Acamprosate formulations, methods of using the same, and combinations comprising the same

Abstract

Embodiments disclosed herein generally relate to acamprosate formulations, methods of use of the formulations, to methods of using the formulations in combination with at least one other medication, and to combination products and compositions comprising the formulations and at least one other medication, such as neuroleptic (antipsychotic) and / or antidepressant drugs.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of Ser. No. 13 / 745,619, filed on Jan. 18, 2013, entitled “ACAMPROSATE FORMULATIONS, METHODS OF USING THE SAME, AND COMBINATIONS COMPRISING THE SAME,” which is a continuation in part of PCT Application No. PCT / US2012 / 067507, filed on Dec. 2, 2012, entitled “ACAMPROSATE FORMULATIONS, METHODS OF USING THE SAME, AND COMBINATIONS COMPRISING THE SAME,” which claimed the benefit of priority under 35 U.S.C §119(e) of U.S. Provisional Application No. 61 / 566,550 filed on Dec. 2, 2011, and U.S. Provisional Application No. 61 / 649,137, filed on May 18, 2012, both entitled “METHODS OF USING ACAMPROSATE FORMULATIONS AND COMPOSITIONS COMBINING ACAMPROSATE FORMULATIONS WITH NEUROLEPTIC DRUGS,” each of which is hereby incorporated herein by reference in its entirety and is to be considered a part of this specification.BACKGROUND[0002]1. Field[0003]Embodiments disclosed herein generally relate to methods of use of improved...

AI Technical Summary

Benefits of technology

[0009]Some embodiments described herein are based upon the discovery of benefits associated with formulating acamprosate utilizing technology, such as GR formulation technology. Without being limited thereto, two practical benefits of the altered PK discovered when using such formulations are efficacy with less frequent dosing and avoidance of dose-dependent side effects related to the Cmax, which is lower with GR formulations than with immediate-release (IR) formulations containing the same amount of acamprosate. An additional non-limiting benefit is the potential efficacy of a lower total oral dose of the drug for its clinical indication. Furthermore, even in embodiments where the GR system does not offer greater bioavailability—i.e., a larger area under the time-concentration curve (AUC) for a given oral dose—it can increase the efficacy of an oral dose by increasing the target site residence time at which the concentration exceeds a minimal threshold for efficacy.

[0010]Embodiments described herein generally relate to the use of improved formulations of acamprosate and other salts of N-acetylhomotaurine or other related compounds. Some particular embodiments relate to formulations based on gastric-retentive (GR) delivery systems. Some embodiments relate to the use of improved formulations of acamprosate to treat neuropsychiatric disorders including tardive dyskinesia using dosages and dosage schedules not heretofore known to be efficacious. These dosages and dosage schedules can provide greater convenience and greater tolerability of treatment, and thus greater effectiveness of treatment because of better treatment adherence and tolerability of dosages sufficient for more complete relief of symptoms.

[0013]Some embodiments also concern compositions and use of fixed-dose combinations of improved formulations of acamprosate with first-generation neuroleptic (antipsychotic) drugs, second generation neuroleptic drugs, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), or the anti-nausea drug metoclopramide. For example, the decreased dosage amount and frequency of dosing made possible by the improved formulations makes it feasible to formulate fixed-dose combinations of acamprosate and other medications, such as first-generation neuroleptic drugs. The fixed dose combinations with neuroleptics, for example, can provide effective treatment of psychosis with a lesser risk of metabolic side effects than seen with second-generation neuroleptic drugs, a lesser risk of tardive dyskinesia than seen with first and second generation neuroleptic drugs given alone, and with, unexpectedly, increased relief of mental symptoms compared with first-generation neuroleptic drugs given alone.

