COMPOSITIONS AND METHODS TO AVOID THE ABUSE OF OPIOIDS BACKGROUND OF THE INVENTION Opioid analgesics are sometimes a matter of abuse. In general, a particular dose of an opioid analgesic is more potent when administered parenterally compared to the same dose administered orally. Therefore, a popular mode of abuse of oral opioid formulas involves the extraction of the opioid from the dosage form, and the subsequent injection of the opioid (using any "adequate" vehicle for injection) in order to "rise". In the prior art, attempts to control the abuse potential associated with opioid analgesics have previously been presented. For example, the combination of pentazocine and immediate release naloxone has been used in tablets available in the United States, commercially available as Talwin ^ Nx from Sanote-Winthrop. Talwin¾x is indicated for the relief of moderate to severe pain. Talwin¾x contains pentazocine hydrochloride immediate release equivalent to 50 mg of base and naloxone hydrochloride equivalent to 0.5 mg of base. The amount of naloxone present in this combination has low activity when taken orally, and minimally interferes with the pharmacological action of pentazocine.
However, this amount of naloxone provided parenterally has a huge antagonistic action against narcotic analgesics. Thus, the inclusion of naloxone is intended to control a form of misuse of oral pentazocine that occurs when the dosage form is solubilized and injected. Therefore, this dosage has a lower potential for parenteral misuse than previous oral pentazocine formulas. A fixed combination therapy that includes tilidine (50 mg) and naloxone (4 mg) has been available in Germany for the management of severe pain since 1978 (Valoron ^ N, Goedecke). The fundamental reason for the combination of these drugs is the effective relief of pain and the prevention of tilidine addiction through antagonists induced by naloxone in the morphine receptor. A fixed combination of buprenorphine and naloxone was introduced in 1991 in New Zealand (Temgesic¾x, eckitt &Colman) for the treatment of pain. Purdue Pharma L.P. currently marketing sustained release oxycodone in dosage forms containing 10, 20, 40 and 80 mg oxycodone hydrochloride under the tradename OxyContin. The Patents of the United States Numbers,266,331; 5,508,042; 5,549,912 and 5,656,295 present prolonged-release oxycodone formulas.
U.S. Patent No. 4,769,372 and 4,785,000 to Kreek describe methods for the treatment of patients suffering from chronic pain or chronic cough without causing dysmotility by administering from 1 to 2 dosage units including from about 1.5 to about 100 mg of analgesic. opioid or antitussive and from about 1 to about 18 mg of an opioid antagonist having little or no systemic antagonistic activity when administered orally, 1 to 5 times daily. U.S. Pat. No. 6,228,863 to Palermo et al. Describes the compositions and methods for preventing abuse of opioid dosage forms. International Patent WO 99/32119 to Kaiko et al. Describes compositions and methods for preventing abuse of opioid dosage forms. U.S. Patent No. 5,472,943 to Crain et al. Describes methods for improving the analgesic potency of bimodally acting opioid agonists by administering the agonist with an opioid antagonist. Additionally, Shaw et al., In U.S. Patent Number 3,980,766, refer to drugs that are suitable for therapy in the treatment of addiction of narcotic drugs by oral use., for example, methadone, formulated to avoid abuse of the injection by concentrating the active component in aqueous solution by incorporating in a solid dosage or tablet form of the aforementioned medicament a solid which can be ingested and which possesses thickening properties that cause a rapid increase in viscosity after the concentration of an aqueous solution thereof. However, there remains a need for safe and effective treatment of pain with opioid analgesic dosage forms that are less subject to abuse than current therapies. All documents cited herein, including the foregoing, are incorporated by reference in their totals for all purposes. OBJECTIVES AND SUMMARY OF THE INVENTION An objective of some embodiments of the invention is to provide an oral dosage form of an opioid analgesic that is subject to less parenteral abuse than other dosage forms. An object of some embodiments of the invention is to provide an oral dosage form of an opioid analgesic that is subject to less intranasal abuse than other dosage forms.
An objective of some embodiments of the invention is to provide an oral dosage form of an opioid analgesic that is subject to less oral abuse than other dosage forms. A further objective of some embodiments of the invention is to provide an oral dosage form of an opioid analgesic that is subject to less deviation than other dosage forms. A further objective of some embodiments of the invention is to provide a method for treating pain in human patients with an oral dosage form of an opioid analgesic while reducing the abuse potential of the dosage form. A further objective of some embodiments of the invention is to provide a method of manufacturing an oral dosage form of an opioid analgesic in such a manner that it has less potential for abuse. These and other objectives are achieved through the present invention, which is directed in part to an oral dosage form that includes an opioid analgesic; an opioid antagonist, and at least one aversion agent to reduce the abuse of the opioid analgesic. In certain embodiments of the present invention, the oral dosage forms of the present invention include an opioid analgesic; an opioid antagonist; and an aversive agent or agents as components of the dosage form that help to avoid abuse of the injection by decreasing the "attractive qualities" of the dosage form for a potential addict. In certain embodiments of the present invention, the dosage form includes an aversive agent such as, for example, a bitter agent to demotivate an addict from altering the dosage form and subsequently inhaling or ingesting the altered dosage form. Preferably, the bitter agent is released when the dosage form is altered and provides an unpleasant taste to the addict after inhaling and / or ingesting the altered dosage form. In certain embodiments of the present invention, the dosage form includes an aversive agent such as, for example, an irritant to demotivate an addict to alter the dosage form and subsequently inhale, inject, or ingest the altered dosage form. Preferably, the irritant is released when the dosage form is altered and produces a burn or irritant effect to the addict after inhalation, injection and / or ingestion of the altered dosage form. In certain embodiments of the present invention, the dosage form includes an aversive agent such as for example a gelling agent to demotivate an addict to alter the dosage form and subsequently inhale, inject or ingest the altered dosage form. Preferably, the gelling agent is released when the dosage form is altered and produces a gel-like quality in the altered dosage form which reduces the absorption of the opioid analgesic in such a way that it is unlikely that an addict will obtain an " "fast" lift. In certain preferred embodiments, when the dosage form is altered and exposed to a small amount (e.g., less than about 10 ml) of an aqueous liquid (e.g., water), the dosage form will be unsuitable for injection. and / or inhalation. After the addition of the aqueous liquid, the altered dosage form preferably becomes thick and viscous, which makes it unsuitable for injection. The term "unsuitable for injection" is defined for purposes of the present invention in such a way that it means that the person would have a substantial difficulty in injecting the dosage form (e.g., due to pain caused by administration or difficulty in pushing the way of dosing through a syringe) due to the resulting viscosity in the dosage form, thus reducing the abuse potential of the opioid analgesic in the dosage form. In certain embodiments, the gelling agent is present in such an amount in the dosage form as when attempting evaporation (by application of heat) to an aqueous mixture of the dosage form in an effort to produce a further concentration. high of the therapeutic agent, a highly viscous substance unsuitable for injection is produced. When the altered dosage form is inhaled nasally, the gelling agent can be turned into a gel after administration to the nasal passages due to the moisture of the mucous membranes. This also makes these formulas aversive for nasal administration, since the gel will adhere to the nasal route and minimize the absorption of the altered substance. In certain embodiments of the present invention, the dosage form includes a combination of any or all of the aforementioned aversion agents (eg, a bitter agent, an irritant, and / or a gelling agent) to demotivate a addicted to altering the dosage form and subsequently inhaling, injecting, and / or ingesting the altered dosage form. Specifically contemplated embodiments include bitter agent; gelling agent; irritating; bitter agent and gelling agent; bitter and irritating agent; gelling agent and irritant; bitter agent and gelling agent; bitter and irritating agent; gelling agent and irritant; and bitter agent and gelling agent and irritant. In certain preferred embodiments, the dosage forms are controlled release oral dosage forms that include a therapeutically effective amount of an opioid analgesic and an opioid antagonist together with one or more of the aversion agents described above, such that The dosage form provides effective relief for pain for at least about 12 hours, or at least about 24 hours, when administered orally to a human patient. In some embodiments of the present invention, the opioid antagonist present in the dosage form is present in a substantially non-releasable (ie, "inhibited") form when the dosage form is administered intact according to the instructions. Preferably, because the opioid antagonist is present in the dosage form in a substantially non-releasable form, it does not substantially block the analgesic effect of the opioid antagonist when the dosage form is administered orally intact, and does not imply a risk of precipitation or withdrawal in patients who are tolerant or dependent on the opioid. In certain embodiments of the present invention, the aversive agent present in the dosage form is present in a substantially non-releasable (ie, "inhibited") form instead of, or in addition to, the opioid antagonist that is found in a substantially non-releasable form. In other embodiments, the aversion agent may not be "inhibited" as disclosed above, where the aversive agent is not released or is released minimally from an intact dosage form, but may have a modified release or sustained in order not to empty the aversive agent in a particular section of the gastrointestinal tract; for example, the stomach, where it could cause an unwanted effect such as excessive irritation. The aversive agent can be combined with an enteric carrier to delay its release or be combined with a carrier to provide a prolonged release of the aversion agent. However, it is contemplated in the present invention that the aversion agent will preferably not have any significant side effects (eg, a gastrointestinal side effect) even when all the aversion agent is released immediately after oral administration in a manner dosing intact according to the instructions. Aversing agents can also be found in the dosage form in a releasable form and a non-releasable form in any combination. For example, a dosage form may have a bitter, irritant, gel or a combination of these in a releasable form and a non-releasable form according to that disclosed in the U.S. Patent Application entitled "Compositions and Methods for Avoid Opioid Abuse "filed on August 6, 2002. Likewise, the antagonist of the present invention can be found in a releasable form, non-releasable form or a combination of the releasable form and the non-releasable form in accordance with disclosed in the U.S. Patent Application entitled "Pharmaceutical Formulations Containing Opioid Agonist, Releasable Antagonist, and Inhibited Antagonist" filed on August 6, 2002 and incorporated herein by reference in its entirety, in combination with one of the agents of aversion described herein. For example, the antagonist of the present invention can be an antagonist with minimal oral activity such as naloxone in a releasable or "non-inhibited" form. The inclusion of this antagonist would be a deterrent to the parenteral abuse of the dosage form and the aversion agents of the present invention (e.g., bitter agent, irritant, gelling agent) would be a deterrent to oral and nasal abuse of the dosage form. In addition, the dosage form may contain an "inhibited" antagonist such as for example a bioavailable antagonist to further deter oral and nasal abuse of the dosage form after administration of an altered dosage form. The term "aversion agent" is defined for purposes of the present invention in such a way as to mean a bitter agent, an irritant, or a gelling agent. The term "altered dosage form" is defined for purposes of the present invention in such a way that means that the dosage form has been manipulated by mechanical, thermal and / or chemical means that change the physical properties of the dosage form, by example, to release the opioid agonist for immediate release if it is in a prolonged release form, or for the opioid agonist to be used inappropriately such as for example administration by an alternate route, for example parenterally. The alteration can be, for example, by means of crushing, cutting, grinding, chewing, dissolving in a solvent, heating (e.g., to more than about 45 ° C), or any combination of the foregoing. The term "substantially non-releasable form" for purposes of the present invention refers to an opioid antagonist and / or an aversion agent that is not released or substantially not released within one hour after the intact dosage form containing an agonist opioid, an opioid antagonist and at least one aversive agent is administered orally (ie, without having been altered). Formulas that include an opioid antagonist in a dosage form that is in a substantially non-releasable form are described in U.S. Application Serial Number 09 / 781,081, entitled "Alteration-Resistant Oral Opioid Agonist Formulas," filed on February 8, 2001, the presentation of which is hereby incorporated by reference in its entirety. For purposes of the present invention, the amount released after oral administration of the intact dosage form can be measured in vitro by dissolving the dosage form in 900 ml of Simulated Gastric Fluid using a Type II apparatus for one hour. USP (pallet) at 75 rpm at 37 ° C. This dosage form is also referred to in such a way as to include an "inhibited antagonist" and / or an "inhibited aversion agent" depending on the agent or agents that are not released or substantially not released. In some preferred embodiments of the invention, the substantially non-releasable form of the antagonist and / or the aversion agent is resistant to laxatives (e.g., mineral oil) used to handle delayed colon transit and resistant to hydrochloric conditions . Preferably, the aversion agent is not released or is not substantially released 4, 8, 12 and / or 24 hours after oral administration. The phrase "at least partially block the opioid effect" is defined for purposes of the present invention in such a way that it means that the opioid antagonist at least significantly blocks the euphoric effect of the opioid antagonist, thereby reducing the potential of abuse of the opioid agonist in the dosage form. The phrase "analgesic efficacy" is defined for purposes of the present invention as a satisfactory reduction in or elimination of pain, together with a tolerable level of side effects, as determined by the human patient. The phrase "does not substantially block the analgesic effect of an opioid agonist" for purposes of the present invention means that the opioid antagonist does not block the effects of the opioid agonist in a sufficient degree in order that the dosage form is therapeutically less effective in providing analgesia. The term "prolonged release" is defined for purposes of the present invention as the release of the opioid analgesic from the oral dosage form at a rate such that the concentrations (levels) of the blood (eg plasma) are kept within the range therapeutic but below toxic levels for an extended period of time, for example, from about 12 to about 24 hours compared to an immediate release product. Preferably, the prolonged release is sufficient to offer a formula twice a day or once a day. The term "particles" of an opioid antagonist, as used herein, refers to granules, steroids, beads or pills that include the opioid antagonist. In certain preferred embodiments, the opioid antagonist particles are from about 0.2 to about 2 mm in diameter, more preferably from about 0.5 to about 2 mm in diameter. The term "parenterally" as used herein includes subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections, infusion techniques, or other injection methods known in the art. The term "inhaled" as used herein includes transmucosal-transbronchial and transnasal addiction.
The term "bitter agent" as used herein includes a compound used to produce a bitter taste, bitter taste, etc., to an addict that is administered an altered dosage form of the present invention. The term "irritant" as used herein includes a compound used to produce an irritation, eg, burn or uncomfortable feeling to an addict, which is administered an altered dosage form of the present invention. The term "gelling agent" as used herein includes a compound or composition used to produce a gel-like quality or a thickening to an altered dosage form after the addition of moisture or liquid. DETAILED DESCRIPTION OF THE INVENTION The aversive agents of the present invention are preferably to be used in connection with oral dosage forms including opioid analgesics and opioid antagonists, which provide valuable analgesia but which may be a subject of abuse. This is particularly seen in controlled-release opioid analgesic products having a broad dose of a convenient opioid analgesic intended to be released over a period of time in each dosage unit. Drug addicts can usually take a controlled release product and crush, cut, crush, chew, dissolve and / or heat, extract or otherwise damage the product in such a way that the total content of the dosage form it is available for immediate absorption by injection, inhalation, and / or oral intake. In certain embodiments, the present invention includes a method for preventing or deterring the abuse of opioid analgesics by including an opioid antagonist and at least one aversive agent in the dosage form with the opioid analgesic. In certain embodiments of the present invention where the dosage form includes an aversion agent consisting of a bitter agent, various bitter agents may be employed including, for example and without limitation, natural, artificial and synthetic flavor oils and aromatic plants and / or flavor oils, oleoresins and extracts derived from plants, leaves, flowers, fruits and so on, and combinations thereof. Representative non-limiting flavor oils include spearmint oil, peppermint oil, eucalyptus oil, nutmeg oil, allspice, mace, bitter almond oil, menthol and the like. Also useful bitter agents are flavors of artificial, natural and synthetic fruits such as citrus oils including lemon, orange, lime, grape and fruit essences, etc. Additional bitter agents include sucrose derivatives (eg, sucrose octaacetate), chlorosucrose derivatives, quinine sulfate and the like. The preferred bitter agent for use in the present invention is Denatonium Benzoate NF-Anhydrous, sold under the name Bitrex ™ (Macfarlan Smith Limited, Edinburgh, United Kingdom). With the inclusion of a bitter agent in the formulation, the taking of the altered dosage form produces a bitter taste after inhalation or oral administration which in certain embodiments spoils or avoids the pleasure of obtaining an elevation from the form of altered dosage, and preferably avoids abuse of the dosage form. A bitter agent may be added to the formula in an amount less than about 50% by weight, preferably less than about 10% by weight, more preferably less than about 5% by weight of the dosage form, and more preferably in an amount ranging from about 0.1 to 1.0% by weight of the dosage form depending on the particular bitter agent used. A dosage form that includes a bitter agent preferably discourages the improper use of the altered dosage form by producing an unpleasant taste or taste to the altered dosage form.
