U.S. patent application number 13/745619 was filed with the patent office on 2013-06-06 for acamprosate formulations, methods of using the same, and combinations comprising the same.
This patent application is currently assigned to SYCHRONEURON INC.. The applicant listed for this patent is SYCHRONEURON INC.. Invention is credited to Barry S. Fogel, Kei-Lai Fong, William D. Kerns.
Application Number | 20130143867 13/745619 |
Document ID | / |
Family ID | 48524447 |
Filed Date | 2013-06-06 |
United States Patent
Application |
20130143867 |
Kind Code |
A1 |
Fogel; Barry S. ; et
al. |
June 6, 2013 |
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.
Inventors: |
Fogel; Barry S.; (Lexington,
MA) ; Kerns; William D.; (Harvard, MA) ; Fong;
Kei-Lai; (Berkeley, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SYCHRONEURON INC.; |
Lexington |
MA |
US |
|
|
Assignee: |
SYCHRONEURON INC.
Lexington
MA
|
Family ID: |
48524447 |
Appl. No.: |
13/745619 |
Filed: |
January 18, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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PCT/US2012/067507 |
Dec 2, 2012 |
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13745619 |
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61649137 |
May 18, 2012 |
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61566550 |
Dec 2, 2011 |
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Current U.S.
Class: |
514/211.13 ;
514/220; 514/225.5; 514/225.8; 514/226.2; 514/235.2; 514/252.13;
514/253.07; 514/254.04; 514/259.41; 514/321; 514/327; 514/410;
514/438; 514/469; 514/578 |
Current CPC
Class: |
A61K 31/185 20130101;
A61K 31/5415 20130101; A61K 31/137 20130101; A61K 47/38 20130101;
A61K 31/185 20130101; A61K 31/385 20130101; A61K 31/385 20130101;
A61K 31/55 20130101; A61K 31/15 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 31/554 20130101; A61K 31/165 20130101;
A61K 31/381 20130101; A61K 31/4515 20130101; A61K 9/0065 20130101;
A61K 31/519 20130101; A61K 45/06 20130101; A61K 47/22 20130101;
A61K 47/32 20130101; A61K 9/2054 20130101; A61K 31/138 20130101;
A61K 31/553 20130101; A61K 31/135 20130101; A61K 31/4525 20130101;
A61K 31/496 20130101; A61K 31/343 20130101; A61K 31/5377 20130101;
A61K 9/2027 20130101; A61K 31/164 20130101; A61K 31/166 20130101;
A61K 31/454 20130101; A61K 31/551 20130101 |
Class at
Publication: |
514/211.13 ;
514/578; 514/469; 514/438; 514/321; 514/225.5; 514/226.2;
514/252.13; 514/225.8; 514/327; 514/235.2; 514/253.07; 514/410;
514/254.04; 514/220; 514/259.41 |
International
Class: |
A61K 31/185 20060101
A61K031/185; A61K 45/06 20060101 A61K045/06 |
Claims
1. A method of treating a neuropsychiatric disorder comprising
administering to a patient in need thereof a total daily dosage of
acamprosate of less than 1000 mg, wherein the acamprosate is
administered once or twice daily to achieve the total daily dosage,
and the administered acamprosate is in a composition that is
formulated to release acamprosate at a controlled rate, and
formulated to release less than 50% of the acamprosate within the
stomach of the recipient within the first two hours after delivery
and to release greater than 50% of the acamprosate within the
stomach within six hours of delivery.
2. The method of claim 1, wherein the composition comprises one or
more gastric retentive excipients, one or more controlled release
excipients or one or more gastric retentive excipients and one or
more controlled release excipients.
3. The method of claim 1, wherein the administered composition is
formulated to achieve a mean AUC for acamprosate that is greater
than the mean AUC for an immediate release composition of a
acamprosate, to have a C.sub.max for acamprosate that is less than
the C.sub.max for an immediate release composition, and/or to have
a T.sub.max for acamprosate that is longer than the T.sub.max for
an immediate release composition.
4. The method of claim 2, wherein the composition comprises one or
more of Carbopol 974P (carbomer homopolymer type B) and
carboxymethylcellulose.
5. The method of claim 1, wherein the acamprosate is administered
once daily.
6. The method of claim 1, wherein the acamprosate is administered
twice daily.
7. The method of claim 1, further comprising administering the
acamprosate to a patient in a fed state or inducing a fed state in
the patient.
8. The method of claim 1, wherein the neuropsychiatric disorder is
selected from the group consisting of tardive dyskinesia and other
movement disorders induced by chronic exposure of patients to
neuroleptic (antipsychotic) drugs, peak-dose dyskinesia associated
with Parkinson's disease treated with levodopa, Tourette syndrome,
posttraumatic stress disorder (PTSD), alcohol dependence and
obsessive-compulsive disorder (OCD).
9. The method of claim 1, further comprising administering at least
a second medication that comprises one or more of a selective
serotonin reuptake inhibitor (SSRI), and a serotonin-norepinephrine
reuptake inhibitor (SNRI)
10. The method of claim 9, wherein the SSRI or SNRI is selected
from the group consisting of citalopram, desvenlafaxine,
duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran,
paroxetine, sertraline, and venlafaxine.
11. The method of claim 1, further comprising administering alpha
lipoic acid or a salt or chelate of alpha lipoic acid in an amount
of 50 mg to 600 mg.
12. The method of claim 11, wherein the alpha lipoic acid is either
racemic alpha lipoic acid, a racemic mixture enriched in R-alpha
lipoic acid, R-alpha lipoic acid, or a salt or chelate of alpha
lipoic acid that is a salt or chelate of either racemic alpha
lipoic acid, a racemic mixture enriched in R-alpha lipoic acid, or
R-alpha lipoic acid.
13. A composition comprising acamprosate in a dosage of less than
or equal to 900 mg that is formulated to retain the composition in
the stomach of the recipient and to control the release of the
acamprosate for a period of time sufficient to release less than
50% of the acamprosate from the composition into the stomach within
a 2 hours after administration, and to release more than 50% of the
acamprosate at a controlled rate within 6 hours of
administration.
14. The composition of claim 13, wherein the composition is
formulated to release at least 90% of the acamprosate within 8
hours.
15. The composition of claim 3 wherein the composition comprises a
gastric retentive technology, a controlled release technology, or
both a gastric retentive and a controlled release technology.
16. The composition of claim 13, wherein the composition comprises
one or more of Carbopol 974P (carbomer homopolymer type B) and
carboxymethylcellulose.
17. The composition of claim 13, wherein the composition is
formulated such that upon administration to a recipient the mean
AUC for acamprosate is greater than the mean AUC for an immediate
release composition of a acamprosate, the C.sub.max for acamprosate
is less than the C.sub.max for an immediate release composition,
and/or the T.sub.max for acamprosate is longer than for immediate
release acamprosate.
18. The composition of claim 13, wherein the dosage of acamprosate
is between 100 mg and 800 mg.
19. The composition of claim 13, further comprising alpha lipoic
acid, where the alpha lipoic acid is either racemic alpha lipoic
acid, racemic alpha lipoic acid enriched in R-alpha lipoic acid or
R-alpha lipoic acid, or a salt or a chelate of either racemic alpha
lipoic acid, racemic alpha lipoic acid enriched in R-alpha lipoic
acid or R-alpha lipoic acid, and the dosage of said alpha lipoic
acid is between 50 mg and 600 mg.
20. The composition of claim 13, further comprising at least a
second medication that comprises one or more of a selective
serotonin reuptake inhibitor (SSRI), and a serotonin-norepinephrine
reuptake inhibitor (SNRI).
21. The composition of claim 20, wherein the SSRI or SNRI is
selected from the group consisting of citalopram, desvenlafaxine,
duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran,
paroxetine, sertraline, and venlafaxine.
22. The composition of claim 21 wherein the dosage of the SSRI or
SNRI is greater than or equal to one-half of its lowest approved
dosage and less than or equal to its highest approved dosage.
23. A combination product comprising acamprosate in a dosage of
less than or equal to 900 mg and at least a second medication that
comprises an antipsychotic (neuroleptic) medication, wherein the
product formulated to be retained in the stomach of the recipient
and to control the release of the acamprosate for a period of time
sufficient to release less than 50% of the acamprosate from the
composition into the stomach within a 2 hours after administration,
and to release more than 50% of the acamprosate at a controlled
rate within 6 hours of administration.
24. The product of claim 23, wherein the product comprises a single
dosage form unit comprising both acamprosate and the second
medication.
25. The product of claim 23, wherein the antipsychotic medication
is a first or a second generation antipsychotic.
26. The product of claim 25, wherein the first or a second
generation antipsychotic is selected from the group consisting of
thioridazine, chlorpromazine, thiothixene, trifluoperazine,
fluphenazine, haloperidol, perphenazine, loxapine, molindone,
metoclopramide, aripiprazole, asenapine, iloperidone, lurasidone,
olanzapine, paliperidone, quetiapine, risperidone, and
ziprasidone.
27. The product of claim 26, wherein the dosage of the
first-generation antipsychotic or second-generation antipsychotic
is greater than or equal to one-half of its lowest approved dosage
and less than or equal to its highest approved dosage.
28. A method of treating a neuropsychiatric disorder comprising
administering to a patient in need thereof the combination product
of claim 23, wherein the total daily dosage of the acamprosate is
less than 900 mg and the product is administered once or twice
daily to achieve the total daily dosage.
29. A method of reducing the risk or delaying the onset or
diminishing the severity of tardive dyskinesia in a patient who
requires antipsychotic medication, comprising administering to such
a patient the combination product of claim 23, wherein the total
daily dosage of the acamprosate is less than 900 mg and the product
is administered once or twice daily to achieve the total daily
dosage.
30. A method of reducing anxiety in a patient receiving an
antipsychotic, anti-anxiety or antidepressant medication,
comprising, administering to a patient in need thereof the
composition of claim 20 or the combination product claim 23,
wherein the total daily dosage of the acamprosate is less than 900
mg and the product is administered once or twice daily to achieve
the total daily dosage.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims is a continuation 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. .sctn.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 formulations of acamprosate (calcium
N-acetylhomotaurinate) and to compositions and use of compositions
comprising medications, such as neuroleptic (antipsychotic) and/or
antidepressant drugs, combined with improved formulations of
acamprosate.
[0004] 2. Description of the Related Art
[0005] Acamprosate (calcium N-acetylhomotaurinate) is the calcium
salt of a derivative of the amino acid taurine. It is known to
facilitate GABA-A neurotransmission and to modulate neuronal
responses to the stimulation of both NMDA-type glutamate receptors
and certain classes of metabotropic glutamate receptors. In
particular, it reduces the response of the voltage-operated calcium
channel to high levels of stimulation by glutamate. (Wilde &
Wagstaff, Drugs 53:1039-53, 1997). Acamprosate is used clinically
in the treatment of abstinent alcoholics to reduce or inhibit the
craving for alcohol. Several U.S. patents (e.g., U.S. Pat. Nos.
6,057,373, 6,294,583, 6,391,922, 6,689,816, and 7,498,361; each of
which is incorporated herein by reference in its entirety) describe
the use of acamprosate to treat neuropsychiatric disorders,
including tardive dyskinesia and other movement disorders induced
by chronic exposure of patients to neuroleptic (antipsychotic)
drugs, Tourette's syndrome, and mental disorders such as
posttraumatic stress disorder (PTSD) and obsessive-compulsive
disorder (OCD).
SUMMARY
[0006] Acamprosate is a compound with high solubility and low
permeability--Class III under the Biopharmaceuticals Classification
System (BCS). 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.
[0007] Some embodiments herein are related to methods and
compositions where the pharmacokinetics (PK) of acamprosate are
altered. The PK of acamprosate can be altered, for example, when
the acamprosate is formulated for controlled release by
gastroretentive (GR) delivery systems--solid state dosage forms
that are retained in the stomach for several hours, during which
time the formulations gradually release the acamprosate into the
gastric milieu.
[0008] There are several different methods for creating GR delivery
systems; they have been described in review articles (not an
exhaustive or limiting list) over the past several years, e.g.,
Pharmainfo.net, Volume 6, Issue 1, Feb. 3, 2008; Garg S and Sharma
S, Gastroretentive Drug Delivery System, Business Briefing,
Pharmatech 2003, Nayak A K, Maji R, Das B, Gastroretentive Drug
Delivery Systems, a Review, Asian Journal of Pharmaceutical and
Clinical Research, Volume 3, Number 1, January-March 2010, pp 1-10;
each of which is incorporated herein by reference in its entirety.
These systems all can be applied to acamprosate. Their effect is to
deliver the drug to the proximal duodenum at a controlled rate,
usually over several hours.
[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 C.sub.max, 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.
[0011] In some aspects, the improved formulations can be used treat
conditions, such as those listed above and elsewhere herein, with
total daily dosages of acamprosate of less than 1 gram, given on a
once-daily or twice-daily schedule, for example. This contrasts
with heretofore-described therapeutic use of the currently-marketed
enteric-coated acamprosate tablets. These must be given in doses of
2 grams or more per day to be efficacious in treating alcoholism,
usually on a three times daily schedule, and many patients require
more than 2 grams or more to get relief of symptoms.
[0012] The efficacy of the lower doses is not necessarily based on
the improved formulations being bioequivalent to higher doses of
the currently-marketed enteric coated preparation. In fact the
total AUC produced by the lower doses of the new formulations may
be, in some embodiments, equal to or significantly lower than those
produced with usual doses of the currently-marketed formulations,
and in some embodiments the C.sub.max produced by the new
formulations can be lower than that produced with the currently
marketed formulation at a dose with equal efficacy.
[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.
[0014] Some embodiments relate to combinations of from 100 mg to
less than 1 gram (e.g., 800 mg) of acamprosate with a drug from a
second class, for example, where the second drug is given in a dose
ranging from half of the lower end of its usual dosage range to the
upper end of its dosage range. The combination pill may be given
either once or twice a day to treat a neuropsychiatric disorder,
for example.
