U.S. patent application number 13/315127 was filed with the patent office on 2012-04-05 for noribogaine in the treatment of pain and drug addiction.
This patent application is currently assigned to DemeRx, Inc.. Invention is credited to Deborah C. Mash.
Application Number | 20120083485 13/315127 |
Document ID | / |
Family ID | 22013572 |
Filed Date | 2012-04-05 |
United States Patent
Application |
20120083485 |
Kind Code |
A1 |
Mash; Deborah C. |
April 5, 2012 |
NORIBOGAINE IN THE TREATMENT OF PAIN AND DRUG ADDICTION
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.
Inventors: |
Mash; Deborah C.; (Miami,
FL) |
Assignee: |
DemeRx, Inc.
|
Family ID: |
22013572 |
Appl. No.: |
13/315127 |
Filed: |
December 8, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12815908 |
Jun 15, 2010 |
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13315127 |
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11784343 |
Apr 6, 2007 |
7754710 |
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12815908 |
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09486613 |
Feb 29, 2000 |
7220737 |
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PCT/US98/18284 |
Sep 3, 1998 |
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11784343 |
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60057921 |
Sep 4, 1997 |
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Current U.S.
Class: |
514/214.02 |
Current CPC
Class: |
A61P 25/30 20180101;
A61K 31/55 20130101; A61P 25/36 20180101; A61K 31/485 20130101;
A61P 25/22 20180101; A61P 25/04 20180101; A61K 31/485 20130101;
A61K 2300/00 20130101; A61K 31/55 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/214.02 |
International
Class: |
A61K 31/55 20060101
A61K031/55; A61P 25/22 20060101 A61P025/22; A61P 25/04 20060101
A61P025/04 |
Claims
1. A method of treating a patient to alleviate pain, comprising:
administering systemically an amount of noribogaine to said patient
effective to reduce or eliminate pain in said patient.
2-24. (canceled)
25. A method for treating anxiety comprising administering a
pharmaceutical composition comprising noribogaine or a
pharmaceutically acceptable acid addition salt thereof in an amount
sufficient to bind to the .mu.-opioid receptor to thereby treat
said anxiety.
Description
FIELD OF THE INVENTION
[0001] The present invention is concerned with novel pharmaceutical
compositions and novel treatment methods. In particular, the
invention relates to novel methods for providing analgesia and to
novel pharmaceutical compositions containing the drug noribogaine.
The compositions particularly include those containing, in addition
to noribogaine, one or more' opioid antagonists. In addition, the
present invention provides novel compositions and methods useful in
treating patients for the symptoms associated with withdrawal from
drug dependency or abuse.
BACKGROUND OF THE INVENTION
[0002] Ibogaine is an indole alkaloid derived from Tabernanth
iboga, a shrub of West Africa, and is used by 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 as follows:
##STR00001##
[0003] In 1956 Salmoiraghi and Page elucidated ibogaine's
relationship to serotonin (J. Pharm. and Exp. Ther. 120(1):20-25
(1957)). About the same time Schneider published three important
papers: "Potentiation Action of Ibogaine on Morphine Analgesia"
(Experiential 12:323-24 (1956)); "Neuropharmacological Studies of
Ibogaine: An Indole 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. Pharmacodyn.
110:92-102 (1957)). Dhahir published a review of the pharmacology
and toxicology of ibogaine in his doctoral thesis, "A Comparative
Study of the Toxicity of Ibogaine and Serotonin" (University
Microfilms International 71-25-341, Ann Arbor, Mich.). The thesis
gives an overview of much of the work accomplished with
ibogaine.
[0004] Additional studies of interest include: "The Effects of Some
Hallucinogens on Aggressiveness of Mice and Rats " (Kostowski, et
al., Pharmacology 7:259-63 (1972)), "Cerebral Pharmacokinetics of
Tremor-Producing Harmala and Iboga Alkaloids" (Zetler, et al.,
Pharmacology 7(4):237-248 (1972)), "High Affinity .sup.3H-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-(.sup.3H)Lysergic
Acid Diethylamide in Calf Caudate" (Proc. Natl. Acad. Sci., U.S.A.