In certain embodiments of the present invention where the dosage form includes an aversive agent that includes an irritant, various irritants may be employed including, for example and without limitation, capsaicin, a capsaicin analog with similar type properties as capsaicin, and similar. Some analogs of capsaicin or derivatives include, for example, and without limitation, resiniferatoxin, tiniatoxin, heptanoylisobutylamide, heptanoyl guaiacylamide, other isobutylamides or guaiacylamides, dihydrocapsaicin, omovainyl octyl ester, nonanoyl vanillylamide, or other compounds of the class known as vanilloids. Resiniferatoxin is described, for example, in U.S. Patent No. 5,290,816 (Blumberg), issued March 1, 1994. U.S. Patent No. 4,812,446 (Brand), issued March 14, 1989, describes capsaicin analogues and methods for their preparation. Subsequently, U.S. Patent Number 4,424,205 (LaHann et al.), Issued January 3, 1984, cites Neman, "Substances with Natural and Synthetic Mint Flavors" published in 1954 as an acute listing of analogues similar to the capsaicin. Ton et al., In the British Bulletin of Pharmacology, 10, pages 175-182 (1955) discuss the pharmacological actions of capsaicin and its analogues.
With the inclusion of an irritant (eg, capsaicin) in the dosage form, when the dosage form is altered with it, capsaicin produces a burn or quality of discomfort to the addict to preferably discourage inhalation, injection or oral administration of the altered dosage form, and preferably to avoid abuse of the dosage form. Suitable capsaicin compositions include capsaicin (trans-8-methyl-M-vanillill-6-noneamide) or analogs thereof in a concentration between about 0.00125% and 50% by weight, preferably between about 1 and about 7.5% by weight. weight, and more preferably, between about 1 and about 5% by weight. In certain embodiments of the present invention where the dosage form includes an aversive agent that includes a gelling agent, various gelling agents can be employed including, for example and without limitation, sugars or sugar alcohols, such as for example mannitol, sorbitol and the like, starch and starch derivatives, cellulose derivatives, such as for example microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose, attapulgites, bentonites, dextrins, alginates, carrageenan, gum tragacanth, acacia gum, guar gum, xanthan gum, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, carbomers and carbonates, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, surfactants, mixed agent systems surfactant / humidification, emulsifier is, other polymeric materials, and mixtures of the above, etc. In certain preferred embodiments, the gelling agent is xanthan gum. In other preferred embodiments, the gelling agent of the present invention is pectin. The pectin or pectic substances useful for this invention include not only purified or isolated pectates but also raw natural pectin sources, such as apple, citrus or beet residues which have been subjected, where necessary, to esterification or de-esterification, for example , by alkali or enzymes. Preferably, the pectins used in this invention are derived from citrus fruits such as lime, lemon, grape and orange. With the inclusion of a gelling agent in the dosage form, when the dosage form is altered with it, the gelling agent preferably produces a gel-like quality to the altered dosage form which preferably impairs or avoids pleasure. of obtaining a rapid rise from the altered dosage form due to gel-like consistency in contact with the mucous membrane, and in certain embodiments, avoids abuse of the dosage form by minimizing absorption, for example, in the nasal passages. A gelling agent can be added to the formula in a ratio of the gelling agent to the opioid agonist of from about 1:40 to about 40: 1 by weight, preferably from about 1: 1 to about 30: 1 by weight, and most preferably from about 2: 1 to about 10: 1 by weight of the opioid agonist. In some other embodiments, the dosage form forms a viscous gel after the dosage form is altered therewith, dissolved in an aqueous liquid (from about 0.5 to about 10 ml, and preferably from 1 to about 5 ml) , causing the resulting mixture to have a viscosity of at least about 10 cP. More preferably, the resulting mixture will have a viscosity of at least about 60 cP. In some other embodiments, the dosage form forms a viscous gel after the dosage form is altered therewith, dissolved in an aqueous liquid (from about 0.5 to about 10 ml, and preferably from 1 to about 5 ml) and then heated (eg, to more than about 45 ° C), causing the resulting mixture to have a viscosity of at least about 10 cP. More preferably, the resulting mixture will have a viscosity of at least about 60 cP. In some embodiments, the dosage form may include one or more of the aforementioned aversives. For safety reasons, the amount of the bitter agent, irritant, or gelling agent in the formula of the present invention should not be toxic to humans. Opioid antagonists useful in the present invention include, for example and without limitation, naltrexone, naloxone, nalmefene, nalide, nalmexone, nalorphine, nalorphine dinicotinate, cyclazocine, levalorphan, pharmaceutically acceptable salts thereof and mixtures thereof. In certain preferred embodiments, the opioid antagonist is naloxone or naltrexone. In certain embodiments, the amount of the opioid antagonist included in the dosage form may be from about 10 mg to 275 mg. Naloxone is an opioid antagonist that is almost devoid of agonist effects. Subcutaneous doses of up to 12 mg of naloxone do not produce discernible subjective effects, 24 mg of naloxone cause only slight drowsiness.
Small doses (0.4-0.8 mg) of naloxone given intramuscularly or intravenously in humans prevent or immediately reverse the effects of the opioid agonist similar to morphine. It has been reported that one mg of naloxone given intravenously completely blocks the effect of 25 mg of heroin. The effects of naloxone are observed almost immediately after intravenous administration. The drug is absorbed after oral administration, but it has been reported that it is metabolized in an inactive form rapidly in its first passage through the liver, in such a way that it is reported to have a significantly lower potency than when administered parenterally. . It has been reported that oral doses of more than 1 g are almost completely metabolized in less than 24 hours. It has been reported that 25% of naloxone administered sublingually is absorbed. Weinberg, et al., Sublingual Absorption of Selected Opioid Analgesics, Ter. Clinical Pharmacology (1988); 44: 335-340. Other opioid antagonists, for example, cyclazocine and naltrexone, which both have cyclopropylmethyl substitutes on nitrogen, retain much of their effectiveness by the oral route and their duration of action is much larger, approaching 24 hours after oral administration. In the treatment of patients previously addicted to opioids, naloxone has been used in large oral doses (more than 100 mg) to avoid the euphorigenic effects of opioid agonists. It has been reported that naltrexone exerts a strong preferential blocking action against mu on the delta sites. Naltrexone is known as a synthetic congener of oxymorphone without opioid agonist properties, and differs in structure from oxymorphone by replacing the methyl group located on the nitrogen atom of oxymorphone with a cyclopropylmethyl group. The naltrexone hydrochloride salt is soluble in water up to about 100 mg / cc. The pharmacological and pharmacokinetic properties of naltrexone have been evaluated in several animal and clinical studies. Consult, for example, González JP, and collaborators. Naltrexone: A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of opioid dependence. Drugs 1988; 35: 192-213, incorporated herein by reference. After oral administration, naltrexone is rapidly absorbed (in a period of 1 hour) and has an oral bioavailability ranging from 5 to 40%. The ligation of the naltrexone protein is approximately 21% and the volume of distribution after the administration of the single dose is 16.1 1 / kg. Naloxone is commercially available in the form of a tablet (Revia®, DuPont) for the treatment of alcohol dependence and for the blockade of opioids administered exogenously. See, for example, Revia (Naltrexone hydrochloride tablets). Physician's Desk Reference (Physician's Desk Reference) 59th edition, Montéale, NJ. "Medical Economy" 1997; 51: 957-959. A dosage of 59 mg of Revia® blocks the pharmacological effects of 25 mg of heroin administered IV for up to 24 hours. It is known that when coadministered with morphine, heroin or other opioids chronically, naltrexone blocks the development of physical dependence on opioids. It is believed that the method by which naltrexone blocks the effects of heroin is through competitive ligation in opioid receptors. Naltrexone has been used to treat narcotic addiction by completely blocking the effects of opioids. It has been discovered that the most successful use of naltrexone for a narcotic addiction is when narcotics addicts have a good prognosis, as part of a complete occupational or rehabilitation program that involves behavioral control or other methods to improve the performance For the treatment of narcotic dependence with naltrexone, it is convenient that the patient is free of opioids for at least 7-10 days. The initial dosage of naltrexone for these purposes has generally been about 25 mg, and if rejection symptoms do not occur, the dosage may be increased to 50 mg per day. It is considered that a daily dosage of 50 mg produces an adequate clinical blockade of the actions of the opioids administered parenterally. Naltrexone has also been used for the treatment of alcoholism as an auxiliary to social and psychotherapeutic methods. In certain embodiments, the aversion agent and / or the opioid antagonist included in the dosage form may be in a substantially non-releasable form. When the opioid antagonist is in a substantially non-releasable form, the substantially non-releasable form of the opioid antagonist includes an opioid antagonist that is formulated with one or more pharmaceutically acceptable hydrophobic materials, such that the antagonist is not released or is not released. substantially during its transit through the gastrointestinal tract when administered orally as intended, without having been altered. Furthermore, in certain embodiments, in which the aversive agent is in a substantially non-releasable form, the substantially non-releasable form of the aversive agent includes an aversive agent that is formulated with one or more pharmaceutically acceptable materials or materials. acceptable hydrophobic agents, such that the aversive agent is not released or substantially released during its transit through the gastrointestinal tract when administered orally as intended, without having been altered. In some embodiments of the present invention, the substantially non-releasable form of the opioid antagonist is vulnerable to mechanical, thermal and / or chemical alteration, for example, an alteration by means of crushing, cutting, grinding, chewing and / or dissolving. in a solvent in combination with heating (e.g., greater than about 45 ° C) of the oral dosage form. When the dosage form is altered, the integrity of the substantially non-releasable form of the opioid antagonist is compromised, and the opioid antagonist will become available for release. In certain embodiments, when the dosage form is chewed, crushed or dissolved and heated in a solvent, and administered orally, intranasally, parenterally or sublingually, the analgesic or euphoric effect of the opioid is reduced or reduced. delete. In certain embodiments, the effect of the opioid agonist is at least partially blocked by the opioid antagonist. In some other embodiments, the effect of the opioid agonist is substantially blocked by the opioid antagonist.
Additionally, the substantially non-releasable form of the aversive agent is vulnerable to mechanical, thermal and / or chemical alteration, for example, alteration by means of crushing, cutting, grinding, chewing and / or dissolving in a solvent in combination with heating ( for example, greater than about 45 ° C) of the oral dosage form. When the dosage form is altered, the integrity of the substantially non-releasable form of the aversion agent will be compromised, and the aversion agent will be available for release. In certain embodiments, when the dosage form is chewed, crushed or dissolved and heated in a solvent, the release of the aversion agent hinders, deters or prevents the administration of the orally, intranasally altered dosage form. , parenteral and / or sublingual. In some embodiments of the present invention, the ratio of the opioid agonist to the substantially non-releasable form of an opioid antagonist in the oral dosage form is such that the effect of the opioid agonist is at least partially blocked when the dosage form it is chewed, crushed or dissolved in a solvent and heated, and administered orally, intranasally, parenterally or sublingually. As the oral dosage form of certain embodiments described herein, when administered in an appropriate manner as intended, would not substantially release the opioid antagonist and / or the aversion agent, the amount of this antagonist and / or agent of aversion may vary more broadly than if the opioid antagonist and / or the aversion agent were available to be released into the gastrointestinal system after oral administration. For safety reasons, the amount of the antagonist and / or the aversion agent present in a substantially non-releasable form should not be harmful to humans even when it is fully released. The ratio of the particular opioid agonist to the antagonist can be determined without undue experimentation by a person skilled in the art. In some embodiments of the present invention, the ratio of the opioid agonist to the opioid antagonist, present in a substantially non-releasable form, is from about 1: 1 to about 50: 1 by weight, preferably about 1: 1 to about 20: 1 by weight. In some preferred embodiments, the ratio is from about 1: 1 to about 10: 1 by weight. In a preferred embodiment of the invention, the opioid agonist includes oxycodone or hydrocodone and is present in the amount of about 15:45 mg and the opioid antagonist includes naltrexone and is present in an amount of about 0.5 to about 10 mg, preferably about 0.5 to about 5 mg. In an alternative embodiment, the opioid antagonist of the present invention can be included in the dosage form, such that it is analgesically effective when administered orally, but that after parenteral administration, does not produce analgesia, euphoria or physical dependence. In this particular embodiment, preferably the opioid antagonist is naloxone which is in an amount that is not orally effective, but which is effective parenterally, as described in U.S. Patent Number 3,773,955 , the presentation of which is incorporated herein by reference in its entirety. In this embodiment, naloxone is released from the dosage form when administered orally, but does not suppress the oral activity of the opioid analgesic included in the dosage form. Alternatively, the opioid antagonist of the present invention is released from the dosage form after oral administration and can be included in the dosage form in an amount as described in WO 99/32119, the presentation of which is incorporated herein by reference in its entirety, (i) that does not elicit a reaction at the level of analgesia produced from the dosage form after oral administration at a non-therapeutic level and (ii) that provide at least a mildly negative experience of "aversion" in physically dependent subjects (for example, precipitous withdrawal syndrome) when people try to take at least twice the prescribed dose usually at some time (and often 2) -3 times that dose or more), compared to a comparable dose of opioid without the opioid antagonist present. Preferably, the amount of antagonist included in the oral dosage form is less positively enhancing (eg, less "liked") for an opioid addict not physically dependent than a comparable oral dosage form without the included antagonist. Preferably, the formula offers effective analgesia when administered orally. In some preferred embodiments, the oral dosage form includes an orally therapeutically effective effective dose of an opioid agonist, and an opioid antagonist in a ratio that offers a combination product that is analgesically effective when the combination is administered from orally, but which causes aversion in physically dependent humans when administered in the same dose or in a higher dose than the aforementioned therapeutically effective dose. Based on a preferred ratio of naltrexone in an amount of about 0.5 to about 4 mg per 15 mg of hxdrocodone as described in WO 99/32119, the approximate ratio of naltrexone to 1 mg of certain opioids is set forth in Table A :Table A; Weight Ratio of Naltrexone by Opioid DosageBased on the most preferred ratio of about 0.75 mg to about 3 mg of naltrexone per 15 mg of naltrexone hydrocodone as described in WO 99/32119, the approximate ratio of naltrexone to 1 mg of certain opioids is stipulated in the next Table B:Table B; Weight Ratio of altrexone by Opioid DosageIn some embodiments, the present invention is directed in part to an oral dosage form that includes an orally analgesically effective amount of an opioid agonist and an opioid antagonist in a ratio as described above together with one or more agents of aversion as described herein. In some alternative embodiments, when the opioid antagonist is naloxone, the opioid agonist and the antagonist (e.g., naloxone) included in the current dosage forms may be found in preferred relationships as described in U.S. Pat. 4,457,933 for Gordon et al., Whose presentation is hereby incorporated by reference in its entirety, so that both the oral and parenteral abuse potentials of the opioid agonist decrease without appreciably affecting the oral analgesic activity of the opioid agonist. In some alternative embodiments, the opioid antagonist can be included in the dosage form in such an amount that the opioid antagonist reduces the side effects of the opioid agonist, these side effects are anti-analgesia, hyperalgesia, hyperexcitability, physical dependence, tolerance, and combinations of any of the above. For example, in some preferred embodiments, the amount of the opioid antagonist is from about 100 to about 1,000 times less than the amount of the opioid agonist. Some preferred amounts of the opioid antagonist to the agonist in accordance with this embodiment are described, for example, in U.S. Patent Nos. 5,472,943; 5,512,578; 5,580,876; 5,767,125; RE36,547; and 6,096,256, all for Crain and collaborators, whose presentations are incorporated herein by reference in their totals. All known combinations of opioid antagonists releasable with opioid agonists as described in U.S. Patent Number 3,773,955 (Pachter et al.); U.S. Patent Number 3,493,657 (Lewenstein, et al.) U.S. Patent Number 4,457,933 (Gordon, et al.), U.S. Patent Number 4,582,835 (Lewis) U.S. Patents Numbers,512,578; 5,472,943; 5,580,876; and 5,767.125 (Crain) andU.S. Patent Nos. 4,769,372 and 4,785,000 (reek) may be combined with the aversion agents presented in this invention and all of these references are incorporated herein by reference. All commercial releasable opioid agonist and antagonist products can be combined with an aversive agent presented in this invention. For example, Talwin NX can be formulated with an aversive agent, for example, a bitter agent to reduce oral abuse as well as parenteral abuse of the opioid within it. Opioid agonists useful in the present invention include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenofine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocin, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimefeptanol, dimetiltiambuteno, dioxafetil butirate, dipipanone, eptazocine, etho eptacin, hemylmethyldiambutene, ethylmorphine, etonitazene, etorphine, di idroetorphine, fentanyl and derivatives, heroin, hydrocodone, hydromorphone, hydroxypetidine, isomethadone, ketobemidone, levorphanol, levofenacilmorfan, lofentanil, Meperidina, meptazinol, metazocina, metdona, metopón, morphine, mirofina, narceina, nicomorfina, norlevorfanol, normetadona, nalorfina, nabulfeno, normorfina, norpipanona, opium, oxycodone, oxymorphone, papaveretum, pentazocine, fenadoxona, fenomorfan, fenazocina , fenopyridine, pimindin, piritramide, profeptazine, promedol, properidin, propoxyphene, sufentanil, tilidine, tramadol, mixtures of any of the foregoing, salts of any of the foregoing, and the like. In certain embodiments, the amount of the opioid agonist in the claimed opioid composition may be from about 75 ng to about 750 mg. In some preferred embodiments, the opioid agonist is selected from the group consisting of hydrocodone, morphine, Hydromorne, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, buprenorphine, fentanyl and derivatives thereof, dipipanone, heroin, tramadol, etorphine. , dihydroetorphine, butorphanol, levorphanol, or salts of the above or mixtures thereof. In some preferred embodiments, the opioid agonist is oxycodone or hydrocodone.
