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    • 专利摘要:
    BENZOIC ACID, BENZOIC ACID DERIVATIVES AND HYDROCODONE HETEROARYL CARBOXYLIC ACID CONJUGATES, PRO-DRUGS, PRODUCTION METHODS AND USE OF THESE. The technology currently described provides compositions comprising aryl carboxylic acids chemically conjugated to the hydrocodone (norfinan-6-one, 4,5-alpha-epoxy-3-methoxy-17-methyl) to form new hydrocarbon prodrugs / compositions, which include benzoates and heteroaryl carboxylic acids, which have a reduced potential for hydrocodone dependence. The present technology also provides methods of treating patients, pharmaceutical kits and methods of synthesis of the conjugates of the present technology.
    公开号:BR112012000569B1
    申请号:R112012000569-3
    申请日:2010-07-01
    公开日:2021-02-02
    发明作者:Travis Mickle；Sven Guenther；Christal Mickle；Guochen Chi；Jaroslaw Kanski；Andrea K. Martin；Bindu Bera
    申请人:Kempharm, Inc.；
    IPC主号:
    专利说明:

    RELATED REQUESTS
    This order claims priority from Provisional U.S. Order Serial No. 61 / 222,718, filed on July 2, 2009, which is incorporated by reference in its entirety. RESEARCH OR DEVELOPMENT WITH FEDERAL FINANCING [Not applicable] BACKGROUND OF THE INVENTION
    Opioids are highly effective as pain killers and are commonly prescribed for the treatment of acute and chronic pain. They are also commonly used as antitussives. Opioids, however, also produce euphoria and are highly addictive. As a result, they are often misused and often have health and social consequences.
    Because of the inherent potential for addiction, it is desirable that any pharmaceutical composition that contains an opioid agonist is made as resistant to addiction or that prevents abuse as practical. Illicit users have often tried to circumvent the extended release properties of these dosage forms by injecting or otherwise misusing the product in order to obtain an immediate release of the opioid agonist.
    Despite their addictive properties and the potential for addiction, morphine-like drugs, particularly codeine, hydrocodone and oxycodone, have been routinely prescribed as treatment for severe and chronic severe pain in recent decades. This is partly because there are no alternatives to relieve severe pain that is resistant to other less potent analgesics, such as non-steroidal anti-inflammatory drugs (NSAIDS). In that regard, there is a need to decrease the potential for addiction. Until today, the approaches used, unfortunately, have not solved the problem.
    Hydrocodone is an opioid and antitussive pain reliever and occurs as white, fine crystals, or as a crystalline powder. Hydrocodone is a semi-synthetic narcotic analgesic prepared from codeine with multiple actions qualitatively similar to those of codeine. It is mainly used for moderate to moderately severe pain relief. Additionally, it is used as an antitussive in cough syrups and tablets in subanalgesic doses (2.5-5 mg).
    Patients taking opioid analgesics, such as hydrocodone, for pain relief may become unintentionally dependent. As tolerance to opioids develops, more drug is needed to relieve pain and generate the feeling of well-being initially achieved with the prescribed dose. This leads to dose escalation, which, if not found, can quickly lead to addiction. In some cases, patients become very dependent in just thirty days. BRIEF SUMMARY OF THE INVENTION
    The present technology uses covalent conjugation of the hydrocodone opioid with certain aryl carboxylic acids to decrease its potential to cause overdose or dependence by requiring that the active hydrocodone be released through enzymatic or metabolic degradation of the conjugate in vivo. The present technology also provides hydrocodone delivery methods as conjugates that release the hydrocodone after oral administration while being resistant to dependence by tortuous routes, such as intravenous injection ("sting") and intranasal administration ("sniffing" ).
    The technology currently described, in at least one aspect, provides a slow / sustained / controlled release composition of the conjugated hydrocodone that allows the slow / sustained / controlled release of the hydrocodone and / or its active metabolite, hydromorphone, into the blood system of a being human or animal within a safe therapeutic window by, for example, oral administration. At least some compositions / formulations of current technology can reduce the potential for addiction / abuse and / or other common side effects associated with hydrocodone and similar compounds.
    In one aspect, the present technology provides a composition comprising at least one hydrocodone conjugate and at least one benzoic acid or derivative thereof, a salt thereof, or a combination thereof, the benzoic acid or derivative thereof having the following formula I:
    where X, Y and Z are selected independently from the group consisting of H, O, S, NH and - (CH2) x-; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are selected independently from 0 or 1; ex is an integer between 1 and 10. In some respects, the benzoic acid or derivative of this is an aminobenzoate, a hydroxybenzoate, an aminohydroxybenzoate, a derivative of these, or a combination of these.
    In another aspect, the present technology provides a composition that comprises at least one hydrocodone conjugate and at least one benzoic acid, a derivative thereof, or a combination thereof.
    In yet another aspect, the present technology provides hydrocodone conjugates for use to treat pain, preferably moderate to severe pain, or for use to reduce or prevent oral, intranasal or intravenous drug abuse. In some respects, conjugates provide resistance to oral, intranasal or parenteral drug dependence.
    In another aspect, the present technology provides at least one hydrocodone conjugate that exhibits a slower release rate over time and a greater or equal AUC when compared to an equivalent molar amount of unconjugated hydrocodone over the same period. time. In other respects, the hydrocodone conjugate exhibits less variability in the oral PK profile when compared to unconjugated hydrocodone. In yet another aspect, at least one conjugate has reduced side effects when compared to unconjugated hydrocodone or prevents adulteration of the drug by physical or chemical manipulation.
    In another aspect, at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC when compared to an equivalent molar amount of unconjugated hydrocodone. In additional aspects, at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC when compared to an equivalent molar amount of unconjugated hydrocodone, but does not provide a peak Cmax or has a Cmax less than a therapeutically amount equivalent of unconjugated hydrocodone. In yet another aspect, at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC, when compared to an equivalent molar amount of unconjugated hydrocodone, but does not provide an equivalent peak of Cmax. In some respects, at least one conjugate provides an equivalent peak of Cmax when compared to unconjugated hydrocodone.
    In yet another aspect, the present technology provides a method for treating a patient who has a disease, disorder or condition that needs or is mediated by the attachment of an opioid to the patient's opioid receptors, which comprises oral administration to the patient of a pharmaceutically effective amount of at least one hydrocodone conjugate and at least one benzoic acid or derivative thereof, a salt thereof, or a combination thereof, the benzoic acid or derivative thereof having formula I:
    where X, Y and Z are selected independently from the group consisting of H, O, S, NH and - (CH2) x-; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are selected independently from 0 or 1; ex is an integer between 1 and 10.
    In another aspect, at least one conjugate binds irreversibly to the patient's opioid receptors. In yet another aspect, at least one conjugate binds irreversibly to the patient's opioid receptors without a CNS depressant effect.
    In a further aspect, the present technology provides a method for treating a patient who has a disease, disorder or condition that needs or is mediated by inhibiting the binding of an opioid to the patient's opioid receptors, which comprises oral administration to the patient. patient of a pharmaceutically effective amount of at least one hydrocodone conjugate and at least one benzoic acid or derivative thereof, a salt thereof, or a combination thereof, the benzoic acid or derivative thereof having formula I:
    where: X, Y and Z are selected independently from the group consisting of H, O, S, NH and - (CH2) x-; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are selected independently from 0 or 1; ex is an integer between 1 and 10.
    In some respects, the present technology provides at least one conjugate that reversibly inhibits the binding of an opioid to the patient's opioid receptor. In other respects, at least one conjugate reversibly inhibits the binding of an opioid to the patient's opioid receptor without a CNS depressant effect.
    In an additional aspect, the present technology provides a method for treating a patient who has a disease, disorder or condition (such as pain) that can be treated by attaching an opioid to the patient's opioid receptors, the a method comprising administering to the patient an pharmaceutically effective amount of at least one hydrocodone conjugate and at least one benzoic acid, a salt thereof, a derivative thereof, or a combination thereof.
    In another aspect, the present technology provides a method for treating a patient who has a disease, disorder or condition (such as, for example, addiction) that can be treated by inhibiting the binding of an opioid to the patient's opioid receptors, which comprises the oral administration to the patient of a pharmaceutically effective amount of at least one hydrocodone conjugate and at least one benzoic acid, a salt thereof, a derivative thereof, or a combination thereof.
    In yet another aspect, the present technology provides a pharmaceutical kit that includes a specified amount of individual doses in a package that contains a pharmaceutically effective amount of at least one hydrocodone conjugate and at least one benzoate, a salt thereof, a derivative thereof, or a combination of these, the benzoate having formula I:
    where X, Y and Z are selected independently from the group consisting of H, O, S, NH and - (CH2) x-; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q can be selected independently from 0 or 1; ex is an integer between 1 and 10. In some respects, the kit even includes instructions for using the kit in a method for treating or preventing symptoms of drug withdrawal or pain in a human or animal patient.
    In another aspect, the present technology provides a pharmaceutical kit that includes a specified amount of individual doses in a package that contains a pharmaceutically effective amount of at least one hydrocodone conjugate and at least one benzoic acid, a salt thereof, a derivative thereof, or a combination of these. In some ways, the kit even includes instructions for using the kit in a method for treating or preventing symptoms of drug withdrawal or pain in a human or animal patient.
    In yet another aspect, the present technology provides a composition that comprises at least one hydrocodone conjugate and at least one heteroaryl carboxylic acid, a derivative thereof, or a combination thereof.
    In yet another aspect, the present technology provides at least one hydrocodone conjugate and at least one heteroaryl carboxylic acid, a derivative thereof, or a combination thereof, wherein at least one heteroaryl carboxylic acid is selected from formula II, formula III or formula IV, where formula II, formula III and formula IV are:
    where X, Y and Z are selected independently from the group consisting of H, O, S, NH and - (CH2) x-; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are selected independently from 0 or 1; ex is an integer from 1 to 10. In some respects, at least one heteroaryl carboxylic acid is a pyridine derivative.
    In some respects, the present technology provides at least one conjugate that prevents adulteration of the drug by physical or chemical manipulation.
    In another aspect, the present technology provides a method for treating a patient who has a disease, disorder or condition that needs or is mediated by the attachment of an opioid to the patient's opioid receptors, which comprises oral administration to the patient of a pharmaceutically effective amount of at least one hydrocodone conjugate and at least one heteroaryl carboxylic acid.
    In an additional aspect, the present technology provides a method for treating a patient who has a disease, disorder or condition that needs or is mediated by the attachment of an opioid to the patient's opioid receptors, which comprises oral administration to the patient of a pharmaceutically effective amount of at least one hydrocodone conjugate and at least one heteroaryl carboxylic acid, wherein the heteroaryl carboxylic acid is selected from formula II, formula III or formula IV, in which formulas
    where X, Y and Z are selected independently from the group consisting of H, O, S, NH and - (CH2) x-; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are selected independently from 0 or 1; ex is an integer from 1 to 10.
    In another aspect, the present technology provides a method for treating a patient who has a disease, disorder or condition that needs or is mediated by the attachment of an opioid to the patient's opioid receptors, which comprises oral administration to the patient of a pharmaceutically effective amount of at least one hydrocodone conjugate and at least one nicotinic acid, a derivative thereof, or a combination thereof.
    In another aspect, the present technology provides a method for treating a patient who has a disease, disorder or condition that needs or is mediated by inhibiting the binding of an opioid to the patient's opioid receptors, which comprises oral administration to the patient. of a pharmaceutically effective amount of at least one hydrocodone conjugate and at least one heteroaryl carboxylic acid. In some respects, heteroaryl carboxylic acid is selected from formula II, formula III or formula IV, where formula II, formula III and formula IV are:
    where X, Y and Z are selected independently from the group consisting of H, O, S, NH and - (CH2) x-; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are selected independently from 0 or 1; ex is an integer from 1 to 10.
    In another aspect, the present technology provides a method for treating a patient who has a disease, disorder or condition that needs or is mediated by inhibiting the binding of an opioid to the patient's opioid receptors, which comprises oral administration to the patient. of a pharmaceutically effective amount of at least one hydrocodone conjugate and at least one nicotinic acid, a derivative thereof, or a combination thereof.