75(12):5783-87 (1978)); and "A Common Mechanism of Lysergic Acid,
Indoleakylamine and Phenethylamine Hallucinogens: Serotonergic
Mediation of Behavioral Effects in Rats" (Sloviter, et al., J.
Pharm. Exp. Ther. 214(2):231-38 (1980)). More current work has been
reported by Dzoljic, et al., "Effect of Ibogaine on
Naloxone-Precipitated Withdrawal Syndrome in Chronic Morphine
Dependent Rats," (Arch. Int. Pharmacodyn., 294:64-70 (1988)).
[0005] Ibogaine administration has been reported to reduce the
withdrawal symptoms associated with drug dependency and to
alleviate drug cravings in addicts. It has been disclosed to be
effective in the treatment of dependencies resulting from a wide
range of drugs, including narcotics (U.S. Pat. No. 4,499,096);
cocaine and amphetamines (U.S. Pat. No. 4,587,243); alcohol (U.S.
Pat. No. 4,857,523); and nicotine/tobacco (U.S. Pat. No.
5,026,697). In addition it has been reported to be effective in
patients addicted to multiple drugs and drug combinations (U.S.
Pat. No. 5,152,994). Among the specific drug dependencies
reportedly amenable to ibogaine treatment are heroin, cocaine,
alcohol, nicotine, caffeine, amphetamine, desoxyephedrine,
methadone and combinations thereof.
[0006] Other pharmacological agents that have been used in the
treatment of certain types of drug addiction or dependency include
naloxone and naltrexone. However, these agents typically fail to
alleviate the often severe suffering that accompanies the drug
withdrawal process and are generally ineffective in treating
polydrug 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 clearly needed.
SUMMARY OF THE INVENTION
[0007] In accordance with the present invention, surprising and
unexpected properties of noribogaine have been discovered. This
compound is known to be 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 as a
treatment for drug dependency or abuse. Pharmaceutical compositions
of noribogaine can be combined with one or more known opioid
antagonists to treat addiction such that withdrawal symptoms are
substantially eliminated or, at a minimum, surprisingly reduced.
Such compositions are conveniently prepared in unit dose form with
one or more unit doses providing a therapeutically effective amount
of active ingredient.
[0008] In its first aspect, the invention is directed to a method
of alleviating pain in a patient by administering systemically
noribogaine at a therapeutically effective dosage. In a preferred
embodiment, administration is by means of a pharmaceutical
composition in which noribogaine is the sole analgesic agent. In
patients for whom opioid analgesics are contraindicated,
noribogaine is administered systemically in an amount of effective
to reduce or eliminate pain in the absence of any concomitant
opioid analgesic therapy. In each case, the dosage 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.
[0009] The present invention also includes a method of treating a
patient to alleviate pain by administering systemically noribogaine
and one or more opioid antagonists, such that the respective
amounts of noribogaine and antagonist are effective to reduce or
eliminate pain. If desired, one or more opioid antagonists may also
be administered to patients, with the preferred antagonist being
naloxone, naltrexone or nalorphine, preferably at a concentration
of between 0.15 mg and 0.5 mg for each mg of noribogaine
administered. Although, the method is compatible with any route of
administration, the transdermal route will generally be the most
convenient.
[0010] The invention is also directed to a method for treating drug
addiction (involving drug dependency or drug abuse) during
withdrawal therapy by administering noribogaine to a patient at a
dosage sufficient to reduce or eliminate one or more symptoms
associated with withdrawal. Such symptoms include nausea, vomiting,
anxiety, abdominal cramps, muscle pain, chills and headache. In
addition, noribogaine treatment decreases the drug cravings
normally experienced by addicts after cessation of the self
administration of the abused substance. Noribogaine is especially
useful in the treatment of addiction to narcotics such as heroin
and methadone. However, it is also useful in treating patients
addicted to cocaine, alcohol, amphetamines and combinations of
these drugs. It is preferred that the noribogaine be administered
to patients suffering from drug dependance or abuse in conjunction
with an opioid antagonist such as naloxone, naltrexone or
nalorphine. The dosage of noribogaine should be as discussed above
in conjunction with its use in the alleviation of pain. Again, the
transdermal route of administration is generally preferred.