In embodiments in which the opioid analgesic includes hydrocodone, the dosage forms may include analgesic doses from about 2 mg to about 50 mg of hydrocodone bitartrate. In embodiments in which the opioid analgesic includes hydromorphone, the dosage form can include from about 2 mg to about 64 mg of hydromorphone hydrochloride. In embodiments in which the opioid analgesic includes morphine, the dosage form can include from about 2.5 mg to about 800 mg of morphine sulfate, by weight. In embodiments in which the opioid analgesic includes oxycodone, the dosage form can include from about 2.5 mg to about 320 mg oxycodone hydrochloride. The dosage form may contain more than one opioid analgesic to provide a therapeutic effect. Alternatively, the dosage form may include equivalent molar amounts of other salts of the opioids useful in the present invention. Although hydrocodone and oxycodone are effective in the management of pain, an increase in their abuse has been observed by people who are psychologically dependent on opioids or who misuse opioids for non-therapeutic reasons. Previous experience with other opioids has shown a potential for decreased abuse when opioids are administered in combination with a narcotic antagonist, especially in patients who are exadicts. Weinhold LL, et al., Buprenorphine Alone and in Combination with Naltrexone in Non Dependent Humans, Drug and Alcohol Dependence 1992; 30: 263-274; Mendelson J., et al., Interactions of Buprenorphine and Naloxone in Volunteers Dependent of Opiates, Clin Pharm Ther. (Ter. Clinical Pharmacology) 1996; 60: 105-114; both of which are incorporated herein by reference. These combinations, however, do not contain the opioid antagonist that is in a substantially non-releasable form. Rather, the opioid antagonist is released into the gastrointestinal system when administered orally and is available for absorption, based on the physiology of the host to differentially metabolize the agonist and antagonist and negate the effects of the agonist. Idrocodone is a semisynthetic and antitussive narcotic analgesic with multiple gastrointestinal actions and in the central nervous system. Chemically, hydrocodone is 5-epoxy-3-methoxy-17-methylmorphinan-6-one, and is also known as dihydrocodeinone. Like other opioids, hydrocodone can be habit-forming and may lead to morphine-type medication dependence. In excessive doses, hydrocodone, like other opiate derivatives, will decrease respiration. Oral hydrocodone is also available in Europe (Belgium, Germany, Greece, Italy, Luxembourg, Norway and Switzerland) as an antitussive agent. A parenteral formula is also available in Germany as an antitussive agent. To be used as an analgesic, hydrocodone bitartrate is commercially available in the United States only as a fixed combination with non-opiate medications (eg, ibuprofen, acetaminophen, aspirin, etc.) for the relief of moderately or severely severe pain. A common dosage form of hydrocodone is in combination with acetaminophen, and is commercially available, for example, as Lortab® in the United States from UCB Pharma, Inc., in the form of 2.5 / 500 mg hydrocodone / acetaminophen tablets, 5/500 mg, 7.5 / 500 mg and 10/500 mg. Hydrocodone in combination with aspirin is provided in an oral dosage form for adults generally in 1-2 tablets every 4-6 hours as needed to relieve pain. The tablet form is 5 mg of hydrocodone bitartrate and 224 mg of aspirin with 32 mg of caffeine; or 5 mg of hydrocodone bitartrate and 500 mg of aspirin. A relatively new formula includes hydrocodone bitartrate and ibuprofen. Vicoprofen®, commercially available in the United States from Knoll Laboratories, is a tablet that contains 7.5 mg of hydrocodone bitartrate and 200 mg of ibuprofen. The present invention is contemplated to encompass all of these formulas, with the inclusion of opioid antagonist particles coated with a coating that makes the antagonist substantially non-releasable. Oxycodone, chemically known as 4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one, is an opioid agonist whose main therapeutic action is analgesia. Other therapeutic effects of oxycodone include anxiolysis, euphoria and relaxing sensations. The precise mechanism of its analgesic action is not known, but specific CNS opioid receptors have been identified for endogenous compounds with opioid-like activity throughout the brain and spinal cord and have a role in the analgesic effects of this drug. Oxycodone is commercially available in the United States, for example, as Oxycontin® in Purdue Pharma LP, as controlled release tablets for oral administration containing 10 mg, 20 mg, 40 mg or 80 mg oxycodone hydrochloride, and as Oxyl® ™, also from Purdue Pharma LP, as immediate release capsules containing 5 mg oxycodone hydrochloride. The present invention is contemplated to encompass all of these formulas, with the inclusion of an opioid antagonist and one or more aversion agents. PREPARATION OF THE AVERSION AGENT IN A SUBSTANTIALLY NON-LIBERABLE FORM: In some embodiments of the present invention, an aversive agent in a substantially non-releasable form can be prepared by combining the aversion agent with one or more pharmaceutically acceptable hydrophobic materials. For example, the particles of the aversive agent can be coated with a coating that substantially prevents the release of the aversive agent, the coating includes the hydrophobic materials. Another example would be an aversive agent that is dispersed in a matrix that makes the aversive agent substantially non-releasable, and the matrix includes the hydrophobic materials. In some embodiments, the hydrophobic pharmaceutically acceptable material includes a cellulose polymer selected from the group consisting of ethyl cellulose, cellulose acetate, cellulose propionate (lower, middle or higher molecular weight), cellulose acetate propionate, butyrate cellulose acetate, cellulose acetate phthalate and cellulose triacetate. An example of ethyl cellulose is one that has an ethoxy content of 44 to 55%. The ethylcellulose can be used in the form of an alcohol solution. In some other embodiments, the hydrophobic material includes polylactic acid, polyglycolic acid or a copolymer of polylactic and polyglycolic acid. In some embodiments, the hydrophobic material can include a cellulose polymer selected from the group consisting of cellulose ether, cellulose ester, ether of the cellulose ester, and cellulose. The cellulosic polymers have a Degree of Substitution, on the anhydroglucose unit, from higher steel and up to 3 inclusive. Degree of substitution means the average number of hydroxyl groups present in the anhydroglucose unit including the cellulose polymer that are replaced by a substitution group. Representative materials include a polymer selected from the group consisting of cellulose acylate cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono alkylate, di and tricellulose, mono aroylates, di and tricellulose, and mono, di and tricellulose alkenylates. The polymers of the example include cellulose acetate having a degree of substitution and an acetyl content of up to 21%; cellulose acetate has an acetyl content of up to 32 to 39.8%; cellulose acetate possesses a degree of substitution of 1 to 2 and an acetyl content of 21 to 35%; Cellulose acetate has a degree of substitution of 2 to 3 and an acetyl content of 35 to 44.8%. More specific cellulosic polymers include cellulose propionate having a substitution degree of 1.8 and propyl content of 39.2 to 45 and a hydroxyl content of 2.8 to 5.4%; Cellulose acetate butyrate has a substitution degree of 1.8, an acetyl content of 13 to 15% and a butyryl content of 34 to 39%; cellulose acetate butyrate has an acetyl content of 2 to 29%, a butyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7%; cellulose triacilate has a degree of substitution of 2.9 to 3 such as cellulose triacetate, cellulose trivalerate, cellulose trilaurate, cellulose tripalmitate, cellulose trisuccinate, and cellulose trioctanoate; cellulose diacylates have a degree of substitution of 2.2 to 2.6 such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose dipentanoate, and cellulose coesters such as cellulose acetate butyrate, octanoate butyrate of cellulose acetate, cellulose and cellulose acetate propionate. Additional cellulose polymers useful for the preparation of an aversive agent in a substantially non-releasable form include acetaldehyde dimethyl cellulose acetate, cellulose acetate ethylcarbamate, cellulose acetate methylcarbamate, and cellulose acetate dimethylaminocellulose acetate . Acrylic polymers useful for the preparation of the aversive agent in a substantially non-releasable form include, but are not limited to, acrylic resins which include copolymers synthesized from esters of acrylic and methacrylic acid (e.g., the lower alkyl ester copolymer of acrylic acid and the lower alkyl ester of methacrylic acid) containing about 0.02 to 0.03 moles of a group of tri (lower alkyl) ammonium per mole of the acrylic and methacrylic monomers used. An example of a suitable acrylic resin is a polymer manufactured by Rohm Pharma GmbH and sold under the trademark of Eudragit® RS. Eudragit RS30D is the one that is preferred. Eudragit® RS is a water-insoluble copolymer of ethyl acrylate (EA), methyl methacrylate (MM) and trimethylammonioethyl methacrylate chloride (TAM) where the molar ratio of TA to the remaining components (EA and MM) is 1:40. Acrylic resins such as Eudragit® RS can be used in the form of an aqueous suspension. In some embodiments of the invention, the acrylic polymer can be selected from the group consisting of the copolymers of acrylic acid and methacrylic acid, copolymers of methyl methacrylate, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly (acrylic acid), poly (acid) methacrylic), methacrylic acid alkylamide copolymer, poly (methyl methacrylate), polymethacrylate, poly (methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic acid anhydride), and glycidyl methacrylate copolymers . When the aversive agent in a substantially non-releasable form includes particles of the aversive agent coated with a coating that converts the aversive agent to substantially non-releasable, and when a cellulose polymer or an acrylic polymer is used for the preparation of the composition of coating, suitable plasticizers, for example acetyl triethyl citrate and / or acetyl tributyl citrate, can also be mixed with the polymer. The coating may also include additives such as coloring agents, talc and / or magnesium stearate, which are well known in the coating art. The coating composition can be applied to the particles of the aversive agent by spraying it onto the particles by the use of any suitable spray equipment known in the art. For example, a Wuster fluidized bed system can be used wherein an air jet, injected from below, fluidizes the coated material and performs drying when the insoluble polymer coating is roiled. The thickness of the coating will depend on the characteristics of the particular coating composition that is used. However, it is within the ability of the person performing the technique to determine by routine experimentation the optimum thickness of a particular coating required for a particular dosage form of the present invention. The pharmaceutically acceptable hydrophobic material useful for preparing an aversive agent in a substantially non-releasable form includes a biodegradable polymer that includes a poly (lactic / glycolic acid) ("PLGA"), a polylactide, a polyglycolide, a polyanhydride, a polyorthoester, polycaprolactones, polyphosphazenes, polysaccharides, proteinaceous polymers, polyesters, polydioxanone, polygluconate, polyethylene oxide copolymers of polylactic acid, poly (hydroxybutyrate), polyphosphoester or mixtures or combinations of any of these. In some embodiments, the biodegradable polymer includes a poly (lactic / glycolic acid), a copolymer of lactic and glycolic acid, with a molecular weight of from about 2,000 to about 500,000 daltons. The ratio of lactic acid to glycolic acid is from about 100: 0 to about 25:75, with the ratio of lactic acid to glycolic acid of 65:35 being preferred. The poly (lactic acid / glycolic acid) can be prepared with the procedure specified in U.S. Patent No. 4,293,539 (Ludwig et al.), The disclosure of which is incorporated herein by reference in its entirety. In brief, Ludwig prepares the copolymer by condensing the lactic acid and the glycolic acid in the presence of an easily removable polymerization catalyst (for example, an ion exchange resin of a strong acid such as Dowex HCR-W2-H). The amount of catalyst is not important for the polymerization, but it is generally from about 0.01 to about 20 parts by weight in relation to the total weight of the lactic acid and the glycolic acid combined. The polymerization reaction can be carried out without solvents at a temperature from about 100 ° C to about 250 ° C for about 48 to about 96 hours, preferably under reduced pressure to facilitate the removal of water and by-products. The poly (lactic acid / glycolic acid) is subsequently coated by filtering the molten reaction mixture in an organic solvent such as dichloromethane or acetone and then filtering to remove the catalyst.