[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.
[0017] Some embodiments relate to compositions or methods of using
compositions where the compositions further include a substance to
induce a fed state in a patient. For example, the compositions can
include alpha-lipoic acid, either as racemic alpha-lipoic acid or
as R enantiomer of alpha-lipoic acid. In some aspects of the above
uses, compositions or methods, the alpha-lipoic acid can be in a
dosage of from about 40 to 600 mg or any value or sub range there
between. In some aspects, the alpha-lipoic acid can be in a dosage
of from about 100 to about 300 mg, or any value or sub range there
between. In some aspects, the alpha-lipoic acid can be at least
part of a gastric-retentive composition. In some aspects, the
alpha-lipoic acid can at least partially be in the coating of the
gastric-retentive system. In some aspects, the alpha-lipoic acid
can be incorporated into a gastric-retentive system. In some
aspects, the gastric-retentive system may be designed to release
the alpha-lipoic acid within a period of time after ingestion, for
example, the first hour after ingestion. In some aspects,
alpha-lipoic acid may be included in a formulation or dosage form
that also includes acamprosate, where the acamprosate is in a dose,
for example, of 100 to less than 1 gram (e.g., 800-900 mg), or any
value or sub range there between. In some aspects, alpha-lipoic
acid may be included in a formulation or dosage form that includes
acamprosate and that further includes a second medication, for
example, a neuroleptic (antipsychotic) drug.
[0018] Also presented herein is a composition comprising
acamprosate in a dose of about 100 to less than 1 gram (e.g.,
100-700 mg or 100-900 mg; or any value or sub range there between)
and alpha-lipoic acid in a dosage of about 100 to about 600 mg (or
any value or sub range there between).
[0019] Also presented herein is a composition comprising
alpha-lipoic acid in a dosage of about 100 to about 300 mg in a
gastric-retentive composition comprising acamprosate and another
medication (e.g., a neuroleptic (antipsychotic) drug), for example,
as active pharmaceutical ingredients.
[0020] Some embodiments relate to methods of treating a
neuropsychiatric disorder, which methods can include for example,
administering to a patient in need thereof a total daily dosage of
acamprosate of less than 1000 mg, wherein the acamprosate is
administered once or twice daily to achieve the total daily dosage,
and the administered acamprosate is in a composition that is
formulated to release at least 50% of the acamprosate within the
stomach of the recipient at a controlled rate over a 4-8 hour
period.
[0021] In some aspects the composition can be formulated to release
from about 50% to 99% of the acamprosate in the stomach. The
composition may include for example, one or more gastric retentive
excipients, one or more controlled release excipients, or one or
more gastric retentive excipients and one or more controlled
release excipients. The one or more gastric retentive excipients
can be, for example, a floating excipient that is non-effervescent,
a floating excipient that is effervescent, a bioadhesive excipient,
a mucoadhesive excipient, an excipient that swells, an excipient
that expands, a magnetic excipient, and the like. The one or more
controlled release excipients can include, for example, a
technology that forms a matrix, forms a coated bead, is osmotic or
acts by ion exchange. The administered composition may be
formulated to achieve a mean AUC for acamprosate that is greater
than the mean AUC for an immediate release composition of a
acamprosate, to have a C.sub.max for acamprosate that is less than
the C.sub.max for an immediate release composition, and/or to have
a T.sub.max for acamprosate that is delayed compared to the
T.sub.max for an immediate release composition.
[0022] The composition may include, for example, one or more
polymers that promote retention in the stomach of the recipient,
for example, one or more of Carbopol 974P (carbomer homopolymer
type B) and carboxymethylcellulose. The polymers may be present in
any suitable amount or range, for example, in some non-limiting
embodiments from about 3% to 70% or any range or value within that
broader range. For example, one or more hydrophilic polymers can be
present in an amount of about 5% to about 20%.
[0023] The acamprosate can be administered once daily or twice
daily for example. The administered once or twice daily acamprosate
respectively can be a dosage of less than 1 gram, for example, in a
dosage of 200 mg to 450 mg or 350 mg to 900 mg. Without being
limited thereto, when administered the acamprosate can be
administered as one or two units of a dosage form, for example, one
or two pills, tablets or capsules. The single unit of a dosage form
or the multiple units of a dosage form can have, for example, a
total weight of less than 1200 mg. For example, in some embodiments
herein, the total unit dosage form wait can be between 400 and 1200
mg, between 500 and 1200 mg, between 600 and 1200 mg, or any value
or sub range within those ranges.
[0024] The methods further can include administering the
acamprosate to a patient in a fed state or can include inducing a
fed state in the patient. The neuropsychiatric disorder can be for
example, tardive dyskinesia and other movement disorders induced by
chronic exposure of patients to neuroleptic (antipsychotic) drugs,
Tourette syndrome, posttraumatic stress disorder (PTSD)
obsessive-compulsive disorder (OCD), and the like.
[0025] Some embodiments relate to improved methods of treating
tardive dyskinesia with acamprosate, the improvement comprising
providing an acamprosate dosage form once or twice per day wherein
the dosage form comprises less than 1 gram of acamprosate, for
example, from 50 to 900 mg of acamprosate (more preferably 50-500
mg), which dosage form upon administration releases acamprosate
into the stomach of a patient at a controlled rate over a period
from 3 to 10 hours, wherein the total daily dose of acamprosate
provided is less than 1000 mg. In some aspects at least 50% of the
acamprosate is released into the stomach within at least 3-4
hours.
[0026] Some embodiments relate to compositions that include
acamprosate in a dosage of less than 1 gram or less than 900 mg
that is formulated to retain the composition in the stomach of the
recipient and to control the release of the acamprosate for a
period of time sufficient to release at least 50% of the
acamprosate from the composition into the stomach within a 4 hour
period and to release acamprosate at a controlled rate over a
period of 4 to 8 hours, wherein at least 90% of the acamprosate is
released from the composition within 8 hours.
[0027] The composition can include for example, a gastric retentive
technology, a controlled release technology, or both a gastric
retentive and a controlled release technology. The one or more
gastric retentive excipients are selected from the group consisting
of a floating excipient that is non-effervescent, a floating
excipient that is effervescent, a bioadhesive excipient, a
mucoadhesive excipient, an excipient that swells, an excipient that
expands, a magnetic excipient, and the like. The one or more
controlled release excipients can include, for example, a
technology that forms a matrix, that forms a coated bead, that is
osmotic, that acts by ion exchange, or the like. The composition
may include, for example, one or more polymers, such as one or more
of Carbopol 974P (carbomer homopolymer type B) and
carboxymethylcellulose, and the like. The composition can be
formulated such that upon administration to a recipient the mean
AUC for acamprosate is equal to or greater than the mean AUC for an
immediate release composition of a acamprosate, the C.sub.max for
acamprosate is less than the C.sub.max for an immediate release
composition, and/or the T.sub.max for acamprosate is longer than
for immediate release acamprosate.
[0028] The acamprosate dosage can be, for example, between less
than 1 gram (e.g., 100 mg and 800 mg) or any value or range within
that range. The composition can be formulated, for example, as a
tablet, a pill, a capsule, or the like. The composition further may
include, for example, alpha lipoic acid, where the alpha lipoic
acid is either racemic alpha lipoic acid or the R-enantiomer of
alpha-lipoic acid, and the dosage of alpha lipoic acid is between
50 mg and 600 mg.
[0029] Some embodiments relate to methods of treating a
neuropsychiatric disorder by administering to a patient in need
thereof a composition as set forth above or 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.
[0030] Some embodiments relate to combination products that
include, for example, a composition as described above and
elsewhere herein and at least a second medication that includes one
or more of an antipsychotic (neuroleptic) medication, a selective
serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine
reuptake inhibitor (SNRI), an antidepressant, an anti-anxiety
medication, or the like. The antipsychotic medication can be, for
example, a first or a second generation antipsychotic. The first or
a second generation antipsychotic can be for example, one or more
of thioridazine, chlorpromazine, thiothixene, trifluoperazine,
fluphenazine, haloperidol, perphenazine, loxapine, molindone,
metoclopramide, aripiprazole, asenapine, iloperidone, lurasidone,
olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, and
the like. The SSRI or SNRI can be, for example, one or more of
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine,
fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, and
the like. The product may include, for example, a single dosage
form unit that includes, consists or consists essentially of both
acamprosate and at least one second medication.
[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.
[0032] Also, some embodiments relate to methods of or uses of
acamprosate for improving compliance with an acamprosate treatment
regimen. The methods can include for example, providing to a
patient a total daily dosage of acamprosate of less than 1 gram
(e.g., 900 mg) and administering an effective amount of an
acamprosate formulation once or twice daily, which formulation is
formulated to release at least 50% of the acamprosate within the
stomach of the recipient at a controlled rate over a 4-8 hour
period. In some aspects, at least 50% is released within the first
4 hours. In some aspects, at least 90% is released from the
composition within 8 hours. In some aspects, the patient can be a
patient is selected, identified or by virtue of having been at
least partially non-compliant with a previous treatment regimen.
The treatment regimen can include, for example, alcoholism,
treatment of a movement disorder, treatment of anxiety, treatment
of depression, and the like.
[0033] Some embodiments relate to methods of or uses of acamprosate
for reducing anxiety in a patient receiving a neuroleptic, anxiety
or antidepressant medication. The methods can include for example,
providing to a patient a total daily dosage of acamprosate of less
than 1 gram (e.g., 900 mg) and administering an effective amount of
an acamprosate formulation once or twice daily, which formulation
is formulated to release at least 50% of the acamprosate within the
stomach of the recipient at a controlled rate over a 4-8 hour
period. In some aspects, at least 50% is released within the first
4 hours. In some aspects, at least 90% is released from the
composition within 8 hours. The methods further can include, for
example, identifying a patient suffering from anxiety despite
receiving one of said medications or a patient in need of at least
some reduction in anxiety despite receiving one of said
medications.
[0034] Some embodiments relate to methods for or uses of
acamprosate for reducing acamprosate side effects associated with
treatment with dosages of greater than 1 gram. The methods can
include, for example, administering to a patient in need thereof a
total daily dosage of acamprosate of less than 1000 mg, wherein the
acamprosate is administered once or twice daily to achieve the
total daily dosage, and the administered acamprosate is in a
composition that is formulated to release at least 50% of the
acamprosate within the stomach of the recipient at a controlled
rate over a 4-8 hour period. In some aspects, at least 50% is
released within the first 4 hours. In some aspects, at least 90% is
released from the composition within 8 hours. The side effect can
be, for example, nausea and/or vomiting.
[0035] Some embodiments relate to methods of or uses of acamprosate
for treating alcohol dependence comprising administering to a
patient in need thereof a total daily dosage of acamprosate of less
than 1000 mg, wherein the acamprosate is administered once or twice
daily to achieve the total daily dosage, and the administered
acamprosate is in a composition that is formulated to release at
least 50% of the acamprosate within the stomach of the recipient at
a controlled rate over a 4-8 hour period. In some aspects, at least
50% is released within the first 4 hours. In some aspects, at least
90% is released from the composition within 8 hours.
[0036] A method of treating alcohol dependence, comprising
administering an effective amount of a pharmaceutical formulation
comprising acamprosate to a patient in need thereof, wherein the
formulation is formulated with one or more gastroretentive
technologies and one or more controlled release technologies, which
one or more gastroretentive technologies is selected from the group
consisting of floating--non-effervescent, floating--effervescent,
bioadhesive, mucoadhesive, swelling, expanding, and magnetic and
which one or more controlled release technologies is selected from
the group consisting of matrix, coated beads, osmotic, and ion
exchange. In some aspects, the methods of treating alcoholism can
include GR acamprosate plus alpha lipoic acid; the combination pill
being taken either in the fed state or in the fasting state.
[0037] Furthermore, some embodiments relate to methods of or uses
of acamprosate for treating a neuropsychiatric disorder, comprising
administering once or twice daily a composition comprising
acamprosate in a composition that releases at least 50% of the
acamprosate at a controlled rate over a 4-8 hour period, and
wherein the total daily dosage of acamprosate is less than 1000 mg.
In some aspects, at least 50% is released within the first 4 hours.
In some aspects, at least 90% is released from the composition
within 8 hours.
[0038] Some embodiments relate to uses of acamprosate in the
treatment of a neuropsychiatric disorder, wherein the acamprosate
is administered once or twice daily as part of a composition
comprising the acamprosate, wherein the composition releases at
least 50% of the acamprosate at a controlled rate over a 4-8 hour
period, and wherein the total daily dosage of acamprosate is less
than 1000 mg. In some aspects, at least 50% is released within the
first 4 hours. In some aspects, at least 90% is released from the
composition within 8 hours. The disorder can be, for example,
schizophrenia, schizoaffective disorder, bipolar disorder, major
depressive disorder, delusional disorder, organic psychoses,
Tourette Syndrome, and the like. Some embodiments relate to uses of
acamprosate in the treatment of a neuropsychiatric disorder,
wherein the acamprosate is formulated for once or twice daily
administration in a composition that releases the acamprosate at a
controlled rate over a 4-8 hour period, and wherein the total daily
dosage of acamprosate is less than 1000 mg. In some aspects, at
least 50% is released within the first 4 hours. In some aspects, at
least 90% is released from the composition within 8 hours.
[0039] Some embodiments relate to compositions that include for
example, a fixed dose of acamprosate in a gastroretentive
controlled-release formulation where the dose of acamprosate is
less than 1 gram (e.g., between 50 and 900 mg). Also, some
embodiments relate to compositions that include a fixed dose of
acamprosate in a gastroretentive controlled-release formulation and
a fixed dose of a first-generation neuroleptic or a
second-generation neuroleptic, a second generation neuroleptic or a
fixed dose of metoclopramide, where the dose of acamprosate is less
than 1 gram (e.g., between 50 and 900 mg). The dosage of the
first-generation neuroleptic can be, for example, 1/2 of its lowest
approved dosage up to its highest approved dosage, for example, 50%
of its lowest approved dosage up to 90% of its lowest approved
dosage.