[0011] In addition to the methods discussed above, the present
invention is directed to a pharmaceutical composition, preferably
in unit dose form, comprising noribogaine and one or more opioid
antagonists. When administered to a patient, one or more unit doses
provide an amount of noribogaine and of opioid antagonist effective
to treat drug dependency or to provide analgesia. Noribogaine
should generally be present in such compositions at a concentration
of between about 0.1 and 20 mg/ml. When either naloxone or
naltrexone is used as an opioid antagonist in compositions, they
should be present at 0.05 to 0.5 mg for each mg of noribogaine.
[0012] The present invention contemplates that the administration
of active ingredients will be accomplished by any systemic route
which is convenient and readily accessible to the attending
physician. While all of the various conventional routes of
administration are contemplated (e.g., transdermal, intranasal,
intramuscular, subcutaneous, intravenous, vaginal, rectal, buccal
and oral), the preferred route of administration is
transdermally.
[0013] The present invention further contemplates the use of
noribogaine as an adjunct to conventional drug withdrawal therapy,
specifically providing for the administration of noribogaine
concomitantly with one or more opioid antagonists.
"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 are manifest in the
patient at the same time. Thus, concomitant administration does not
require that a single pharmaceutical composition, the same dosage
form, or even the same route of administration be used for
administration of both noribogaine and opioid antagonist or that
the two agents be administered at precisely the same time. However,
concomitant administration will be accomplished most conveniently
by the same dosage form and the same route of administration, at
substantially the same time. Obviously, such administration most
advantageously proceeds by delivering both active ingredients
simultaneously in a novel pharmaceutical composition in accordance
with the present invention.
[0014] Pharmaceutical compositions in accordance with the invention
are prepared by conventional means using methods known in the art.
For example, there are known in the art methods for the preparation
of opioid antagonist pharmaceutical compositions fully adaptable to
the preparation of compositions of both noribogaine and opioid
antagonists. Solid pharmaceutical compositions are provided in
accordance with the present invention in unit dosage form. A unit
dosage for a solid pharmaceutical composition refers to the amount
of each of the active ingredients which is administered in any one
entity. Thus, the unit dosage form of a solid pharmaceutical
composition makes reference to a discreet entity (e.g., a capsule,
tablet, suppository, or drug-releasing device), one or more of
which entities contains an appropriate dosage for a single
administration.
[0015] Accordingly, solid pharmaceutical compositions in accordance
with the invention are adaptable to provide administration by
transdermal, intranasal, oral, vaginal, rectal, and buccal routes.
However, for parenteral routes (e.g., subcutaneous, intravenous,
and intraarterial) novel liquid pharmaceutical compositions in
accordance with the present invention are provided. Also provided
are novel liquid pharmaceutical compositions suitable for oral
administration (e.g., syrups and elixirs). Each of these
pharmaceutical compositions is prepared by methods known in the
art.
BRIEF DESCRIPTION OF THE FIGURES
[0016] FIG. 1 (panels A and B): Panel A shows the stimulation of
[.sup.35S]GTP.gamma.S binding to rat thalamic membranes by various
concentrations of noribogaine (.box-solid.) and ibogaine ( ).
Results are expressed as percent maximal stimulation (defined by 10
.mu.M DAMGO). Panel B shows the inhibitory shift of
noribogaine-stimulated [.sup.35S]GTP.gamma.S binding by naloxone
(0.1 .mu.M).
DETAILED DESCRIPTION OF THE INVENTION
[0017] Noribogaine, a metabolite of ibogaine, has properties that
are well suited to the treatment of pain and to the withdrawal
symptoms associated with drug dependency or abuse. In particular,
it has been discovered that noribogaine binds to two classes of
opioid receptors that have been associated with pain relief, the
.mu. and .kappa. receptors. In the case of the .mu.-type receptors,
it appears that noribogaine acts as a full opiate agonist. In
addition, noribogaine elevates brain serotonin levels by blocking
synaptic reuptake. It is believed that such levels (as well as
ligand interactions at the .mu. and .kappa. opiate receptors) play
a role in the anxiety and drug cravings experienced by addicts
during withdrawal.