Once the aversive agent is prepared in a substantially non-releasable form, it can be combined with an opioid agonist and the opioid antagonist (which may also be in a substantially non-releasable form as described herein), together with the excipients conventional ones known in the art, for preparing the oral dosage form of the present invention. It is contemplated that a bitter agent or capsaicin would be the most likely aversive agents to be included in an inhibited formula. The polymers and other ingredients above can also be used to formulate the aversion agents in order to decrease the release or delay the release as indicated above. In some preferred embodiments of the invention, the oral dosage form is a capsule or a tablet. When formulated as a tablet, the aversion agent and the opioid agonist and the opioid antagonist can be combined with one or more inert, non-toxic pharmaceutical excipients, which are suitable for the manufacture of tablets. These excipients include, for example, an inert diluent such as lactose; granulation and disintegration agents such as corn starch; binding agents such as starch; and lubricating agents such as magnesium stearate. The oral dosage form of the present invention can be formulated to offer immediate release of the opioid agonist contained therein. In other embodiments of the invention, however, the oral dosage form offers a prolonged release of the opioid agonist. In some embodiments, dosage forms that provide prolonged release of the opioid agonist can be prepared by mixing the aversion agent in a substantially non-releasable form with the opioid agonist and the opioid antagonist and convenient pharmaceutical excipients to provide a tablet, and then coating the tablet with a prolonged-release tablet coating. In some embodiments of the invention, prolonged-release opioid agonist tablets can be prepared by mixing the substantially non-releasable form of an aversion agent with an aversion agent in a matrix that delivers the tablets with prolonged release properties. DOSAGE FORMS The formulation of the opioid analgesic / opioid antagonist in combination with one or more aversion agents can be formulated as an immediate-release formula or a controlled-release oral formula in any suitable tablet, coated tablet or multiparticulate formula known to trained persons in the technique. The controlled release dosage form can include a controlled release material that is incorporated into a matrix together with the opioid analgesic and the opioid antagonist. In addition, the aversion agent can be separated from the matrix, or incorporated within the matrix. The controlled release dosage form may optionally include particles containing or including the opioid analgesic, wherein the particles have a diameter from about 0.1 mm to about 2.5 mm, preferably from about 0.5 mm to about 2 mm. The opioid antagonist can be incorporated into these particles, or it can be incorporated into a tablet or capsule containing these particles. Additionally, the aversive agent can be incorporated into these particles, or it can be incorporated into a tablet or capsule containing these particles. Preferably, the particles are coated with a film with a material that allows the release of the opioid analgesic at a controlled rate in an environment of use. The film coating is chosen in order to achieve, in combination with other declared properties, a desired in vitro release rate. The controlled release coating formulas of the present invention should be capable of producing a strong and continuous film that is smooth and elegant, able to withstand pigments and other coating additives, non-toxic, inert, and non-sticky. In some embodiments, the dosage forms of the present invention include normal release matrices containing the opioid analgesic, the opioid antagonist and the aversion agent. COATED PEARLS In some embodiments of the present invention, a hydrophobic material is used to coat inert pharmaceutical beads such as nu pariel 18/20 beads including an opioid analgesic, and a variety of the resulting solid controlled release beads can then placed in a gelatin capsule in an amount sufficient to provide an effective controlled release dose when ingested and in contact with an environmental fluid, for example, gastric fluid or dissolution media. Pearls that include the opioid analgesic may also include the opioid antagonist and / or one or more aversion agents, or the opioid antagonist and one or more aversion agents may be prepared as separate beads and then combined in a dosage form that includes the controlled release beads that include an opioid analgesic, or the opioid antagonist and / or one or more aversion agents can be mixed in the dosage form with the controlled release beads that include the opioid analgesic. In the preferred embodiments in which the opioid analgesic and the aversion agent are mixed in a capsule as different beads, the beads have an exact or similar appearance in order to discourage an addict from manually separating the beads before using them in order to avoid the aversion substance. In tablet dosage forms, the aversive agent is preferably not included as a distinct layer that can be easily separated from the active agent, although the present invention does not include these embodiments. The controlled release pearl formulas of the present invention gradually release the opioid analgesic, for example, when ingested and exposed to gastric fluids, and then to intestinal fluids. The controlled release profile of the formulas of the invention can be altered, for example, by varying the amount of coating with the hydrophobic material, altering the manner in which a plasticizer is added to the hydrophobic material, varying the amount of plasticizer relative to the hydrophobic material, through the inclusion of additional ingredients or excipients, altering the manufacturing method, etc. The dissolution profile of the final product can also be modified, for example by increasing or decreasing the thickness of the retardant coating. Spheroids or beads coated with an opioid analgesic are prepared, for example, by dissolving the opioid analgesic in water and then spraying the solution onto a substrate, eg, nu pariel 18/20 beads, using a Wuster insert. Subsequently, the opioid antagonist and / or the aversive agent are optionally added to the beads before coating. Optionally, additional ingredients are also added before the coating of the beads. For example, a product that includes hydroxypropylmethylcellulose, etc. (for example, Opadry®, readily available from Colorcon, Inc.) can be added to the solution and the solution mixed (for example, for about 1 hour) before the application of the same to the beads. The resulting coated substrate, in this example the beads, can then optionally be coated with a barrier agent, to remove the opioid analgesic from the hydrophobic controlled release coating. An example of a suitable barrier agent is one that includes hydroxypropylmethylcellulose. However, any film former known in the art can be used. It is preferred that the barrier agent does not affect the rate of dissolution of the final product. The beads can be subsequently coated with an aqueous dispersion of the hydrophobic material. The aqueous dispersion of the hydrophobic material preferably also includes an effective amount of plasticizer, for example, triethyl citrate. The preformulated aqueous dispersions of ethylcellulose, such as Aquacoat® or Surelease®,. They can also be used. If Surelease® is used, it is not necessary to add a plasticizer separately. Alternatively, preformulated aqueous dispersions of acrylic polymers such as Eudragit® can also be used. The plasticized hydrophobic material can be applied to the substrate including the opioid analgesic by spraying using any suitable spray equipment known in the art. In a preferred method, a Wurster fluidized bed system is used in which an air jet, injected from below, fluidizes the core material and performs drying while spraying the acrylic polymer coating. A sufficient amount of the hydrophobic material to obtain a predetermined controlled release of the aforementioned opioid analgesic when the coated substrate is exposed to aqueous solutions, eg, gastric fluid, is preferably applied, taking into account the physical characteristics of the opioid analgesic, the form of incorporation of the plasticizer, etc. After coating with the hydrophobic material, an additional coating of a film former, such as Opadry®, is optionally applied to the beads. This coating is provided, if applicable, in order to substantially reduce the agglomeration of the beads. The release of the opioid analgesic from the controlled release formula of the present invention may be further influenced, i.e., adjusted to a desired rate, by the addition of one or more release modifying agents, or by providing one or more passages through. of the coating. The ratio of the hydrophobic material to the water soluble material is determined, among other factors, by the required release rate and the solubility characteristics of the selected materials. The release modifying agents that function as pore formers can be organic or inorganic, and include materials that can be dissolved, extracted or leached from the coating in the environment of use. The pore formers can include one or more hydrophilic materials such as hydroxypropylmethylcellulose. The controlled release coatings of the present invention can also include erosion promoting agents such as starch and gums. The controlled release coatings of the present invention may also include materials useful for making microporous sheet in the environment of use, such as polycarbonates consisting of linear polyesters of carbonic acid where carbonate groups reappear in the polymer chain. The release modifying agent may also include a semipermeable polymer. In some required embodiments, the release modifying agent is selected from hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of the foregoing. The controlled release coatings of the present invention may also include an outlet means that includes at least one passage, orifice or the like. The passage may be formed with the methods presented in U.S. Patent Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864. The passage can have any shape such as round, triangular, square, elliptical, irregular, etc. FORMULAS OF THE MATRIX In some embodiments of the present invention, the sustained release formula is achieved by means of a matrix optionally possessing a controlled release coating as set forth herein. The present invention may also utilize an extended release matrix that allows the in vitro dissolution rates of the opioid analgesic and / or antagonist within the desired ranges and releases the opioid analgesic and / or antagonist in a pH dependent or pH independent manner. . A non-limiting list of suitable prolonged release materials that may be included in a prolonged release matrix according to the invention includes hydrophilic and / or hydrophobic materials, such as gums, cellulose ethers, acrylic resins, protein derived materials, waxes, shellac, and oils such as hydrogenated resin oil and hydrogenated vegetable oil. However, any pharmaceutically acceptable hydrophobic or hydrophilic prolonged release material that is capable of producing the prolonged release of the opioid analgesic can be used in accordance with the present invention. Preferred extended release polymers include alkylcelluloses such as ethylcellulose, polymers and copolymers of acrylic and methacrylic acid; and cellulose ethers, especially the hydroxyalkyl celluloses (especially hydroxypropylmethylcellulose) and carboxyalkylcelluloses. Preferred polymers and copolymers of acrylic and methacrylic acid include methyl methacrylate, copolymers of methyl methacrylate, ethoxyethyl methacrylates, ethyl acrylate, trimethyl ammonium methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly (acrylic acid), poly (methacrylic acid), alkylamine copolymer of methacrylic acid, poly (methyl methacrylate), poly (methacrylic acid) (anhydride), polymethacrylate, polyacrylamide, poly (methacrylic acid anhydride), and glycidyl methacrylate copolymers. Some preferred embodiments use mixtures of any of the aforementioned extended release materials in the matrix of the invention. The matrix can also include a binder. In these embodiments, the binder preferably contributes to the prolonged release of oxycodone or the pharmaceutically acceptable salt thereof from the extended release matrix. If an additional hydrophobic binder material is included, it is preferably selected from natural and synthetic waxes, fatty acids, fatty alcohols and mixtures thereof. Examples include beeswax, carnauba wax, stearic acid and stearyl alcohol. This list is not intended to be exclusive. In certain preferred embodiments, a combination of two or more hydrophobic binder materials is included in the matrix formulas. Preferred hydrophobic binder materials that can be used in accordance with the present invention include substituted or unsubstituted, long-chain, digestible hydrocarbons (C8-C5o, especially C12-C4o), such as fatty acids, fatty alcohols, glyceryl esters of fatty acids , mineral and vegetable oils, natural and synthetic waxes and polyalkylene glycols. Hydrocarbons having a melting point between 25 ° and 90 ° C are preferred. Of the long chain hydrocarbon binder materials, fatty alcohols (aliphatic) are preferred in certain embodiments. The oral dosage form may contain up to 80% (by weight) of at least one long chain, digestible hydrocarbon. In some embodiments, the hydrophobic binder material may include natural or synthetic waxes, fatty alcohols (such as lauryl alcohol, myristyl, stearyl, cetyl or preferably ketoestearyl), fatty acids, including but not limited to esters of fatty acids, fatty acid glycerides (mono-, di-, and tri-glycerides) , hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol and hydrophobic and hydrophilic materials that have hydrocarbon columns. Suitable waxes include, for example, beeswax, glycol wax, resin wax and carnauba wax. For purposes of the present invention, a substance similar to wax is defined as any material that is normally solid at room temperature and has a melting point of from about 30 to about 100 ° C. In some preferred embodiments, the form Dosage includes a prolonged-release matrix that includes an opioid analgesic; opioid antagonist; one or more aversive agents; and at least one hydroxyalkyl cellulose soluble in water, at least one Ci2-C36, preferably Ci4-C22, aliphatic alcohol and, optionally, at least one polyalkylene glycol. The hydroxyalkyl cellulose is preferably a hydroxy (Ci to C6) alkyl cellulose, such as, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose and, in particular, hydroxyethyl cellulose. The amount of at least one hydroxyalkyl cellulose in the present oral dosage form can be determined, inter alia, by the precise rate of the required release of the opioid analgesic. The aliphatic alcohol can be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol. In particularly preferred embodiments of the present oral dosage form, however, the at least one aliphatic alcohol is cetyl alcohol or cetostearyl alcohol. The amount of the aliphatic alcohol in the present oral dosage form can be determined, as indicated above, by the precise rate of the required release of the opioid analgesic. It may also depend on whether at least one polyalkylene glycol is present in or absent from the oral dosage form. In the absence of at least one polyalkylene glycol, the oral dosage form preferably contains between about 20% and about 50% (by weight) of the aliphatic alcohol. When a polyalkylene glycol is present in the oral dosage form, then the combined weight of the aliphatic alcohol and the polyalkylene glycol preferably constitutes between about 20% and about 50% (by weight) of the total dosage form. In a preferred embodiment, the ratio of, for example, the at least one hydroxyalkyl cellulose or acrylic resin to the at least one polyalkylene glycol / aliphatic alcohol determines, to a considerable degree, the release rate of the analgesic opioid of the formula. In some embodiments, a ratio of the hydroxyalkyl cellulose to the polyalkylene glycol / aliphatic alcohol of between 1: 1 and 1: 4 is preferred, with a ratio of between 1: 2 and 1: 3 being preferred by particular way. In some embodiments, the polyalkylene glycol may be, for example, polypropylene glycol, or polyethylene glycol which is preferred. The average molecular weight of the at least one polyalkylene glycol is preferably between 1,000 and 15,000, especially between 1,500 and 12,000. Another suitable prolonged release matrix includes an alkylcellulose (especially ethylcellulose), a C2 to C36 aliphatic alcohol and, optionally, a polyalkylene glycol. In addition to the above ingredients, a prolonged release matrix may also contain suitable amounts of other materials, for example, diluents, lubricants, binders, granulation aids and glidants which are conventional in the pharmaceutical art. In order to facilitate the preparation of a solid sustained release oral dosage form, according to this invention, a process for the preparation of a solid sustained release oral dosage form is provided in a further aspect of the present invention. according to the present invention which includes the incorporation of an opioid analgesic in a prolonged release matrix. The incorporation into the matrix can be effected, for example, by: (a) the formation of granules that include at least one hydrophobic and / or hydrophilic material as stipulated above (eg, a water soluble hydroxyalkyl cellulose) together with the opioid analgesic, the opioid antagonist and at least one aversion agent; (b) the mixture of at least one hydrophobic and / or hydrophilic material containing granules with at least one Ci2-C36 aliphatic alcohol and (c) optionally, the compression and molding of the granules. The granules can be formed by any of the methods known to those skilled in the pharmaceutical formulating art. For example, in a preferred method, the granules can be formed by wet granulation of the hydroxyalkyl cellulose, the opioid analgesic, the opioid antagonist, and one or more water aversion agents. In a particularly preferred embodiment of this process, the amount of water added during the wet granulation step is preferably between 1.5 and 5 times, especially between 1.75 and 3.5 times, the dry weight of the opioid analgesic. Optionally, the opioid analgesic, the opioid antagonist, and / or the one or more aversive agents are added extragranularly. A prolonged release matrix can also be prepared by, for example, melt granulation or molten extrusion techniques. In general, melted granulation techniques involve the melting of a normally solid hydrophobic binder material, for example, a wax, and the incorporation of a powder drug therein. To obtain a prolonged release dosage form, it may be necessary to incorporate a hydrophobic prolonged release material, eg, ethylcellulose or a water-insoluble acrylic polymer, into the hydrophobic molten wax binder material. Examples of sustained release formulations prepared by melt granulation techniques are found, for example, in U.S. Patent No. 4,861,598. The additional hydrophobic binder material may include one or more water-insoluble wax-like thermoplastic substances, possibly mixed with one or more wax-like thermoplastic substances that are less hydrophobic than the aforementioned water-insoluble wax-like substances. In order to achieve prolonged release, substances similar to the individual wax in the formulation must be substantially non-degradable and insoluble in gastrointestinal fluids during the initial release phases. Useful water-insoluble wax-like binding substances can be those with a solubility in water that is less than about 1: 5,000 (w / w). The preparation of a suitable fused extruded matrix according to the present invention can, for example, include the steps of melting the opioid analgesic, the opioid antagonist, and at least one aversive agent, together with a prolonged release and release material. preferably a binder material to obtain a homogeneous mixture. The homogeneous mixture is subsequently heated to a temperature sufficient to at least soften the mixture sufficiently to extrude it. The resulting homogenous mixture is subsequently extruded, for example, using a twin screw extruder, to form filaments. The extruded product is preferably cooled and cut into multiparticulates by any means known in the art. The multiparticulates of the matrix are subsequently divided into unit doses. The extruded product preferably has a diameter of from about 0.1 to about 5 mm and provides the prolonged release of oxycodone or pharmaceutically acceptable salt thereof for a period of time of at least about 24 hours. An optional process for the preparation of the molten extruded formulas of the present invention includes the dosage directly into an extruder of a hydrophobic prolonged release material, the opioid analgesic, the opioid antagonist, one or more aversion agents, and a binder material. optional; the heating of the homogeneous mixture; the extrusion of the homogeneous mixture to thereby form filaments; he56 cooling of the filaments containing the homogeneous mixture; cutting the multiparticulate filaments of the matrix with a size from about 0.1 mm to about 12 mm; and the division of these particles into unit doses. In this aspect of the invention, a relatively continuous manufacturing process is carried out. Optionally, the opioid antagonist and / or the one or more aversion agents can be prepared as separate multiparticulates (without the opioid agonist) and subsequently the multiparticulates can be combined with multiparticulates that include opioid analgesic (without the antagonist and / or the one or more aversion agents) in a dosage form. Plasticizers, such as those described above, can be included in the molten extruded matrices. The plasticizer is preferably included from about 0.1 to about 30% by weight of the matrix. Other pharmaceutical excipients, eg, talc, mono or polysaccharides, lubricants and the like can be included in the extended release matrices of the present invention as desired. The amounts included will depend on the desired characteristic to be achieved. The diameter of the extruder opening or outlet port can be adjusted to vary the thickness of the extruded filaments. In addition, the extruder outlet part need not be round; It can be oblong, rectangular, etc. The output filaments can be reduced to particles using a hot wire cutter, guillotine, etc. A multiparticulate system of the molten extruded matrix can be, for example, in the form of granules, spheroids or pills depending on the exit orifice of the extruder. For purposes of the present invention, the terms "molten extruded multiparticulates" and "molten extruded matrix multiparticulates" and "molten extruded matrix particles" will refer to a variety of units, preferably within a range of size and / or similar form and containing one or more active agents and one or more excipients, preferably including a hydrophobic prolonged release material as described herein. Preferably, the molten extruded matrix multiparticulates will be within a range from about 0.1 to about 12 mm in length and will have a diameter of from about 0.1 to about 5 mm. Furthermore, it should be understood that the molten extruded matrix multiparticulates may have any geometric shape within their size range. In some embodiments, the extrudate can simply be cut to the desired length and divided into unit doses of the therapeutically active agent without the need for a spherification step. In a preferred embodiment, oral dosage forms are prepared which include an effective amount of molten extruded multiparticulates within a capsule. For example, a variety of the molten extruded matrix multiparticulates can be placed in a gelatin capsule in an amount sufficient to provide an effective prolonged release dose when ingested and in contact with the gastrointestinal fluid. In another embodiment, a suitable amount of the extruded product of the multiparticulate is compressed into an oral tablet using conventional tabletting equipment, using standard techniques. The techniques and compositions for the manufacture of tablets (compressed and molded), capsules (hard and soft gelatin) and pills are also described in Remington's Pharmaceutical Sciences, (Art ur Osol, editor), 1553- 1593 (1980). In yet another preferred embodiment, the extrudate can be molded into tablets as stipulated in U.S. Patent Number 4,957,681 (Klimesch, et al.).