[0040] Some embodiments relate to improved method of treating a
mental disorder with a first or second generation neuroleptic, the
improvement comprising administering a composition that comprises
acamprosate in an amount of less than 1 gram, for example, 50 to
900 mg (or any value or sub range of less than 1 gram), and a
first-generation neuroleptic, wherein the composition is formulated
to release at least 50% of the acamprosate into the stomach of the
recipient over a 4 to 8 hour period. The mental disorder can be,
for example, one or more of schizophrenia, schizoaffective
disorder, bipolar disorder, major depressive disorder, delusional
disorder, organic psychosis, or Tourette Syndrome.
[0041] It should be understood that in the methods, uses and
compositions described herein, that acamprosate can be substitute
for by or included with any other salt or analog, for example, one
more of sodium N-acetylhomotaurinate, magnesium
N-acetylhomotaurinate, or lithium N-acetylhomotaurinate at the same
milligram dose and/or free acid equivalent dose at the same
milligram dose.
[0042] Still further embodiments relate to the inclusion of a
substance to induce a fed mode in the patient, for example, in
order minimize or reduce stomach clearance so as to maintain
acamprosate in the stomach for a longer period of time. The
methods, uses, products, formulations and compositions described
herein, further may include, for example, alpha lipoic acid in an
amount of 50 mg to 700 mg or any amount or sub range therein (e.g.,
100-500 mg.). The alpha lipoic acid can be, for example, either
racemic alpha lipoic acid, an enriched racemic mixture for one
enantiomer or an enantiomer of alpha lipoic acid, such as the R
enantiomer. The alpha lipoic acid can be included, for example, at
least partially in the coating of a formulation. The formulation
further can include a gastric-retentive system. In some aspects the
alpha lipoic acid can be incorporated into a gastric retentive
system. For example, a gastric retentive systems designed to
release the alpha lipoic acid within the 30-120 minutes hours after
ingestion. The alpha lipoic acid can be combined with acamprosate
in a dosage of 100 to 700 mg (or any value or sub range there
between such as 500 mg). Such compositions can include the alpha
lipoic acid in combination with acamprosate and in combination with
a neuroleptic (antipsychotic) drug. In some aspects the
alpha-lipoic acid can be in a dosage of 100 to 300 mg in a
gastric-retentive composition comprising a neuroleptic
(antipsychotic) drug and acamprosate as active pharmaceutical
ingredients.
[0043] The foregoing is a summary and thus contains, by necessity,
simplifications, generalization, and omissions of detail;
consequently, those skilled in the art will appreciate that the
summary is illustrative only and is not intended to be in any way
limiting. Other aspects, features, and advantages of the devices
and/or processes and/or other subject matter described herein will
become apparent in the teachings set forth herein. The summary is
provided to introduce a selection of concepts in a simplified form
that are further described below in the Detailed Description. This
summary is not intended to identify key features or essential
features of the claimed subject matter, nor is it intended to be
used as an aid in determining the scope of the claimed subject
matter.
BRIEF DESCRIPTION OF THE FIGURES
[0044] FIG. 1 illustrates the pharmacokinetic plot of immediate
release versus simulated GR controlled-release acamprosate from a
pharmacokinetic study (see EXAMPLE 3 below) conducted in four dogs
(beagles). FIG. 1 illustrates the results for dog 1 from the
study.
[0045] FIG. 2 illustrates the results for dog 2 from a
pharmacokinetic study conducted in four dogs, which study is
described below in EXAMPLE 3.
[0046] FIG. 3 illustrates the results for dog 3 from a
pharmacokinetic study conducted in four dogs, which study is
described below in EXAMPLE 3.
[0047] FIG. 4 illustrates the results for dog 4 from a
pharmacokinetic study conducted in four dogs, which study is
described below in EXAMPLE 3.
DETAILED DESCRIPTION
Introduction
[0048] Acamprosate (calcium bis acetyl-homotaurine;
[3-(acetylamino)-1-propanesulfonic acid] calcium salt), is a
derivative of the amino acid taurine) with effects on both GABA and
glutamate-mediated neurotransmission. It is approved in several
countries for the treatment of alcoholism--specifically, the
inhibition of craving for alcohol in alcohol-dependent patients who
are currently abstinent. For this purpose acamprosate has limited
effectiveness; some controlled studies have failed to show
efficacy, and adoption of the drug in practice has not been
widespread. Clinical experience, described in the specification of
several issued US patents, has shown acamprosate to be impressively
efficacious in the treatment of tardive dyskinesia and other
movement disorders, and in recurrent unwanted stereotypic
movements, behaviors, perceptions, or thoughts, such as those that
occur in obsessive-compulsive disorder, tic disorders, Tourette
Syndrome, post-traumatic stress disorder, depression, and
schizophrenia. The therapeutically active moiety in acamprosate is
the acetylhomotaurine ion; thus, in any of the therapeutic
applications of acamprosate described here and elsewhere the drug
can be replaced by another salt of the same anion, with either a
univalent or divalent cation--e.g., sodium acetylhomotaurinate,
lithium acetylhomotaurinate, or magnesium acetylhomotaurinate. For
purposes of the embodiments described herein, acamprosate (or
another salt of acetylhomotaurine) can be used alone or in
combination to treat various conditions characterized by recurrent,
unwanted, stereotypic movements, behaviors, perceptions, or
thoughts, including without limitation movement disorders (e.g.,
hyperkinetic movement disorders such as tardive dyskinesia ("TD"),
tardive dystonia, tardive akathisia, peak-dose dyskinesia
associated with Parkinson's disease treated with levodopa,
dystonia, tics, Tourette Syndrome, chorea associated with
Huntington's disease) obsessive-compulsive disorder, posttraumatic
stress disorder (PTSD), recurrent intrusive thoughts in depression
and stereotypic behavior in schizophrenia and autism.
[0049] TD is a chronic disorder of the nervous system,
characterized by involuntary, irregularly rhythmic movements most
often involving the mouth, tongue, and facial muscles. Choreatic or
dystonic movements of the extremities can be involved, as can
dystonic movements of the neck or trunk, and rocking movements of
the trunk. TD with prominent limb movements most often is tardive
dystonia, a subtype of TD tends to be severe, disabling, and
difficult to treat. TD can be accompanied by tardive akathisia, an
irresistible impulse to move which is often manifest as continual
restless movements of the legs. Another potential accompaniment is
disruption of respiratory movements leading to irregular breathing
and subjective shortness of breath--respiratory dyskinesia. Most
cases of TD are caused by long-term use of neuroleptics
(antipsychotic drugs); the remainder are caused by chronic use of
dopamine blocking drugs such as metoclopramide or prochlorperazine
that are given to relieve or to prevent nausea and vomiting.
However, there are numerous well-documented cases in which those
drugs have induced TD after only a few weeks of exposure. Unlike
many drug side effects tardive dyskinesia can actually get worse
when the causative drug is discontinued, and the condition can
persist for months, years, or even permanently afterwards. The
prevalence of tardive dyskinesia with long-term treatment with
first-generation antipsychotic drugs is over 25%, and even higher
in elderly patients.
[0050] Second-generation antipsychotic drugs are associated with a
lower but still significant prevalence of tardive
dyskinesia--between 1% and 5% depending on the population studied,
the specific second-generation neuroleptic given, and the dose of
the second-generation neuroleptic. (At higher dosages of some of
the second generation neuroleptics, the dopamine receptor blocking
action predominates over other neurotransmitter actions and its
pharmacodynamic effect is essentially that of a first generation
agent.) The second generation drugs, however, have a major
problem--they frequently cause weight gain and glucose intolerance
that can lead to frank diabetes and accelerated atherosclerosis,
with significant impact on patients' life expectancy. Thus the
second generation neuroleptics do not provide a safe alternative to
first generation neuroleptics--simply an alternative with a lesser
propensity to cause movement disorders. They are not in general
more efficacious than first generation drugs in the treatment of
schizophrenia, with the sole exception of clozapine, a drug with
numerous other adverse effects including seizures and
agranulocytosis that limit its clinical use.
[0051] Acamprosate can be used as a treatment for obsessive
compulsive disorder (OCD), posttraumatic stress disorder (PTSD),
and other neuropsychiatric conditions characterized by recurrent,
involuntary, unwanted, and stereotyped movements, behaviors,
thoughts, or perceptions--the symptoms of OCD and PTSD falling
within that broader ambit. Serotonin reuptake inhibitors--both
selective serotonin reuptake inhibitors and
serotonin-norepinephrine reuptake inhibitors--can have therapeutic
benefits in PTSD and OCD. Thus, some embodiments relate to the
combination of acamprosate and an SSRI or SNRI. The fact that GR
acamprosate formulations as described herein can be efficacious in
total doses of less than 1 gram per day, given on a once-daily or
twice-daily basis, makes such combinations feasible, which they
were not heretofore when only enteric-coated acamprosate was
available and therapeutic efficacy typically required 2 grams per
day or more, entailing six or more enteric-coated tablets per day
on a three times daily schedule.
[0052] Thus, some embodiments relate to combinations of GR
acamprosate with either an SSRI or an SNRI. Examples of
non-limiting amounts or dosages are provided herein. These
combinations can be given once or twice daily, for example. Also,
some embodiments relate to the treatment of neuropsychiatric
conditions characterized by recurrent, involuntary, unwanted and
stereotyped movements, behaviors, thoughts, or perceptions, and in
particular PTSD and OCD.
[0053] Acamprosate when used to treat alcoholism is typically
administered in 333-mg enteric-coated tablets. The dose is two
tablets (666 mg) three times daily, for a total dose of
approximately two grams. Doses of up to 3 grams (three tablets
three times a day) have been studied as alcoholism treatment; the
higher dose does not appear to be more effective and it has more
gastrointestinal side effects. One reported study assessed the
pharmacokinetics of acamprosate using liquid chromatography
(Hammarberg, et al., "Acamprosate Determinations in Plasma and
Cerbrospinal Fluid After Multiple Dosing Measured by Liquid
Chromatography--Mass Spectroscopy: A Pharmacokinetic Study in
Healthy Volunteers," The Drug Monit, 2010, 32:489-496). It showed
that blood levels of acamprosate build up with repeated dosing, for
example, 666 mg doses. The instant technology that can
efficaciously provide sub 1 gram total daily doses is surprising
and unexpected in view of such earlier studies.
[0054] When used to treat TD and other neuropsychiatric disorders
it has been used at dosages ranging from 1 gm to 3.6 grams per day
(3 to 11 tablets daily) on a thrice-daily schedule. The average
dose for treating TD has been 3 grams daily. Prior to the instant
technology, in general clinical practice no patient has had an
optimal response on less than 2 grams per day.
[0055] The most common side effects of acamprosate are
gastrointestinal symptoms--including nausea, vomiting, diarrhea,
and dyspepsia. For patients with alcoholism these side effects
often lead to noncompliance, and in turn to decreased effectiveness
of treatment. For patients with TD, who often are so distressed by
their movements that they will adhere to effective treatment
despite side effects, the gastrointestinal side effects make
treatment unpleasant, or limit the acamprosate dose to one that
does not completely relieve their involuntary movements. For all
patient groups taking multiple pills three times daily is
inconvenient and burdensome.
[0056] The gastrointestinal side effects of acamprosate are thought
to be due to the local irritation of the stomach and intestine by
the drug, and not due to central effects of the acetylhomotaurinate
ion in the blood. Thus, enhancing the bioavailability of oral
acamprosate can reduce the gastrointestinal side effects without
compromising its efficacy.
[0057] Some embodiments provided herein relate to alternative
formulations of acamprosate that allow a smaller dose to be used,
but that surprisingly and unpredictably have sufficient or equal
efficacy. Such formulations can have greater bioavailability, for
example, than the existing enteric-coated formulation.
[0058] Without being limited thereto, in some instances the greater
therapeutic potency of the new oral formulations can come from
changes in the drug's PK profile that allow the same therapeutic
benefits to be obtained from a smaller total area under the
time-concentration curve (AUC). Greater oral bioavailability, if it
is attained, is an additional benefit that may enable even greater
oral potency. However, what is surprising, unpredicted and
unexpected here in some embodiments is the increase in therapeutic
potency that is independent of any increase in oral
bioavailability. Thus, in some embodiments, greater therapeutic
potency of oral formulations can be attained by altering the
pharmacokinetics (PK) of the drug to make it more efficacious
despite a smaller AUC in the blood. In particular, some embodiments
relate to formulations and dosage schedules that maintain the
acamprosate concentration above a threshold for a sufficient time
during each 24-hour day. Such formulations and schedules are
efficacious even though the acamprosate concentration does not
exceed the threshold for the entire 24 hour period.
[0059] There are at least several ways to reformulate drugs to
alter their PK profiles according to the instant technology. The
technology described here relates to the use of any of such
formulation technologies to alter the PK profile of acamprosate in
a way that makes it efficacious (including in some aspects, more
efficacious) with a lower area under the curve than that produced
by three times daily administration of the currently-marketed
enteric-coated formulation. This in turn makes possible the
administration of lower oral doses of acamprosate--less than one
gram per day--on a less frequent schedule--once or twice
daily--than has been described heretofore. The lower oral daily
doses of acamprosate described herein are not necessarily
bioequivalent to higher daily doses of enteric-coated acamprosate
that have been previously shown efficacious for the various
indications for the drug. In fact, in some embodiments the lower
daily doses and once- or twice-daily schedule described for the new
formulations usually will produce a lower total area under the
curve (AUC) than the therapeutically equivalent doses of the
enteric-coated preparation given three times a day, so their equal
efficacy is an unexpected finding.