    In yet another aspect, the present technology provides a pharmaceutical kit that includes a specified number of individual doses in a package that contains a pharmaceutically effective amount of at least one hydrocodone conjugate and at least one heteroaryl carboxylic acid, a derivative thereof, or a combination thereof, in which heteroaryl carboxylic acid is selected from formula II, formula III or formula IV, in which formula II, formula III and formula IV are:
    where X, Y and Z are selected independently from the group consisting of H, O, S, NH and - (CH2) x-; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are selected independently from 0 or 1; ex is an integer from 1 to 10. In some respects, the kit even includes instructions for using the kit in a method for treating or preventing symptoms of drug withdrawal or pain in a human or animal patient.
    In yet another aspect, the present technology provides a prodrug that comprises at least one hydrocodone conjugate and at least one benzoic acid or benzoic acid derivative, a salt thereof, or a combination thereof, the benzoic acid or benzoic acid derivative having the following formula I:
    where X, Y and Z are selected independently from the group consisting of H, O, S, NH and - (CH2) x-; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are selected independently from 0 or 1; ex is an integer between 1 and 10.
    In another aspect, the present technology provides a prodrug that comprises at least one hydrocodone conjugate and at least one benzoic acid, a derivative thereof, or a combination thereof.
    In yet another aspect, the present technology provides a prodrug that comprises at least one hydrocodone conjugate and at least one heteroaryl carboxylic acid, a derivative thereof, or a combination thereof. In some respects, the prodrug includes at least one heteroaryl carboxylic acid selected from formula II, formula III or formula IV, where formula II, formula III and formula IV are:
    where X, Y and Z are selected independently from the group consisting of H, O, S, NH and - (CH2) x-; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are selected independently from 0 or 1; ex is an integer from 1 to 10.
    In yet another aspect, the present technology provides a prodrug that comprises at least one hydrocodone conjugate and at least one nicotinic acid, a derivative thereof, or a combination thereof.
    In some respects, the prodrug includes an aminobenzoate, a hydroxybenzoate, an aminohydroxybenzoate, a derivative of these, or a combination of these.
    In some respects, at least one conjugate binds reversibly to the patient's opioid receptors. In some additional aspects, at least one conjugate binds reversibly to the patient's opioid receptors without a CNS depressant effect. In yet another aspect, at least one conjugate prevents or reduces at least one constipating side effect of unconjugated hydrocodone. BRIEF DESCRIPTION OF VARIOUS VIEWS OF THE DRAWINGS
    Figure 1. Chemical structures of hydroxybenzoic acids and benzoic acid derivatives for use in the production of the conjugates of the present technology.
    Figure 2. Chemical structures of aminobenzoic acids for use in the production of the conjugates of the present technology.
    Figure 3. Chemical structures of aminohydroxybenzoic acids for use in the production of conjugates of the present technology.
    Figure 4. Figure 4A is a Table of common hydrocodone products and dosage ranges and Figure 4B is a Table of common hydrocodone products used in cough syrups.
    Figure 5. Graph of the PK profile of plasma concentrations of hydrocodone released by Bz-HC (benzoate-hydrocodone), YYFFI-HC (Tyr-Tyr-Phe-Phe-Ile-Hydrocodone) and Diglicolato-HC over time by oral administration in rats.
    Figure 6. Graph of the PK profile of plasma concentrations of active metabolite hydromorphone over time by oral administration of Bz-HC, YYFFI-HC and Diglycolate-HC in rats.
    Figure 7. Graph of the PK profile of plasma concentrations of hydrocodone released by Bz-HC and Adipate-HC over time by intranasal administration in rats.
    Figure 8. Graph of the PK profile of plasma concentrations of active metabolite hydromorphone over time by intranasal administration of Bz-HC and Adipato-HC in rats.
    Figure 9. Graph of the PK profile of plasma concentrations of hydrocodone released by Bz-HC, Nicotinate-HC and Hydrocodone-BT over time by oral administration in rats.
    Figure 10. Graph of the PK profile of plasma concentrations of active metabolite hydromorphone over time, through oral administration of Bz-HC, Nicotinate-HC and Hydrocodone-BT in rats.
    Figure 11. Graph of the PK profile of plasma concentrations of hydrocodone released by Bz-HC, 2-ABz-HC and Hydrocodone-BT over time by oral administration in rats.
    Figure 12. Graph of the PK profile of plasma concentrations of active metabolite hydromorphone over time by oral administration of Bz-HC, 2-ABz-HC and Hydrocodone-BT in rats.
    Figure 13. Diagrams of synthesis of hydrocodone conjugates. Figure 13A reveals the synthesis of hydrocodone benzoate. Figure 13B reveals the synthesis of hydrocodone nicotinate (nicotinic acid). Figure 13C shows the synthesis of 2-aminobenzoate hydrocodone. Figure 13D reveals the synthesis of hydrocodone salicylate.
    Figure 14. Graph of the PK profile of plasma concentrations of intact Bz-HC, active metabolite hydromorphone and hydrocodone released by Bz-HC over time by oral administration in rats.
    Figure 15. Graph of the PK profile of plasma concentrations of hydrocodone released by Bz-HC and hydrocodone-BT over time by oral administration in dogs.
    Figure 16. Graph of the PK profile of plasma concentrations of the active metabolite hydromorphone over time by oral administration of Bz-HC and hydrocodone-BT in dogs.
    Figure 17. Graph of the PK profile of plasma concentrations of intact Bz-HC and hydrocodone released by Bz-HC over time by oral administration in dogs.
    Figure 18. Graph of the PK profile of plasma concentrations of intact Bz-HC, hydromorphone and hydrocodone active metabolite released by Bz-HC over time by intravenous administration in rats at 0.30 mg / kg.
    Figure 19. Graph of the PK profile of plasma concentrations of hydrocodone released by Bz-HC over time by oral administration to rats in six different dosages.
    Figure 20. Graph of the PK profile of plasma concentrations of active metabolite hydromorphone over time by oral administration of Bz-HC to rats in six different dosages. DETAILED DESCRIPTION OF THE INVENTION
    The present technology provides compositions that comprise aryl carboxylic acids chemically conjugated to the hydrocodone (morfinan-6-one, 4,5-alpha-epoxy-3-methoxy-17-methyl) to form new prodrugs and hydrocodone compositions. In some embodiments, the chemical bond between these two portions can be established by reacting the hydrocodone C-6 enol tautomer with the activated carboxylic acid function of an aryl carboxylic acid, thereby creating an enol-ester conjugate.
    The use of "opioid" is intended to include any drug that activates the opioid receptors found in the brain, spinal cord and intestine. There are four broad classes of opioids: naturally occurring opium alkaloids, for example, morphine (the prototypical opioid), codeine and thebain; endogenous opioid peptides, for example, endorphins; semi-synthetics such as heroin, oxycodone and hydrocodone, which are produced by modifying natural opium alkaloids (opiates) and have similar chemical structures; and pure synthetics, such as fentanyl and methadone, which are not produced from opium and may have chemical structures quite different from opium alkaloids. Additional examples of opioids are hydromorphone, oxymorphone, methadone, levoranol, dihydrocodeine, meperidine, diphenoxylate, sufentanil, alfentanil, propoxyphene, pentazocine, nalbuphine, butorphanol, buprenorphine, meptazinol, dezocine, and pharmaceutically acceptable salts.
    The use of “hydrocodone” aims to include a narcotic analgesic and semi-synthetic antitussive prepared from codeine with multiple actions qualitatively similar to those of codeine. It is commonly used for the relief of moderate to moderately severe pain. Trade names include AnexsiaTM, HycodanTM, HycomineTM, LorcetTM, LortabTM, NorcoTM, TussionexTM, TyloxTM and VicodinTM. Other forms of hydrocodone salt, for example, hydrocodone bitartrate and polistirex hydrocodone, are encompassed by the present technology.
    Some modalities of the present technology provide carboxylic acids conjugated to the hydrocodone, in which the carboxylic acid group is attached directly to the aryl portion. Carboxylic acids attached directly to the aryl portion include benzoates and heteroaryl carboxylic acids.
    Some embodiments of the present technology provide at least one hydrocodone conjugate and at least one benzoic acid or benzoic acid derivative, a salt thereof, or a combination thereof. Benzoates are common in nature and include, for example, without limitation, aminobenzoates (for example, anthranilic acid analogs such as, for example, phenamates), aminohydroxybenzoates and hydroxybenzoates (for example, salicylic acid analogs).
    The general structure of benzoic acid and benzoic acid derivatives of the present technology is:
    wherein X, Y and Z can be independently any combination of H, O, S, NH or - (CH2) -; R1, R2 and R3 can be independently any of the following: H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl, and o, p, q can independently be 0 or 1.
    Suitable hydroxybenzoic acids can be found in Figure 1 and include, without limitation, benzoic acid, salicylic acid, acetylsalicylic acid (aspirin), 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 6-methylsalicylic acid, o, m, p-cresotinic acid , anacardic acids, 4,5-dimethylsalicylic acid, o, m, p-thymotic, diflusinal acid, o, m, p-anisic acid, 2,3-dihydroxybenzoic acid (2,3-DHB), α, β acid, y-resorcylic, protocatechuic acid, gentisic acid, piperonyl acid, 3-methoxysalicylic acid, 4-methoxysalicylic acid, 5-methoxysalicylic acid, 6-methoxysalicylic acid, 3-hydroxy-2-methoxybenzoic acid, 4-hydroxy-2-methoxybenzoic acid , 5-hydroxy-2-methoxybenzoic acid, vanylic acid, isovanilic acid, 5-hydroxy-3-methoxybenzoic acid, 2,3-dimethoxybenzoic acid, 2,4-dimethoxybenzoic acid, 2,5-dimethoxybenzoic acid, 2,6 -dimethoxybenzoic acid, vertric acid (3,4-dimethoxybenzoic acid), 3,5-dimethoxybenzoic acid, gallic acid, 2,3,4-trihydroxyib acid nzoic acid, 2,3,6-trihydroxybenzoic acid, 2,4,5-trihydroxybenzoic acid, 3-O-methylgalic acid (3-OMGA), 4-O-methylgalic acid (4-OMGA), 3,4-O acid -dimethylgalic, siringic acid, 3,4,5-trimethoxybenzoic acid.
    Suitable aminobenzoic acids are shown in Figure 2 and include, without limitation, anthranilic acid, 3-aminobenzoic acid, 4,5-dimethylanthranilic acid, N-methylanthranilic acid, N-acetylanthranilic acid, phenolic acids (eg tolfenamic acid, mefenamic acid , flufenamic acid), 2,4-diaminobenzoic acid (2,4-DABA), 2-acetylamino-4-aminobenzoic acid, 4-acetylamino-2-aminobenzoic acid, 2,4-diacetylaminobenzoic acid.
    Suitable aminohydroxybenzoic acids include, without limitation, 4-aminosalicylic acid, 3-hydroxyanthranilic acid, 3-methoxyanthranilic acid.
    In some embodiments, the composition includes a benzoate conjugate that comprises at least one hydrocodone conjugated to at least one benzoic acid or derivative of benzoic acid, salt thereof, or a combination thereof.
    In some embodiments, benzoates include numerous benzoic acid analogs, benzoate derivatives with hydroxyl or amino groups, or a combination of both. The hydroxyl and amino functions can be presented in free form or covered with another chemical moiety, preferably, without limitation, methyl or acetyl groups. The phenyl ring may have additional substituents, but the total number of substituents may be four or less, three or less, or two or less.
    In another modality, a prodrug or conjugated composition of the present technology is benzoate-hydrocodone, which has the structure:
    Benzoate-hydrocodone (Bz-HC)
    In yet another embodiment, the present technology provides a prodrug or composition that comprises at least one hydrocodone conjugate and at least one heteroaryl carboxylic acid, a derivative thereof, or a combination thereof. Heteroaryl carboxylic acid can be selected from formula II, formula III or formula IV, where formula II, formula III and formula IV are:

    For these formulas, X, Y and Z are selected independently from the group consisting of H, O, S, NH and - (CH2) x-; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are selected independently from 0 or 1; and x is an integer from 1 to 10.
