MXPA00002211A - Noribogaine in the treatment of pain and drug addiction - Google Patents

Abstract

The present invention is directed to methods of treating patients for pain by administering noribogaine. Noribogaine may also be used to treat patients for the symptoms associated with withdrawal from drug dependency. In the latter case, the noribogaine treatment should be supplemented with the administration of an opioid antagonist such as naloxone.

Description

NORIBOGAIN IN THE TREATMENT OF PAIN AND ADDICTION TO DRUGS FIELD OF THE INVENTION The present invention relates to new pharmaceutical compositions and new treatment methods. In particular, the present invention relates to novel methods for providing analgesia and new pharmaceutical compositions containing the drug noribogaine. The compositions particularly include those which contain, in addition to noribogaine, one or more opioid antagonists. In addition, the present invention provides novel compositions and methods useful for the treatment of patients for symptoms associated with abstinence in drug dependence or drug abuse. BACKGROUND OF THE INVENTION Ibogaine is an alkaloid indole derivative from the Tabernanth iboga, which is a shrub from West Africa and is used by the indigenous people of that region in religious rituals. The structure of ibogaine has been determined and procedures for its synthesis have been reported (see Buchi, et al., J. Am. Chem. Soc., 88: 3099 (1966); Rosenmund, et al., Chem. Ber. 108: 1871 (1975) and Huffman, et al., J. Org. Chem. 50: 1460 (1985)). The chemical structure is the following: REF .: 32993 In 1956, Salmoiraghi and Page elucidated the relationship of ibogaine with serotonin (< J. Pharm. And Exp. Ther. 120 (1): 20-25 (1957)). Almost at the same time, Schneider published three important documents: "Potentiation Action of Ibogaine on Morphine Analgesia" (Experimental 12: 323-24 (1956)); "Neuropharmacological Studies of Ibogaine: Nature of Alkaloid with Central Stimulant Properties," (Ann. Of N. Y. Acad. Sci. 66: 765-76 (1957)); and "An Analysis of the Cardiovascular Action of Ibogaine HCl", (Arch. Int. Phamacodyn. 110: 92-102 (1957)). Dhahir published a review of the pharmacology and toxicology of ibogaine in his doctoral thesis "Comparative Study of the Toxicity of Ibogaine and Serotonin" (University Microfilms International 71-25-341, Ann Arbor, Mich.). This thesis provides a review of much of the work that has been done with ibogaine. Additional studies of interest include: "The Effects of some Hallucinogens on Aggressiveness of Mice and Rtas" (Kostowski, et al., Pharmacology 7: 259-63 (1972)); "Cerebral Pharmacokinetics of Tremor-Producing Har ala and Iboga Alkaloids" (Zetler, et al., Pharmacology 7 (4): 237-248 (1972)); "High Affinity H-Serotonin Binding to Caudate: Inhibition by Hallucinogenic and Serotonergic Drugs "(Whitaker, et al., Psychopharmacology 59: 1-5 (1978)); "Selective Labeling of Serotonin Receptors by d-3 (H) Lysergic Acid Diethylamide in Calf Caudate" (Proc. Nati, Acad. Sci., U. S. A. 75 (12): 5783-87 (1978)); and "A Common Mechanism of Lysergic Acid, Indolealkilamine and Phenethylamin Hallucinogens: Serotonergic Mediation of Behavioral Effects in Rats" (Sloviter, et al., J. Pharm. Exp. Ther. 214 (2): 231-38 (1980)). More recently Dzoljic et al. , reported the work "Effect of Ibogaine on Naloxone-Precipitated Withdrawal Syndrome in Chronic Morphine Dependent Rats," (Arch. Int. Pharmacodyn., 294: 64-70 (1988)). It has been reported that the administration of ibogaine reduces the withdrawal symptoms associated with drug dependence and relieves the intense desire for drugs in addicts. It has been described as effective in the treatment of resulting dependencies by a wide range of drugs, including narcotics (US Patent 4,499,096); cocaine and amphetamines (US Patent 4,587,243); alcohol (U.S. Patent No. 4,857,523); and nicotine / tobacco (U.S. Patent No. 5,026,697). In addition, it has been reported to be effective in patients addicted to multiple drugs and drug combinations (US Patent 5,152,954). Among the specific afflictions that have been reported to be possible to treat ibogaine, are heroin, cocaine, alcohol, nicotine, caffeine, amphetamines, deoxiefedrine, methadone and combinations thereof. Other pharmacological agents that have been used in the treatment of certain types of drug addiction or dependence include naloxone and naltrexone. However, these agents typically do not alleviate the often intense suffering that accompanies the drug abstinence process and are generally not effective in the treatment of multiple drug abuse or addiction. Thus, the prior art has failed to provide a completely satisfactory therapy for drug addiction or abuse and new agents and methods are needed. BRIEF DESCRIPTION OF THE INVENTION In accordance with the present invention, surprising and unexpected properties of noribogaine have been discovered. It is known that this compound is a metabolite of ibogaine and is chemically identified as 12-hydroxyibogamine. In particular, noribogaine has been found to be useful as a non-addictive analgesic agent and in the treatment of drug dependence or drug abuse. The noribogaine pharmaceutical compositions can be combined with one or more known opioid antagonists, for the treatment of the addition, such that the withdrawal symptoms are substantially eliminated or at least surprisingly reduced. Such