Optionally, the multiparticulate systems of the sustained release matrix, tablets or capsules may be coated with a prolonged release coating as the extended release coatings described herein. These coatings preferably include a sufficient amount of hydrophobic and / or hydrophilic prolonged release material to obtain a weight gain level of from about 2 to about 25%, although the coating may be higher depending on, for example, the desired release speed. The coating may optionally include one or more of the aversives. In these embodiments, a second optional coating can be applied in order to minimize the perception of the aversive agent when a dosage form of the present invention is administered intact. Dosage forms of the present invention may further include combinations of fused extruded matrix microparticles containing an opioid analgesic; an opioid antagonist; one or more aversive agents; or mixtures of these. In addition, the dosage forms may also include an amount of an immediate release opioid analgesic for a rapid therapeutic effect. The immediate release opioid analgesic can be incorporated, for example, in the form of separate multiparticulates within a gelatin capsule, or it can be coated on the surface of, for example, molten extruded multiparticulates of the matrix. The prolonged release profile of the molten extruded formulas of the invention can be altered, for example, by varying the amount of the prolonged release material, varying the amount of the plasticizer relative to other components of the matrix, varying the amount of the hydrophobic material, by the inclusion of additional ingredients or excipients, altering the manufacturing method, etc. In other embodiments of the invention, the fused extracted formulas are prepared without the inclusion of the opioid analgesic, the opioid antagonist, one or more aversion agents or mixtures thereof, which are subsequently added to the extruded product. These formulas will usually have the opioid analgesic; the opioid antagonist; one or more aversive agents; or mixtures thereof combined with each other with the extruded matrix material, and then the mixture would be converted into tablets in order to provide a slow release formula. These formulas can be beneficial, for example, when the opioid analgesic; the opioid antagonist; one or more aversive agents; or mixtures of these included in the formula is sensitive to temperatures necessary to soften the hydrophobic material and / or the retardant material. Typical molten extrusion production systems suitable for use in accordance with the present invention include a suitable extruder transmission motor having a variable speed and constant torque control, start-stop controls and a meter. In addition, the production system will include a temperature control console that includes temperature sensors, cooling media and temperature indicators along the length of the extruder. In addition, the production system will include an extruder such as a double screw extruder consisting of two counter-rotating constant tapping screws that are inside a cylinder or barrel that has an opening or die at the outlet thereof. The feed materials enter through a feed hopper and move through the barrel through the screws and are forced through the die into filaments that are subsequently transported as for example by a continuous moving belt to allow cooling and are directed to a pill-making machine or other suitable device for carrying the extruded cords within the multiparticulate system of the matrix. The machine for making pills can be formed of rollers, fixed blade, rotary cutter and the like. The appropriate instruments and systems are available with distributors such as C.W. Brabender Instruments, Inc., of South Hackensack, New Jersey. Other suitable apparatuses will be apparent to those skilled in the art. A further aspect of the invention relates to the preparation of cast extruded multiparticulates of the matrix as set forth above in a form that controls the amount of air included in the extruded product. By controlling the amount of air included in the extruded product, the rate of release of the opioid analgesic, the opioid antagonist, one or more aversion agents, or mixtures of these can be altered. Thus, in a further aspect of the invention, the molten extruded product is prepared in a form that substantially excludes air during the extrusion phase of the process. This can be achieved, for example, by using a Leistritz extruder that has a vacuum auxiliary. The extruded matrix multiparticulates prepared according to the invention using the Leistritz extruder under vacuum provides a molten extruded product having different physical characteristics. In particular, the extruded product is substantially non-porous when expanded, for example, by using a scanning electron microscope that provides an SEM (scanning electron micrograph). These substantially non-porous formulas can provide a more rapid release of the therapeutically active agent, relative to the same formula prepared without a vacuum. The SEMs of the matrix multiparticulates prepared using a vacuum extruder appear very smooth, and the multiparticulates tend to be more robust than the multiparticulates prepared without vacuum. It has been observed that in at least some formulas, the use of vacuum extrusion provides a multiparticulate product of the extruded matrix that is more pH dependent than its counterpart formula prepared without vacuum. Alternatively, the molten extruded product is prepared using a Werner-Pfleiderer double screw extruder. In some embodiments, a spherification agent is added to a granulate or multiparticulate matrix and then spherified to produce extended release spheroids. The spheroids are then optionally coated with an extended release coating by the methods described above. The spherification agents that can be used to prepare the multiparticulate formulas of the matrix of the present invention include any spherification agent known in the art. Cellulose derivatives are preferred, and microcrystalline cellulose is especially preferred. A suitable microcrystalline cellulose is, for example, the material sold as Avicel PH 101 (Trade Mark, FMC Corporation). The spherification agent is preferably included as about 1 to about 99% of the multiparticulate matrix by weight. In some embodiments, in addition to the opioid analgesic, the opioid antagonist, one or more aversion agents, and the sphering agent, the spheroids may also contain a binder. Suitable binders, such as, for example, low viscosity water soluble polymers, will be well known to those skilled in the pharmaceutical art. However, water-soluble hydroxy lower alkyl cellulose, such as hydroxypropylcellulose, is preferred. Additionally (or alternatively), the spheroids may include a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer, such as an ethyl acrylate-methacrylic acid copolymer, or ethyl cellulose. In some embodiments, a prolonged release coating is applied to the spheroids, granules, or multiparticulates of the extended-release matrix. In these embodiments, the extended release coating may include a water-insoluble material such as (a) a wax, either alone or in combination with a fatty alcohol; or (b) shellac or zein. The coating is preferably derived from an aqueous dispersion of the hydrophobic extended release material. In some embodiments, it is necessary to coat the spheroids, granules, or multiparticulates of the extended release matrix including the opioid analgesic, the opioid antagonist, one or more aversion agents, and the extended release carrier with a sufficient amount of the aqueous dispersion of, for example, alkylcellulose or acrylic polymer, to obtain a weight gain level of from about 2 to about 50%, for example, from about 2 to about 25%, in order to obtain a sustained release formula. The coating may be smaller or larger depending on, for example, the desired release rate, the inclusion of a plasticizer in the aqueous dispersion and the manner of incorporation thereof. Cellulosic and polymeric materials, including alkylcelluloses, are prolonged release materials perfectly adapted for coating the spheroids, granules or multiparticulates of the extended release matrix according to the invention. Simply by way of example, a preferred alkyl cellulosic polymer is ethyl cellulose, although the skilled artisan will appreciate that other cellulose and / or alkyl cellulose polymers can be readily used, individually or in any combination, as all or part of a hydrophobic coating according to the invention. A commercially available aqueous dispersion of ethylcellulose is Aquacoat® (FMC Corp., Philadelphia, Pa., USA). Aquacoat® is prepared by dissolving the ethylcellulose in an organic solvent immiscible with water and then emulsifying it in water in the presence of a surfactant and a stabilizer. After homogenization to generate submicron droplets, the organic solvent is evaporated under vacuum to form a pseudolatex. The plasticizer is not incorporated into the pseudolatex during the manufacturing phase. In this way, before using it as a coating, it is necessary to thoroughly mix the Aquacoat® with a suitable plasticizer before use. Another aqueous dispersion of ethylcellulose is commercially available as Surelease® (Colorcon, Inc., West Point, Pennsylvania, E.U.A.). This product is prepared by incorporating the plasticizer into the dispersion during the manufacturing process. A hot mixture of polymer, plasticizer (dibutyl sebacate), and a stabilizer (oleic acid) is prepared as a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion that can be applied directly to the spheroids, granules, or multiparticulates of the extended-release matrix. In other preferred embodiments of the present invention, the sustained release material that includes the sustained release coating is a pharmaceutically acceptable acrylic polymer, including but not limited to copolymers of acrylic acid and methacrylic acid, copolymers of methyl methacrylate, methacrylates of ethoxyethyl, cyanoethyl methacrylate, poly (acrylic acid), poly (methacrylic acid), methacrylic acid alkylamide copolymer, poly (methyl methacrylate), polymethacrylate, poly (methyl methacrylate) copolymer, polyacrylamide, methacrylate copolymer of aminoalkyl, poly (methacrylic acid anhydride), and glycidyl methacrylate copolymers. In some preferred embodiments, the acrylic polymer is formed by one or more copolymers of ammonium methacrylate. Ammonium methacrylate copolymers are well known in the art, and are described in the National Formulary (NF) XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. In order to obtain a convenient dissolution profile, it may be necessary to incorporate two or more copolymers of ammonium methacrylate with different physical properties, such as different molar ratios of the quaternary ammonium groups with the neutral (meth) acrylic esters. Some ester-type polymers of methacrylic acid are useful for the preparation of pH-dependent coatings which can be used in accordance with the present invention. For example, there is a family of copolymers synthesized from diethylaminoethyl methacrylate and other neutral methacrylic esters, also known as methacrylic acid copolymer or polymeric methacrylates, commercially available as Eudragit® from Rohm GmbH and Co. Kg Darmstadt, Germany. There are several different types of Eudragit®. For example, Eudragit E is an example of a methacrylic acid copolymer that is inflated and dissolved in acid media. Eudragit L is a methacrylic acid copolymer that does not inflate at about pH <; 5.7 and is soluble at about pH < 6. Eudragit S does not inflate at approximately pH < 6.5 and is soluble at about pH < 7. Eudragit RL and Eudragit RS are inflatable in water, and the amount of water absorbed by these polymers depends on the pH; however, the dosage forms coated with Eudragit RL and RS are independent of pH. In some preferred embodiments, the acrylic coating includes a mixture of two acrylic resin lacquers commercially available from Rohm under the Trade Names Eudragit® RL30D and Eudragit® RS30D, respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of the ammonium groups to the remaining neutral (meth) acrylic esters is 1:20 in Eudragit® RL30D and 1:40 on Eudragit® RS30D. The average molecular weight is about 150,000. The designations of the code RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents. The mixtures of Eudragit® RL / RS are insoluble in water and in digestive fluids. However, the coatings formed therefrom are inflatable and permeable in aqueous solutions and digestive fluids. The Eudragit® RL / RS dispersions of the present invention can be mixed together in any desired ratio in order to finally obtain an extended release formula with a convenient dissolution profile. Suitable prolonged release formulas can be obtained, for example, from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit® RL and 50% Eudragit® RS, and 10% Eudragit® RL: Eudragit ® 90% RS. Of course, a person skilled in the art will recognize that other acrylic polymers can also be used, such as, for example, Eudragit® L. In embodiments of the present invention where the coating includes an aqueous dispersion of a hydrophobic extended release material, the inclusion of an effective amount of a plasticizer in the aqueous dispersion of the hydrophobic material will further improve the physical properties of the extended release coating. For example, because the ethylcellulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, it is preferable to incorporate a plasticizer within an ethylcellulose coating containing a prolonged release coating before using the same as coating material. In general, the amount of plasticizer included in a coating solution is based on the concentration of the film former, eg, more frequently from about 1 to about 50% by weight of the film former. However, the concentration of the plasticizer can only be determined suitably after careful experimentation with the particular coating solution and the method of application. Examples of suitable plasticizers for ethylcellulose include water-insoluble plasticizers such as for example dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and triacetin, although it is possible to use other water-insoluble plasticizers (such as, for example, acetylated monoglycerides, phthalate esters, resin oil, etc.). Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of the ethylcellulose of the present invention. Examples of suitable plasticizers for the acrylic polymers of the present invention include, but are not limited to, citric acid esters such as for example triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene glycol. Other plasticizers that have proven to be suitable for improving the elasticity of films formed from acrylic films such as Eudragit® RL / RS lacquer solutions include polyethylene glycols, propylene glycol, diethyl phthalate, resin oil and triacetin. Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of the ethylcellulose of the present invention. In some embodiments, the spheroids, granules or multiparticulates of the uncoated / coated prolonged release matrix containing the opioid analgesic; the opioid antagonist; and one or more aversive agents are cured to an end point in which the spheroids, granules, or multiparticulates of the extended release matrix provide a stable opioid solution. The curing end point can be determined by comparing the dissolution profile (curve) of the dosage form immediately after curing the dissolution profile (curve) of the dosage form after exposure to accelerated storage conditions of, for example, at least one month at a temperature of 40 ° C and a relative humidity of 75%. Cured formulas are described in detail in U.S. Patent Nos. 5,273,760; 5,286,493; 5,500,227; 5,580,578; 5,639,476; 5,681,585; and 6,024,982. Other examples of sustained release formulations and coatings that can be used in accordance with the present invention include those described in U.S. Patent Nos. 5,324,351; 5,356,467; and 5,472,712. In addition to the above ingredients, the spheroids, granules, or multiparticulates of the matrix may also include suitable amounts of other materials, for example, diluents, lubricants, binders, granulation aids, and glidants that are conventional in the pharmaceutical art in amounts of up to about 50% by weight of the formula if desired. The amounts of these additional materials will be sufficient to provide the desired effect in the desired formula. Specific examples of pharmaceutically acceptable carriers and excipients that can be used to formulate oral dosage forms are described in the Handbook of Pharmaceutical Excipients, North American Pharmaceutical Association (1986), incorporated by reference herein. It has further been discovered that the addition of a small amount of talc to the extended release coating reduces the tendency of the aqueous dispersion to stick during the process, and acts as a polishing agent. OSMOTIC DOSAGE FORMS The prolonged release dosage forms according to the present invention can also be prepared as osmotic dosage forms. Osmotic dosage forms preferably include a two-layer core that includes a drug layer (containing the opioid analgesic and optionally the opioid antagonist and one or more aversion agents) and a delivery or push layer (which may contain the opioid antagonist and / or one or more aversion agents), wherein the two-ply core is surrounded by a semipermeable wall and optionally has at least one passage placed therein. The term "passage" as used for the purpose of this invention includes an opening, orifice, cavity, pore, porous element through which the opioid analgesic (with or without the antagonist) can be pumped, diffused or migrated through. of a fiber, capillary tube, porous coating, porous insert, microporous member, or porous composition. The passage may also include a compound that erodes or is leached from the wall in the environment of the fluid of use to produce at least one passage. Representative compounds to form a passage include erodible poly (glycolic) acid, or poly (lactic acid) in the wall; a gelatinous filament; a polyvinyl alcohol removable in water; leachable compounds such as for example polysaccharides, acids, salts or pore-forming oxides that can be removed in fluid. A passage can be formed by leaching a compound from the wall, such as sorbitol, sucrose, lactose, maltose or fructose, to form a prolonged-release dimensional pore passage. The passage can have any shape, such as round, triangular, square and elliptical, to aid in the prologued, dosed release of the opioid analgesic from the dosage form. The dosage form can be made with one or more spaced-apart spaced apart passages on one or more surfaces of the dosage form. A passage and the equipment to form the passage are presented in the Patents of the United States Nos. 3,845,770; 3,916,899; 4,063,064 and 4,088,864. The passages that include measured release dimensions, formed and adapted as a release pore formed by an aqueous leachate to provide a release pore with a prolonged release rate are presented in U.S. Patent Nos. 4,200,098 and 4,285. , 987. In some embodiments, the two-layer core includes a drug layer with an opioid analgesic and a pusher or displacement layer optionally containing the antagonist and / or one or more aversion agents. The antagonist and / or one or more aversion agents can optionally be included in the drug layer instead of or in addition to its inclusion in the push layer. In some embodiments, the drug layer may also include at least one polymer hydrogel. The polymer hydrogel can have an average molecular weight of between about 500 and about 6,000,000. Examples of polymer hydrogels include but are not limited to, a maltodextrin polymer that includes the formula (C6 H12 05)? ·? 2 ?, where n is 3 to 7,500, and the maltodextrin polymer includes a number average molecular weight 500 to 1,250,000; a poly (alkylene oxide) represented by, for example, a poly (ethylene oxide) and a poly (propylene oxide) having a weight average molecular weight of 50,000 to 750,000, and more specifically represented by a poly ( ethylene oxide) of at least one of an average molecular weight of 100,000, 200,000, 300,000 or 400,000 weight; an alkali carboxyalkylcellulose, where the alkali is sodium or potassium, the alkyl is methyl, ethyl, propyl, or butyl of an average molecular weight of 10,000 to 175,000 weight; and an ethylene-acrylic acid copolymer, including methacrylic and ethacrylic acid of an average molecular weight of 10,000 to 500,000. In some embodiments of the present invention, the delivery or thrust layer includes an osmopolymer. Examples of an osmopolymer include but are not limited to a member selected from the group consisting of a polyalkylene oxide and a carboxyalkylcellulose. The polyalkylene oxide has an average molecular weight of 1,000,000 to 10,000,000 weight. The polyalkylene oxide may be a member selected from the group consisting of polymethylene oxide, polyethylene oxide, polypropylene oxide, polyethylene oxide having an average molecular weight of 1,000,000, polyethylene oxide including an average molecular weight of 5,000,000, of polyethylene including an average molecular weight of 7,000,000, crosslinked polymethylene oxide having an average molecular weight of 1,000,000, and polypropylene oxide of an average molecular weight of 1,200,000. The carboxyalkylcellulose of the typical osmopolymer includes a member selected from the group consisting of alkali carboxyalkylcellulose, sodium carboxymethylcellulose, potassium carboxymethylcellulose, sodium carboxyethylcellulose, lithium carboxymethylcellulose, sodium carboxyethylcellulose, carboxyalkylhydroxyalkylcellulose, carboxymethylhydroxyethylcellulose, carboxyethylhydroxyethylcellulose and carboxymethylhydroxypropylcellulose. The osmopolymers used for the displacement layer have an osmotic pressure gradient across the semipermeable wall. The osmopolymers absorb the fluid within the dosage form, inflating and expanding in this manner as an osmotic hydrogel (also known as osmogel), thereby pushing the contents of the drug layer from the osmotic dosage form. The push layer may also include one or more osmotically effective compounds also known as osmagents and osmotically effective solutes. These absorb an environmental fluid, for example from the gastrointestinal tract, into the dosage form and contribute to the delivery kinetics of the displacement layer. Examples of the osmotically active compounds include a member selected from the group consisting of the osmotic salts and osmotic carbohydrates. Examples of specific osmoagents include but are not limited to sodium chloride, potassium chloride, magnesium sulfate, lithium phosphate, lithium chloride, sodium phosphate, potassium sulfate, sodium sulfate, potassium phosphate, glucose, fructose and maltose. The push layer may optionally include a hydroxypropyl alkyl cellulose having an average molecular weight of number 9,000 to 450,000. Hydroxypropyl alkylcellulose is represented by a member selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylisopropylcellulose, hydroxypropylbutylcellulose, and hydroxypropylpentylcellulose. The push layer may also optionally include an antioxidant to inhibit the oxidation of the ingredients. Some examples of antioxidants include but are not limited to a member selected from the group consisting of ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, a mixture of 2 and 3 tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene, isoascorbate sodium, acid dihydroguarate, potassium sorbate, sodium disulfate, sodium metabisulfite, sorbic acid, potassium ascorbate, vitamin E, 4-chloro-2-6-diteriarate butylphenol, alpha-tocopherol, and propylgalate. In certain alternative embodiments, the dosage form includes a substantially homogeneous core that includes an opioid analgesic, an opioid antagonist, one or more aversion agents, a pharmaceutically acceptable polymer (e.g., polyethylene oxide), optionally a disintegrant ( for example, polyvinyl pyrrolidone), optionally an absorption enhancer (for example, a fatty acid, a surfactant, a chelating agent, a bile salt, etc.). The substantially homogeneous core is surrounded by a semipermeable wall having a passageway (as defined above) for the release of the opioid analgesic, the opioid antagonist and the one or more aversion agents. In some embodiments, the semipermeable wall includes a member selected from the group consisting of a cellulose ester polymer, a cellulose ether polymer and a cellulose ether ester polymer. Representative wall polymers include a member selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tricellulose alkenylates, and alkynylates of mono-, di- and tricellulose. The poly (cellulose) used for the present invention includes an average molecular weight of number 20,000 to 7,500,000. Additional semipermeable polymers for the purpose of this invention include acetaldehyde dimethylcellulose acetate, cellulose acetate ethylcarbamate, cellulose acetate methylcarbamate, cellulose diacetate, propylcarbamate, cellulose acetate diethylaminoacetate; semipermeable polyamide; semipermeable polyurethane; semipermeable sulfonated polystyrene; semipermeable crosslinking polymer formed by the coprecipitation of a polyanion and a polycation such as is presented in U.S. Patent Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,876; semipermeable polymers as presented by Loeb and Sourirajan in U.S. Patent Number 3,133,132; cross-linked semi-permeable polystyrenes; semipermeable crosslinked poly (sodium styrene sulfonate); cross-linked semipermeable poly (vinylbenzyltrimethylammonium chloride); and semipermeable polymers that have a fluid permeability of 2.5X10"8 to 2.5x10 ~ 2 (cm2 / hr'atm) expressed by hydrostatic or osmotic pressure difference atmosphere through the semipermeable wall Other polymers useful in the present invention are known in the art in U.S. Patent Nos. 3,845,770, 3,916,899 and 4,160,020, and in the Handbook of Common Polymers, Scott, JR and WJ Roff, 1971, CRC Press, Cleveland, Ohio. certain embodiments, preferably the semipermeable wall is non-toxic, inert, and maintains its physical and chemical integrity during the drug dosing life In some embodiments, the dosage form includes a binder An example of a binder includes, but is not limited to, a therapeutically acceptable vinyl polymer having an average viscosity-molecular weight of 5,000 to 350,000, represented by a selected member One of the group consisting of poly-n-vinylamide, poly-n-vinylacetamide, poly (vinyl pyrrolidone), also known as poly-n-vinyl-pyrrolidone, poly-n-vinyl caprolactone, poly-n-vinyl-5-methyl -2-pyrrolidone, and copolymers of poly-n-vinyl pyrrolidone with a member selected from the group consisting of vinyl acetate, vinyl alcohol, vinyl chloride, vinyl fluoride, vinyl butyrate, vinyl laureate, and vinyl stearate. Other binders include, for example, acacia, starch, gelatin and hydroxypropyl alkylcellulose of an average molecular weight of from 9,200 to 250,000. In some embodiments, the dosage form includes a lubricant, which can be used during manufacturing in the form of dosage to prevent adhesion to the die wall or punch surfaces. Examples of lubricants include but are not limited to magnesium stearate, sodium stearate, stearic acid, calcium stearate, magnesium oleate, oleic acid, potassium oleate, caprylic acid, sodium stearyl fumarate, and magnesium palmitate.
TRANSDERMAL DELIVERY SYSTEMS The formulas of the present invention can be formulated as a transdermal delivery system, such as, for example, transdermal patches. In certain embodiments of the present invention, a transdermal patch includes an opioid agonist contained in a reservoir or a matrix, and an adhesive that allows the transdermal device to adhere to the skin, allowing the passage of the active agent from the transdermal device through the skin of the patient, with the inclusion of the aversive agents and the opioid antagonists as presented in this invention, which are not releasable when the dosage form is administered intact, but which are releasable when the dosage form it is broken or altered in order to release the opioid from the transdermal system. The transdermal delivery system that provides a controlled release of an opioid agonist is well known. For example, the Duragesic® patch (commercially available from Janssen Pharmaceutical) contains an opioid agonist (fentanyl) and is known to provide adequate analgesia for up to 48 to 72 hours (2 to 3 days). This formula can be reformulated with an aversive agent and an antagonist as presented in this invention. There are several types of buprenorphine transdermal formulas reported in the literature. See, for example, U.S. Patent Number 5,240,711 (Hille et al.), U.S. Patent Number 5,225,199 (Hidaka et al.), U.S. Patent Number 5,069,909 (Sharma et al.), United States No. 4,806,341 (Chien et al.) and United States Patent Number 5,026,556 (Drust et al.), all of which are incorporated herein by reference. These transdermal devices can also be reformulated with the aversives and antagonists as presented in this invention. The transdermal delivery system used in the present invention can also be prepared in accordance with U.S. Patent No. 5,069,909 (Sharma et al.), Incorporated herein by reference. This patent describes a laminated compound for administering buprenorphine transdermally to treat pain. The transdermal delivery system used in the present invention can also be prepared in accordance with U.S. Patent No. 4,806,341 (Chien et al.), Incorporated herein by reference. This patent discloses a narcotic analgesic drug or antagonist (including buprenorphine) transdermal morphine matrix drug dosage unit that possesses a support layer that is substantially hermetic to buprenorphine, and a disc layer of the polymer matrix that is adheres to the support layer and has microdispersed in the same effective dosage amounts of buprenorphine. The transdermal delivery system used in the present invention may also be that described in U.S. Patent No. 5,026,556 (Drust et al.), Incorporated herein by reference. In this, compositions for the transdermal delivery of buprenorphine include buprenorphine in a carrier of a polar solvent material selected from the group consisting of C3-C4 diols, C3-C6 triols, and mixtures thereof, and a polar lipid material selected from the group formed by esters of fatty alcohol, esters of fatty acid, and mixtures of these; wherein the polar solvent material and the lipid material are present in a weight ratio of solvent material: lipid material of from 60:40 to about 99: 1. The transdermal delivery system used in the present invention may also be that described in U.S. Patent No. 4,588,580 (Gale, et al.), Incorporated herein by reference. This system includes a reservoir for the drug that has a surface area of material release, close to the skin, in the range of approximately 5-100 era2 and containing between 0.1 and 50% by weight of a permeable skin form of buprenorphine. The reservoir contains an aqueous gel that includes up to about 47-95% ethanol, 1-10% gelling agent, 0.1-10% buprenorphine, and means of controlling the rate of release disposed in the drug flow path towards the skin that limits the flow of buprenorphine from the system through the skin. The transdermal delivery system used in the present invention may also be that described in PCT / US01 / 04347 for Oshlack et al. The present invention is contemplated to encompass all transdermal formulas, for example, the technologies described above, with the inclusion of an aversive agent and an antagonist, such that the dosage form prevents abuse of the opioid therein. The aversive agent and the antagonist in the non-releasable form when administered intact can be formulated in accordance with U.S. Patent No. 5,149,538 to Granger, incorporated herein by reference. Alternatively, the aversion agent and the opioid agonist can be separated from the opioid by a layer that breaks when the dosage form is altered, thereby mixing the aversion agent with the opioid agonist. Alternatively, a combination of both systems can be used.