    In some embodiments, the carboxy group of aryl carboxylic acids can be attached directly to the aromatic ring. The present technology includes both aryl carbon-only groups and aryl groups with heteroatoms (heteroaryl). The aryl or heteroaryl group that is directly connected to the carboxyl function can be a 6-membered ring and contains 0 or a heteroatom. In some embodiments, the additional aromatic or aliphatic rings, substituted or unsubstituted, can be fused to that 6-membered aryl or heteroaryl portion. In some embodiments, aryl carboxylic acids may have only one free carboxylic acid group and the total number of phenyl substituents on the 6-membered ring should be four or less, for example, 4, 3, 2 or 1.
    In some embodiments of the present technology, depending on the individual aryl carboxylic acid that is connected to the hydrocodone, the hydrocodone conjugate may have a neutral salt, free acid, free base form, or various pharmaceutically acceptable anionic or cationic salt forms or mixtures of salt with any proportion between positive and negative components. These salt forms include, without limitation: acetate, L-aspartate, besylate, bicarbonate, carbonate, D-cansylate, L-cansylate, citrate, edisylate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, D-lactate, L - lactate, D, L-lactate, D, L-malate, L-malate, mesylate, pamoate, phosphate, succinate, sulfate, D-tartrate, L-tartrate, D, L-tartrate, meso-tartrate, benzoate, gluceptate , D-glucuronate, hibenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, acefilinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, hexane, decane, hexane , dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate (enanthate), hydroxybenzoate, hypurate, phenylpropionate, iodide, xionate, malate, xinafoate mandelate, methanesulfonate, myristate, napadisylate, oleate, oxalate, pa lmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicyl sulphate, sulphosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, cansilate, octate, glycolate, stolate, stolate, stolate, stolate, stolate.
    For the present technology, a suitable hydrocodone conjugate includes nicotinate-hydrocodone, which has the following structure:
    Nicotinate-hydrocodone (Nicotinate-HC)
    Some embodiments of the present technology provide a hydrocodone conjugate which is degraded in vivo enzymatically or in some other way, releasing the active hydrocodone and its aryl carboxylic acid or metabolites thereof. The aryl carboxylic acids used in the conjugates of the present technology are non-toxic at the given dosage levels and are preferably composed of known drugs, natural products, metabolites or GRAS (generally considered to be safe) (for example, preservatives, dyes, flavors, etc.), or non-toxic mimetics of these.
    Compounds, compositions and methods of the present technology provide reduced potential for overdose, reduced potential for abuse or dependence, and / or enhance the characteristics of the hydrocodone with respect to elevated toxicities or suboptimal release profiles. Without being limited by the theory below, the present inventors believe that protection against overdose may occur due to the fact that the conjugates are exposed to different enzymes and / or metabolic pathways by oral administration, in which the conjugate is exposed through the intestine and first-pass metabolism, as opposed to exposure to circulating enzymes or mucous membranes, which limits the hydrocodone's ability to be released by the conjugate. Therefore, resistance to dependence is provided by limiting the “rush” or “high” available by the active hydrocodone released by the prodrug and limiting the effectiveness of alternative routes of administration.
    The compositions of the present technology preferably have pharmacological activity absent or substantially decreased when administered by injection or intranasal administration routes. However, they remain bioavailable orally. Again, without sticking to a particular theory, bioavailability may be the result of hydrolysis of the chemical bond (i.e., a covalent bond) after oral administration. In at least one embodiment, the release of hydrocodone is reduced when the composition of the present technology is released via parenteral routes.
    For example, in one embodiment, the composition of the present technology maintains its effectiveness and resistance to dependence after crushing the tablet, capsule or other oral dosage form. In contrast, from unconjugated parental forms of hydrocodone, the hydrocodone is released immediately after crushing, allowing the contents of the crushed tablet to be used by injection or aspiration producing the “rush” effect sought by dependents.
    In some embodiments of the present technology, hydrocodone conjugates can be given orally to an animal or human patient and, after administration, release the active hydrocodone when hydrolyzed in the body. Without being bound by a particular theory, it is believed that, as aryl carboxylic acids are naturally occurring or mimetic metabolites of these or pharmaceutically active compounds, these conjugates can be easily recognized by physiological systems, resulting in hydrolysis and hydrocodone release. The conjugates themselves have absent or limited pharmacological activity as a conjugate and, consequently, can follow a metabolic pathway that differs from the parent drug.
    In some modalities of the present technology, the choice of an aryl carboxylic acid ("binders") to conjugate to the hydrocodone determines the release of hydrocodone in the systemic circulation, and this can be controlled even when the conjugate is administered through different routes than oral. In one embodiment, the modified hydrocodone would release a hydrocodone similar to the free or unmodified hydrocodone. In another embodiment, the conjugated hydrocodone releases hydrocodone in a controlled or sustained manner. In some modalities, this controlled release can alleviate certain side effects and improve the safety profile of the parent drug. These side effects can include, without limitation, anxiety, bruising, constipation, decreased appetite, difficulty breathing, dizziness, drowsiness, dry throat, diarrhea, headache, nausea, stomach cramps, stomach pain, vomiting. In another embodiment, the conjugated hydrocodone would selectively allow the hydrocodone to be metabolized to hydromorphone. In some embodiments, these conjugates can be used for pain relief, for example, moderate to severe pain relief.
    Hydrocodone and other opioids are also highly addictive and tend to abuse the substance. The recreational abuse of opioid drugs is a common problem and usually starts with oral doses taken in order to obtain euphoria ("rush", "high"). Over time, the user often increases oral dosages to obtain more powerful "highs" or to compensate for increased opioid tolerance. This behavior can progress and result in the exploration of other routes of administration, such as, for example, the intranasal ("sniff") and intravenous ("sting") route.
    In some embodiments of the present technology, the hydrocodone that is conjugated to a suitable aryl carboxylic acid ligand does not result in rapid spikes in plasma concentrations after oral administration that are sought by a potential dependent. In some embodiments, the hydrocodone released by these conjugates has a delayed Tmax and possibly less Cmax than the unconjugated hydrocodone. Without adhering to a particular theory, it is believed that the conjugates of the present technology, when taken orally or by other non-oral routes, do not provide the feeling of "rush", even when taken in larger doses, but still maintain relief of pain.
    In addition, in some embodiments, the hydrocodone conjugated to appropriate binders of the present technology is not efficiently hydrolyzed when administered by non-oral routes. As a result, these conjugates do not generate high plasma or blood concentrations of hydrocodone released when injected or aspirated, compared to the free hydrocodone administered by these routes.
    In some embodiments, the conjugates of the present technology, insofar as they consist of covalently linked hydrocodone, are not able to be physically manipulated to release the hydrocodone opioid from the hydrocodone conjugated by methods, for example, of crushing or crushing solid forms. In addition, the conjugates of the present technology exhibit resistance to chemical hydrolysis under conditions that a potential dependent could apply to "extract" the active portion of the molecule, for example, by boiling, or treatment with acidic or basic solution of the conjugate.
    The compositions and prodrugs of the present technology can be oral dosage forms. Such dosage forms include, without limitation, tablets, capsules, pills, lozenges, lozenges, powders, suspensions, syrups, solutions or thin oral films (OTF). Preferred forms of oral administration are capsules, tablets, solutions and OTF.
    Solid dosage forms may include, without limitation, the following types of excipients: non-stick, binders, coatings, disintegrants, fillers, flavorings and dyes, glidants, lubricants, preservatives, absorbents and sweeteners.
    Oral formulations of the present technology can also be included in a solution or a suspension in an aqueous liquid or a non-aqueous liquid. The formulation can be an emulsion, for example, an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The oils can be administered by adding the purified and sterilized liquids to a prepared enteral formula, which is then placed in the enteral tube of a patient unable to swallow.
    Soft gel or soft gelatin capsules can be prepared, for example, by dispersing the formulation in an appropriate vehicle (vegetable oils are commonly used) to form a high viscosity mixture. This mixture is then encapsulated with a gelatin-based film using technology and machinery known to those in the soft gel industry. The individual units thus formed are then dried to a constant weight.
    Chewable tablets, for example, can be prepared by mixing the formulations with excipients designed to form a relatively soft, flavored tablet dosage form that should be chewed rather than swallowed. Conventional tablet machinery and procedures, for example, direct compression and granulation, that is, or crushing, before compression, can be used. Those involved in the production of solid pharmaceutical dosage forms know the processes and machinery used, since the chewable dosage form is a dosage form that is very common in the pharmaceutical industry.
    Film-coated tablets, for example, can be prepared by coating tablets using techniques such as, for example, rotary boiler coating methods or air suspension methods to deposit an adjoining layer of film on a tablet.
    Compressed tablets, for example, can be prepared by mixing the formulation with excipients that aim to add binder qualities to the disintegrating qualities. The mixture is directly compressed or granulated and then compressed using methods and machinery known to those in the industry. The resulting compressed dosage units are then packaged according to the needs of the market, for example, in unit dose, rolls, bottles, blister packs, etc.
    The present technology also contemplates the use of biologically acceptable vehicles that can be prepared by a wide range of materials. Without limitation, these materials include thinners, binders and adhesives, lubricants, plasticizers, disintegrants, dyes, bulk substances, flavorings, sweeteners and various materials such as buffers and adsorbents in order to prepare a particular medicated composition.
    Binders can be selected from a wide range of materials such as, for example, hydroxypropylmethylcellulose, ethylcellulose, or other suitable cellulose derivatives, povidone, acrylic and methacrylic acid copolymers, pharmaceutical enamel, gums, milk derivatives, for example, whey , starches and derivatives, as well as other conventional binders known to those skilled in the art. Exemplary non-limiting solvents are water, ethanol, isopropyl alcohol, methylene chloride, or mixtures and combinations thereof. Exemplary non-limiting volume substances include sugar, lactose, gelatin, starch and silicon dioxide.
    It should be understood that, in addition to the ingredients particularly mentioned above, the formulations of the present technology may include other suitable agents such as, for example, flavoring agents, preservatives and antioxidants. These antioxidants would be acceptable for use in food and could include vitamin E, carotene, BHT, or other antioxidants.
    Other compounds that can be included by mixing are, for example, medically inert ingredients, for example, solid and liquid diluents, for example, lactose, dextrose, sucrose, cellulose, starch or calcium phosphate for tablets or capsules, olive oil or ethyl oleate, for soft capsules, and water or vegetable oil, for suspensions or emulsions; lubricating agents such as, for example, silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols; gelling agents such as, for example, colloidal clays; thickening agents such as, for example, gum tragacanth or sodium alginate, binding agents such as, for example, starches, gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrating agents such as, for example, starch, alginic acid, alginates or sodium starch glycolate; effervescent mixtures; dyes; sweeteners; wetting agents such as, for example, lecithin, polysorbates or lauryl sulfates; and other therapeutically acceptable accessory ingredients, for example, humectants, preservatives, buffers and antioxidants, which are known additives to such formulations.
    For oral administration, fine powders or granules containing diluting, dispersing and / or surfactant agents can be presented in an elixir, in water or in a syrup, in capsules or sachets in the dry state, in a non-aqueous suspension in which the suspending agents can be be included, either in a suspension in water or a syrup. When desirable, flavoring, preserving, suspending, thickening or emulsifying agents may be included.
    Liquid dispersions for oral administration can be syrups, emulsions or suspensions. Syrups may contain as a vehicle, for example, sucrose or sucrose with glycerol and / or mannitol and / or sorbitol. In particular, a syrup for diabetic patients may contain as vehicles only products, for example, sorbitol, which are not metabolized to glucose or which are only metabolized in a very small amount of glucose. Suspensions and emulsions may contain a vehicle, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.