compositions are conveniently prepared in a unit dosage form, wherein one or more dosage units provide a therapeutically effective amount of the active ingredient. In its first aspect, the present invention relates to a. method for alleviating pain in a patient by systemic administration of noribogaine, at a therapeutically effective dose. In a preferred embodiment, the administration is by means of a pharmaceutical composition in which noribogaine is the only analgesic agent. In patients for whom opioid analgesics are contraindicated, noribogaine is administered systemically in an effective amount to reduce or eliminate pain, in the absence of any concomitant opioid analgesic therapy. In each case, the dose of noribogaine administered to a patient should be between 0.1 and 100 mg per kg of body weight and, preferably, between 1 and 30 mg per kg of body weight. The present invention also includes a method for treating a patient to alleviate pain, by systemic administration of noribogaine and one or more opioid antagonists, such that the respective amounts of noribogaine and the antagonist are effective to reduce or eliminate the pain. If desired, one or more opioid antagonists may also be administered to the patients, with the preferred antagonists being naloxone, naltrexone or nalorphine, preferably at a concentration between 0.15 and 0.5 mg per mg of noribogaine administered. Although the method is compatible with any route of administration, the transdermal route will usually be the most convenient. The present invention also relates to a method for the treatment of drug addiction (including drug dependence and drug abuse) during abstinence therapy, by administering noribogaine to a patient, at a dose sufficient to reduce or eliminate one or more symptoms associated with abstinence. Such symptoms include nausea, vomiting, anxiety, abdominal cramps, muscle pain, chills and headache. In addition, treatment with noribogaine decreases the intense desire for drugs normally experienced by addicts after cessation of self-administration of the substance of abuse. Noribogaine is especially useful in the treatment of addiction to narcotics such as heroin and methadone. However, it is also useful in the treatment of patients addicted to cocaine, alcohol, amphetamines and combinations of these drugs. It is preferred that noribogaine be administered to the patient suffering from drug dependence or abuse, in conjunction with an opioid antagonist such as naloxone., naltrexone or nalorphine. The dose of noribogaine should be as described above in conjunction with its use to relieve pain. Again, the transdermal route is generally the preferred route of administration. In addition to the methods described above, the present invention relates to a pharmaceutical composition, preferably a unit dosage form, comprising noribogaine and one or more opioid antagonists. When administered to a patient, one or more dose units provide an amount of noribogaine and the opioid antagonist effective for the treatment of drug dependence or to promote analgesia. Noribogaine should generally be present in such compositions, at a concentration between about 0.1 and 20 mg / ml. When either naloxone or naltrexone is used as an opioid antagonist in the compositions, these substances must be present at a ratio of 0.05 to 0.5 mg per mg of noribogaine. The present invention contemplates that the administration of the active ingredients will be carried out by any systemic way that is convenient and easily accessible to the attending physician. While all the various conventional routes of administration are contemplated (e.g., transdermal, intranasal, intramuscular, subcutaneous, intravenous, vaginal, buccal, rectal and now), the preferred route of administration is transdermal. The present invention further contemplates the use of noribogaine as an adjunct to conventional drug abstinence therapy, specifically providing the administration of noribogaine concomitantly with one or more opioid antagonists. The term "concomitant" administration refers to the administration of the two agents (i.e., noribogaine and an opioid antagonist) in any manner in which the pharmacological effects of both substances are manifested in the patient at the same time. Thus, concomitant administration does not require that a single pharmaceutical composition, the same pharmaceutical form or even the same route of administration be used for the administration of noribogaine and the opioid antagonist nor that the two agents be administered precisely at the same time. weather. However, concomitant administration, more conveniently, can be performed with the same dosage form and the same route of administration, substantially at the same time. Obviously, such administration is advantageously carried out by administering both active ingredients simultaneously in a new pharmaceutical composition, in accordance with the present invention. The pharmaceutical compositions according to the present invention are prepared by conventional procedures, using methods known in the art. For example, methods for the preparation of opioid antagonist pharmaceutical compositions, fully adaptable to the preparation of compositions containing noribogaine and opioid antagonists, are known in the art. Solid pharmaceutical compositions are provided in accordance with the present invention, in dosage unit dosage