composition according to any of paragraphs 35-37, wherein the addition increasing the hydrophobicity of the sequestering polymer is talc.

39. A pharmaceutical composition according to any of paragraphs 2-24 and 26, wherein both the charge neutralizing additive and the hydrophobicity enhancing additive of the sequestering polymer are present in an amount sufficient to reduce the amount of antagonist released from the in vivo composition.

40. A pharmaceutical composition according to any of paragraphs 1-39, wherein the sequestering polymer comprises Eudragit RS.

41. A pharmaceutical composition according to any of paragraphs 1-40, wherein the agonist is in a controlled release form.

42. A pharmaceutical composition according to paragraph 41, wherein the agonist is in contact with a sequestering polymer.

43. A pharmaceutical composition according to any of paragraphs 1-42, wherein the antagonist is not substantially released in vivo after administration to the patient.

44. A pharmaceutical composition according to any of paragraphs 1-42, wherein the antagonist is not substantially released in vivo after administration to the subject after a meal.

45. The pharmaceutical composition according to paragraph 43 or 44 wherein less than about 10% of the antagonist is released.

46. ​​The pharmaceutical composition according to paragraph 43 or 44, wherein less than about 5% of the antagonist is released.

47. A pharmaceutical composition according to paragraph 43 or 44 wherein less than about 3% of the antagonist is released.

48. The pharmaceutical composition according to paragraph 43 or 44, wherein the released antagonists are determined by measuring the levels of naltrexone in the plasma.

49. The pharmaceutical composition according to paragraph 43 or 44, wherein the released antagonists are determined by measuring 6-beta-naltrexol plasma levels.

50. A pharmaceutical composition according to any of paragraphs 1-49, wherein the antagonist is an opioid antagonist.

51. The pharmaceutical composition according to paragraph 50, wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, cyclazocine and levallorphan.

52. The pharmaceutical composition of paragraph 51, wherein the opioid antagonist is naltrexone.

53. A pharmaceutical composition according to any of paragraphs 1-52, wherein the agonist is an opioid agonist.

54. The pharmaceutical composition according to paragraph 53, wherein the opioid agonist is selected from the group consisting of morphine, hydromorphone, hydrocodone and oxycodone.

55. The pharmaceutical composition according to paragraph 54, wherein the opioid agonist is morphine.

56. A method of correlating the amount of naltrexone released from a pharmaceutical composition comprising naltrexone by measuring 6-beta-naltrexol plasma levels.

57. A method of measuring the amount of an antagonist or derivative thereof in a biological sample, wherein the antagonist or derivative has been released from the pharmaceutical composition in vivo, the method comprising a USP paddle method at 37 ° C, 100 rpm, but further including incubation in a buffer containing a surfactant.

58. The method of paragraph 57, wherein the surfactant is Triton X-100.

59. The method of paragraph 58, wherein the buffer is 0.2% Triton X-100, 0.2% sodium acetate, 0.002 N HCl, pH 5.5.

60. The method of any of paragraphs 56-59, wherein the antagonist or derivative is naltrexone or 6-beta-naltrexol.

61. The method of paragraph 60, wherein the derivative is 6-beta-naltrexol.

62. A method of preparing a pharmaceutical composition comprising attaching the antagonist to a pharmaceutically inert carrier substance, coating the antagonist with a seal coating, coating the agonist with a seal coating, and coating the agonist with a sequestering polymer.

63. The method of paragraph 62, wherein the sequester polymer provides controlled release action with respect to the agonist.

64. A method of preparing a pharmaceutical composition according to any of paragraphs 1-56, wherein: the antagonist is applied to the inert core material to form an inert layer; the sealing coating is then applied to the inert layer; and then the composition comprising the agonist is applied to the sealing coating.

65. The method of paragraph 64, wherein the additional layer comprising the blocking agent is applied to the layer of the active ingredient.

66. The method of paragraph 64, wherein the core is water-soluble.

67. A multilayered pharmaceutical composition, comprising an agonist and an antagonist in discrete layers of the composition, wherein at least 90% of the antagonist is sequestered for at least 24 hours after administration to a human.

68. A multilayered pharmaceutical composition, comprising an agonist and an antagonist in discrete layers of the composition, wherein at least 95% of the antagonist is sequestered for at least 24 hours after administration to a human.

69. A composition according to paragraph 67 or 68 wherein the antagonist is an opioid antagonist.

70. The composition of paragraph 69, wherein the antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, cyclazocin, levallorphan, their derivatives or complexes, and their pharmaceutically acceptable salts.

71. Composition according to paragraph 70, wherein the antagonist is naltrexone.

72. Composition according to paragraph 67 or 68, wherein the agonist is an opioid.

73. The composition of paragraph 72, wherein the opioid is selected from the group consisting of alfentanyl, allylprodin, alpha-lepine, anil eridine, benzylmorphine, beztramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocin, desomorphine, dextromoramide, desocin, diampromide, dihydrocodeine, dihydroetorphine, dihydromorphine , dimenoxadol, dimefeptanol, dimethylthiamide, dioxafethyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphin, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypetidine, isomethadone, ketobemidone, levallorphan, levorphanol, levofenacylmorphan, lofentanil, meperidine, meptaZinol, metazocine, methadone, metophone, morphine, mirofin, nalbuphine, narcein, nicomorphine, norleworphanol, normetadon, nalorphine, normorfine, norpipanone, opium, oxycodone, oxymorphone, papaweretum, pentazocine,fenadoxone, phenazocin, fenomorphan, phenoperidin, piminodin, pyrithromide, profeptaZine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, their derivatives, their complexes and their pharmaceutically acceptable salts.

74. Composition according to paragraph 73, in which the agonist is morphine.

75. A composition according to paragraph 67 or 68 wherein the antagonist is an opioid antagonist and the agonist is an opioid.

76. Composition according to paragraph 75, wherein the antagonist is naltrexone and the agonist is morphine.

77. A pharmaceutical composition comprising naltrexone in the sequestering subunit and morphine in contact with said subunit, but not with naltrexone, wherein administration of the composition within 24 hours results in release of substantially all of morphine from the composition but less than 10% of naltrexone from the composition.

78. A pharmaceutical composition comprising naltrexone in the sequestering subunit and morphine in contact with said subunit, but not with naltrexone, wherein administration of the composition within 24 hours results in release of substantially all of morphine from the composition but less than 5% of naltrexone from the composition.

79. The pharmaceutical composition according to paragraph 77 or 78, wherein the released naltrexone is determined by measuring the amount of 6-beta-naltrexone in human plasma.