    The currently approved hydrocodone formulations are combined hydrocodone therapies and one or more non-narcotic active ingredients, depending on the desired indication. Examples of such active pharmaceutical substances include, without limitation, acetaminophen, phenylpropanolamine, homatropin, ibuprofen, aspirin, pheniramine, chlorpheniramine, phenylephrine, pseudoephedrine, pyrilamine and guaifenesin. The conjugated hydrocodone of the present technology can be formulated with one or a combination of these or other active substances or as an isolated active ingredient, without any other active substances.
    The conjugated compositions or prodrugs can be used in methods of treating a patient who has a disease, disorder or condition that needs or is mediated by binding or inhibiting the binding of an opioid to the patient's opioid receptors. The treatment comprises the oral administration to the patient of a pharmaceutically effective amount of at least one hydrocodone conjugate, as described in the present technology. The conjugate may exhibit a slower release rate over time and AUC, when compared to an equivalent molar amount of unconjugated hydrocodone. In other modalities, at least one conjugate may exhibit less variability in the oral PK profile when compared to unconjugated hydrocodone.
    In other embodiments, at least one conjugate is supplied in an amount sufficient to provide a
    AUC therapeutically bioequivalent (area under the curve), when compared to an equivalent molar amount of unconjugated hydrocodone. In additional embodiments, the conjugate is supplied in an amount sufficient to provide a therapeutically bioequivalent AUC when compared to unconjugated hydrocodone, but either has a lower Cmax (peak concentration) in plasma or does not provide an equivalent Cmax in plasma concentrations. In some respects, the conjugate is supplied in an amount sufficient to provide a therapeutically bioequivalent Cmax when compared to unconjugated hydrocodone.
    Diseases, disorders or suitable conditions that can be treated by prodrugs or compositions of the present technology are narcotic dependence or pharmacological dependence and / or acute or chronic pain.
    The dosages for the conjugates of the present technology depend on their molecular weight and the respective weight percentage of hydrocodone as part of the total conjugate and, therefore, can be higher than the dosages of free hydrocodone. Dosages can be calculated based on the dosage potencies of hydrocodone bitartrate, which vary between 2.5 mg and 15 mg per dose. Dose conversion from hydrocodone bitartrate to hydrocodone prodrug can be performed using the following formula:
    Dose (HC prodrug / conjugate) = [dose (HC bitartrate) x (molecular weight (HC prodrug / conjugate) / 494.49)] / proportion of hydrocodone released per prodrug / HC conjugate: hydrocodone
    Suitable dosages of the conjugated hydrocodone of the present technology include, without limitation, formulations that include about 0.5 mg or more, alternatively about 2.5 mg or more, alternatively about 5.0 mg or more, alternatively about 7.5 mg or more, alternatively about 10 mg or more, alternatively about 20 mg or more, alternatively about 30 mg or more, alternatively about 40 mg or more, alternatively about 50 mg or more, alternatively about 60 mg or more, alternatively about 70 mg or more, alternatively about 80 mg or more, alternatively about 90 mg or more, alternatively about 100 mg or more, and include any additional increments thereof, for example, 0.1, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.75, 0.8, 0.9 or 1.0 mg and factors multiplied therewith (for example, x1, x2, x2.5, x5, x10, x100 etc.). The present technology also includes dosage formulations that include currently approved hydrocodone formulations (see Figure 4), where the dosage can be calculated using the formula above determined by the amount of hydrocodone bitartrate. The present technology provides dosage forms formulated as a single therapy or as a combined therapy with other API's (Figure 4).
    Hydrocodone conjugates with benzoic acid or nicotinic acid derivatives of the present technology have several advantages, including, without limitation, reduced patient variability in plasma concentrations of hydrocodone or hydromorphone when compared to free hydrocodone, reduced potential for drug dependence, reduced risk chemical or physical manipulation that results in full dosing of released hydrocodone, improved dosage forms through covalent bonding to carboxylic acids or derivatives thereof, increased or decreased hydrocodone metabolism in hydromorphone and / or decreased side effects (other than dependence).
    Hydrocodone is a narcotic pain reliever, which acts as a weak agonist at opioid receptors in the central nervous system (CNS). It primarily affects the μ (mu) (OP3) receptor, but also exhibits agonist activity at the δ (delta) (OP1) and K (kappa) (OP2) receptor. Additionally, the hydrocodone exhibits antitussive properties by suppressing the cough reflex in the spinal cord of the brain.
    Side effects of opioid analgesics include gastrointestinal dysfunction caused by the binding of opioids to mu (μ) receptors present in the gastrointestinal tract. Side effects in the stomach include a reduction in hydrochloric acid secretion, decreased gastric motility, and thus prolonged gastric emptying time, which can result in esophageal reflux. The passage of gastric contents through the duodenum can be delayed by up to 12 hours, and the absorption of drugs administered orally is delayed. In the small intestine, opioid analgesics decrease bile, pancreatic and intestinal secretions, and delay the digestion of food in the small intestine. The propulsive peristaltic waves in the colon are diminished or abolished after administration of opioids, and the tone is increased to the point of spasm. The resulting delay in the passage of intestinal contents causes considerable desiccation of the stool, which, in turn, slows its progress through the colon. These actions, combined with inattention to normal sensory stimuli for the defecation reflex caused by the central action of the drug, contribute to opioid-induced constipation.
    Hydrocodone is used to treat moderate to moderately severe pain and to inhibit coughing (especially dry, non-productive cough). The prodrugs of the present technology can be administered to relieve cough pain or depression or to treat any condition that may require opioid receptor blockage.
    The conjugates of the present technology may provide a decrease in the side effects of the opioid analgesic, including reduced or inhibited constipating effects.
    The present technology also provides a synthetic method for the preparation of the conjugated hydrocodone of the present technology. In one embodiment, the synthesis of the present technology includes the steps of: 1. Protection of the binder, if necessary; 2. Activation of the carboxylic acid binding group, if not in the activated form; 3. Addition of the activated ligand to the hydrocodone or vice versa in the presence of base; and 4. Removal of binder protection groups, if applicable.
    If aryl carboxylic acid contains any additional reactive functional group that may interfere with hydrocodone coupling, it may be necessary to first attach one or more protecting groups. Any suitable protection group can be used, depending on the type of functional group and the reaction conditions. Some examples of protecting groups are: acetyl (Ac), β-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), p-methoxybenzyl ether (PMB), trimethylsilyl (TMS), tert-butyldimethylsily (TBDPS), triisopropylsily (TIPS ), carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz), tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyl (Bn), p-methoxybenzyl (MPM), tosyl (Ts). Temporary formation of acetals or ketals from carbonyl functions may also be appropriate.
    The carboxylic acid group of the ligands must be activated in order to react with hydrocodone and generate appreciable amounts of conjugate. This activation can be achieved in several ways by various coupling agents known to those skilled in the art. Examples of such coupling agents are: N, N'-dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) - N'-ethylcarbodiimide (EDCI), N, N'-diisopropylcarbodiimide (DIC), 1,1'-carbonyldiimidazole ( CDI) or other carbodiimides; (benzotriazol-1-yloxy) hexafluorphosphate tris (dimethylamino) phosphonium (BOP), bromotripyrrolidinophosphonium hexafluorphosphate (PyBroP), tripyrrolidinophosphonium (benzotriazol-1-ylox) hexafluorophosphate (other); O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium (HBTU), O- (benzotriazol-1-yl) hexafluorphosphate -N, N, N', N'- tetramethyluronium (TBTU), fluorine hexafluorophosphate-N, N, N ', N'-tetramethylformamidinium (TFFH), N, N, N', N'-tetramethyl-O- (N-succinimidyl) uronium (TSTU) or others amidinium based reagents. Aryl carboxylic acid can also be converted to an appropriate acyl halide, acyl azide or mixed anhydride.
    A base may be required at any stage in the synthetic scheme of a hydrocodone aryl carboxylic acid conjugate. Suitable bases include, without limitation: 4-methylmorpholine (NMM), 4- (dimethylamino) pyridine (DMAP), N, N-diisopropylethylamine, bis (trimethylsilyl) lithium amide, lithium diisopropylamide (LDA), any tert-butoxide alkali metal (for example, potassium tert-butoxide), any alkali metal hydride (for example, sodium hydride), any alkali metal alkoxide (for example, sodium methoxide), triethylamine or any other tertiary amine.
    Suitable solvents that can be used for any reaction in the synthetic scheme of a hydrocodone aryl carboxylic acid conjugate include, without limitation: acetone, acetonitrile, butanol, chloroform, dichloromethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dioxane, ethanol, ethyl acetate, diethyl ether, heptane, hexane, methanol, methyl tert-butyl ether (MTBE), isopropanol, isopropyl acetate, diisopropyl ether, tetrahydrofuran, toluene, xylene or water.
    In some modalities, the prodrug is hydrophobic and, therefore, little water-soluble. This results in a gel-like consistency or lumpy suspension when the compound is mixed with water. Examples of such prodrugs include, without limitation, Piperonylate-HC, 3-OH-4-MeO-Bz-HC, 3-OH-Bz-HC and Galate-HC. These prodrugs cannot be dosed intranasally in rats due to their lack of water solubility. Without being bound by a theory, it is assumed that these compounds would also crystallize or become lumpy when a person tries to inhale them intranasally ("smell"). This property would not only make an attempt at intranasal misuse unpleasant, but it would probably also prevent the prodrug from permeating the nasal mucosa. As a result, these compounds become ineffective for this route of administration.
    The present technology provides pharmaceutical kits for the treatment or prevention of symptoms of drug withdrawal or pain in a patient. The patient can be a human or animal patient. Suitable human patients include pediatric patients, geriatric patients (elderly) and normative patients. The kit comprises a specific amount of individual doses in a package that contains a pharmaceutically effective amount of at least one hydrocodone conjugate of the present technology. The kit may also include instructions for using the kit. The specified amount of individual doses can contain from about 1 to about 100 individual dosages, alternatively from about 1 to about 60 individual dosages, alternatively from about 10 to about 30 individual dosages, including about 1, about 2, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 70, about 80, about 100, and includes any additional increments of these, for example, 1, 2, 5, 10 and multiplied factors of these (for example, x1, x2, x2.5, x5, x10, x100 etc.).
    The technology currently described and its advantages will be better understood by reference to the following examples. These examples are provided to describe specific modalities of the present technology. The provision of these specific examples is not intended to limit the scope and spirit of the present technology. It will be understood by those skilled in the art that the full scope of the technology currently described encompasses the subject matter defined by the claims attached to this specification, and any changes, modifications or equivalents to those claims. EXAMPLES
    Example 1: Chemical stability of hydrocodone benzoate and heteroaryl carboxylate conjugates.
    Exemplary hydrocodone conjugates of the present technology and control test conjugates that are not of the present technology have been tested for chemical stability under conditions similar to those that a potential drug addict can use to "extract" the active portion of the molecule, for example , dissolved in water, hydrochloric acid or sodium bicarbonate at room temperature or 100 ° C. The conjugates were placed in a water solution at room temperature (about 20 ° C) or in an oil bath at 100 ° C for one hour, and the amount of the conjugate that was hydrolyzed under these conditions was measured. Table 1 demonstrates the results, which show that the conjugates did not release hydrocodone at room temperature or when heated in water at 100 ° C for one hour.

    In addition, samples of hydrocodone conjugates of the present technology were tested and compared with samples of other conjugates that are not of the present hydrocodone technology (Adipate-HC) for their hydrolysis in hydrocodone after dilution in 1 N hydrochloric acid (HCl) by 1 hour at room temperature (approximately 20 ° C) or in an oil bath at 100 ° C. The percentages indicate how much of the initial amount of conjugate was hydrolyzed under these conditions. The results are shown in Table 2. Table 2

    Samples of each conjugate were dissolved in a 5% NaHCO3 solution for one hour at room temperature (approximately 20 ° C) or in an oil bath at 100 ° C. The percentages indicate how much of the initial amount of conjugate was hydrolyzed under these conditions, as shown in Table 3 for the conjugates of the present technology and comparison conjugates that are not of the present technology (Tyr-Tyr-Phe-Phe-Ile-Hidrocodona (YYFFI -HC) or Adipate-HC). Table 3
    Example 2: Oral PK profiles of conjugated hydrocodone of the present technology.