forms. A unit dose or dosage unit for a pharmaceutical composition refers to the amount of each of the active ingredients that is administered in a single shot. Thus, the dosage unit dosage form of a solid pharmaceutical composition refers to a discrete entity (eg, a capsule, a tablet, a suppository or a device that releases the drug), wherein one or more of these entities contains an appropriate dose for a single administration. Accordingly, the solid pharmaceutical compositions according to the present invention are adaptable for transdermal, intranasal, oral, vaginal, rectal and buccal administration. However, for parenteral (e.g., subcutaneous, intravenous and intraarterial) routes, new liquid pharmaceutical compositions are provided in accordance with the present invention. Likewise, new liquid pharmaceutical compositions suitable for oral administration (e.g., syrups and elixirs) are provided. Each of these pharmaceutical compositions is prepared by methods known in the art. BRIEF DESCRIPTION OF THE FIGURES Figure 1 (panels A and B): Panel A shows the stimulation of the binding of [35S] GTP? S to rat thalamic membranes by various concentrations of noribogaine (") and ibogaine (•). The results are expressed as the maximum stimulation percent (defined by 10 μM DAMGO) Panel B shows the inhibitory change of the [35 S] GTP S binding stimulated by nopbogama, by naloxone (0.1 uM). DETAILED DESCRIPTION OF THE INVENTION Noribogaine, which is a metabolite of ibogaine, has very suitable properties for the treatment of pain and withdrawal symptoms associated with drug dependence or drug abuse. It binds to two classes of opioid receptors that have been associated with pain relief, the μ and K receptors. In the case of μ-type receptors, it seems that noribogaine acts as a complete opioid antagonist. noribogaine raises serotonin levels in the brain by blocking synaptic reincorporation. It is believed that such levels (as well as ligand interactions in μ and K opiate receptors) play a role in the anxiety and intense drug craving experienced by addicts in abstinence. Noribogaine is synthesized by O-demethylation of ibogaine. This can be carried out, for example, by reacting ibogaine with boron tribromide / methylene chloride at room temperature and then purifying the product by known procedures. To date, noribogaine can also be obtained from the National Institute of Drug Abuse (Rockville, MD, USA). The compound has the following structure: Chemical form of noribogaine. The present invention is not limited to any particular chemical form of noribogaine and the drug can be administered to patients either in free base form, or in the form of a pharmaceutically acceptable acid addition salt. In the latter case, the hydrochloride salt is generally preferred, but other salts derived from organic or inorganic acids may also be used. Examples of such acids include, without limitation, hydrobromic acid, phosphoric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, acid malic, maleic acid, aconitic acid, salicylic acid, thalic acid, embonic acid, enanthic acid and the like. As described above, noribogaine itself can be formed by O-demethylation of ibogaine, which, in turn, can be synthesized by methods known in the art (see, eg, Huffman, et al., J. Org. Chem., 50: 1460 (1985)).

Preferred pharmaceutical forms and route of administration. As noted above, any route of administration and dosage form is compatible with the treatments described above and noribogaine can be administered either as a single active ingredient or in combination with other therapeutically active drugs. In this regard, it is preferred that pharmaceutical compositions, especially those used in the treatment of drug addiction or abuse, contain one or more opioid antagonists. Although compositions suitable for oral administration are likely to be used more frequently, other routes that may be used include the peroral, internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial, intramuscular, intraperitoneal, intracutaneous, and subcutaneous routes. Especially preferred is the transdermal route or administration in which the drug is applied as part of a cream, gel or, preferably, patches (e.g., transdermal formulations, see U.S. Patent Nos. 4,806,341, 5,149,538, and 4,626,539). Other dosage forms include tablets, capsules, pills, powders, aerosols, suppositories, parenterals and oral fluids, including suspensions, solutions and emulsions. Sustained-release dosage forms can also be used. All pharmaceutical forms can be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., A. Oslo publisher, Easton, PA (1980)). The noribogaine is preferably used in conjunction with any of the carriers and excipients commonly employed in pharmaceutical preparations, eg, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, derivatives of paraffin, glycols, etc. Coloring and flavoring agents can also be added to the preparations, particularly those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1,2-propylene glycol, polyglycols, dimethisulfoxide, fatty alcohols, triglycerides, partial glycerin esters and the like. Parenteral compositions containing noribogaine can be prepared using conventional techniques, which may include sterile isotonic saline, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with water, Ringer's solution, etc. When formulating compositions containing noribogaine