[0015]As noted, some embodiments relate to combinations of acamprosate combined with a second medication, such as for example, a neuroleptic medication. The fixed dose compositions comprising a first or second generation neuroleptic combined with an improved formulation of acamprosate can be used to treat any of the disorders treated with, for example, neuroleptic drugs or metoclopramide, including schizophrenia, schizoaffective disorder, bipolar disorder, major depression, delusional disorder, organic psychoses, delirious agitation, or nausea and vomiting. They can be given for this purpose on a once-daily or twice-daily schedule (or more if desired), typically with a single pill given each time. They can provide for a given dosage of neuroleptic, equal or greater benefit for the neuropsychiatric disorder or symptoms being treated, and can offer greater relief of anxiety and agitation when these are among the symptoms. Compared with the same dose of a first-generation neuroleptic given without acamprosate, these combinations entail a lower risk of tardive dyskinesia and other tardive movement disorders, and they cause movement disorder of lesser severity, if they cause one at all. In contrast with second-generation neuroleptics of equal therapeutic efficacy, these combinations can carry a lesser risk of significant metabolic disturbances including weight gain, glucose intolerance, and increased risk of atherosclerotic cardiovascular disease.

[0016]In the case of acamprosate combined with a neuroleptic, the combination can reduce the risk of tardive dyskinesia (TD) associated with giving the neuroleptic drug. Also, unexpectedly, the combination has additional benefits for the patient's mental status, such as decreased anxiety and / or agitation (as shown in the patient example). If the patient has pre-existing TD associated with cognitive impairment the acamprosate may also have, as claimed in prior patents, improvement in cognition. The action of acamprosate to treat—and consequentially to prevent the manifestation of—tardive dyskinesia, combined with the additional benefit of improving some mental symptoms—makes higher-potency and first-generation neuroleptic drugs more attractive when they are given in combination with acamprosate. At present the first-generation, high-potency neuroleptic drugs are avoided because they are more likely than second-generation neuroleptic drugs to produce tardive dyskinesia. However, those drugs are no less efficacious in treating psychosis than the second-generation drugs (with the sole exception of clozapine), which usually are more expensive, and which have serious metabolic effects with potentially life-threatening consequences. It is rational to combine even second-generation neuroleptics with acamprosate, because those drugs still carry some risk of TD, and the additional psychiatric benefit can still apply. Tables 10 and 11 below show non-limiting examples of the dose ranges for the neuroleptic drugs and the GR acamprosate formulation to be used in fixed dose combinations.

[0031]Some embodiments relate to methods of treating a neuropsychiatric disorder, for example, by administering to a patient in need thereof a combination product as described above, and elsewhere herein, wherein the total daily dosage of acamprosate administered is less than 1000 mg, wherein the composition is administered once or twice daily to achieve the total daily dosage. The product can be or may include, for example, a pill, a tablet, a capsule or the like comprising acamprosate and at least one second medication. Still some embodiments relate to methods of reducing the risk or delaying the onset of tardive dyskinesia comprising administering to a patient in need thereof a combination product as described herein, wherein the total daily dosage of acamprosate administered is less than 1000 mg, wherein the composition is administered once or twice daily to achieve the total daily dosage. The product can be or may include, for example, a pill, a tablet, a capsule or the like comprising acamprosate and at least one second medication.

Problems solved by technology

In particular, it reduces the response of the voltage-operated calcium channel to high levels of stimulation by glutamate.

The bioavailability of BCS Class III compounds tends to be low because the absorption of such compounds occurs either via diffusion—which is slow and inefficient because of the low permeability—or via specialized transporters in the membranes of intestinal mucosal cells—which may not exist, may poorly bind the compound, or may be easily saturated, implying zero-order kinetics.

Furthermore, even in embodiments where the GR system does not offer greater bioavailability—i.e., a larger area under the time-concentration curve (AUC) for a given oral dose—it can increase the efficacy of an oral dose by increasing the target site residence time at which the concentration exceeds a minimal threshold for efficacy.

In contrast with second-generation neuroleptics of equal therapeutic efficacy, these combinations can carry a lesser risk of significant metabolic disturbances including weight gain, glucose intolerance, and increased risk of atherosclerotic cardiovascular disease.

However, those drugs are no less efficacious in treating psychosis than the second-generation drugs (with the sole exception of clozapine), which usually are more expensive, and which have serious metabolic effects with potentially life-threatening consequences.

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