    Oral PK curves were determined for benzoate-hydrocodone (Bz-HC), a prodrug of the present technology, when compared with two conjugates outside the scope of the present technology: YYFFI-HC and Diglicolato-HC. The rats received oral administration of an amount of the conjugate equivalent to 2 mg / kg of hydrocodone free base and the plasma concentrations of released hydrocodone and the active metabolite hydromorphone were measured over time by LC-MS / MS. As shown in Figure 5, the oral PK curves for released hydrocodone were somewhat similar for Bz-HC and YYFFI-HC, but the plasma hydrocodone concentrations produced by Bz-HC were significantly higher than the hydrocodone concentrations generated by Diglycolate -HC (AUC and Cmax for Bz-HC were approximately 40% and 50% higher, respectively). Additionally, Bz-HC created higher plasma concentrations of the more potent hydromorphone active metabolite (Figure 6) than both, YYFFI-HC (AUC and Cmax for hydromorphone released by Bz-HC were approximately 60% and 80% higher, respectively) and Diglycolate -HC (AUC and Cmax for hydromorphone released by Bz-HC were approximately 55% and 180% higher, respectively). This suggests that all three compounds go through a different metabolic pathway and that Bz-HC would have potentially greater pain-relieving effects than any of the examples. Example 3: Intranasal PK profile of hydrocodone conjugates.
    The hydrocodone conjugates of the present technology have been tested for resistance to dependence by examining the efficiency of a hydrolysis when administered via routes other than oral. The rats were treated intranasally with conjugate in an amount equivalent to 2 mg / kg of hydrocodone free base and the concentration of hydrocodone released and the active metabolite hydromorphone in the plasma of the rat was measured over time by LC-MS / MS . Plasma hydrocodone concentrations were significantly lower for Bz-HC (AUC and Cmax for hydromorphone released by Adipato-HC were approximately 280% and 60% higher, respectively) as shown in Figure 7. In addition, Bz-HC produced a plasma concentration very low hydromorphone when compared to Adipato-HC (AUC and Cmax for hydromorphone released by Adipato-HC were approximately 750% and 660% higher, respectively), as shown in Figure 8.
    The prodrugs of the present technology provide plasma concentrations of hydrocodone and hydromorphone that are significantly lower than the respective plasma concentration for unbound Hydrocodone-BT or for other classes of prodrug when administered intranasally. Example 4: Intravenous PK profiles exemplary of conjugates of the present technology.
    The hydrocodone conjugates of the present technology are hydrophobic, for example, Bz-HC, Nicotinate-HC, 4-MeO-Bz-HC, Piperonylate-HC, 4-OH-Bz-HC, Salicylate-HC, 3-OH-4 - MeO-Bz-HC, 3-OH-Bz-HC and Galate-HC. Therefore, these compounds cannot be administered intravenously in equivalent oral doses, as they do not dissolve in a practical amount of water, since injectable compounds must be completely in solution, since any solid particle can cause an embolism. The amount of water needed to dissolve a desirable amount of conjugate would make an injection impractical and, therefore, the present compositions and prodrugs have antidependent potential, unlike other hydrocodone conjugates that are water-soluble, for example, Adipato-HC and Diglycolate-HC, which can be administered intravenously in equivalent oral doses. Example 5: Comparison of oral PK profiles of hydrocodone conjugates.
    Plasma concentrations of hydrocodone released
    by Bz-HC and Nicotinate-HC were compared with plasma concentrations of hydrocodone generated by unconjugated Hydrocodone-BT after oral administration to rats. The rats were treated with conjugated or unconjugated drug in an amount equivalent to 2 mg / kg of hydrocodone free base, and the plasma concentration of hydrocodone or hydromorphone was measured by LC-MS / MS, as shown in Figures 9 and 10, respectively. The oral plasma concentration of hydrocodone released by Bz-HC increased similarly with the plasma concentrations of hydrocodone observed with Hydrocodone-BT, until reaching Cmax (Cmax was approximately equal for both compounds). After Tmax, the plasma concentration of hydrocodone for Bz-HC decreased in a slower and more controlled way than for non-conjugated Hydrocodone-BT (Figure 9 and Figure 10). Bz-HC had a higher AUC (AUC was approximately 25% higher, Figure 9), when compared to Hydrocodone-BT, and similar results were observed for plasma concentrations of the active hydromorphone metabolite (Figure 10).
    Nicotinate-HC produced plasma concentrations of hydrocodone and hydromorphone which were below the respective concentrations found for unconjugated Hydrocodone-BT. The corresponding AUC values, however, were within the bioequivalence range for the same dose (based on the hydrocodone free base). 2-ABz-HC demonstrated a different release profile after oral administration to rats, compared to Bz-HC or the non-conjugated drug Hidrocodona-BT. The rats were treated with an amount equivalent to 2 mg / kg of hydrocodone free base and the plasma concentration of hydrocodone or hydromorphone was measured by LC-MS / MS over time as shown in Figure 11 or Figure 12, respectively. 2-ABz-HC released hydrocodone very slowly, which is indicated by a gradual increase in plasma concentration, followed by an attenuated decrease (Figure 11). This resulted in a flattened PK curve when compared to Hydrocodone-BT (Tmax for 2- ABz-HC was approximately four times longer, AUC and Cmax were approximately 35% and 60% less, respectively). Overall, the hydromorphone PK curve was also flatter for 2-ABz-HC than for Hydrocodone-BT (Figure 12), but did not show the small initial peak (AUC and Cmax for 2-ABz-HC were approximately 25% and 50% lower, respectively). Example 6: Determination of variation in plasma concentrations of benzoate-hydrocodone.
    To determine the variability of the plasma concentration of hydrocodone (HC) and hydromorphone (HM), the coefficient of variation (CV) was calculated for individual animals that were dosed with an amount equivalent to 2 mg / kg of benzoate-hydrocodone-free base. hydrocodone or unconjugated hydrocodone bitartrate (BT), and plasma concentrations of hydrocodone and hydromorphone were measured by LC-MS / MS over time. The CV was calculated by dividing the standard deviation of plasma concentrations in individual animals by the mean plasma concentrations of all animals dosed for a given point in time. The “average CV” is the average CV for all time points, as shown in Table 4. Table 4

    The lower mean CV for Bz-HC indicates that this prodrug has less relative variability in plasma concentrations of hydrocodone and hydromorphone across all animals and dosed time points than the unconjugated drug, hydrocodone bitartrate. Example 7: Synthesis of hydrocodone conjugates.
    Synthesis of Benzoate-Hydrocodone free base
    To a solution of hydrocodone free base (0.596 g, 1.99 mmol) in tetrahydrofuran (25 ml), 1 M LiN (SiMe3) 2 in tetrahydrofuran (5.98 ml) was added. The resulting orange suspension was stirred at room temperatures for 30 min, and then benzoate-succinic ester (1.25 g, 5.98 mmol) was added. The resulting mixture was stirred overnight at room temperatures and was quenched after 18 h by the addition of 100 ml of saturated ammonium chloride solution, and was stirred for an additional 2 h. Ethyl acetate (100 ml) was added to the mixture and washed with saturated ammonium chloride solution (3 x 100 ml) and water (1 x 100 ml). The organic extracts were dried over anhydrous MgSO4, the solvent was removed and the residue collected in 2-isopropanol (50 ml). Water was added until a solid formed. The resulting mixture was cooled, filtered and dried to obtain hydrocodone-free benzoate-base (0.333 g, 0.826 mmol, 42% yield) as a dark brown solid. This synthesis is revealed in Figure 13A.
    Synthesis of 2-Boc-aminobenzoic succinate: 2-Boc-aminobenzoic acid (2.56 g, 10.8 mmol) and N-hydroxysuccinimide (1.37 g, 11.88 mmol) were dissolved in 25 ml of THF. DCC (2.45 g, 11.88 mmol) was added in one portion. The reaction was stirred overnight. The solid was removed by filtration and rinsed with acetone (2 x 10 ml). The filtrate was concentrated to dryness and dissolved in 100 ml of acetone. The resulting precipitate (DCU) was removed by filtration and the filtrate was concentrated to generate a solid, which was collected and rinsed with methanol (3 x 4 ml) to generate 3.26 g (90%) of white product.
    Synthesis of 2-Boc-aminobenzoic acid ester and hydrocodone: To the hydrocodone-free base (0.449 g, 1.5 mmol) dissolved in 20 ml of anhydrous THF, a solution of LiHMDS in THF (1 M, 4.5 ml, 4.5 mmol) over 20 min. The mixture was stirred for 30 min and 2-Boc-aminobenzoic succinate (1.50 g, 4.5 mmol) was added in one portion. The reaction was stirred for 4 hours and subsequently quenched with 100 ml of saturated NH4Cl. The mixture was stirred for 1 hour and extracted with 200 ml of ethyl acetate. The ethyl acetate layer was washed with saturated NaHCO3 (2 x 80 ml) and 5% brine (80 ml), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (7% MeOH / CH2Cl2) to generate 449 mg (58%) of an amorphous solid.
    Synthesis of 2-aminobenzoic acid ester of hydrocodone dihydrochloride salt: 2-Boc-aminobenzoic acid ester of hydrocodone (259 mg, 0.5 mmol) was stirred in 4 ml of 4 N HCl / dioxane for 4 hours. The solvent was evaporated to dryness and to the residue was added 5 ml of ethyl acetate. The solid was collected and rinsed with ethyl acetate to generate 207 mg (84%) of product. Synthesis of 2-MOM-salicylic succinate:
    2-MOM-salicylic acid (3.2 g, 17.6 mmol) and N-hydroxysuccinimide (2.23 g, 19.36 mmol) were dissolved in 40 ml of THF. DCC (3.99 g, 19.36 mmol) was added in one portion. The reaction was stirred overnight. The solid was removed by filtration and rinsed with acetone (2 x 10 ml). The filtrate was concentrated and the residue was recrystallized from 10 ml of methanol to generate 2.60 g (53%) of a white solid. Synthesis of hydrocodone 2-MOM-salicylic acid ester:
    To the hydrocodone free base (0.449 g, 1.5 mmol) dissolved in 20 ml of anhydrous THF, a solution of LiHMDS in THF (1 M, 4.5 ml, 4.5 mmol) was added over 20 min. The mixture was stirred for 30 min and 2-MOM-salicylic succinate (1.26 g, 4.5 mmol) was added in one portion. The reaction was stirred for 4 hours and subsequently quenched with 100 ml of saturated NH4Cl. The mixture was stirred for 1 hour and extracted with 200 ml of ethyl acetate. The ethyl acetate layer was washed with saturated NaHCO3 (2 x 80 ml) and 5% brine (80 ml), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (8% MeOH / CH2Cl2) to generate 381 mg (58%) of a syrup. Synthesis of salicylic acid ester of hydrocodone hydrochloride salt:
    To the hydrocodone 2-MOM-salicylic acid ester (380 mg, 0.82 mmol) in 12 ml of methanol, 0.5 ml of concentrated HCl (12 N) was added. The reaction was stirred for 6 hours. The solution was concentrated and residual water was removed by co-evaporation with methanol (5 x 5 ml). The resulting residue was dissolved in 1 ml of methanol, followed by 20 ml of ethyl acetate. The cloudy mixture was evaporated to about 4 ml. The resulting solid was collected and rinsed with ethyl acetate to generate 152 mg (41%) of product. Example 8: Oral PK profiles of conjugated hydrocodone, hydrocodone and hydromorphone in rats.