in combination with an opioid antagonist, the preferred antagonist will be naloxone, naltrexone or nalorphine. These agents are commercially available and have been approved for the treatment of opioid abstinence. In general, noribogaine or a pharmaceutically acceptable salt of noribogaine, they should be present in the pharmaceutical compositions at a concentration between 0.1 and 20 mg / ml. Naloxone, naltrexone or nalorphine should preferably be present at a concentration of about 0.05 to about 0.5 mg per mg of noribogaine. The antagonist can be added in any chemical form that is stable in the particular formulation being prepared. Method of treatment Patients will be administered noribogaine or a composition containing noribogaine together with an opioid antagonist, either for the treatment of pain or for the treatment of drug dependence or drug abuse. In any case, the dose will be selected to reduce or eliminate one or more of the symptoms experienced by the patient. Thus, when noribogaine is being administered as an analgesic, it should be administered enough to reduce or eliminate the patient's pain. In the case of abstinence from the drug, noribogaine should be administered at a sufficient dose to reduce the symptoms commonly associated with this process, for example, headache and muscle pain and, preferably, at a sufficient dose to also reduce intense desire for the drug. For both treatments, the daily dose will typically be between 0.1 and 100 mg of noribogaine per kg of body weight of the patient and preferably between 1 and 30 mg per kg of body weight of the patient. The dose may be given in a single dose or in divided doses. These doses are simply guidelines and the actual dose selected for an individual patient will be determined by the attending physician based on clinical conditions and using methods already known in the art. Compositions can be provided in a single dose or multiple dose regimen (e.g., a patient could take 3 mg of an oral noribogaine composition three times a day). Alternatively, the drug can be administered essentially continuously using a transdermal preparation or a patch. When noribogaine is used in the treatment of pain, long-term administration may be required and the drug may be taken in a prescribed regimen (as described above) or as needed by the patient. Long-term treatment may also be necessary in patients who are being treated for drug dependence or drug abuse. In general, sustained-release dosage forms or transdermal patches are preferred in the treatment of these patients. Advantages One of the main advantages of noribogaine is that it does not form a habit. Thus, pain relief can be achieved without the risk of dependence associated with chronic narcotic use. Similarly, patients treated for drug dependence or drug abuse may be administered noribogaine without the abuse / dependency problems presented by treatment with agents such as methadone. In fact, patients who participate in drug substitution programs may wish to consume noribogaine to eliminate the substitute. Also, by alleviating some of the worst aspects of the drug abstinence process, noribogaine could be a form of therapy that drug abusers or drug abusers would find acceptable. EXAMPLES The binding of [35S] GTP? S stimulated by noribogaine to rat thalamic membranes was used to measure the activation of G protein receptors and the results are shown in Figure 1 and Table 1. The percent of maximum stimulation (DAMGO 10 μM, EC50 = 7.4 +/- 0.1 nM) of [35S] GTP? S binding stimulated by noribogaine was determined in the presence of an excess of GDP. The EC50 value for the union stimulated by noribogaine was 0.324 +/- 0.015 μM. In contrast, ibogaine caused a weak stimulation of the binding of [35S] GTP? S, even at concentrations above 100 μM. The union stimulated by noribogaine was blocked in the presence of naloxone (competitive antagonist, EC50 = 35 +/- 1.8 μM), which further demonstrates that the effect of noribogaine was mediated by μ receptors. The deviation to the right of the concentration / effect relationship of the union stimulated by noribogaine when increasing the concentration of naloxone was similar to that measured by DAMGO in the presence of a competitive antagonist. The level of union of [35S] GTPyS stimulated by noribogaine, was very in agreement with the maximum number of binding sites of [S] GTP? S that could be occupied after DAMGO stimulation of G proteins. Taken together, these results demonstrate that noribogaine acts as a full opioid receptor agonist μ and that it has efficacy as an antinociceptive agent that is You can use it without the risk of inherent abuse of opiates. The results also indicate that noribogaine can be used effectively, either alone or in conjunction with an opioid antagonist, in the treatment of drug addiction. Table 1: Stimulation of binding of [S] GTP? S to rat thalamic membranes (Sprage Dawley) by opioid agonists of variable efficacy.

Drug Union of [35S] GTP? S EC50 Buprenorphine 0.7 ± 0.1 DAMGO 7.4 ± 0.1 Morphine 52 ± 6.3 Noribogaine 324 ± 15.5 Naloxone NE Buprenorphine + Naloxone 301 + 44 DAMGO + Naloxone 2,230 ± 131 Morphine + Naloxone 26,000 ± 842 Noribogaine + Naloxone 236,000 ± 3,410 The values are the mean ± the standard deviation (SD) of three or more separate experiments. EC50 = concentration of the drug that produces half of the maximum stimulation of the union.