[0018] Noribogaine is synthesized by the O-demethylation of
ibogaine. This may be accomplished, for example, by reacting
ibogaine with boron tribromide/methylene chloride at room
temperature and then purifying the product using known procedures.
At present, noribogaine may also be obtained from the National
Institute on Drug Abuse (Rockville, Md.)). The compound has the
following structure:
##STR00002##
[0019] Chemical Form of Noribogaine
[0020] The present invention is not limited to any particular
chemical form of noribogaine and the drug may be given to patients
either as a free base or as 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, sulfuric
acid, methane sulfonic acid, phosphorous acid, nitric acid,
perchloric acid, acetic acid, tartaric acid, lactic acid, succinic
acid, citric acid, malic acid, maleic acid, aconitic acid,
salicylic acid, thalic acid, embonic acid, enanthic acid, and the
like. As discussed above, noribogaine itself may be formed by the
O-demethylation of ibogaine which, in turn, may be synthesized by
methods known in the art (see e.g., Huffman, et al., J. Org. Chem.
50:1460 (1985)).
[0021] Preferred Dosage Forms and Route of Administration
[0022] As noted above, any route of administration and dosage form
is compatible with the treatments discussed above and noribogaine
may be administered as either the sole active agent 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 delivery will probably be used most frequently,
other routes that may be used include peroral, internal, pulmonary,
rectal, nasal, vaginal, lingual, intravenous, intraarterial,
intramuscular, intraperitoneal, intracutaneous and subcutaneous
routes. Especially preferred is the transdermal route of delivery
in which drug is applied as part of a cream, gel or, preferably,
patch (for examples of transdermal formulations, see U.S. Pat. Nos.
4,806,341; 5,149,538; and 4,626,539). Other dosage forms include
tablets, capsules, pills, powders, aerosols, suppositories,
parenterals, and oral liquids, including suspensions, solutions and
emulsions. Sustained release dosage forms may also be used. All
dosage forms may be prepared using methods that are standard in the
art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., A.
Oslo editor, Easton Pa. 1980)).
[0023] Noribogaine is preferably used in conjunction with any of
the vehicles and excipients commonly employed in pharmaceutical
preparations, e.g., talc, gum arabic, lactose, starch, magnesium
stearate, cocoa butter, aqueous or non-aqueous solvents, oils,
paraffin derivatives, glycols, etc. Coloring and flavoring agents
may also be added to preparations, particularly to those for oral
administration. Solutions can be prepared using water or
physiologically compatible organic solvents such as ethanol,
1,2-propylene glycol, polyglycols, dimethylsulfoxide, fatty
alcohols, triglycerides, partial esters of glycerine and the like.
Parenteral compositions containing noribogaine may be prepared
using conventional techniques that may include sterile isotonic
saline, water, 1,3-butanediol, ethanol, 1,2-propylene glycol,
polyglycols mixed with water, Ringer's solution, etc.
[0024] 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 withdrawal. hi general, noribogaine or a pharmaceutically
acceptable salt of noribogaine should be present in the
pharmaceutical compositions at a concentration of between 0.1 and
20 mg/ml. Naloxone, naltrexone, or nalorphine should preferably be
present at about 0.05 to about 0.5 mg for each mg of noribogaine.
The antagonist may be added in any chemical form which is stable in
the particular formulation being prepared.
[0025] Method of Treatment
[0026] Patients will be administered noribogaine or a composition
containing noribogaine together with opioid antagonist, either for
the treatment of pain or for the treatment of drug dependency or
abuse. In either case, dosage 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,
sufficient drug should be given to reduce or eliminate the
patient's pain. In the case of drug withdrawal, noribogaine should
be given at a dosage sufficient to reduce symptoms commonly
associated this process, for example, headache and muscular pain,
and preferably at a dosage sufficient to also reduce drug cravings.