    After oral administration of benzoate-hydrocodone (Bz-HC) to rats, PK curves were determined for intact Bz-HC, hydrocodone and the active hydromorphone metabolite. The rats received an oral administration of an amount of the conjugate equivalent to 2 mg / kg of hydrocodone free base and the plasma concentrations of intact Bz-HC, released hydrocodone and the active metabolite, hydromorphone, were measured over time by LC- MS / MS. As shown in Figure 14, exposure to intact Bz-HC prodrug was much less than exposure to hydrocodone or hydromorphone (AUC for intact Bz-HC was
    approximately 10% and 3% of the AUC values for hydrocodone and hydromorphone, respectively). Example 9: Oral PK profiles of conjugated hydrocodone, hydrocodone and hydromorphone in dogs.
    After oral administration of benzoate-hydrocodone (Bz-HC) or Hydrocodone-BT to dogs, PK curves were determined for intact Bz-HC (Bz-HC arm alone), hydrocodone and the active metabolite hydromorphone. The dogs received oral administration of an amount of Hydrocodone-BT or the conjugate equivalent to 2 mg / kg of hydrocodone free base. Plasma concentrations of intact Bz-HC, released hydrocodone and the active metabolite, hydromorphone, were measured over time by LC-MS / MS.
    A comparison of the plasma concentrations of hydrocodone released by Bz-HC and Hydrocodone-BT is shown in Figure 15. In general, the plasma concentrations of hydrocodone generated by both compounds were very similar. Systemic exposure to hydrocodone was somewhat reduced for Bz-HC when compared to Hydrocodone-BT (the hydrocodone AUC value for Bz-HC was approximately 72% of the AUC value for Hydrocodone-BT). The Cmax value of hydrocodone for Bz-HC was approximately 92% of the Cmax value for Hydrocodone-BT.
    A comparison of plasma concentrations of the active metabolite, hydromorphone, after oral administration of Bz-HC or Hydrocodone-BT, is shown in Figure 16. Systemic exposure and maximum plasma concentrations of hydromorphone were similar for both compounds. The hydromorphone AUC and Cmax values for Bz-HC were approximately 103% and 109% of the respective values for Hydrocodone-BT.
    A comparison of the plasma concentrations of intact Bz-HC and hydrocodone released by Bz-HC is shown in Figure 17. Similar to the results observed in rats, the
    plasma concentrations of intact Bz-HC prodrug in dogs were low when compared to plasma hydrocodone concentrations (the AUC value for intact Bz-HC was approximately 10% of the AUC value for hydrocodone). Example 10: Intravenous PK profiles of conjugated hydrocodone, hydrocodone and hydromorphone in rats.
    Bz-HC (0.30 mg / kg) was administered intravenously to the rats. Due to its low water solubility (or solubility in PBS), 0.30 mg / kg was close to the maximum dose that could be administered intravenously to rats. PK curves were determined for intact Bz-HC, hydrocodone and the active metabolite hydromorphone. Plasma concentrations of intact Bz-HC, released hydrocodone and the active metabolite, hydromorphone, were measured over time by LC-MS / MS. The resulting PK curves are shown in Figure 18. Example 11: Oral PK profiles of hydrocodone and hydromorphone after several dosages of Bz-HC in rats.
    Bz-HC was administered orally to rats in dosages of 0.25, 0.50, 1.00, 2.00, 3.00 or 4.00 mg / kg. Plasma concentrations of hydrocodone or hydromorphone were measured by LC-MS / MS, as shown in Figures 19 and 20, respectively. Exposures (AUC) to hydrocodone and hydromorphone at doses of Bz-HC between 0.25 and 4.00 mg / kg were very linear. The respective Cmax values, however, were more variable, particularly for hydromorphone. Maximum hydromorphone plasma concentrations did not change significantly at doses above 2.00 mg / kg of Bz-HC.
    In the present specification, the use of the singular includes the plural, except where specifically indicated.
    The compositions, prodrugs and methods described herein can be illustrated by the following modalities listed in the numerous paragraphs below:
    1. A composition comprising at least one hydrocodone conjugate and at least one benzoic acid or benzoic acid derivative, a salt thereof, or a combination thereof, at least one benzoic acid or benzoic acid derivative having the following formula I:
    where, X, Y and Z are selected independently from the group consisting of H, O, S, NH and - (CH2) x-; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are selected independently from 0 or 1; ex is an integer between 1 and 10.
    2. A composition comprising at least one hydrocodone conjugate and at least one benzoic acid, a derivative thereof, or a combination thereof.
    3. A composition comprising a benzoate conjugate, wherein the benzoate conjugate comprises at least one hydrocodone conjugated to at least one benzoic acid or derivative of benzoic acid.
    4. The composition of paragraph 1, wherein at least one benzoic acid or benzoic acid derivative is an aminobenzoate, a hydroxybenzoate, an aminohydroxybenzoate, a derivative thereof, or a combination thereof.
    5. The composition of paragraph 4, in which the aminobenzoate is selected from the group consisting of: anthranilic acid, 3-aminobenzoic acid, 4,5-dimethylanthranilic acid, N-methylanthranilic acid, N-acetylanthranilic acid, phenolic acids (for example , tolfenamic acid, mefenamic acid, flufenamic acid), 2,4-diaminobenzoic acid (2,4-DABA), 2-acetylamino-4-aminobenzoic acid, 4-acetylamino-2-aminobenzoic acid, 2,4-diacetylaminobenzoic acid, derivatives thereof, and combinations thereof.
    6. The composition of paragraph 4, in which hydroxybenzoate is selected from the group consisting of salicylic acid, acetylsalicylic acid (aspirin), 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 6-methylsalicylic acid, o, m, p- cresotinic, anacardic acids, 4,5-dimethylsalicylic acid, o, m, p-thymotic, diflusinal acid, o, m, p-anisic acid, 2,3-dihydroxybenzoic acid (2,3-DHB), α, β acid , y-resorcylic, protocatechuic acid, gentisic acid, piperonyl acid, 3-methoxysalicylic acid, 4-methoxisalicylic acid, 5-methoxysalicylic acid, 6-methoxysalicylic acid, 3-hydroxy-2-methoxybenzoic acid, 4-hydroxy-2- methoxybenzoic acid, 5-hydroxy-2-methoxybenzoic acid, vanylic acid, isovanilic acid, 5-hydroxy-3-methoxybenzoic acid, 2,3-dimethoxybenzoic acid, 2,4-dimethoxybenzoic acid, 2,5-dimethoxybenzoic acid, 2, 6-dimethoxybenzoic acid, vertric acid (3,4-dimethoxybenzoic acid), 3,5-dimethoxybenzoic acid, gallic acid, 2,3,4-trihydroxybenzoic acid, acid 2,3,6-trihydroxybenzoic acid, 2,4,5-trihydroxybenzoic acid, 3-O-methylgalic acid (3-OMGA), 4-O-methylgalic acid (4-OMGA), 3,4-O-dimethylgalic acid, siringuic acid, 3,4,5-trimethoxybenzoic acid, derivatives thereof, and combinations thereof.
    7. The composition of paragraph 4, wherein the aminohydroxybenzoate is selected from the group consisting of 4-aminosalicylic acid, 3-hydroxyanthranilic acid, 3-methoxyanthranilic acid, derivatives thereof, and combinations thereof.
    8. The composition of paragraph 1, 2, 3, or 4, where at least one conjugate is a treatment or preventive composition used to treat narcotic or opioid addiction or prevent withdrawal.
    9. The composition of paragraph 1, 2, 3, or 4, wherein at least one conjugate is a composition for treating pain.
    10. The composition of paragraph 1, 2, 3, or 4, wherein at least one conjugate is a composition for treating moderate to severe pain.
    11. The composition of paragraph 1, 2, 3, or 4, in which at least one conjugate reduces or avoids oral, intranasal or intravenous drug abuse.
    12. The composition of paragraph 1, 2, 3, or 4, wherein at least one conjugate provides resistance to oral, intranasal or parenteral drug dependence.
    13. The composition of paragraph 1, 2, 3, or 4, in which at least one conjugate exhibits an increased release rate over time and AUC when compared to unconjugated hydrocodone over the same period of time.
    14. The composition of paragraph 1, 2, 3, or 4, in which at least one conjugate exhibits less variability in the oral PK profile when compared to unconjugated hydrocodone.
    15. The composition of paragraph 1, 2, 3, or 4, in which at least one conjugate has reduced side effects when compared to unconjugated hydrocodone.
    16. The composition of paragraph 1, 2, 3, or 4, in which at least one conjugate prevents adulteration of the drug by physical or chemical manipulation.
    17. The composition of paragraph 1, 2, 3, or 4, in which at least one conjugate is provided in a dosage form selected from the group consisting of: a tablet, a capsule, a tablet, a suppository, a lozenge, a rhombus, an oral powder, a solution, an oral film, a thin ribbon, a broth and a suspension.
    18. The composition of paragraph 1, 2, 3, or 4, wherein at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC when compared to unconjugated hydrocodone.
    19. The composition of paragraph 1, 2, 3, or 4, wherein at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC and Cmax compared to an equivalent molar amount of unconjugated hydrocodone.
    20. The composition of paragraph 1, 2, 3 or 4, wherein at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC and a lower Cmax, compared to an equivalent molar amount of unconjugated hydrocodone.
    21. The composition of paragraph 1, 2, 3 or 4, wherein at least one conjugate is present in an amount of about 0.5 mg or more.
    22. The composition of paragraph 1, 2, 3 or 4, wherein at least one conjugate is present in an amount of about 2.5 mg or more.
    23. The composition of paragraph 1, 2, 3 or 4, wherein at least one conjugate is present in an amount of about 5 mg or more.
    24. The composition of paragraph 1, 2, 3 or 4, wherein at least one conjugate is present in an amount of about 10 mg or more.
    25. The composition of paragraph 1, 2, 3 or 4, wherein at least one conjugate is present in an amount of about 20 mg or more.
    26. The composition of paragraph 1, 2, 3 or 4, wherein at least one conjugate is present in an amount of about 50 mg or more.
    27. The composition of paragraph 1, 2, 3 or 4, wherein at least one conjugate is present in an amount of about 100 mg or more.
    28. A method for treating a patient who has a disease, disorder or condition that needs or is mediated by binding an opioid to the patient's opioid receptors, which comprises oral administration to the patient of a pharmaceutically effective amount of at least a hydrocodone conjugate and at least one benzoic acid or benzoic acid derivative, a salt thereof, or a combination thereof, the benzoic acid or benzoic acid derivative having the formula I:
    where: X, Y and Z are selected independently from the group consisting of H, O, S, NH and - (CH2) x-; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are selected independently from 0 or 1; ex is an integer between 1 and 10.
    29. The method of paragraph 28, in which at least one conjugate exhibits a slower release rate over time and a higher AUC when compared to an equivalent molar amount of unconjugated hydrocodone over the same period of time.
    30. The method of paragraph 28, in which at least one conjugate exhibits less variability in the oral PK profile when compared to unconjugated hydrocodone.
    31. The method in paragraph 28, in which at least one conjugate has reduced side effects when compared to unconjugated hydrocodone.
    32. The method of paragraph 28, in which at least one conjugate is provided in a dosage form selected from the group consisting of: a tablet, a capsule, a tablet, a suppository, a lozenge, a lozenge, an oral powder, a solution, an oral film, a thin strip, a broth and a suspension.
    33. The method of paragraph 28, wherein at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC, when compared to an equivalent molar amount of unconjugated hydrocodone.
    34. The method of paragraph 28, wherein at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC and when compared to an equivalent molar amount of unconjugated hydrocodone.
    35. The method of paragraph 28, wherein at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC and a lower Cmax when compared to an equivalent molar amount of unconjugated hydrocodone.
    36. The method of paragraph 28, wherein at least one conjugate is present in an amount of about 0.5 mg or more.
    37. The method of paragraph 28, wherein at least one conjugate is present in an amount of about 2.5 mg or more.
    38. The method of paragraph 28, wherein at least one conjugate is present in an amount of about 5 mg or more.
    39. The method of paragraph 28, wherein at least one conjugate is present in an amount of about 10 mg or more.
    40. The method of paragraph 28, wherein at least one conjugate is present in an amount of about 20 mg or more.
    41. The method of paragraph 28, wherein at least one conjugate is present in an amount of about 50 mg or more.
    42. The method of paragraph 28, wherein at least one conjugate is present in an amount of about 100 mg or more.
    43. The method of paragraph 28, in which at least one conjugate binds reversibly to the patient's opioid receptors.
    44. The method of paragraph 28, in which at least one conjugate reversibly binds to the patient's opioid receptors without a CNS depressant effect.