All references cited herein are incorporated by reference in their entirety. Having described the present invention, it will be understood by those skilled in the art that the invention may be practiced within a broad equivalent range of conditions, perimeters and the like, without departing from the spirit or scope of the present invention or any of its modalities. . It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (24)

1. CLAIMS Having described the invention as an antecedent, the content of the following claims is claimed as property: 1. A method for treating a patient to alleviate pain, characterized in that it comprises: administering systemically an amount of noribogaine to the patient, which is effective to reduce or eliminate pain in said patient.
2. 2. The method according to claim 1, characterized in that the patient is administered a pharmaceutical composition comprising noribogaine and wherein noribogaine is the only analgesic agent in the pharmaceutical composition.
3. 3. A method for alleviating pain in a patient for whom opioid analgesics are contraindicated, characterized in that it comprises: administering systemically an amount of noribogaine to the patient, which is effective to reduce or eliminate pain in said patient, in the absence of any therapy Opioid analgesic concomitant.
4. 4. The method according to any of claims 1-3, characterized in that the noribogaine is administered to the patient at a dose between 0.1 and 100 mg per kg of body weight.
5. 5. The method according to claim 4, characterized in that the noribogaine is administered at a dose between 1.0 and 30 mg per kg of body weight.
6. 6. A method for treating a patient to alleviate pain, characterized in that it comprises: a) administering a quantity of noribogaine to the patient systemically; and b) concomitantly administering to the patient a quantity of one or more opioid antagonists; wherein the respective amounts of noribogaine and the opioid antagonist (s) are effective to reduce or eliminate pain in the patient. The method according to claim 6, characterized in that the opioid antagonist is naloxone, administered to the patient at a dose between 0.05 and 05 mg per mg of noribogaine. The method according to claim 6, characterized in that the opioid antagonist is naltrexone, administered to the patient at a dose between 0.05 and 0.5 mg per mg of noribogaine. 9. The method according to claim 6, characterized in that the noribogaine and the opioid antagonist are administered transdermally. 10. A method for the treatment of a patient for drug dependence or drug abuse during abstinence therapy, characterized in that it comprises: systemically administering a quantity of noribogaine to the patient, which is effective in reducing one or more symptoms of abstinence to the drug. 11. The method according to claim 10, characterized in that the patient is treated for addiction to a narcotic. The method according to claim 10, characterized in that the patient is patient is treated by addiction to a drug that is selected from the group consisting of: cocaine, heroin, alcohol, methadone, amphetamines and combinations thereof. The method according to claim 10, characterized in that the noribogaine is administered at a dose between 0.1 and 100 mg per kg of body weight. The method according to claim 13, characterized in that the noribogaine is administered at a dose between 1.0 and 30 mg per kg of body weight. 15. The method according to claim 10, characterized in that it further comprises administering an opioid antagonist to the patient. 16. The method according to claim 15, characterized in that the opioid antagonist is naloxone, administered to the patient at a dose between 0.05 and 0.5 mg per mg of noribogaine administered to the patient. 1
7. 7. The method according to claim 15, characterized in that the opioid antagonist is naltrexone administered at a dose between 0.05 and 0.5 mg per mg of noribogaine administered to the patient. 1
8. 8. The method according to claim 15, characterized in that the noribogaine and the opioid antagonist are administered transdermally. 1
9. 9. A pharmaceutical composition characterized in that it comprises: a) noribogaine; and .b) one or more opioid antagonists. The pharmaceutical composition according to claim 19, characterized in that the composition is a dosage unit dosage form and wherein one or more of the dosage units provide an amount of noribogaine and an amount of the opioid antagonist (s) that It is effective to treat drug dependence or drug abuse, or to produce analgesia in a patient to whom the unit or dose units are administered. 21. The pharmaceutical composition according to any of claims 19 or 20, characterized in that the noribogaine is present at a concentration between 0.1 and 20 mg / ml. 22. The pharmaceutical composition according to any of claims 19 or 20, characterized in that the opioid antagonist is naloxone, present at a ratio of 0.05 to 0.5 mg per mg of noribogaine. 23. The pharmaceutical composition according to any of claims 19 or 20, characterized in that the opioid antagonist is naltrexone, present at a ratio of 0.05 to 0.5 mg per mg of noribogaine. 24. The pharmaceutical composition according to any of claims 19 or 20, characterized in that the pharmaceutical composition is formulated for transdermal administration.