[0060] The technology according to some embodiments described
herein is based on several original observations: (1) There are
clinical cases in which giving the existing enteric-coated
acamprosate to patients on a twice-daily schedule made a daily dose
more efficacious than when given on a thrice-daily schedule. Thus,
it has been discovered that the shape of the PK curve and not just
the AUC can make a difference to efficacy. Specifically, that
having a blood concentration above a threshold for several hours
per day may be more efficacious than maintaining a concentration
just below that threshold for 24 hours a day. (2) In a dog model of
a GR controlled release system applicable to a wide range of GR and
controlled release technologies it was shown (see EXAMPLE 3 below)
that controlled presentation of acamprosate over eight hours
yielded a significantly longer residence time above a threshold
concentration than immediate release of the same dosage, even when
there was not a significant decrease in the AUC. In the model of
controlled release, the drug "saved" by avoiding a high C.sub.max
was distributed across several hours, giving a several hour period
in which the blood concentration of acamprosate was higher than the
blood concentration after administration of a single dose of the
immediate release version. (3) Clinical observations of TD cases
where enteric coated acamprosate given three times daily had
greater efficacy at a given daily dosage when the daily dosage was
divided unevenly among the three doses. (4) The therapeutic action
of acamprosate in TD is based on its effects on glutamate
transmission. These effects are not based on direct interaction of
acamprosate with glutamate receptors, but rather on downstream
effects of acamprosate modulation at other sites on the neuron.
These downstream effects are based in part on modulation of RNA
transcription, a mechanism implying the potential for persistence
of effect after the drug is no longer present at a threshold level
for clinical efficacy.
[0061] Further, a controlled release GR version of acamprosate can
cause significantly less GI side effects than the immediate-release
version, since the maximum concentration of the drug in the gastric
juice or in the intestine will be lower than with the immediate
release version.
[0062] It is known that immediate release acamprosate (which is
equivalent to acamprosate solution because acamprosate is
immediately and completely soluble in gastric juice) has twice the
bioavailability as enteric-coated acamprosate (Saivin S et al.,
Clinical Pharmacokinetics of Acamprosate, Clinical Pharmacokinetics
Vol. 35, Number 5, November 1998, pp. 331-345, which is
incorporated herein by reference in its entirety). The new
observations and discoveries reported here demonstrate that
controlled release acamprosate delivered by a GR system can be at
least 50% more potent than IR acamprosate for treating TD and other
neuropsychiatric disorders. Thus, controlled release GR
formulations can be efficacious at total daily doses of less than 1
gram per day, and these formulations can be given on a twice-daily
schedule, and even on a once-daily schedule, depending on the
threshold blood level and daily time above that level required for
efficacy in a given patient. The model system studied was based on
gastric retention and controlled release over eight hours. It is
evident that GR and controlled release over six hours or controlled
release over four hours can be satisfactory for therapeutic
advantage, depending on the time and concentration thresholds for
efficacy in particular patient populations and for particular
indications.
[0063] The dog study of simulated GR acamprosate (EXAMPLE 3 below)
showed that comparing the PK curve (time.times.plasma concentration
curve) for simulated GR acamprosate (intra-gastric administration
of IR acamprosate every half hour in amounts that decrease linearly
with the square root of time) with the PK curve for intra-gastric
administration of the same total dose of IR acamprosate all at
once, the curve for simulated GR acamprosate lies above the curve
for IR acamprosate for more than six hours (see PK plots from the
dog study). Thus, the time above critical threshold is hours
greater for simulated GR acamprosate than for IR acamprosate, for a
significant range of values for the critical threshold.
Furthermore, the area under the curve (AUC) for GR acamprosate
usually is greater than the AUC for IR acamprosate--and sometimes
significantly greater.
[0064] Enteric-coated acamprosate is only half as bioavailable as
IR acamprosate and has a lower maximum concentration (C.sub.max)
and longer time to peak concentration (T.sub.max) than IR
acamprosate. GR acamprosate has an even greater therapeutic
advantage over enteric-coated acamprosate than over IR acamprosate.
Furthermore, the steady-state concentration in the blood when
enteric-coated acamprosate is given three times a day is approached
slowly over 5-7 days, with the plasma level of acamprosate during
the first several days of administration below the eventual
steady-state plasma level. By contrast, a gastric retentive
formulation of acamprosate according to embodiments described
herein that provides controlled delivery of acamprosate into the
stomach and thence the duodenum--with a single dose can reach the
blood level of acamprosate attained only after several days on the
enteric-coated version, and it might maintain that level for
several hours. One or two doses daily of the acamprosate
formulations described herein can be efficacious even though the
daily AUC might lie below the daily AUC for enteric-coated
acamprosate dosed three times a day on an ongoing basis.
[0065] GR formulations of acamprosate can produce a PK curve almost
identical to that of simulated GR acamprosate if that formulation
releases acamprosate into gastric juice at a rate proportional to
the square root of time. Some embodiments herein relate to the use
of any GR formulation that releases acamprosate at such a rate (or
close to it). One non-limiting example of a specific GR formulation
described herein (see EXAMPLE 6 below) does release acamprosate at
such a rate (see for example the tables showing the composition of
the 400 mg and 800 mg GR acamprosate tablets tested; see the in
vitro drug release data in two different media--one highly acidic
and typical of fasting gastric juice and the other with a pH
typical of gastric juice in the fed state). The PK curve of such GR
acamprosate in dogs (and in humans) lies above the PK curve for the
same dose of IR acamprosate or of enteric-coated acamprosate for
several hours.
[0066] GR acamprosate can be more than twice as bioavailable as
enteric-coated acamprosate. Thus, less than 1.3 gm per day of GR
acamprosate can have the therapeutic effect of 2.6 gm of
enteric-coated acamprosate, the latter being the upper limit of
dose ranges for acamprosate in the treatment of TD and other
neuropsychiatric disorders described in previously issued patents.
Thus, dosing of GR acamprosate at 400 mg three times a day can give
therapeutic results equivalent to 2.6 gm per day of enteric coated
acamprosate.
[0067] However, consistent with the human case set forth in EXAMPLE
1 that evidences that there is a therapeutic threshold that need be
exceeded for significantly less than 24 hours, for example, eight
hours per 24 hours, the dosing of 400 mg of GR acamprosate twice a
day, or possibly 800 mg once a day, can be effective. This results
in the total acamprosate dose for the GR formulation being below 1
gm per day--less than the previously recognized therapeutic
range--even for a case that would require 2.6 mg per day of the
enteric-coated formulation for efficacy, in a situation where the
GR formulation at that dose did not produce as high an AUC as 2.6
mg of the enteric-coated formulation.
[0068] Further, it should be understood that according to some
embodiments the sub gram, twice or once a day regimens (e.g., 400
mg twice a day or 800 mg once a day regimens) of GR acamprosate do
not give equivalent concentrations in the blood to those produced
by enteric-coated acamprosate given in a higher total daily dose on
a three times daily schedule. The latter would give--after 5-7
days--a stable level of acamprosate, whereas the GR regimens can
produce a fluctuating level of acamprosate that might be below the
steady state level for enteric-coated acamprosate, at some times of
the day. Thus, the GR formulation given at less than 1 gm per day
would not necessarily be bio-equivalent to the enteric-coated
formulation given at dosages of 1 gm to 2.6 gm on a three times a
day schedule, and in fact it can even have a lower total AUC in 24
hours than that produced by 2.6 grams daily of acamprosate. For
these reasons the use of GR acamprosate at a daily dose of less
than 1 gm per day given on a once-daily or twice-daily basis is not
suggested by the prior art, and its efficacy for TD (and for other
neuropsychiatric disorders) is a novel and unexpected
discovery.
[0069] The GR acamprosate formulations (e.g., tablets) according to
some embodiments herein can thus be of size such that the total
tablet or pill is easy to swallow. For example, the specifically
described formulations herein, in particular, 400 mg GR acamprosate
tablets and even 800 GR acamprosate tablets are small enough to be
easily swallowed. They thus make possible reasonably-sized
fixed-dose combination tablets comprising GR acamprosate and
another drug that is given in a lower dosage than the GR
acamprosate. In some embodiments these formulations are novel
compositions because they are made feasible by the reduction in
daily acamprosate dose and dosage frequency made possible by the GR
formulation of acamprosate and the finding that a threshold level
of acamprosate need not be maintained for 24 hours per day for
efficacy.
[0070] Some embodiments of the present technology introduce a way
to administer a therapeutic dosage of acamprosate in one
(relatively) small dose that only has to be taken once or twice
daily. The smaller dosage form also can have ancillary benefits.
First of all, the smaller dosage can lead to lesser side-effects.
It also can lead to improved patient compliance due to being taken
fewer times each day, for example, once daily. Additionally,
smaller dosage forms allow for more convenient co-administration of
acamprosate with other drugs, for example as part of a single
dosage form or as separate dosage forms.
Acamprosate Formulations
[0071] Some embodiments relate to formulations comprising
acamprosate designed for sustained or controlled release. Examples
of sustained or controlled release pharmaceutical formulations that
can be used with acamprosate include, for example, the materials
and methods described in U.S. Pat. Nos. 3,536,809; 3,598,123;
3,845,770; 3,916,899; 4,008,719; 4,404,1834,690,820; 4,851,232;
4,861,598; 4,871,548; 4,970,075; 4,992,278; 5,007,790; 5,059,595;
5,073,543; 5,120,548; 5,273,758; 5,354,556; 5,458,887; 5,582,837;
5,591,767; 5,674,533; 5,718,700; 5,733,566; 5,736,159; 5,783,212;
5,840,754; 5,912,268; 5,972,389; 6,120,803; 6,340,475; 6,365,183;
6,403,120; 6,451,808; 6,488,962; 6,548,083; 6,635,280; 6,635,281;
6,682,759; 6,723,340; 6,797,283; 7,405,238; 7,413,751; 7,438,927;
7,514,100; 7,612,112; 7,731,989; Re. 34,990; 7,736,667; and
7,976,870; U.S. Patent Pub Nos. 20110091542; 20090304768;
20090304753; foreign patent publication numbers EP 0,661,045, A1;
JP Kokei 61233632 and PCT publication numbers WO 9929297; WO
9912527; WO 9930692; WO 9921551; WO 9929305, WO 9917745; WO
9906045, WO 9833489; WO 9855107; WO 9811879; WO 9815264; WO
9737640; WO 9733566; WO 9748385; WO 9747285; WO 9718814; WO
9637202; WO 9637189; WO 9613248; WO 9608253; WO 9600065; WO
9626718; WO 9626717; WO 9632097; WO 9529665; WO 9519174; WO
9,591,174; WO 9530422; WO 9427587; WO 9625153; each of which is
incorporated herein by reference in its entirety. In each of the
listed patents and publications, acamprosate in a dosage of less
than 1 gram (e.g., 100 mg to 900 mg) can be used as an active agent
replacing or in addition to other agents described in the
respective document using the particular formulation technology
that is described, for example. In particular, the 7,514,100 patent
provides a description regarding how to incorporate various
technologies to obtain extended release formulations, and the
description can be used for acamprosate formulations.
[0072] Some embodiments disclosed herein relate to pharmaceutical
dosage forms comprising gastroretentive controlled release
acamprosate at a specified dosage in combination with a first
generation neuroleptic or metoclopramide at a specified dosage,
with a second generation neuroleptic at a specified dosage, or with
a serotonin reuptake inhibitor (SSRI or SNRI drug) at a specified
dosage.
Active Agent
[0073] The controlled release oral dosage forms of the present
technology preferably include less than 1 gram (e.g., from about 50
mg to 900 mg) acamprosate or an equivalent amount of a
pharmaceutically acceptable salt thereof, such as for example the
magnesium, sodium, or lithium salt. For example, the dosage can be
100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500
mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg
or any value or sub range within that larger range. As noted
elsewhere herein, other salts are contemplated, as are analogs of
acamprosate and salts thereof.
[0074] If a second drug is included in the formulation, such drug
may be included in controlled release form or in immediate release
form. The additional drug may be incorporated into the matrix
(e.g., controlled release matrix) along with the acamprosate;
incorporated into a coating (e.g., a controlled release coating);
incorporated as a separate band or layer (e.g., a separated
controlled release layer or immediate release layer); or may be
incorporated as a powder, granulation, etc., in a gelatin capsule
with the substrates.
Dosage Forms
[0075] The controlled-release dosage form may optionally include a
controlled release material which is incorporated into a matrix
along with the acamprosate, or which is applied as a sustained
release coating over a substrate comprising the drug (the term
"substrate" encompassing beads, pellets, spheroids, tablets, tablet
cores, etc.). The controlled release material may be hydrophobic or
hydrophilic as desired. The oral dosage form may be provided as,
for example, granules, spheroids, pellets or other multi
particulate formulations. An amount of the multi particulates which
is effective to provide the desired dose of acamprosate over time
may be placed in a capsule or may be incorporated in any other
suitable oral solid form, e.g., compressed into a tablet. On the
other hand, the oral dosage form may be prepared as a tablet core
coated with a controlled-release coating, or as a tablet comprising
a matrix of drug and controlled release material, and optionally
other pharmaceutically desirable ingredients (e.g., diluents,
binders, colorants, lubricants, etc.). The controlled release
dosage form may also be prepared as a bead formulation or an
osmotic dosage formulation.
Controlled Release Matrix Formulations
[0076] U.S. Pat. No. 7,514,100 (the '100 patent) describes in
detail methods of achieving controlled release formulations in
dosages of drugs and is included by reference, herein. The '100
patent explains how to achieve a controlled-release formulation via
a matrix which includes a controlled release material--either a
hydrophilic or hydrophobic material.
[0077] Controlled release can be accomplished by (a) forming
granules comprising at least one hydrophobic and/or hydrophilic
material (e.g., a water soluble hydroxyalkyl cellulose) together
with the acamprosate; (b) mixing the at least one hydrophobic
and/or hydrophilic material containing granules with at least one
C.sub.12-C.sub.36 aliphatic alcohol, and (c) optionally,
compressing and shaping the granules.