    45. The method of paragraph 28, in which at least one conjugate avoids or reduces at least one constipating side effect of unconjugated hydrocodone.
    46. The method of paragraph 28, in which at least one conjugate exhibits reduced or absent constipating effects when compared to unconjugated hydrocodone.
    47. The method of paragraph 28, in which at least one conjugate binds irreversibly to the patient's opioid receptors.
    48. The method of paragraph 28, in which at least one conjugate binds irreversibly to the patient's opioid receptors without a CNS depressant effect.
    49. A method for treating a patient who has a disease, disorder or condition that needs or is mediated by inhibiting the binding of an opioid to the patient's opioid receptors, which comprises oral administration to the patient of a pharmaceutically effective amount of at least one hydrocodone conjugate and at least one benzoic acid or benzoic acid derivative, a salt thereof, or a combination thereof, the benzoic acid or benzoic acid derivative having the formula I:
    the top (I) where: X, Y and Z are selected independently from the group consisting of H, O, S, NH and - (CH2) x-; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are selected independently from 0 or 1; ex is an integer between 1 and 10.
    50. The method of paragraph 49, wherein at least one conjugate reversibly inhibits the binding of an opioid to the patient's opioid receptor.
    51. The method of paragraph 49, wherein at least one conjugate reversibly inhibits the binding of an opioid to the patient's opioid receptor without a CNS depressant effect.
    52. The method of paragraph 49, in which at least one conjugate prevents or reduces at least one hydrocodone constipating side effect alone.
    53. A method for the treatment of a patient who has a disease, disorder or condition that needs or is mediated by binding an opioid to the patient's opioid receptors, which comprises oral administration to the patient of a pharmaceutically effective amount of at least a hydrocodone conjugate and at least one benzoic acid, a salt thereof, a derivative thereof, or a combination thereof.
    54. The method of paragraph 53, in which at least one conjugate provides a slower release rate over time and a higher AUC when compared to an equivalent molar amount of unconjugated hydrocodone over the same period of time.
    55. The method of paragraph 53, in which at least one conjugate exhibits less variability in the oral PK profile, when compared to hydrocodone alone.
    56. The method of paragraph 53, in which at least one conjugate has reduced side effects, when compared to hydrocodone alone.
    57. The method of paragraph 53, in which at least one conjugate is provided in a dosage form selected from the group consisting of: a tablet, a capsule, a tablet, a suppository, a lozenge, a lozenge, an oral powder, a solution, an oral film, a thin strip, a broth and a suspension.
    58. The method of paragraph 53, wherein at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC, when compared to hydrocodone alone.
    59. The method of paragraph 53, wherein at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC and Cmax, when compared to hydrocodone alone.
    60. The method of paragraph 53, in which at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC, when compared to hydrocodone alone with a lower Cmax.
    61. The method of paragraph 53, in which at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC, when compared to hydrocodone alone, but does not provide an equivalent Cmax.
    62. The method of paragraph 53, wherein at least one conjugate is present in an amount of about 0.5 mg or more.
    63. The method of paragraph 53, wherein at least one conjugate is present in an amount of about 2.5 mg or more.
    64. The method of paragraph 53, wherein at least one conjugate is present in an amount of about 5 mg or more.
    65. The method of paragraph 53, wherein at least one conjugate is present in an amount of about 10 mg or more.
    66. The method of paragraph 53, wherein at least one conjugate is present in an amount of about 20 mg or more.
    67. The method of paragraph 53, wherein at least one conjugate is present in an amount of about 50 mg or more.
    68. The method of paragraph 53, wherein at least one conjugate is present in an amount of about 100 mg or more.
    69. The method of paragraph 53, wherein at least one conjugate reversibly binds to the patient's opioid receptors.
    70. The method of paragraph 53, in which at least one conjugate reversibly binds to the patient's opioid receptors without a CNS depressant effect.
    71. The method of paragraph 53, in which at least one conjugate prevents or reduces at least one hydrocodone constipating side effect alone.
    72. The method of paragraph 53, in which at least one conjugate exhibits reduced or absent constipating effects.
    73. The method of paragraph 53, in which at least one conjugate permanently binds to the patient's opioid receptors.
    74. The method of paragraph 53, in which at least one conjugate permanently binds to the patient's opioid receptors without a CNS depressant effect.
    75. A method for treating a patient who has a disease, disorder or condition that requires or is mediated by inhibiting the binding of an opioid to the patient's opioid receptors, which comprises administering to the patient an oral amount of a pharmaceutically effective amount of at least one hydrocodone conjugate and at least one benzoic acid, a salt thereof, a derivative thereof, or a combination thereof.
    76. The method of paragraph 75, wherein at least one conjugate reversibly inhibits the binding of an opioid to the patient's opioid receptor.
    77. The method of paragraph 75, wherein at least one conjugate reversibly inhibits the binding of an opioid to the patient's opioid receptor without a CNS depressant effect.
    78. The method of paragraph 75, in which at least one conjugate prevents or reduces at least one hydrocodone constipating side effect alone.
    79. A pharmaceutical kit comprising: - a specified amount of individual doses in a package containing a pharmaceutically effective amount of at least one hydrocodone conjugate and at least one benzoic acid or benzoic acid derivative, a salt thereof, or a combination of these, benzoic acid or benzoic acid derivative having the formula I:
    where: X, Y and Z are selected independently from the group consisting of H, O, S, NH and - (CH2) x-; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q can be selected independently from 0 or 1; ex is an integer between 1 and 10.
    80. The kit in paragraph 79, where the kit further comprises: (11) instructions for using the kit in a method for treating or preventing symptoms of drug withdrawal or pain in a human or animal patient.
    81. The kit in paragraph 80, where the patient is a pediatric patient.
    82. The kit in paragraph 80, in which the patient is an elderly patient.
    83. The kit in paragraph 80, in which the patient is a normative patient.
    84. A pharmaceutical kit comprising: - a specified amount of individual doses in a package containing a pharmaceutically effective amount of at least one hydrocodone conjugate and at least one benzoic acid, a salt thereof, a derivative thereof, or a combination thereof .
    85. The kit in paragraph 84, where the kit further comprises: (11) instructions for using the kit in a method for treating or preventing symptoms of drug withdrawal or pain in a human or animal patient.
    86. The kit in paragraph 85, in which the patient is a pediatric patient.
    87. The kit in paragraph 85, in which the patient is an elderly patient.
    88. The kit in paragraph 85, in which the patient is a normative patient.
    89. The kit of paragraph 79, 80, 84 or 85, wherein the individual dosages comprise at least about 0.5 mg or more than at least one conjugate.
    90. The kit of paragraph 79, 80, 84 or 85, wherein the individual dosages comprise at least about 2.5 mg or more than at least one conjugate.
    91. The kit of paragraph 79, 80, 84 or 85, wherein the individual dosages comprise at least about 5.0 mg or more than at least one conjugate.
    92. The kit of paragraph 79, 80, 84 or 85, wherein the individual dosages comprise at least about 10 mg or more than at least one conjugate.
    93. The kit of paragraph 79, 80, 84 or 85, wherein the individual dosages comprise at least about 20 mg or more than at least one conjugate.
    94. The kit of paragraph 79, 80, 84 or 85, wherein the individual dosages comprise at least about 50 mg or more than at least one conjugate.
    95. The kit of paragraph 79, 80, 84 or 85, wherein the individual dosages comprise at least about 100 mg or more than at least one conjugate.
    96. The kit of paragraph 79, 80, 84 or 85, wherein the kit comprises from about 1 to about 60 individual doses.
    97. The kit of paragraph 79, 80, 84 or 85, wherein the kit comprises from about 10 to about 30 individual doses.
    98. A composition comprising at least one hydrocodone conjugate and at least one heteroaryl carboxylic acid, a derivative thereof, or a combination thereof.
    99. The composition of paragraph 98, in which at least one heteroaryl carboxylic acid is selected from formula II, formula III or formula IV, in which formula II, formula III and formula IV are:
    where: X, Y and Z are selected independently from the group consisting of H, O, S, NH and - (CH2) x-; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are selected independently from 0 or 1; ex is an integer from 1 to 10.
    100. A composition comprising at least one hydrocodone conjugate and at least one nicotinic acid, a derivative thereof, or a combination thereof.
    101. The composition of paragraph 98, wherein at least one heteroaryl carboxylic acid is a pyridine derivative.
    102. The composition of paragraph 98, in which heteroaryl carboxylic acid is selected from the group consisting of isonicotinic acid, picolinic acid, 3-hydroxypicolinic acid, 6-hydroxynicotinic acid, citrazinic acid, 2,6-dihydroxynicotinic acid, cinurenic acid, xanthurenic acid, 6-hydroxycinurenic acid, 8-methoxycinurenic acid, 7,8-dihydroxycinurenic acid, 7,8-dihydro-7,8-dihydroxycinurenic acid, derivatives thereof, and combinations thereof.
    103. The composition of paragraph 98, 99 or 100, in which at least one conjugate is used to treat drug, narcotic or opioid addiction, or to avoid withdrawal.
    104. The composition of paragraph 98, 99 or 100, in which at least one conjugate is used to treat pain.
    105. The composition of paragraph 98, 99 or 100, in which at least one conjugate is used to treat moderate to severe pain.
    106. The composition of paragraph 98, 99 or 100, in which at least one conjugate reduces or avoids oral, intranasal or intravenous drug abuse.
    107. The composition of paragraph 98, 99 or 100, wherein at least one conjugate provides resistance to oral, intranasal or parenteral drug dependence.
    108. The composition of paragraph 98, 99 or 100, in which at least one conjugate prevents adulteration of the drug by physical or chemical manipulation.
    109. The composition of paragraph 98, 99 or 100, where at least one conjugate exhibits an increased release rate over time and AUC, when compared to an equivalent molar amount of unconjugated hydrocodone alone over the same period of time. .
    110. The composition of paragraph 98, 99 or 100, in which at least one conjugate exhibits less variability in the oral PK profile, when compared to an equivalent molar amount of unconjugated hydrocodone alone.
    111. The composition of paragraph 98, 99 or 100, in which at least one conjugate has reduced side effects, when compared to hydrocodone alone.
    112. The composition of paragraph 98, 99 or 100, in which the composition is provided in a dosage form selected from the group consisting of: a tablet, a capsule, a tablet, a suppository, a lozenge, a lozenge, a powder oral, a solution, an oral film, a thin strip, a broth and a suspension.
    113. The composition of paragraph 98, 99 or 100, wherein at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC, when compared to an equivalent molar amount of unconjugated hydrocodone alone.
    114. The composition of paragraph 98, 99 or 100, wherein at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC and Cmax, when compared to hydrocodone alone.
    115. The composition of paragraph 98, 99 or 100, wherein at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC, when compared to hydrocodone alone, with a lower Cmax.
    116. The composition of paragraph 98, 99 or 100, wherein at least one conjugate is present in an amount of about 0.5 mg or more.
    117. The composition of paragraph 98, 99 or 100, wherein at least one conjugate is present in an amount of about 2.5 mg or more.
    118. The composition of paragraph 98, 99 or 100, wherein at least one conjugate is present in an amount of about 5 mg or more.
    119. The composition of paragraph 98, 99 or 100, wherein at least one conjugate is present in an amount of about 10 mg or more.
    120. The composition of paragraph 98, 99 or 100, wherein at least one conjugate is present in an amount of about 20 mg or more.
    121. The composition of paragraph 98, 99 or 100, wherein at least one conjugate is present in an amount of about 50 mg or more.