SUPPOSITORIES The controlled release formulas of the present invention can be formulated as a pharmaceutical suppository for rectal administration which includes an opioid analgesic, an opioid antagonist, and at least one aversion agent in a controlled release matrix, and a suppository vehicle ( base) . The preparation of controlled release suppository formulas is described in, for example, U.S. Patent No. 5,215,758. The base of the chosen suppository must be compatible with the agents of the present invention. In addition, the suppository base is preferably non-toxic and non-irritating to the mucous membranes, melts or dissolves in rectal fluids, and is stable during storage. In certain preferred embodiments of the present invention for both water-soluble and water-insoluble medicaments, the suppository base includes a fatty acid wax selected from the group consisting of mono-, di- and triglycerides of saturated natural fatty acids of the stretch of chain Cí2 to Ci8. Other excipients may be used in the preparation of the suppositories of the present invention. For example, a wax may be used to mold the shape suitable for administration via the rectal route. This system can also be used without wax, but with the addition of a diluent filled in a gelatin capsule for both rectal and oral administration. Examples of suitable commercially available mono-, di- and triglycerides include natural saturated fatty acids of the chain of 12-18 carbon atoms sold under the trade name Novata ™ (types AB, AB, B, BC, BD, BBC, E, BCF, C, D and 299), manufactured by Henkel, and Witepsol TM (types H5, H12, H15, H175, H185, H19, H32, H35, H39, H42, W25, W31, W35, W45, S55, S58, E75, E76 and E85), manufactured by Dynamit Nobel. Other pharmaceutically acceptable suppository bases can be replaced in whole or in part by the aforementioned mono-, di- and triglycerides. The amount of base in the suppository is determined by the size (i.e., actual weight) of the dosage form, the amount of base (eg, alginate) and the medicine used. In general, the amount of the suppository base is from about 20 percent to about 90 percent by weight of the total weight of the suppository. Preferably, the amount of base in the suppository is from about 65 percent to about 80 percent, by weight of the total weight of the suppository. In certain embodiments of the dosage forms of the present invention, a surfactant may also be included. Surfactants useful in accordance with the present invention include, for example, ionic and nonionic surfactants or humidifying agents commonly used in the formulation of pharmaceutical products, including but not limited to derivatives of resinous oil, cholesterol, polyglycolized glycerides, acetylated monoglycerides. , sorbitan fatty acid esters, poloxamers, polysorbates, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene compounds, monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, docusate sodium, sodium lauryl sulfate, acid colic or derivatives thereof, ethoxylated alcohols, ethoxylated esters, ethoxylated amides, polyoxypropylene compounds, propoxylated alcohols, polymers of the ethoxylated / propoxylated block, propoxylated esters, alkanolamides, amine oxides, fatty acid esters of polyhydric alcohols, ethylene esters glycol, diethylene glycol esters, propylene glycol esters, glycerol esters, polyglycerol fatty acid esters, SPA's (for example, sorbitan esters), TWEEN's (ie, sucrose esters), glucose esters (dextrose) ) Alkali metal sulfates, quaternary ammonium compounds, amidoamines, and aminimides, simethicone, lecithins, alcohols, phospholipids and mixtures thereof. The combined surfactant / humidification agents useful in accordance with the present invention include, for example, sodium lauryl sulfate / polyethylene glycol (PEG) 6000 and sodium lauryl sulfate / PEG 6000 stearic acid, etc. In some embodiments of the present invention, the dosage form may also include an emulsifying agent. Emulsifying agents useful in accordance with the present invention include, for example, monoglycerides, fatty acid / sucrose esters, fatty acid / polyglycerol esters, fatty acid / sorbitan esters, lecithins, potassium and sodium salts of fatty acids. rosin and higher fatty acids, as well as sulfates and sulfonates of these acids, hydroxylamine amine salts of long-chain fatty acid esters, quaternary ammonium salts such as, for example, stearyl-dimethylbenzylammonium chloride and tridecylbenzene-hydroxyethylimidazole chloride, esters phosphorics or higher alcohols such as for example caprylic and octyl alcohol, and monoesters of oleic acid and pentaerythritol such as for example sorbitan monooleates, and mixtures thereof. The oral dosage form and methods of use of the present invention may further include, in addition to an opioid analgesic and an opioid antagonist, one or more drugs that may or may not act synergistically with the opioid analgesic. Thus, in some embodiments, a combination of two opioid analgesics may be included in the dosage form. For example, the dosage form may include two opioid analgesics with different properties, such as, for example, half-life, solubility, potential, and a combination of any of the foregoing. In still other embodiments, one or more opioid analgesics is included and an additional non-opioid medicament is also included. These non-opioid medications would preferably provide additional analgesia, and include, for example, aspirin, acetaminophen; non-steroidal anti-inflammatory drugs ("NSAIDs"), eg, ibuprofen, ketoprofen, etc., N-methyl-D-aspartate (MDA) receptor antagonists, eg, a morphinan such as dextromethoron-dextrorphan, or ketamine, inhibitors of cyclooxygenase-II ("COX-II inhibitors"), and / or glycine receptor antagonist In certain preferred embodiments of the present invention, the invention allows the use of lower doses of the opioid analgesic by virtue of the inclusion of an analgesic no additional opioid, such as an NSAID or a COX-2 inhibitor.Using minor amounts of either or both medications, the side effects associated with effective pain management in humans are reduced.
Non suitable steroidal anti-inflammatory agents, including ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetln, somepirac, thiopinac, cidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, and the like. The useful dosages of these medicaments are well known to those skilled in the art. Antagonists of the N-methyl-D-aspartate (NMDA) receptor are well known in the art, and include, for example, morphinan as dextromethorphan or dextrorphan, ketamine, or pharmaceutically acceptable salts thereof. For purposes of the present invention, the term "NMDA antagonist" is also considered to encompass drugs that block a greater intracellular consequence of NMDA receptor activation, for example, a ganglioside such as GMi or GTib, a phenothiazine such as trifluoperazine. or a naphthalenesulfonamide such as N- (6-amino-ethyl) -5-chloro-l -nane-tanesulfonamide. These drugs are known to inhibit the development of tolerance to and / or dependence on addictive drugs, for example, narcotic analgesics such as morphine, codeine, etc., in United States Patents Nos. 5,321,012 and 5,56,838 (both for yesterday , et al.), and for treating chronic pain in U.S. Patent No. 5,502,058 (Mayer, et al.), all of which are incorporated herein by reference. The NMDA antagonist can be included alone or in combination with a local anesthetic such as lidocaine, as described in these Mayer patents, et al. The treatment of chronic pain through the use of glycine receptor antagonists and the identification of these drugs are described in U.S. Patent No. 5,514,680 (Weber, et al.). COX-2 inhibitors have been reported in the art and several chemical structures are known to produce cyclooxygenase-2 inhibition. COX-2 inhibitors are described, for example, in U.S. Patent Nos. 5,616,601; 5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,474,995; 5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,409,944; and 5,130,311, all of which are incorporated herein by reference. Some preferred COX-2 inhibitors include celcoxib (SC-58635), DUP-697, (flosulide (CGP-28238), meloxicam, 6-methoxy-2 naphthylacetic acid (6-MNA), MK-966 (also known as Vioxx ), nabumetone (a prodrug for 6-MNA), nimesulide, NS-398, SC-5766, SC-58215, T-614, or combinations thereof The dosage levels of the COX-2 inhibitor in the order of from about 0.005 mg at about 140 mg per kilogram of body weight per day are therapeutically effective in combination with an opioid analgesic.Alternatively, about 0.25 mg is administered to about 7 g per patient per day of a COX-2 inhibitor in combination with an analgesic In other additional embodiments, a non-opioid drug may be included to provide a desired effect other than analgesia, for example, antitussive, expectorant, decongestant, antihistamine, local anesthetic, and the like. The invention presented herein is for the purpose of encompassing the use of any pharmaceutically acceptable salt of the same presented opioid analgesics. Pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as for example calcium salt, magnesium salt and the like; amino-organic salts such as, for example, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, α, β-dibenzylethylenediamine salt and the like; salts of inorganic acid such as, for example, hydrochloride, hydrobromide, sulfate, phosphate and the like; salts of organic acid such as for example formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; amino acid salts such as arginate, asparginate, glutamate and the like. Some of the opioid analgesics presented herein may include one or more asymmetric centers and therefore may give rise to enantiomers, diastereoisomers, and other stereoisomeric forms. The present invention also has the purpose of encompassing the use of any possible form of those mentioned as well as their racemic and resolved forms and mixtures thereof. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended to include the geometric isomers both E and. The use of all tautomers is also encompassed by the present invention. The oral dosage forms of the present invention may be in the form of tablets, troches, lozenges, powders or granules, hard or soft capsules, microparticles (eg, microcapsules, microspheres and the like), buccal tablets, etc. In certain embodiments, the present invention provides a method for preventing abuse of an oral controlled release dosage form of an opioid analgesic that includes the preparation of the dosage forms as described above. In certain embodiments, the present invention provides a method for preventing the deviation of an oral controlled release dosage form from an opioid analgesic that includes the preparation of the dosage forms as described above. In certain embodiments, the present invention provides a method for treating pain by administering to a human patient the dosage forms described above. The following examples illustrate various aspects of the present invention. They should not be interpreted in such a way as to limit the claims in any way. EXAMPLE 1 A 20 mg formula of oxycodone containing naloxone is prepared as the antagonist and xanthan gum as the aversion agent. In this example, a small amount of xanthan gum is added to the oxycodone formula during the granulation process. Other gelling agents such as curdlan, carrageenan, alginates, pectin, gelatin, furceler, aggra, guar gum, locust bean gum, tara gum, tragacanth, acacia, glucomannan, karaya, starch and starch derivatives, egg white powder, lactalbumin, soy protein, Jargel, gelan gum, welan gum, rahmsan gum, and the like, can also be used as gelling agents. Other semisynthetic materials such as chitosan, swarm, polyvinyevulan, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, ethillihydroxyethylcellulose, all ether derivatives of cellulose, and the like, could also be used as alternative gelling materials. The formula of Example 1 is listed in Table 1 below. TABLE 1* adjusted for 99.6% test and 4.2% residual humidity ** adjusted for 99.23% test and 0.5% residual moisture Process 1. Dispersion: Dissolve the HC1 of naloxone in water and the solution is added to the Eudragit / Triacetin dispersion.2. Granulation: Spray the Eudragit / Triacetin dispersion on the Oxycodone HC1, the Dry Lactose in Aerosol, the xanthan gum and the Povidone using a fluid bed granulator. 3. Ground: Download the granulation and pass through a mill. 4. Waxing: Melt the stearyl alcohol and add to the ground granulation using a mixer. Let cool. 5. Ground: Pass the cooled granulation through a mill. 6. Lubrication: Lubricate the granulation with talc and magnesium stearate using a mixer. 7. Compression: Compress the granulation into tablets using a tablet press.
EXAMPLE 2 A formula of 40 mg of oxycodone containing naloxone as the antagonist and xanthan gum as the aversion agent was prepared to determine the effect of a varying amount of xanthan gum on the gelation property and the dissolution rate of a Oxycodone tablet, three levels of xanthan gum were added to a granulation of 40 mg oxycodone and compressed into tablets. The recovery of oxycodone from the extraction of water from the tablet and the release rate of the drug were determined. The granulation formula of oxycodone of Example 2 is listed in Table 2 below. TABLE 2Ingredients Quantity / Unit (mg) Oxycodone 40.0 Lactose Dry Aerosol 39.25 Providone 5.0 Eudragit RS30D (solids) 10.0 Triacetin 2.0 HCL Naloxone 0.9 Stearyl Alcohol 25.0 Talcum 2.5 Magnesium Stearate 1.25 Total 125.9 Examples 2A to 2C were prepared by adding different amounts ( 3mg, 5mg, and 9mg) of xanthan gum at a granulation of 125.9 mg oxycodone of Example 2. EXAMPLE 2AProcess 1. Dispersion: Dissolve the HC1 of naloxone in water and the solution is added to the Eudragit / Triacetin dispersion. 2. Granulation: Spray Eudragit / Triacetin dispersion on Oxycodone HCl, Dry Lactose in Aerosol, xanthan gum and Povidone using a fluid bed granulator.
Ground: Download the granulation and pass through a mill. Waxing: Melt the stearyl alcohol and add to the ground granulation using a mixer. Let cool. Ground: Pass the cooled granulation through a mill. Lubrication: Lubricate the granulation with talc and magnesium stearate using a mixer. 7 Add xanthan gum (3 levels) to the granulation and mix well. 8 Compression: Compress the granulation into tablets using a tablet press.
EXAMPLE 3 The granulation of Example 2 was compressed into tablets using a tablet press without the addition of xanthan, and Examples 2, 2A-C were tested under the following dissolution conditions and yielded the results listed in Table 3 to continuation. 1. Apparatus: Type II USP (palette), 150 rpm. 2. Medium: 700 my SGF during the first hour, later 900 ml were elaborated with phosphate buffer at a pH of 7.5.
Sampling time: 1,2,4,8,12,18 and 24 hours. Analytical: Performance Liquid Chromatography. TABLE 3Results of DissolutionThe results of the dissolution show that all the prepared tablets have similar dissolution profiles. The inclusion of xanthan gum appears to substantially change the rate of dissolution of oxycodone. When 1 mL of water was added to the tablets containing xanthan gum in a teaspoon, the solution was not viscous. However, when the samples were heated and allowed to cool, the samples became very viscous. It was very difficult to pass this solution similar to a gel inside a syringe for injection.
EXAMPLE 4 A 20 mg formula of oxycodone containing naloxone is prepared as the antagonist and a bitter agent as the aversion agent. In this example, a small amount of denatonium benzoate is added to an oxycodone formula during the granulation process. The bitter taste would reduce the abuse of oxycodone by oral or intranasal route. The oxycodone formula of Example 4 is listed in Table 4 below.
TABLE 4* adjusted for 99.6% test and 4.2% residual moisture ** adjusted for 99.23% test and 0.5% residual moisture Process 1. Dispersion: Dissolve the HC1 of naloxone and denatonium benzoate in water and the solution is added to the Eudragit dispersion / Triacetin. 2. Granulation: Spray the Eudragit / Triacetin dispersion on the Oxycodone HC1, the Dry Lactose in Aerosol, the xanthan gum and the Povidone using a fluid bed granulator. 3. Ground: Download the granulation and pass through a mill. 4. Waxing: Melt the stearyl alcohol and add to the ground granulation using a mixer. Let it cool. 5. Ground: Pass the cooled granulation through a mill. 6. Lubrication: Lubricate the granulation with talc and magnesium stearate using a mixer. 7. Compression: Compress the granulation into tablets using a tablet press.
EXAMPLE In Example 5, a substantially non-releasable form of a bitter agent (denatonium benzoate) is prepared by coating the denatonium benzoate particles with a coating that renders the denatonium benzoate substantially non-releasable. The formula of Example 5 is listed in Table 5 below.
; Ingredients Qty / Unit (mg) LOAD Denatonium Benzoate 0.07 Sugar Spheres (50.0 mesh 30/35) Opadry White Y-5-7068 2.5 Purified Water 42.5 * COVER White Opadry Y-5-7068 3.02 Prudent Water 17.11 * UNDETERMINED COATING (FOR CONVERT THE AMARGO AGENT IN SUBSTANTIALLY NOT LIBERABLE) Eudragit RS30D (dry weight) 12.10 Triethyl Citrate 2.42 Talc 4.84 Purified Water 49.21 * COVER White Opadry Y-5-7068 4.12 Purified Water 23.35 * Total 79.07* Remains in the product as residual moisture only. PROCESS: 1. Preparation of the Solution Dissolve the denatonium benzoate in Purified Water. Once dissolved, add Opadry White and continue mixing until a homogeneous dispersion is produced.2. Loading Apply the above dispersion to the Sugar Spheres using a fluid bed coating machine.3. Coating Prepare a coating solution by dispersing the Opadry White in Purified Water. Apply this dispersion on the sugar spheres loaded with denatonium benzoate using a fluid bed coating machine.4. Retardant Coating Prepare the non-releasable coating solution by mixing Eudragit RS30D, Tiethyl Citrate, Talc and Purified Water. Apply this dispersion on the charged and coated sugar spheres using a fluid bed coating machine. 5. Coating Prepare a second coating solution by dispersing the Opadry White in Purified Water. Apply this dispersion on the non-releasable coated denatonium benzoate spheres using a fluid bed coating machine. 6. Curing Cure the spheres at 45 ° C for approximately 48 hours. EXAMPLE 6 In Example 6, a substantially non-releasable form of a bitter agent (denatonium benzoate) is prepared in the form of pellets containing denatonium benzoate. The granulates are formed with denatonium benzoate dispersed in a matrix which renders the denatonium benzoate substantially non-releasable. The formula of Example 6 is listed in Table 6 below.