[0078] The matrices can also be prepared via melt pelletization,
melt-granulation, or melt-extrusion techniques. The controlled
release matrix may also contain suitable quantities of other
materials, e.g., diluents, lubricants, binders, granulating aids,
colorants, flavorants and glidants that are conventional in the
pharmaceutical art in amounts up to about 50% by weight of the
particulate if desired. It may also include combinations of
multi-particulates containing one or more dyskinesia treatments or
cures.
[0079] In certain embodiments, a spheronising agent can be added to
a granulate or to multi particulates and then spheronized to
produce controlled release spheroids. The spheroids are then
optionally over coated with a controlled release coating by methods
such as those described herein.
Preparation of Coated Bead Formulations
[0080] The '100 patent also explains that the oral solid controlled
release dosage form can comprise a plurality of coated substrates.
An aqueous dispersion of hydrophobic material is used to coat the
beads to provide for the controlled release of the acamprosate. The
stabilized controlled-release bead formulations slowly release the
acamprosate, e.g., when ingested and exposed to preferably to
gastric fluids, but also to intestinal fluids. Substrates coated
with a therapeutically active agent are prepared, e.g. by
dissolving the therapeutically active agent in water and then
spraying the solution onto a substrate.
Controlled Release Osmotic Dosage
[0081] Controlled release dosage forms may also be prepared as
osmotic dosage formulations.
Coatings
[0082] The dosage forms as described herein may optionally be
coated with one or more coatings suitable for the regulation of
release or for the protection of the formulation. For instance, a
coating can be added that provides for either pH-dependent or
pH-independent release, e.g., when exposed to gastrointestinal
fluid. When a pH-independent coating is desired, the coating is
designed to achieve optimal release regardless of pH-changes in the
environmental fluid, e.g., the GI tract. Other preferred
embodiments include a pH-dependent coating that releases the
acamprosate in desired areas of the gastrointestinal (GI) tract,
e.g., the stomach or small intestine. It is also possible to
formulate compositions which release a portion of the dose in one
desired area of the GI tract, e.g., the stomach, and release the
remainder of the dose in another area of the GI tract, e.g., the
small intestine.
Alkylcellulose Polymers
[0083] Cellulosic materials and polymers, including alkylcelluloses
are controlled release materials well suited for coating the
substrates, e.g., beads, tablets, etc.
Alkylcellulose Polymers
[0084] Cellulosic materials and polymers, including alkylcelluloses
are controlled release materials well suited for coating the
substrates, e.g., beads, tablets, etc.
Acrylic Polymers
[0085] In other preferred embodiments, the controlled release
material comprising the controlled-release coating is a
pharmaceutically acceptable acrylic polymer.
Plasticizers
[0086] In embodiments where the coating comprises an aqueous
dispersion of a hydrophobic controlled release material, the
inclusion of an effective amount of a plasticizer in the aqueous
dispersion of hydrophobic material will further improve the
physical properties of the controlled-release coating.
[0087] The controlled-release coatings may also include an exit
means comprising at least one passageway, orifice, or the like. The
passageway may be formed by such methods as those disclosed in U.S.
Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864; each of
which is incorporated herein by reference in its entirety. The
passageway can have any shape such as round, triangular, square,
elliptical, irregular, etc.
[0088] Since acamprosate is absorbed in the intestinal tract,
controlled release of the drug preferably entails or in some cases
may require, among other things, that the drug dosage form be
maintained in the stomach for a number of hours. Without any
modifications, the transit time of an oral dosage form in the
stomach is less than three hours. Wen H, Park, K Oral Controlled
Release Formulation Design and Drug Delivery: Theory to Practice.)
Therefore, a preferred method of accomplishing controlled release
is to deliver it with a gastroretentive drug dosage system. Several
approaches to gastroretentive drug dosage systems are described in
Surana A S, Kotecha R K An Overview on Various Approaches to Oral
Controlled Drug Delivery System Via Gastroretention. Intl. J.
Pharm. Sci. Rev. and Research 2010; 2:68-72 and U.S. Pat. App.
2005/0249798, now abandoned; each of which is incorporated herein
by reference in its entirety.
[0089] The first (and most common) is a floating drug delivery
system, which works by using a low density system so that the
drug-containing system has sufficient buoyancy to float over the
gastric contents and remains in the stomach for a prolonged period.
There are two ways to make a buoyant system. The first is an
effervescent system and the second is a non-effervescent
system.
[0090] In effervescent systems the buoyancy is achieved by using
swellable polymers such as Methocel or polysaccharides, and
effervescent components or liquids that gasify at body temperature.
When the system reaches the stomach gas is released into the
polymers--e.g. because reaction in the strongly acidic stomach
causes gas release or because a liquid gasifies at body
temperature--and this maintains the system's buoyancy. Such methods
are described, e.g., in U.S. Pat. Nos. 3,901,232, 3,944,064,
4,996,058, 5,651,985 and German Offenlegungsschrift (DE-A) No.
3,527,852; each of which is incorporated herein by reference in its
entirety. The very same material that swells can also be one that
slowly erodes, thus delivering a controlled release system.
[0091] In non-effervescent systems a high level of gel-forming,
highly swellable, cellulosic hydrocolloids, polysaccharides, or
matrix-forming polymers are used. When they reach the stomach the
compounds "hydrate and form a colloidal gel barrier that controls
the rate of fluid penetration into the device and consequent drug
release." The trapped air confers buoyancy. As the exterior of the
drug delivery device dissolves, the interior swells, thus
maintaining the buoyancy. The slow erosion can also be used to
deliver a controlled release of the drug. Hydrophilic polymers that
swell upon intake of water from gastric fluids have been previously
described, for example, U.S. Pat. Nos. 6,723,340, 6,488,962,
6,340,475 and 6,635,280; each of which is incorporated herein by
reference in its entirety. These patents disclose systems wherein
the dosage form swells to a size large enough that it remains in
the stomach because it cannot pass through the pyloric sphincter
when the sphincter is contracted, such as in the fed mode. As a
result, the dosage remains in the stomach for at least four hours.
These formulations may be designed to produce desired release and
delivery profiles for both highly soluble and poorly soluble
drugs.
[0092] The second system is a bio/mucoadhesive system, which works
by using a substance that binds to the gastric mucosa (either to
mucous cell membranes or to the mucus secreted by them), thus
increasing the system's residence in the stomach. Bioadhesive
polymers bind either to the membranes; mucoadhesive polymers bind
to the mucus lining.
[0093] In some embodiments, the characteristics of these polymers
are, for example, molecular flexibility, hydrophilic functional
groups, and specific molecular weight, chain length, and
conformation. Furthermore, in some embodiments, they can be
nontoxic and nonabsorbable, can form noncovalent bonds with the
mucin-epithelial surfaces, can have quick adherence to moist
surfaces, can easily incorporate the drug and offer no hindrance to
drug release, and have a specific site of attachment, for
example.
[0094] There are three broad categories of bio/mucoadhesive
systems: hydration-mediated adhesion, bonding-mediated adhesion and
receptor-mediated adhesion.
[0095] In hydration-mediated adhesion, the binding substance is a
swellable polymer that absorbs large amounts of water and therefore
becomes sticky. Bonding-mediated adhesion is achieved either
through physical or chemical binding. In physical binding the
adhesive material inserts into crevices or folds of the mucosa. In
chemical bonding the binding substance forms chemical bonds (either
covalent, ionic, or hydrogen bonds or van der Waals interactions).
Finally, in receptor mediated adhesion the binding substance
directly binds to specific receptor cells in the mucus or the
gastrointestinal tract. For instance, certain plant lectins bind
sugar groups present in the mucus or on the glycocalyx. These can
be combined with ion exchange resins. (Burton S; Washington N;
Steele R J C; Musson R; Feely L, J. Phar. Pharm. 47, 901; which is
incorporated herein by reference in its entirety.)
[0096] A third method to obtain gastroretentive drug dosage systems
is to use a swelling/expanding system where the dosage form swells
so that it cannot pass through the pylorus, and is consequently
stuck in the stomach. The swelling can be obtained by using a
polymer that swells when in contact with water, but that has
crosslinks in the hydrophilic polymer network to prevent the dosage
form from coming apart and dissolving. A balance between the extent
and the duration of the swelling is achieved by selecting the
amount of cross linking. If there are many crosslinks, the system
will swell poorly but last for a long time. Conversely, if there
are few crosslinks, the system will swell will but will dissolve
more rapidly. Eventually, the system will dissolve either because
of interactions with the gastric juice or because of abrasion with
other particles in the stomach. Such swelling mechanisms are
described, e.g., in U.S. Pat. Nos. 3,574,820, 4,207,890, 4,434,153,
4,767,727, 4,735,804, 4,758,436, 5,002,772, 5,047,464, 5,217,712,
5,443,843, 5,651,985, 6,685,962, 7,736,667, 7,976,870 and German
Pat. No. 2,328,580; each of which is incorporated herein by
reference in its entirety. A similar approach is suggested by U.S.
Pat. App. 2005/0249798, now abandoned, and U.S. Pat. Apps.
2009/0304753 and 20090304768; each of which is incorporated herein
by reference in its entirety; wherein the drug device is a folded
sheet that unfolds (in some embodiments like an opening accordion)
when it swells. The very same material that swells can also be one
that slowly erodes, thus delivering a controlled release system if
the drug is distributed throughout the pill.
[0097] A fourth approach is to use a high density dosage form where
the drug dosage form sinks to the bottom of the stomach and is
entrapped in the stomach folds, thus allowing it to withstand the
peristaltic waves of the stomach wall. Examples of high density
components that are added to obtain high density drug dosage forms
are barium sulphate, zinc oxide, iron powder, and titanium
dioxide.
[0098] The final approach is a magnetic system. The drug is
administered with a small internal magnet or magnetizable element.
An external magnet is placed over the stomach thus preventing the
drug dosage form from travelling past the stomach.
[0099] Using one of these methods for achieving gastric retention
of the drug delivery system, it next can be necessary to achieve
controlled release of the active pharmaceutical ingredient. There
are a number of potential methods; these are reviewed in the
monograph Wen H, Park, K Oral Controlled Release Formulation Design
and Drug Delivery: Theory to Practice, which is incorporated herein
by reference in its entirety.
[0100] The first method is to use dissolution-controlled
formulations. One approach is the encapsulated dissolution system
where a system comprised of many small beads is coated with a
dissolvable material, such as a polymer. The beads are of varying
thickness, so that the outer layers of the various beads dissolve
at different times (because of the different thicknesses among the
beads). The beads can be compressed into tablets or filled into
capsules. Alternatively, a matrix dissolution system can be used,
wherein the drug is homogenously distributed throughout the polymer
matrix. As the polymer dissolves, the drug trapped in that part of
the polymer is released.
[0101] The second method is diffusion-controlled formulations,
where the drug has to diffuse through a polymer membrane or matrix
to be released. The first approach to diffusion-controlled
formulations is a reservoir system, wherein the drug is surrounded
by a polymer membrane. Alternatively, a monolithic system can be
used, wherein the drug is distributed through the polymer
matrix.
[0102] A third method is osmosis-based formulations, wherein the
drug is surrounded with a semi permeable membrane, such as
cellulose acetate, with at least one small orifice. Only water can
diffuse through the membrane, so the concentration of water in the
dosage form increases and the drug, dissolved in the water, seeps
out of the orifice at a controlled rate.
[0103] A fourth method is ion exchange-based formulations, wherein
the drug is ionically bound to an ion-exchange resin that is
water-insoluble. The drug is released when other ions with the same
charge bind the resin. Finally, some of these methods can be
combined. For instance, it is possible to cover an ion-exchange
resin with a diffusion controlled formulation.
[0104] The PK of acamprosate delivered by any of these formulations
can be expected to be similar to that produced by the
administration of IR capsules containing a fraction of the total
dose, on a periodic basis at intervals of 30 minutes or less. Thus,
the procedure used in the dog PK study reported herein can be a
model for the PK to be obtained from any of the formulations
described here.
[0105] Acamprosate delivered by a GR system can be efficacious for
treating tardive dyskinesia and other neuropsychiatric indications
if it is given at a dose sufficient to give blood concentrations
greater than or equal than those produced by an effective dose of
the currently-marketed enteric-coated preparation. A dose and
dosing schedule cannot be assumed a priori to be efficacious if it
does not produce equal or greater concentrations.
[0106] Two clinical cases demonstrate that the efficacy of
acamprosate for its neuropsychiatric indications can depend on
having an adequate blood level of the drug for substantially less
than 24 hours a day. As such, GR preparations of acamprosate
capable of maintaining a blood level above a target concentration
for 8 hours a day can be effective given once or at most twice a
day. Now, the AUC for IR acamprosate in humans is twice the AUC for
the currently-marked enteric-coated acamprosate utilized in the
cases described in previous patents on neuropsychiatric uses of
acamprosate, and the AUC for the same dose of GR acamprosate can be
at least as high as that--and perhaps higher in some cases, as
shown in the dog study PK study described herein conducted by the
inventors. The case shows that if an effective dose of acamprosate
is divided into three equal parts, then one or two of those parts
will suffice to treat the disorder if they are formulated as a GR
controlled-release system that deliver the dose over eight hours in
a manner that produces an essentially flat time-concentration
curve. If so, less than one-third of the dose given using the
currently-marketed enteric-coated version can have the same
efficacy. The dosage range specified to date for treating
neuropsychiatric disorders with enteric-coated acamprosate is 1 to
2.6 grams. The above considerations show efficacy with a daily dose
of GR acamprosate of less than 1 gram per day given on a once or
twice per day basis. An efficacious dose can potentially be as low
as 100 mg once a day, if in a given case 1 gram per day of the
enteric-coated formulation is efficacious and a single daily dose
of the GR formulation that was 1/3 of the total daily dose was
efficacious, and overall bioavailability of the GR formulation was
40% higher than with an IR formulation (a number within the range
suggested by the dog study reported herein.