    122. The composition of paragraph 98, 99 or 100, wherein at least one conjugate is present in an amount of about 100 mg or more.
    123. A method for treating a patient who has a disease, disorder, or condition that needs or is mediated by binding an opioid to the patient's opioid receptors, which comprises oral administration to the patient of a pharmaceutically effective amount of at least a hydrocodone conjugate and at least one heteroaryl carboxylic acid.
    124. The method of paragraph 123, in which at least one heteroaryl carboxylic acid is selected from formula II, formula III or formula IV, where formula II, formula III and formula IV are:
    where: X, Y and Z are selected independently from the group consisting of H, O, S, NH and - (CH2) x-; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are selected independently from 0 or 1; ex is an integer from 1 to 10.
    125. A method for treating a patient who has a disease, disorder, or condition that needs or is mediated by binding an opioid to the patient's opioid receptors, which comprises oral administration to the patient of a pharmaceutically effective amount of at least a hydrocodone conjugate and at least one nicotinic acid, a derivative thereof, or a combination of these.
    126. The method of paragraph 123, 124 or 125, in which at least one conjugate exhibits an increased release rate over time and AUC, when compared to hydrocodone alone over the same period of time.
    127. The method of paragraph 123, 124 or 125, in which at least one conjugate exhibits less variability in the oral PK profile, when compared to hydrocodone alone.
    128. The method of paragraph 123, 124 or 125, in which at least one conjugate has reduced side effects, when compared to hydrocodone alone.
    129. The method of paragraph 123, 124 or 125, in which at least one conjugate is provided in a dosage form selected from the group consisting of: a tablet, a capsule, a tablet, a suppository, a lozenge, a lozenge, an oral powder, a solution, an oral film, a thin tape, a broth and a suspension.
    130. The method of paragraph 123, 124 or 125, wherein at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC when compared to an equivalent molar amount of unconjugated hydrocodone.
    131. The method of paragraph 123, 124 or 125, wherein at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC and Cmax, when compared to an equivalent molar amount of unconjugated hydrocodone.
    132. The method of paragraph 123, 124 or 125, wherein at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC and a lower Cmax, compared to the same molar amount of unconjugated hydrocodone.
    133. The method of paragraph 123, 124 or 125, in which at least one conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC, when compared to hydrocodone alone, but does not provide an equivalent Cmax.
    134. The method of paragraph 123, 124 or 125, wherein at least one conjugate is present in an amount of about 0.5 mg or more.
    135. The method of paragraph 123, 124 or 125, wherein at least one conjugate is present in an amount of about 2.5 mg or more.
    136. The method of paragraph 123, 124 or 125, wherein at least one conjugate is present in an amount of about 5 mg or more.
    137. The method of paragraph 123, 124 or 125, wherein at least one conjugate is present in an amount of about 10 mg or more.
    138. The method of paragraph 123, 124 or 125, wherein at least one conjugate is present in an amount of about 20 mg or more.
    139. The method of paragraph 123, 124 or 125, wherein at least one conjugate is present in an amount of about 50 mg or more.
    140. The method of paragraph 123, 124 or 125, wherein at least one conjugate is present in an amount of about 100 mg or more.
    141. The method of paragraph 123, 124 or 125, wherein at least one conjugate binds reversibly to the patient's opioid receptors.
    142. The method of paragraph 123, 124 or 125, wherein at least one conjugate binds reversibly to the patient's opioid receptors without a CNS depressant effect.
    143. The method of paragraph 123, 124 or 125, wherein at least one conjugate prevents or reduces at least one hydrocodone constipating side effect alone.
    144. The method of paragraph 123, 124 or 125, in which at least one conjugate exhibits reduced or absent constipating effects.
    145. The method of paragraph 123, 124 or 125, wherein at least one conjugate permanently binds to the patient's opioid receptors.
    146. The method of paragraph 123, 124 or 125, in which at least one conjugate permanently binds to the patient's opioid receptors without a CNS depressant effect.
    147. A method for treating a patient who has a disease, disorder or condition that needs or is mediated by inhibiting the binding of an opioid to the patient's opioid receptors, which comprises oral administration to the patient of a pharmaceutically effective amount of at least one hydrocodone conjugate and at least one heteroaryl carboxylic acid.
    148. The method of paragraph 147, in which at least one heteroaryl carboxylic acid is selected from formula II, formula III or formula IV, wherein formula II, formula III and formula IV are:
    where: X, Y and Z are selected independently from the group consisting of H, O, S, NH and - (CH2) x-; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are selected independently from 0 or 1; ex is an integer from 1 to 10.
    149. A method for treating a patient who has a disease, disorder or condition that needs or is mediated by inhibiting the binding of an opioid to the patient's opioid receptors, which comprises oral administration to the patient of a pharmaceutically effective amount of at least one hydrocodone conjugate and at least one nicotinic acid, a derivative thereof, or a combination of these.
    150. The method of paragraph 147, 148 or 149, wherein at least one conjugate reversibly inhibits the binding of an opioid to the patient's opioid receptor.
    151. The method of paragraph 147, 148 or 149, wherein at least one conjugate reversibly inhibits the binding of an opioid to the patient's opioid receptor without a CNS depressant effect.
    152. The method of paragraph 147, 148 or 149, wherein at least one conjugate prevents or reduces at least one hydrocodone constipating side effect alone.
    153. A pharmaceutical kit comprising: - a specified number of individual doses in a package containing a pharmaceutically effective amount of at least one hydrocodone conjugate and at least one heteroaryl carboxylic acid, a derivative thereof, or a combination thereof, where at least one heteroaryl carboxylic acid is selected from formula II, formula III or formula IV, where formula II, formula III and formula IV are:
    where: X, Y and Z are selected independently from the group consisting of H, O, S, NH and - (CH2) x-; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are selected independently from 0 or 1; ex is an integer from 1 to 10.
    154. The kit in paragraph 153, where the kit further comprises: (11) instructions for using the kit in a method for treating or preventing symptoms of drug withdrawal or pain in a human or animal patient.
    155. The kit in paragraph 154, where the patient is a pediatric patient.
    156. The kit in paragraph 154, in which the patient is an elderly patient.
    157. The kit in paragraph 154, in which the patient is a normative patient.
    158. The kit of paragraph 153 or 154, wherein the individual dosages comprise at least about 0.5 mg or more than at least one conjugate.
    159. The kit of paragraph 153 or 154, wherein the individual dosages comprise at least about 2.5 mg or more than at least one conjugate.
    160. The kit of paragraph 153 or 154, wherein the individual dosages comprise at least about 5.0 mg or more than at least one conjugate.
    161. The kit of paragraph 153 or 154, wherein the individual dosages comprise at least about 10 mg or more than at least one conjugate.
    162. The kit of paragraph 153 or 154, wherein the individual dosages comprise at least about 20 mg or more than at least one conjugate.
    163. The kit of paragraph 153 or 154, wherein the individual dosages comprise at least about 50 mg or more than at least one conjugate.
    164. The kit of paragraph 153 or 154, wherein the individual dosages comprise at least about 100 mg or more than at least one conjugate.
    165. The kit of paragraph 153 or 154, wherein the kit comprises from about 1 to about 60 individual doses.
    166. The kit of paragraph 153 or 154, wherein the kit comprises from about 10 to about 30 individual doses.
    167. A prodrug comprising at least one hydrocodone conjugate and at least one benzoic acid or benzoic acid derivative, a salt thereof, or a combination thereof, benzoic acid or benzoic acid derivative having the following formula I:
    where, X, Y and Z are selected independently from the group consisting of H, O, S, NH and - (CH2) x-; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are selected independently from 0 or 1; ex is an integer between 1 and 10.
    168. A prodrug that comprises at least one hydrocodone conjugate and at least one benzoic acid, a derivative thereof, or a combination thereof.
    169. A prodrug comprising a benzoate conjugate, wherein the benzoate conjugate comprises at least one hydrocodone conjugated to at least one benzoic acid or benzoic acid derivative.
    170. A prodrug that comprises at least one hydrocodone conjugate and at least one heteroaryl carboxylic acid, a derivative thereof, or a combination thereof.
    171. The prodrug of paragraph 170, in which heteroaryl carboxylic acid is selected from formula II, formula III or formula IV, in which formula II, formula III and formula IV are:
    where: X, Y and Z are selected independently from the group consisting of H, O, S, NH and - (CH2) x-; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are selected independently from 0 or 1; ex is an integer from 1 to 10.
    172. A prodrug that comprises at least one hydrocodone conjugate and at least one nicotinic acid, a derivative thereof, or a combination thereof.
    173. The prodrug of paragraph 167, wherein the benzoic acid derivative is an aminobenzoate, a hydroxybenzoate, an aminohydroxybenzoate, a derivative thereof, or a combination thereof.
    174. The composition of paragraph 1 or 2, where at least one conjugate exhibits less variability in intranasal PK profiles when compared to unconjugated hydrocodone.
    175. The composition of paragraph 1 or 2, in which at least one conjugate exhibits less variability in parenteral PK profiles, when compared to unconjugated hydrocodone.
    176. The composition of paragraph 1 or 2, in which at least one conjugate exhibits less variability in intravenous PK profiles, when compared to unconjugated hydrocodone. The technology currently described will now be described 5 in complete, clear, concise and accurate terms in order to allow those skilled in the technique to which it belongs to practice. It should be understood that preferred embodiments of the technology have been described, and that modifications can be made without departing from the spirit or scope of the invention, as defined in the appended claims.
    权利要求:
    Claims (8)
    [0001]
    1. Composition characterized by comprising a conjugate, in which the conjugate is benzoate-hydrocodone (Bz-HC) with the following structure:
    [0002]
    2. Composition according to claim 1, characterized by the fact that it is used to treat addiction to narcotics or opioids; to avoid withdrawal from narcotics or opioids; to treat moderate to severe pain; to reduce or prevent oral, intranasal or intravenous drug abuse; or to provide resistance to oral, intranasal or parenteral drug dependence.
    [0003]
    3. Composition according to claim 1 or 2, characterized by the fact that the conjugate is supplied in a dosage form selected from the group consisting of: one tablet, one capsule, one tablet, one suppository, one lozenge, one rhombus, an oral powder, a solution, an oral film, a thin ribbon, a broth and a suspension.
    [0004]
    Composition according to any one of claims 1 to 3, characterized in that the conjugate is supplied in an amount sufficient to provide a therapeutically bioequivalent AUC when compared to unconjugated hydrocodone.
    [0005]
    Composition according to any one of claims 1 to 4, characterized in that at least one conjugate is supplied in an amount sufficient to provide a therapeutically bioequivalent AUC and Cmax when compared to an equivalent molar amount of unconjugated hydrocodone.
    [0006]
    Composition according to any one of claims 1 to 5, characterized in that at least one conjugate is supplied in an amount sufficient to provide a therapeutically bioequivalent AUC and a lower Cmax when compared to an equivalent molar amount of hydrocodone not conjugated.
    [0007]
    7. Composition for intravenous administration comprising a conjugate or a pharmaceutically acceptable salt thereof, characterized in that the conjugate is benzoate-hydrocodone having the following structure
    [0008]
    8. Composition for oral administration comprising a conjugate or a pharmaceutically acceptable salt thereof, wherein the conjugate is benzoate-hydrocodone (Bz-HC) having the following structure 10when the amount of Bz-HC administered is 0.25, 0.50, 1.00, 2.00, 3.00 or 4.00 mg / kg, and binders, microcrystalline cellulose, pregelatinized starch and povidone, wherein the conjugate exhibits an improved AUC and release rate over time when compared to the unconjugated hydrocodone over the same period of time; exhibits less variability in the oral pharmacokinetic profile when compared to unconjugated hydrocodone; or reduced side effects when compared to unconjugated hydrocodone.
    类似技术:
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    法律状态:
    2016-01-26| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2019-01-29| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-03-19| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|
    2020-07-21| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|
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    PCT/US2010/040775|WO2011002991A1|2009-07-02|2010-07-01|Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of hydrocodone, prodrugs, methods of making and use thereof|
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