TABLE 6Ingredient Qty / Unit (mg) Denatonium Benzoate 0.07 Dicalcium Phosphate 53.0 Poly (DI-Lactide-12.0 Co-Glycolide) Polymer (PLGA) W-100, 000 Total Ethyl Acetate 65.07* Used as a vehicle for the application of PLGA polymer.
PROCESS: 1. Preparation of the Solution: Dissolve the PLGA in Ethyl Acetate by mixing. 2. Granulation: Place the denatonium benzoate, and the Dicalcium Phosphate in a granular fluid bed coating machine spraying the previous solution.
EXAMPLE 7 In Example 7, a substantially non-releasable form of a bitter agent (denatonium benzoate) is prepared in the form of extruded pellets of denatonium benzoate. The formula of Example 7 is listed in Table 7 below. TABLE 7Ingredient Qty / Unit (mg) Denatonium Benzoate 0.07 Eudragit RSPO 180.0 Stearyl Alcohol 55.0 Total 235.07PROCESS; 1. Ground Pass the stearic alcohol flakes through an impact mill. 2. Mixture Mix denatonium benzoate, Eudragit, and ground stearic alcohol in a double wrap mixer. 3. Extrusion Continuously feed the mixed material into a double screw extruder and collect the resulting filaments on a conveyor.4. Cooling Allow the filaments to cool on the conveyor.
. Preparation of pills Cut the cooled filaments into pills using a machine to make pills. 6. Classification Sort the pills and collect the portion of the desired screen. EXAMPLE 8 Naltrexone HC1 beads In Example 8, maltrexone HC1 beads were prepared for incorporation into capsules having the following formula in Table 8 below. TABLE 8 Ingredients Can / unit (mg) Step 1. Naltrexone HC1 2.1 Preparation of drug layers Non-matching beads 39.98 (30/35 mesh) Transparent Opadry 0.4 (Hidoxypropylmethyl cellulose) Sodium ascorbate 0.027 Ascorbic acid 0.05 Step 2. Eudragit L30D (dry) 2.164 Coating of anionic polymer Triethyl citrate 0.433 Cabosil 0.108 Step 3. Eudragit RS30D (dry) 17.475 Extended release coating Triethyl githrate 3.495 Cabosil 0.874 Step 4. Transparent Opadry 1.899 Coating (Hydroxypropylmethyl cellulose sealing) Cabosil 0.271 Total ( base at 69,287 dry)PROCESS: 1. Dissolve the HC1 of naltrexone, ascorbic acid, sodium ascorbate and Transparent Opadry in water. Spray the medication solution on the non-matching beads in a fluid bed coating machine with a Wurster insert. 2. Disperse Eudragit L30D, Triethyl citrate and Cabosil in water. Spray the dispersion on the beads coated with the medicament in the fluid bed coating machine. 3. Disperse Eudragit RS30D, triethyl citrate and Cabosil in water. Spray the dispersion on the beads in the fluid bed coating machine. 4. Dissolve Clear Opadry in water. Spray the solution on the beads in the fluid bed coating machine. 5. Cure the beads at 60 ° C for 24 hours.
EXAMPLE 9 Naltrexone Multiparticulates A formula of fused extruded naltrexone multiparticulates was prepared. The melted extruded multiparticulate formula is listed in Table 9 below. TABLE 9PROCESS; 1. Mix the ground stearic acid, stearyl alcohol, Naltrexone HCl, BHT, and Eudragit RSPO using a V mixer. 2. Extrude the mixture using a Dust Feeder, Foundry Extruder (equipped with the die head). x 1 mm), Conveyor, Lasermike, and Machine to Make Pills.
Powder feed speed-4.2 kg / hr; empty ~ 980 m Barios.
Conveyor - the diameter of the extruded product must be 1 mm. Machine for manufacturing pills - the pills should be cut to 1 mm in length.3. Sort the pills using # 16 mesh screens and # 20 mesh. Collect the material that passes through the mesh screen # 16 and is retained on the mesh screen # 20. 4. Fill the size # 2 transparent gelatin capsules with the pills. Range: NLT 114 and NMT 126 mg.
EXAMPLE 10 Naltrexone Controlled Release Beads A naltrexone prolonged release bead formula was prepared which can be incorporated into a controlled release granulation of the opioid and compressed into tablets. The formula for naltrexone controlled release beads is listed in Table 10 below.
TABLE 10PROCESS; 1. Dissolve Naltrexone and Opadry HC1 (HPMC) in water. Spray the medication solution on the non-matching beads in a fluid bed coating machine with a Wurster insert. 2. Disperse Eudragit L, triethyl citrate and glyceryl monostearate in water. Spray the dispersion on the beads loaded with medicament in the fluid bed coating machine. 3. Disperse Eudragit RS, triethyl citrate and Cabosil in water. Spray the dispersion on the beads in the fluid coating machine. 4. Dissolve Opadry in water. Spray the solution on the beads in the fluid coating machine. 5. Cure the beads at 60 ° C for 24 hours. EXAMPLE 11 Controlled Release Oxycodone In Example 11, a 20 mg controlled release oxycodone formula having the formula listed in Table 11 below was prepared.
TABLE 11Ingredients Qty / Unit (mg) Oxycodone HC1 20.0 Lactose Dry in Aerosol 59.25 Povidone 10.0 Eudragit RS30D (solids) 10.0 Triacetin 2.0 Stearyl Alcohol 25.0 Talcum 2.5 Magnesium Stearate 1.25 Rose Opadry YS-14518A 4.0 Total 129.0 PROCESS: 1. Granulation: Spray the dispersion of Eudragit / Triacetin on the HC1 of Oxycodone, Dry Lactose in Aerosol and Povidone using a fluid bed granulator. 2. Ground: Download the granulation and pass through a mill. 3. Waxing: Mix the stearyl alcohol and add to the ground granulation using a mixer. Let it cool down. 4. Grinding: Pass the cooled granulation through a mill. 5. Lubrication: Lubricate the granulation with talc and magnesium stearate using a mixer. 6. Compression: Compress granulation into tablets using a tablet press. 7. Film coating: Apply a coating of the aqueous film to the tablets.
EXAMPLE 12 In Example 12, the naltrexone beads prepared according to Example 16 are incorporated into the 20 mg prolonged release oxycodone tablets prepared according to Example 11 and having the formula listed in Table 12 to continuation.
TABLE 12Ingredients Qty / unit * (mg)Step 1. Oxycodone HC1 20.0 Dry Lactose Granulation in Aerosol 59.25 Povidone 5.0 Eudragit RS30D (dry) 10.0 Triacetin 2.0 Stearyl Alcohol 25.0 Talc 2.5 Magnesium 1.25Step 2. OxyContin 125 granulationCombination of (Example 3) Naltrexone Controlled Release 140 Pellets Tablet (Formula 2)PROCESS: 1. Spray Eudragit / triacetin dispersion on oxycodone HCl, dry lactose spray and Povidone using a fluid bed granulator. 2. Download the granulation and pass through a mill.3. Mix the stearyl alcohol and add to the ground granulation using a mill. Allow it to cool. 4. Pass the cooled granulation through a mill. 5. Lubricate the granulation with talc and magnesium stearate using a mixer.6. Mix the naltrexone beads with the previous granulation and compress into tablets. ALTERNATIVE PROCESS: 1. Spray Eudragit / triacetin dispersion on oxycodone HCl, dry lactose spray, and Povidone using a fluid bed granulator. 2. Download the granulation and pass through a mill.3. Mix the naltrexone beads (example 2) with the previous granulation in a Hobar mixer. 4. Mix the stearic alcohol and add to the previous mixture. Let it cool down. 5. Pass the cooled granulation through a mill. 6. Lubricate the granulation with talc and magnesium stearate using a mixer. 7. Compress in tablets.
The releasable naltrexone can be a) coated on the pills for example, including in this one an Opadry solution, b) modifying the inhibited component to release the desired naltrexone, c) including the naltrexone with the opioid agonist; or included in any other method known in the art. The amount of naltrexone must be an amount having a convenient pharmacological effect as presented in this invention and so that it may be immediate or prolonged release.
One or more aversives agents as described herein can be incorporated into the oxycodone tablets by a person skilled in the art. The one or more aversive agents may be in a releasable, non-releasable, or substantially non-releasable form or a combination thereof.
EXAMPLE 13 Controlled Release Hydrocodone A prolonged-release Hydrocodone formula was prepared with the formula of Table 13 below.
TABLE 13PROCESS; 1. Mix the ground stearyl acid, Eudragit RLPO, Hydrocodone Bitartrate, and Eudragit RSPO using a Hobart Mixer. 2. Extruding the granulation using a Dust Feeder, Foundry Extruder (equipped with the 6 x 1 mm die head), Conveyor, Lasermike, and Pill Making Machine.
Powder feed speed-40 g / min; empty ~ 980 m Barios. Conveyor - the diameter of the extruded product must be 1 mm. Machine for manufacturing pills - the pills should be cut to 1 mm in length.3. Sort the pills using # 16 mesh screens and # 20 mesh. Collect the material that passes through the mesh screen # 16 and is retained on the mesh screen # 20. 4. Fill the size # 2 transparent gelatin capsules with the pills. Range: NLT (not less than) 114 mg and NMT (not more than) 126 mg.
The inhibited naltrexone formula of Example 9 can be incorporated into a capsule with the Hydrocodone pill. Preferably, the inhibited naltrexone pills are difficult to distinguish from the Hydrocodone pills. The releasable naltrexone can be a) coated on the pills for example, including in this one an Opadry solution, b) modifying the inhibited component to release the desired naltrexone, c) including the naltrexone with the opioid agonist; or included in any other method known in the art. The amount of naltrexone must be an amount that has a convenient pharmacological effect as presented in this invention and so that it may be immediate or prolonged release. One or more aversion agents as described herein may be incorporated into a capsule with the idrocodone pill, hydrocodone pill, or hydrocodone pill by a person skilled in the art. The one or more aversive agents may be in a releasable, non-releasable or substantially non-releasable form or a combination thereof. Preferably, when the pills that include the aversion agents are incorporated into the capsule, these are hardly distinguishable from the hydrocodone pills.
EXAMPLE 14 Oxycodone HCl Beads A prolonged-release oxycodone HCl bead formula was prepared with the formula in Table 14 below.
Ingredients Qty / unit * (mg)Step 1: Making Oxydicone HCl 10.5 layers of the drug Pearls not even 45,349 (mesh 30/35) Transparent Opadry 2.5Step 2: Eudragit RS30D (dry) 7.206Extended release coating Eudragit RL30D (dry) 0.379 Triethyl citrate 1.517 Cabosil 0.379Step 3: Transparent Opadry 1.899Coating of (Hydroxypropylmethyl cellulose sealing) Cabosil 0.271Total 70.0PROCESS; 1. Dissolve oxycodone HCl and Opadry (HPMC) in water. Spray the medication solution on the non-matching beads in a fluid bed coating machine with a Wurster insert. 2. Disperse Eudragit RS, Eudragit RL, triethyl citrate, and Cabosil in water. Spray the dispersion on the beads in the fluid bed coating machine. 3. Dissolve the Opadry in water. Spray the solution on the beads in the fluid bed coating machine. 4. Cure the beads at 60 ° C for 24 hours.
The inhibited naltrexone formula of Example 8 can be incorporated into a capsule with the oxycodone beads. Preferably, the inhibited naltrexone beads are difficult to distinguish from the oxycodone beads. The releasable naltrexone can be a) coated on the pills for example, including in this one an Opadry solution, b) modifying the inhibited component to release the desired naltrexone, c) including the naltrexone with the opioid agonist; or included in any other method known in the art. The amount of naltrexone must be an amount that has a convenient pharmacological effect as presented in this invention and so that it may be immediate or prolonged release. One or more aversion agents as described herein can be incorporated into a capsule with the oxycodone beads, into the hydrocodone pills or into the oxycodone beads by a person skilled in the art. The one or more aversive agents may be in a releasable, non-releasable or substantially non-releasable form or a combination thereof. Preferably, when the beads that include the aversion agents are incorporated into the capsule, they are hardly distinguishable from the oxycodone beads.
EXAMPLE 15 Controlled Release Hydromorphone A prolonged-release hydromorphone HC1 formula was prepared with the formula in Table 15 below:TABLE 15PROCESS; 1. Mix ground stearic acid, etocel, Hydrocodone Bitartrate and RSPO Eudragit using a V mixer. 2. Extrude the mixture using a Dust Feeder, Foundry Extruder (equipped with the 6 x 1 mm die head) , Conveyor, Lasermike, and Machine to Manufacture Pills.
Powder feed speed-4.2 kg / hr; empty ~ 980 m Barios. Conveyor - the diameter of the extruded product must be 1 mm.
Machine for manufacturing pills - the pills should be cut to 1 mm in length.3. Sort the pills using # 16 mesh screens and # 20 mesh. Collect the material that passes through the mesh screen # 16 and is retained on the mesh screen # 20. 4. Fill the size # 2 transparent gelatin capsules with the pills. Range: NLT 114 and NMT 126 mg.
The inhibited naltrexone formula of Example 15 can be incorporated into a capsule with the idromorphone pills. Preferably, inhibited naltrexone pills are difficult to distinguish from hydrocodone pills. The releasable naltrexone can be a) coated on the pills for example, including in this one an Opadry solution, b) modifying the inhibited component to release the desired naltrexone, c) including the naltrexone with the opioid agonist; or included in any other method known in the art. The amount of naltrexone must be an amount that has a convenient pharmacological effect as presented in this invention and so that it may be immediate or prolonged release. One or more aversives agents as described herein can be incorporated into a capsule with the hydromorphone pills, into the hydrocodone pill or into the hydromorphone pills by a person skilled in the art. The one or more aversive agents may be in a releasable, non-releasable or substantially non-releasable form or a combination thereof. Preferably, when the pills that include the aversion agents are incorporated into the capsule, they are difficult to distinguish from the hydromorphone pills.
EXAMPLE 16 Dosage form of 20 mg of oxycodone containing naloxone is prepared as the antagonist and various deterrentsVarious deterrents used in the previous examples are combined into a product to produce a tablet that could provide resistance to alteration for various types of abuse by addicts. A small amount of naloxone hydrochloride, denatonium benzoate and xanthan gum are added to an oxycodone formula during the granulation process. The oxycodone granulation formula of Example 16 is listed in Table 16 below.
TABLE 16* adjusted for 99.6% test and 4.2% residual humidity ** adjusted for 99.23% test and 0.5% residual moistureProcess Dispersion: Dissolve the HC1 of naloxone and denatonium benzoate in water and the solution is added to the Eudragit / Triacetin dispersion. Granulation: Spray the Eudragit / Triacetin dispersion on oxycodone HCl, Dry Lactose in Aerosol, xanthan gum and Povidone using a fluid bed granulator. Ground: Download the granulation and pass through a mill. Waxing: Melt the stearyl alcohol and add to the ground granulation using a mixer. Let cool. Ground: Pass the cooled granulation through a mill. Lubrication: Lubricate the granulation with talc and magnesium stearate using a mixer. Compression: Compress the granulation into tablets using a tablet press.
EXAMPLE 17-20Examples 4-7 can be repeated using a sufficient amount of capsaicin in place of, or in addition to, the aversion agents presented in this invention. Although the invention has been described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art will realize that obvious modifications can be made to the present without departing from the scope and concept of the invention. invention. These variations are contemplated within the scope of the appended claims.