[0107] Any of the foregoing mixtures and compositions can be
appropriate in treatments and therapies in accordance with the
invention disclosed herein, provided that the active ingredient in
the formulation is not inactivated by the formulation and the
formulation is physiologically compatible and tolerable with the
route of administration. See also Baldrick P. "Pharmaceutical
excipient development: the need for preclinical guidance." Regul.
Toxicol. Pharmacol. 32(2):210-8 (2000), Charman W N "Lipids,
lipophilic drugs, and oral drug delivery-some emerging concepts." J
Pharm Sci 89(8):967-78 (2000), and the citations therein for
additional information related to formulations, excipients and
carriers well known to pharmaceutical chemists.
[0108] As noted herein the formulations can include various
materials. Among such materials are fillers. In some embodiments,
the compositions can include one or more fillers, for example,
microcrystalline cellulose, lactose, a compressible sugar, xylitol,
sorbitol, mannitol, pregelatinized starch, maltodextrin, calcium
phosphate dibasic, calcium phosphate tribasic, calcium carbonate
DC, a calcium silicate, a combinations of one or more of the same,
or the like. In one aspect of this embodiment, the at least one
filler can be microcrystalline cellulose. The microcrystalline
cellulose (other filler or combination of fillers) can be provided
in an amount of about 8% to about 90% w/w. The precise amount can
depend upon the amount of the acamprosate and/or the amounts of
other excipients or materials, for example. The compositions can
further comprise at least one of the following second fillers,
lactose, compressible sugars, xylitol, sorbitol, mannitol,
pregelatinized starch, maltodextrin, calcium phosphate dibasic,
calcium phosphate tribasic, calcium carbonate DC, a combinations of
one or more of the same, or the like.
[0109] Any other suitable excipient(s) may be used in the
formulation. For example, excipients suitable for use include, but
are not limited to, binders, diluents, disintegrants, lubricants,
fillers, carriers, and the like.
[0110] In one embodiment, the formulation comprises a mixture of
the acamprosate in a gastric retentive and/or controlled release
formulation. Such formulations can include any of the substances
described herein, and additional processing aides, such as, for
example, magnesium stearate and colloidal silicon dioxide, and
optionally, colorant(s). For example, in some embodiments,
colloidal silicon dioxide, may be added separately to the
formulation as a glidant. Without being limited thereto, colloidal
silicon dioxide can be added at concentrations ranging from about
0.1% to about 5.0% w/w, or from about 0.25% to about 2% w/w, or
from about 0.5% to about 1% w/w.
[0111] In some embodiments, magnesium stearate can be added as a
lubricant, for example, to improve powder flow, prevent the blend
from adhering to tableting equipment and punch surfaces and provide
lubrication to allow tablets to be cleanly ejected from tablet
dies. Magnesium stearate can typically be added to pharmaceutical
formulations at concentrations ranging from about 0.1% to about
5.0% w/w, or from about 0.25% to about 2% w/w, or from about 0.5%
to about 1.25% w/w.
[0112] In some embodiments, color additives also can be included.
The colorants can be used in amounts sufficient to distinguish
dosage form strengths. Preferably, color additives approved for use
in drugs (21 CFR 74, which is incorporated herein by reference in
its entirety) are added to the commercial formulations to
differentiate tablet strengths. The use of other pharmaceutically
acceptable colorants and combinations thereof are encompassed by
the current invention.
[0113] Binders can be used, for example, to impart cohesive
qualities to a formulation, and thus ensure that the resulting
dosage form remains intact after compaction. Suitable binder
materials include, but are not limited to, microcrystalline
cellulose, gelatin, sugars (including, for example, sucrose,
glucose, dextrose and maltodextrin), polyethylene glycol, waxes,
natural and synthetic gums, polyvinylpyrrolidone, cellulosic
polymers (including, for example, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, methyl cellulose, hydroxyethyl
cellulose, and the like).
[0114] One of ordinary skill in the art would recognize additional
binders and/or amounts that can be used in the formulations
described herein. As would be recognized by one of ordinary skill
in the art, when incorporated into the formulations disclosed
herein, the amounts of the major filler(s) and/or other excipients
can be reduced accordingly to accommodate the amount of binder
added in order to keep the overall unit weight of the tablet
unchanged. In one embodiment, the binder(s) is (are) sprayed on
from solution, e.g. wet granulation, to increase binding
activity.
[0115] Disintegrants can be used, for example, to facilitate tablet
disintegration after administration, and are generally starches,
clays, celluloses, algins, gums or crosslinked polymers. Suitable
disintegrants include, but are not limited to, crosslinked
polyvinylpyrrolidone (PVP-XL), sodium starch glycolate, and
croscarmellose sodium. If desired, the pharmaceutical formulation
can also contain minor amounts of nontoxic auxiliary substances
such as wetting or emulsifying agents, pH buffering agents and the
like, for example, sodium acetate, sorbitan monolaurate,
triethanolamine sodium acetate, triethanolamine oleate, sodium
lauryl sulfate, dioctyl sodium sulfosuccinate, polyoxyethylene
sorbitan fatty acid esters, etc. and the like. One of ordinary
skill in the art would recognize additional disintegrants and/or
amounts of disintegrants that can be used in the formulations
described herein. As would be recognized by one of ordinary skill
in the art, when incorporated into the formulations disclosed
herein, the amounts of the major filler(s) and/or other excipients
can be reduced accordingly to accommodate the amount of
disintegrant added in order to keep the overall unit weight of the
tablet unchanged.
[0116] In some embodiments, the formulations can include a coating,
for example, a film coating. Where film coatings are involved,
coating preparations can include, for example, a film-forming
polymer, a plasticizer, or the like. Also, the coatings can include
pigments and/or opacifiers. Non-limiting examples of film-forming
polymers include hydroxypropyl methylcellulose, hydroxypropyl
cellulose, methylcellulose, polyvinyl pyrrolidine, and starches.
Non-limiting examples of plasticizers include polyethylene glycol,
tributyl citrate, dibutyl sebecate, castor oil, and acetylated
monoglyceride. Furthermore, non-limiting examples of pigments and
opacifiers include iron oxides of various colors, lake dyes of many
colors, titanium dioxide, and the like.
[0117] One can also prepare or administer the compounds of the
invention in sustained-release forms or from sustained-release drug
delivery systems. A description of representative sustained release
materials can be found in the incorporated materials in Remington:
The Science and Practice of Pharmacy (20.sup.th ed, Lippincott
Williams & Wilkens Publishers (2003)), which is incorporated
herein by reference in its entirety.
[0118] A variety of techniques for formulation and administration
can be found in Remington: The Science and Practice of Pharmacy
(20.sup.th ed, Lippincott Williams & Wilkens Publishers
(2003)), which is incorporated herein by reference in its
entirety.
[0119] As mentioned above, the compositions and formulations
disclosed herein also can include one or more
pharmaceutically-acceptable carrier materials or excipients. Such
compositions can be prepared for storage and for subsequent
administration. Any acceptable carriers or diluents for therapeutic
use can be used, including those described, for example, in the
incorporated material of Remington: The Science and Practice of
Pharmacy (2003), which is incorporated herein by reference in its
entirety. The term "carrier" material or "excipient" herein can
mean any substance, not itself a therapeutic agent, used as a
carrier and/or diluent and/or adjuvant, or vehicle for delivery of
a therapeutic agent to a subject or added to a pharmaceutical
composition to improve its handling or storage properties or to
permit or facilitate formation of a dose unit of the composition
into a discrete article such as a capsule or tablet suitable for
oral administration. Excipients can include, by way of illustration
and not limitation, diluents, disintegrants, binding agents,
adhesives, wetting agents, polymers, lubricants, glidants,
substances added to mask or counteract a disagreeable taste or
odor, flavors, dyes, fragrances, and substances added to improve
appearance of the composition. Acceptable excipients include
lactose, sucrose, starch powder, maize starch or derivatives
thereof, cellulose esters of alkanoic acids, cellulose alkyl
esters, talc, stearic acid, magnesium stearate, magnesium oxide,
sodium and calcium salts of phosphoric and sulfuric acids, gelatin,
acacia gum, sodium alginate, polyvinyl-pyrrolidone, and/or
polyvinyl alcohol, saline, dextrose, mannitol, lactose, lecithin,
albumin, sodium glutamate, cysteine hydrochloride, and the like.
Examples of suitable excipients for soft gelatin capsules include
vegetable oils, waxes, fats, and semisolid and liquid polyols.
Suitable excipients for the preparation of solutions and syrups
include, without limitation, water, polyols, sucrose, invert sugar
and glucose. Suitable excipients for injectable solutions include,
without limitation, water, alcohols, polyols, glycerol, and
vegetable oils. The pharmaceutical compositions can additionally
include preservatives, solubilizers, stabilizers, wetting agents,
emulsifiers, sweeteners, colorants, flavorings, buffers, coating
agents, or antioxidants. Sterile compositions for injection can be
formulated according to conventional pharmaceutical practice as
described in the incorporated material in Remington: The Science
and Practice of Pharmacy (2003). For example, dissolution or
suspension of the active compound in a vehicle such as water or
naturally occurring vegetable oil like sesame, peanut, or
cottonseed oil or a synthetic fatty vehicle like ethyl oleate or
the like may be desired. Buffers, preservatives, antioxidants and
the like can be incorporated according to accepted pharmaceutical
practice. The compound can also be made in microencapsulated form.
In addition, if desired, the injectable pharmaceutical compositions
may contain minor amounts of nontoxic auxiliary substances, such as
wetting agents, pH buffering agents, and the like. If desired,
absorption enhancing preparations (for example, liposomes), can be
utilized.
Enhancement of Gastric Retention Using Fed Mode Inducing Agent
[0120] Gastric retentive drug delivery systems can have improved
function when the patient is in the fed mode, when the stomach does
not produce the intense peristaltic contractions of Phase III of
the Migrating Motor Complex (MMC). However, food can diminish the
bioavailability of acamprosate by approximately 30%. Without
intending to be bound by theory, although the mechanism of the food
effect on acamprosate bioavailability is unknown, it is likely to
be related to competition for a passive transport mechanism of
limited capacity. The inventors have determined that for even more
optimal pharmacokinetics and bioavailability of acamprosate, the
fed mode can be induced affecting the MMC without interfering with
the absorption of acamprosate in the way that a full meal
would.
[0121] Accordingly, in some embodiments, an agent is
co-administered with acamprosate to induce a "fed mode" in the
stomach, inhibiting contractions of the MMC and increasing gastric
retention time. In some embodiments, the fed mode inducing agent is
any suitable fed mode inducing agent, including without being
limited thereto any of those described in U.S. Pat. No. 7,405,238,
the content of which is incorporated herein by reference in its
entirety. For example, the fed mode inducing agent can be an agent
selected from the group consisting of one or more of: (a) glycine,
glycylglycine, and salts of either of these two compounds (b) C4-C8
sugar alcohols (c) alkali and alkaline earth metal docusates (d)
beta-casomorphins (e) dithioorganic acids such as alpha-lipoic acid
(racemic mixtures, enantiomers such as the R enantiomer, or
enriched enantiomeric mixtures). In typical embodiments, the fed
mode inducing agent is alpha-lipoic acid, for example. In some
embodiments, alpha-lipoic acid can be administered in a dosage of
about 40 mg to 700 mg or any value or sub range there between. For
example, 40, 50, 60, 70, 80, 90, 100, 120, 130, 140, 150, 160, 170,
180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300,
310, 320, 330, 340, 350, 360, 370, 380 390, 400, 450, 500, 550 to
about 600 mg, or any value or sub range there between. In some
aspects, the alpha-lipoic acid is in a dosage of from about 100 to
about 300 mg, for example, or any value or sub range there between.
In some aspects, the alpha-lipoic acid is given in its racemic
form; in other aspects it is given as its R enantiomer. In some
aspects, the alpha-lipoic acid is included in a gastric-retentive
composition. In some aspects, the alpha-lipoic acid is at least
partially in the coating of the gastric-retentive system. In some
aspects, the alpha-lipoic acid is incorporated into a
gastric-retentive system. In some aspects, the gastric-retentive
system is designed to release the alpha-lipoic acid within a
desired period of time, for example, the first hour after ingestion
or any time period within the first hour, for example. In some
aspects, alpha-lipoic acid is included in combination with
acamprosate, for example, acamprosate in a dose of less than 1 gram
(e.g., of 100 to 700 mg), or any value or sub range there between.
In some aspects, alpha-lipoic acid is included in combination with
acamprosate and further in combination with a neuroleptic
(antipsychotic) drug. In some aspects, alpha-lipoic acid is
included in combination with acamprosate and a serotonin reuptake
inhibitor drug (SSRI or SNRI).
[0122] As exemplified in EXAMPLE 10 below, and as taught in the
incorporated materials of U.S. Pat. No. 7,405,238, any suitable fed
mode inducing agent can be utilized as an immediate-release coating
of a gastric-retentive tablet. While not intending to be bound by
theory, it is believed that when a fed mode inducing agent such as
alpha-lipoic acid is incorporated into an immediate-release coating
of a gastric-retentive tablet containing acamprosate, almost all of
the alpha-lipoic acid would pass through the duodenum hours before
most of the acamprosate would reach the duodenum; therefore it
would be expected that little or no reduction in acamprosate
bioavailability would occur, even if alpha-lipoic acid and
acamprosate potentially compete for the same limited-capacity
passive transport system. (In fact it is not known whether there is
a common transporter.).
[0123] A dosage of alpha-lipoic acid in the range of about 40 mg to
about 600 mg, about 60 mg to about 500 mg, about 80 mg to about 400
mg, or about 100 to about 300 mg (or any value or sub range there
between any of those ranges and values) can be suitable when used
as an immediate release component of a gastric retentive
acamprosate tablet. For example, when alpha-lipoic is incorporated
as a coating for the tablet, such a formulation can allow the
patient to enjoy the pharmacokinetic benefits of GR acamprosate
while taking the pill on an empty stomach.