For both treatments, daily dosage will typically be between 0.1 mg
and 100 mg of noribogaine per kg of patient body weight and
preferably between 1 mg and 30 per kg of patient body weight.
Dosage may be provided in single or divided doses. These dosages
are simply guidelines and the actual dose selected for an
individual patient will be determined by the attending physician
based upon clinical conditions and using methods well known in the
art. Compositions may be provided in either a single or multiple
dosage regimen, (e.g., a patient may take 3 mg of a noribogaine
composition orally three times a day). Alternatively, drug may be
administered in an essentially continuous manner using a
transdermal preparation or patch.
[0027] When noribogaine is used in the treatment of pain,
administration may be required on a long term basis and the drug
may be taken in a prescribed regimen (as discussed above) or as
needed by the patient. Long term treatment may also be necessary in
the treating patients for drug dependency or abuse. Sustained
release dosage forms or transdermal patches are generally preferred
in treating these patents.
[0028] Advantages
[0029] One of the main advantages of noribogaine is that it is not
habit forming. Thus, pain relief can be accomplished without the
risk of dependence associated with the chronic use of narcotics.
Similarly, patients treated for drug dependence or abuse may be
given noribogaine without the abuse/dependence problems presented
by treatment with agents such as methadone. In fact, patients
participating in drug substitution programs may want to use
noribogaine to taper off the substitute. Also, by alleviating some
of the worst aspects of the drug withdrawal process, noribogaine
should be a form of therapy that people dependent upon, or abusing,
drugs will find acceptable.
EXAMPLES
[0030] Noribogaine-stimulated [.sup.35S]GTP.gamma.S binding to rat
thalamic membranes was used to measure receptor activation of G
proteins and results are shown in FIG. 1 and Table 1. The percent
maximal stimulation (10 .mu.M DAMGO, EC.sub.50=7.4+/-0.1 nM) of
[.sup.35S]GTP.gamma.S binding stimulated by noribogaine was
determined in the presence of an excess of GDP. The EC.sub.50 value
for noribogaine-stimulated binding was 0.324 +/-0.015 .mu.M. In
contrast, ibogaine caused a weak stimulation of
[.sup.35S]GTP.gamma.S binding even at concentrations above 100
.mu.M. Noribogaine-stimulated binding was blocked in the presence
of naloxone (competitive antagonist, EC.sub.50=35 +/-1.8 .mu.M),
demonstrating further that the effect of noribogaine was
.mu.-receptor mediated. The rightward shift of the
concentration/effect relationship of noribogaine-stimulated binding
with increasing concentration of naloxone was similar to that
measured for DAMGO in the presence of competitive antagonist. The
level of [.sup.35S]GTP.gamma.S binding stimulated by noribogaine
was in close agreement to the maximal number of
[.sup.35S]GTP.gamma.S binding sites that could be occupied after
DAMGO stimulation of G proteins.
[0031] Taken together, these results demonstrate that noribogaine
acts as a full agonist of the .mu.-opioid receptor and that it has
efficacy as an antinociceptive agent that can used without the
abuse liability inherent opiates. Results also indicate that
noribogaine may effectively be used, either alone or in conjunction
with an opioid antagonist, in the treatment of drug addition.
TABLE-US-00001 TABLE 1 Stimulation of [.sup.35S]GTP.gamma.S Binding
to Rat (Sprague Dawley) Thalamic Membranes by Opioid Agonists of
Varying Efficacy [.sup.35S]GTP.gamma.S Binding Drug EC.sub.50(nM)
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.sup. Morphine + Naloxone
26,000 .+-. 842 Noribogaine + Naloxone 236,000 .+-. 3,410 Values
are means .+-. S.E. from three or more separate experiments.
EC.sub.50 = concentration of drug producing half maximal
stimulation of binding.
[0032] All references cited herein are fully incorporated by
reference. Having now fully described in the invention, it will be
understood by those of skill and the art that the invention may be
practiced within a wide and equivalent range of conditions,
perimeters and the like without effecting the spirit or scope of
the invention or any embodiments thereof.
* * * * *