[0124] As a non-limiting example, a GR acamprosate tablet can
contain 350 mg of acamprosate in a swellable matrix, coated with
mixture of inert ingredients and 150 mg of R-alpha-lipoic acid. Two
such tablets taken, for example, once a day can provide the same
therapeutic benefit as two to three grams of enteric-coated
acamprosate tablets (6 to 9 pills, taken on a thrice-daily
schedule), in the treatment tardive dyskinesia or other
neuropsychiatric disorders. The two pills could be taken at bedtime
or on awakening; thus the patient would take the medication, for
example, once daily, at home. This schedule can greatly enhance
convenience and treatment adherence.
[0125] For example, in the case of alcoholism treatment, strict
compliance with treatment can be especially critical. Thus, the
instant methods and compositions, which can provide greater
convenience, ease of use, and compliance can result in better
treatment for such patients. In fact, some embodiments of the
technology described herein relate to methods and compositions for
the treatment of alcohol dependence. The acamprosate can be
formulated as set forth herein in a dosage as set forth herein. For
example, the dosage can be up to 2-3 grams per day, but in some
embodiments when formulated as described herein, it can be less
than one gram per day, for example 40-700 mg or any subvalue or sub
range therein. The improved adherence and/or convenience can be
true and applicable for other conditions regardless of whether
compliance is as important as in the case of treating alcohol
dependence. The fact that the methods and compositions can provide
improved convenience and compliance can be beneficial to many
conditions that can be treated with acamprosate.
[0126] Other nutrients and drugs, including many described in the
specification for U.S. Pat. No. 7,405,238 (incorporated herein in
its entirety), can be used in place of alpha-lipoic acid. In
particular embodiments, alpha-lipoic acid is used as the fed mode
inducing agent. For example, alpha-lipoic acid is very safe.
Second, the metabolic effects of alpha-lipoic acid can be of
specific benefit in mitigating the side effects of antipsychotic
drugs. Alpha-lipoic acid is an antioxidant, and oxidative stress is
one of the mechanisms of neuroleptic-induced cellular damage to the
basal ganglia that can cause TD. Additionally, alpha-lipoic acid
has hypoglycemic actions that can mitigate the potential adverse
effects of neuroleptics on glucose metabolism.
EXAMPLES
Example 1
[0127] Case 1: A 56-year old woman had long-standing tardive
dyskinesia induced by treatment of schizoaffective disorder with a
variety of neuroleptics and mood stabilizers. Her TD was
characterized by side to side movements of the jaw, grimacing
movements, rocking of the trunk, and continual involuntary kicking,
leg-crossing, and twisting movements of her legs and feet. At the
time she presented for treatment of her TD she was treated for her
mental illness with lamotrigine and quetiapine, a second-generation
neuroleptic. She was started on acamprosate 666 mg three times a
day, with partial relief of symptoms. When acamprosate was
increased to 999 mg three times a day she had complete relief of
her TD. After two months free of symptoms of TD she switched from
quetiapine to perphenazine, a first-generation neuroleptic; her TD
symptoms did not return.
[0128] After additional weeks free of TD symptoms she discontinued
the acamprosate. Her TD symptoms returned, as did feelings of
anxiety and agitation that had not been present while she was on
the combination of acamprosate and perphenazine.
[0129] She resumed acamprosate, again finding that 666 mg three
times a day did not give her complete relief, but 999 mg three
times a day did. On this dose she again got relief of anxiety and
agitation.
[0130] To test the hypothesis that the efficacy of acamprosate was
related to adequate time above a threshold blood level the patient
was asked to try taking 1332 mg of acamprosate once a day. On this
dose she continued to be free of involuntary movements of TD, but
did have significant GI side effects of diarrhea and abdominal
cramps.
[0131] The results showed efficacy of acamprosate for TD at a lower
total daily dose, when instead of distributing the dose evenly, a
larger proportion of the dose was given at one time. This
demonstrates that the use of acamprosate at a concentration above a
therapeutic threshold value for a sufficient number of hours per
24-hour day (e.g., 6-14 hours, preferably about 8) is sufficient to
give a 24-hour therapeutic effect.
Example 2
[0132] CASE 2: A 34-year old man had been treated with acamprosate
for several years for TD due to exposure to several neuroleptics
for schizoaffective disorder. He was currently treated with
lamotrigine and quetiapine for his mental illness, and was taking
acamprosate 1032 mg+999 mg+1032 mg on a three times daily basis.
This dose of acamprosate completely relieved his involuntary
movements of TD--the latter including involuntary movements of the
cheeks and mouth, rocking movements of the trunk, and twisting
movements of the both upper and lower extremities. 999 mg three
times a day did not give full relief from his involuntary
movements. To test the therapeutic threshold hypothesis the patient
was asked to try 1032 mg of acamprosate once a day in the morning.
On this dose he was free of movements in the morning and early
afternoon but movements returned in the evening. When he added a
second dose of 1032 mg in the late afternoon--8 to 10 hours after
his first dose--he obtained complete relief of symptoms. He noted
that when he got relief of his involuntary movements he also had
less anxiety and agitation than when the movements were
present.
[0133] Both of these cases support two hypotheses: 1) That the
treatment response to acamprosate in TD (and presumably in other
neuropsychiatric disorders characterized by recurrent unwanted
stereotypic symptoms) is related to the amount of time the
acamprosate level is above a specific threshold, and not on the AUC
of the PK curve. This is so because in both cases the patient did
better on regimens that had a lower total daily dose of acamprosate
but higher individual doses. This is unexpected, because it has not
been known heretofore that lower total daily doses of acamprosate
could work better than higher ones if the former were given once or
twice a day and the latter were given three times a day. (2) That
the combination of acamprosate with a neuroleptic can provide
relief of anxiety and agitation associated with psychosis and TD.
This is unexpected, because though acamprosate by itself does not
have anti-anxiety effects.
[0134] Combining the results from the dog study with the
implications of the reported cases we can infer that acamprosate
delivered by a GR system can relieve symptoms of TD and other
neuropsychiatric disorders given once or twice a day. Considering
the fact that the AUC from a single dose of acamprosate via a GR
system can be more than twice the AUC from a single dose of the
existing enteric-coated tablet formulation of acamprosate it
appears that a total daily dose of less than one gram of GR
acamprosate, given on either a once or twice a day basis would be
adequate to treat TD in the case examples. Therefore in some
cases--probably the majority of cases--of TD cases the minimum
effective daily dose of acamprosate delivered by a GR controlled
release system can be less than 1 gram--the minimum of the range of
efficacious dosages reported heretofore for the enteric-coated
formulation. It should be noted further that experience to date
with the enteric-coated tablets has never shown them to fully
relieve the symptoms of TD at doses of 1 gram, whereas here in some
embodiments daily doses of less than 1 gram can offer complete
symptom relief and not just a detectable therapeutic effect.
Example 3
[0135] A pharmacokinetic study was conducted in four dogs. Dogs
were given immediate-release (IR) acamprosate capsules orally. On
one day they were given a single capsule containing 325 mg of
acamprosate. On another day one week later the dogs were given 325
mg of acamprosate divided into smaller doses administered every 30
minutes, as shown in Table 1 below.
[0136] This mode of delivering acamprosate mimics the delivery of
acamprosate into the stomach by a controlled-release GR system.
FIGS. 1-4 are time-concentration curves for each of the dogs that
compare IR acamprosate with simulated GR controlled-release
acamprosate.
[0137] Table 2 shows pharmacokinetic parameters of the two delivery
versions of acamprosate in each of the four dogs and displays
ratios of interest between the two versions for several parameters
of interest. In the table the residence time above two arbitrarily
selected thresholds--2000 ng/mL and 3000 ng/mL was calculated by
measuring the graphs; an asterisk next to the residence time
indicates that the residence time comprised two discrete segments
rather than a single contiguous period. The AUC was always greater
for the simulated GR system, though the difference in two of the
four dogs would be clinically insignificant. In one case the
difference was more than twofold. These differences in a small
sample are in accord with the well-known variability of acamprosate
absorption between individuals. The C.sub.max was always
significantly lower for the simulated GR system even when the AUC
was significantly higher. The residence time above either of the
two thresholds was significantly higher for the GR system.
TABLE-US-00001 TABLE 1 SIMULATION OF A GATRORETENTIVE CONTROLLED
RELEASE SYSTEM BY HALF-HOURLY ADMINISTRATION OF IMMEDIATE RELEASE
ACAMPROSATE Acamprosate Time (h) Dosage (mg) 0.0 81.2 0.5 33.6 1.0
25.8 1.5 21.8 2.0 19.2 2.5 17.3 3.0 15.9 3.5 14.8 4.0 13.9 4.5 13.2
5.0 12.5 5.5 12.0 6.0 11.5 6.5 11.1 7.0 10.7 7.5 10.3 Total dose
324.8
TABLE-US-00002 TABLE 2 SELECTED PK PARAMETERS FROM DOG STUDY OF IR
VERSUS GR CONTROLLED-RELEASE ACAMPROSATE Hours over Hours over
Treatment Dog N Tmax (h) Cmax (ng/mL) AUClast (h * ng/mL) AUCinf (h
* ng/mL) Cmax/AU 3000 ng/mL 2000 ng/mL IR 1 1 7380 31939 34283 23%
2.6 3.5 IR 2 1 7150 31829 41542 22% 2.4 2.9 IR 3 1 7550 35345 35739
21% 1.8 2.6 IR 4 1 4920 15929 16029 31% 1.8 2.6 GR-CR 1 5 4620
35185 35320 13% 5.3 7.9 GR-CR 2 8 5140 44221 46714 12% 6.8 9.7
GR-CR 3 6 4510 39182 43682 12% 4.4 6.8 GR-CR 4 6 3290 32243 32806
10% 2.6 8.8 GR/IR 1 63% 110% 103% 200% 225% GR/IR 2 72% 139% 112%
288% 330% GR/IR 3 60% 111% 122% 250% 256% GR/IR 4 67% 202% 205%
150% 333% Peak Ratios Biovailability Ratios Residence Time Ratios
indicates data missing or illegible when filed
Example 4
[0138] Table 3 lists gastroretentive (GR) technologies capable of
delivering acamprosate so as to give a nearly constant level of the
drug for four hours or more. Table 4 lists examples of
controlled-release technologies that can be applied in conjunction
with the gastroretentive technologies to produce the formulations
utilized in embodiments described herein.
TABLE-US-00003 TABLE 3 GASTRORETENTIVE TECHNOLOGIES. 1) Floating -
non-effervescent 2) Floating - effervescent 3) Bioadhesive 4)
Mucoadhesive 5) Swelling 6) Expanding 7) Magnetic
TABLE-US-00004 TABLE 4 CONTROLLED-RELEASE TECHNOLOGIES. 1) Matrix
2) Coated beads 3) Osmotic 4) Ion exchange
Example 5
[0139] Composition of gastric retentive formulation of acamprosate
calcium. The tablets swell when they come in contact with gastric
juices; they are retained in the stomach for several hours if they
are administered in the fed state (e.g., at the conclusion of a
meal). The formulation has been manufactured as 400 mg and 800 mg
tablets. These are standard round bi-convex white tablets with
beveled edges. Both tablet strengths are spray coated with
Opadry.RTM. II White (Colorcon, Inc.) for ease of swallowing.
Purified water is the vehicle for the Opadry; it evaporates during
the coating process. The total weight of the coating is between 2%
and 4% of the pre-coating weight.
[0140] The tablets prior to coating comprise the ingredients in the
following table:
TABLE-US-00005 TABLE 5 Amount Amount (mg) in 400 (mg) in 800
Ingredient Function mg tablet mg tablet Acamprosate calcium Active
400 800 ingredient Povidone K-90 Binder 50 50 Microcrystalline
cellulose Diluent 320 100 Colloidal silicon dioxide Glidant 10 10
Citric acid Acidulant 60 0 Carbopol 974P Polymer 60 60
Carboxymethylcellulose Polymer 40 40 Starcap 1500 Disintegrant 40
40 Talc powder Filler 10 10 Magnesium stearate Lubricant 10 10
Total prior to coating 1000 1120
Example 6
[0141] Dissolution profiles of the 400 mg and 800 mg GR acamprosate
tablets. 400 mg or 800 mg tablets were dissolved in either acetate
solution (pH 4.5) or 1N HCl (pH 1.0). The percentage of the active
ingredient released into the solution was determined at 1, 2, 4, 6,
8, and 10 hours. Each release profile was assessed in six different
test vessels. The following tables display the results,
demonstrating that release is approximately linear with the square
root of time. The fourth column in each table displays the amounts
of drug that would be released if the release were exactly
proportional to the square root of time, with a specified
coefficient that ranges from 0.27 to 0.3.
TABLE-US-00006 TABLE 6 Release of Acamprosate from 400 mg Tablets
of SNC-102 (Gastric Retentive Acamprosate formulation) in Acetate
Solution (pH 4.5) - (n = 6) Mean % of Total S.D. of % Drug 27% * of
Total Minimum Maximum Time SQRT Re- SQRT Drug % % (hours) Time
leased Time Released Released Released 0 0.0000 0.00 0.00 0.00 0 0
1 1.0000 24.09 27.00 1.40 23 27 2 1.4142 36.09 38.18 2.34 34 40 4
2.0000 54.39 54.00 4.02 49 60 6 2.4495 70.11 66.14 4.15 64 76 10
3.1623 87.67 85.38 4.21 83 95 12 3.4641 92.31 93.53 4.38 87 99
TABLE-US-00007 TABLE 7 Release of Acamprosate from 400 mg Tablets
of SNC-102 (Gastric Retentive Acamprosate formulation) in 0.1N HCl
(pH 1.0) - (n = 6) Mean % of Total S.D. of % Drug 27% * of Total
Minimum Maximum Time SQRT Re- SQRT Drug % % (hours) Time leased
Time Released Released Released 0 0.0000 0.00 0.00 0.00 0 0 1
1.0000 31.60 27.00 1.58 24 27 2 1.4142 44.83 38.18 3.20 36 41 4
2.0000 63.20 54.00 4.42 56 62 6 2.4495 75.27 66.14 5.42 69 74 10
3.1623 91.31 85.38 3.59 85 91 12 3.4641 95.99 93.53 2.96 90 96
TABLE-US-00008 TABLE 8 Release of Acamprosate from 800 mg Tablets
of SNC-102 (Gastric Retentive Acamprosate formulation) in Acetate
Solution (pH 4.5) - (n = 6) Mean % S.D. of % of Total 30% * of
Total Minimum Maximum SQRT Drug SQRT Drug % % Time Time Released
Time Released Released Released 0 0.0000 0.00 0.00 0.00 0 0 1
1.0000 31.60 30.00 1.58 29 34 2 1.4142 44.83 42.43 3.20 42 51 4
2.0000 63.20 60.00 4.42 58 64 6 2.4495 75.27 73.48 5.42 70 84 10
3.1623 91.31 94.87 3.59 87 97 12 3.4641 95.99 100.00 2.96 91
100
TABLE-US-00009 TABLE 9 Release of Acamprosate from 800 mg Tablets
of SNC-102 (Gastric Retentive Acamprosate formulation) in 0.1N HCl
(pH 1.0) - (n = 6) Mean % of Total S.D. of % Drug 29% * of Total
Minimum Maximum Time SQRT Re- SQRT Drug % % (hours) Time leased
Time Released Released Released 0 0.0000 0.00 0.00 0.00 0 0 1
1.0000 28.11 29.00 1.21 26 29 2 1.4142 41.56 41.01 1.77 40 44 4
2.0000 61.48 58.00 2.38 57 63 6 2.4495 75.41 71.04 1.61 73 77 10
3.1623 92.24 91.71 0.55 92 93 12 3.4641 96.62 100.00 0.65 96 97
Example 7
[0142] Combination of Reformulated Acamprosate with
First-Generation Neuroleptics
[0143] First-generation neuroleptic (antipsychotic drugs) have been
used for over 50 years in the treatment of schizophrenia and other
psychotic disorders, as well as in the treatment and prevention of
nausea and vomiting. The first of these drugs to be introduced to
the market was chlorpromazine; others include thioridazine,
perphenazine, trifluoperazine, haloperidol, fluphenazine, loxapine,
and molindone. Their common feature is that they are all dopamine
antagonists at both D2 and D3 dopamine receptors; each has its own
distinctive set of effects on receptors for other
neurotransmitters. One of the major drawbacks of these drugs is
their propensity to cause movement disorders. With acute
administration that can cause movement disorders including
parkinsonism (tremor, rigidity, bradykinesia and gait instability)
as well as dystonia, dyskinesia, and akathisia. Given chronically
they can cause chronic movement disorders that persist even if the
drug is stopped and may even be permanent. These disorders include
tardive dyskinesia (TD), tardive dystonia, and tardive akathisia.
The incidence of TD and other tardive movement disorders with
long-term use of first-generation neuroleptics exceeds 25%, with an
even higher rate in elderly patients. In part because of the very
high risk of TD, a second generation of neuroleptics was developed
that has a lower risk of causing TD and related movement disorders
with chronic administration. These drugs include risperidone,
quetiapine, clozapine, olanzapine, and aripiprazole. The incidence
of TD with these drugs is less than 5%, but all are associated with
metabolic side effects of sufficient severity to affect life
expectancy. These side effects include weight gain, glucose
intolerance, and disturbances in lipid metabolism. With the
exception of clozapine the second-generation neuroleptics are not
more effective in treating schizophrenia and other psychotic
disorders. Clozapine, while more effective as treatment for severe
mental illness, has additional serious medical side effects
including a significant incidence of agranulocytosis that requires
frequent monitoring of patients' white blood counts as a
requirement for using the drug. The first generation neuroleptics,
especially the higher-potency ones, have a much lower incidence of
metabolic side effects than the second-generation neuroleptics, and
some first generation neuroleptics, e.g., molindone, do not have
them at all.
[0144] If first generation neuroleptics could be given without a
high risk of causing or exacerbating tardive dyskinesia they would
be preferable to second-generation neuroleptics for treating most
patients with psychotic disorders as they would lack the
troublesome metabolic side effects of the latter. Some embodiments
herein relate to utilizing fixed-dose combinations of
first-generation neuroleptics with new formulations of acamprosate
designed for delayed release via a GR delivery system. Such
combinations would not have been practical heretofore because of
the high doses of acamprosate needed to treat TD if the existing
enteric-coated tablet formulation is used. Given the compliance
issues common among psychiatric patients a regimen of more than two
pills daily would risk diminished effectiveness. If significantly
more than a gram of acamprosate were needed to treat TD the
combination of an effective dose of acamprosate for TD with an
effective dose of a first-generation neuroleptic would need to be
divided among at least three pills, as a dose of enteric-coated
acamprosate significantly larger than 500 mg in a single pill might
require that pill to be unpleasantly large, even without the
addition of a second drug. The actual dosage of enteric-coated
acamprosate needed to treat TD might in fact be much higher--more
than 3 grams in some cases. On the other hand, if the needed dose
of different formulation of acamprosate needed were less than one
gram, treatment effective for both psychosis and TD could be
delivered by one or two combination pills. Such is the case with
the instant formulations described herein that provide for sub gram
dosages and formulations of acamprosate.
[0145] While it is not the case that drugs that prevent a disorder
will treat that disorder, it can be expected that that an effective
treatment will attenuate the severity of the disorder, if it does
not prevent it completely. In the two case examples, patients with
established TD and a mental disorder took acamprosate together with
a neuroleptic and had complete relief of their TD symptoms. Those
patients would also be free of TD symptoms if they took the same
combination without having TD at baseline. The incidence of TD will
be lower if a first generation neuroleptic is co-administered with
a dose of acamprosate that would be efficacious to treat
established TD in the majority of patients. If TD did develop in
some patients the severity would necessarily be less than if
acamprosate were not given.
[0146] Some embodiments therefore relate to among other things the
following two technologies: (1) Compositions containing a dose of a
first generation neuroleptic adequate to treat a psychotic disorder
and a dose of acamprosate adequate to treat tardive dyskinesia,
including compositions in which the doses of the neuroleptic and
the acamprosate are combined in a single pill, and compositions in
which the doses are divided into multiple units delivered
concurrently, e.g., one tablet of each drug in a single blister
pack; and (2) The use of such compositions to treat one or more of
schizophrenia, bipolar disorder, schizoaffective disorder,
depression with psychotic features, delusional disorder, other
psychotic conditions, the symptoms of hallucinations and delusions.
The compositions in some aspects further can treat or prevent the
symptoms of nausea and vomiting that often accompany the use of
such medications. In the described technologies the use may be in
patients with or without established TD.
[0147] It is surprising and unexpected that in some embodiments
doses of acamprosate lower than the heretofore-described dosing
range for treating TD can be effectively used, even though such
lower doses may not have the same PK profiles as the enteric-coated
pills utilized in previously-described treatment of TD--and such
lower doses can in some embodiments produce a 24-hour AUC lower
than that produced by similarly efficacious doses of enteric-coated
acamprosate. Further, we note the unexpected finding that patients
with TD and mental disorders who received acamprosate together with
a neuroleptic showed an unexpected improvement in anxiety and
agitation, even though acamprosate alone does not affect these
symptoms.
[0148] It should be evident that the specific technology for
formulating the GR delivery system for acamprosate does not matter;
any system that can maintain an nearly constant level of
acamprosate in the blood for four hours or more can be used.
[0149] Table 8 lists first-generation neuroleptic drugs and range
of daily dosages at which they are usually prescribed. Some
embodiments herein relate to tablets or capsules that implement one
of the GR technologies in Table 9 delivering a dosage of
acamprosate between 50 and 500 mg, together with a dose of one of
the drugs described in Table 8 at one of the dosages specified in
that table or a dosage of one-half of the minimum dose in the table
below, and up to the maximum dose or any value there between. As an
example, a tablet might comprise 4 mg of perphenazine together with
250 mg of acamprosate formulated in a swellable tablet, with the
perphenazine surrounding a core of acamprosate.
TABLE-US-00010 TABLE 10 FIRST GENERATION NEUROLEPTICS AND
METOCLOPRAMIDE: DAILY DOSAGES AND DOSES FOR FIXED-DOSE COMBINATION
PILLS. Daily Example Single Pill Dosages Dose in Combination with
Drug Range Acamprosate Thioridazine 10-200 10, 25, 50, 100
Chlorpromazine 25-200 25, 50, 100 Thiothixene 2-50 2, 5, 10, 25
Trifluoperazine 5-50 5, 10, 25 Fluphenazine 2-50 2, 5, 10, 25
Haloperidol 0.5-50.sup. 0.5, 1, 2, 5, 10, 20 Perphenazine 2-32 2,
4, 8, 16 Loxapine 10-100 1, 10, 25, 50 Molindone 10-200 10, 25, 50,
100 Metoclopramide 5-60 5, 10, 15
Example 8
Combination of Acamprosate with Second-Generation Neuroleptics
[0150] The dose of GR acamprosate can be between 100 mg and 800 mg.
The principle is that the minimum dose is approximately one-half of
the smallest currently-marketed dose of the drug. Examples of the
dosage ranges of some non-limiting examples of first-generation
neuroleptics are given in Table 10. Examples of dosage ranges for
some second-generation neuroleptics are shown in the following
Table 11. For example, the dosage for the neuroleptic can range
from one-half of the minimum dose in the table below, and up to the
maximum dose, or any value there between:
TABLE-US-00011 TABLE 11 Neuroleptic Minimum Dose Maximum Dose
aripiprazole 1 mg 30 mg asenapine 1 mg 10 mg iloperidone 1 mg 24 mg
lurasidone 10 mg 120 mg olanzapine 1 mg 20 mg paliperidone 1 mg 12
mg quetiapine 12.5 mg 400 mg risperidone 0.25 mg 4 mg ziprasidone
10 mg 80 mg
Example 9
Combination of Acamprosate with SSRI and SSRI Antidepressants
[0151] SSRIs and SNRIs are efficacious in OCD and PTSD, both
conditions that also can respond to treatment with acamprosate.
Also, SSRIs and SNRIs are used to treat depressive and anxiety
disorders in which recurrent, unwanted, stereotyped thoughts,
perceptions, and behavior may be part of the syndrome. Since
acamprosate and the serotonin reuptake inhibitors have different
mechanisms of action, their therapeutic effects on these disorders
can be synergistic. The fact that GR acamprosate can be efficacious
at a daily dose of less than one gram a day, on a once or twice
daily schedule, makes fixed-dose combinations of GR acamprosate
with an SSRI or SNRI feasible.
[0152] The dose of GR acamprosate can be between 100 mg and 800 mg.
Some embodiments relate to combinations where the minimum dose is
approximately one-half of the smallest currently-marketed dose of
the drug, for example one-half of the minimum dose in the table
below, and up to the maximum dose or any value there between.
TABLE-US-00012 TABLE 12 SSRI or SNRI Minimum Dose Maximum Dose
Citalopram 5 mg 40 mg Desvenlafaxine 25 mg 100 mg Duloxetine 5 mg
60 mg Escitalopram 2.5 mg 20 mg Fluoxetine 5 mg 40 mg Fluvoxamine
12.5 mg 100 mg Milnacipran 6.25 100 mg Paroxetine 5 mg 40 mg
Sertraline 12.5 mg 200 mg Venlafaxine 12.5 mg 150 mg
Example 10
Therapeutic Threshold
[0153] As noted herein, some embodiments relate to the novel and
unexpected discovery that daily dosages of less than 1 gram of
acamprosate can be formulated to effectively treat various
conditions and disorders. In particular, some embodiments relate to
formulations and dosage schedules that maintain the acamprosate
concentration or blood level above a threshold for a sufficient
time during each 24-hour period. Such formulations and schedules
can be efficacious even though the acamprosate concentration does
not exceed the threshold for the entire 24 hour period or even
though the concentration or levels of acamprosate are very
inconsistent (not at steady levels) during a given period of time
such as a 24 hour period.
[0154] According to some embodiments, there are at least a number
of parameters that can be adjusted to optimize clinical
effectiveness while still keeping the total daily dose of GR
acamprosate under 1 gram and limiting treatment to one or two pills
daily: once or twice a day dosage; controlled release time (from 4
to 8 hours or any value between); retention time in the stomach;
and dose of acamprosate (from 100 mg to 1000 mg). Those parameters
are not meant to be limiting.
[0155] The following helps illustrate the concept. In a 2010 study,
healthy volunteers were given 666 mg three times daily of enteric
coated acamprosate tablets (Hammarberg et al.: Acamprosate
Determinations in Plasma and Cerebrospinal Fluid After Multiple
Dosing Measured by Liquid Chromatography--Mass Spectroscopy: A
Pharmacokinetic Study in Healthy Volunteers. Ther Drug Monit 2010;
32:489-496). It took six days for steady state blood levels to be
attained, after which the average level fluctuated between 760
ng/mL and 915 ng/mL. By contrast, after a single dose of 666 mg,
the C.sub.max averaged 286 ng/mL. The authors note that the
concentrations they observed were higher than those reported by
other authors, citing for example a study of alcoholic patients who
had a mean steady state concentration of 380 ng/mL on the 666 mg
three times daily of the enteric coated formulation. It is likely
given the efficacy of the 666 mg tid dose in the majority of
patients, that the threshold steady state level for therapeutic
efficacy in alcoholism is less than 500 ng/mL.
[0156] The threshold blood level for therapeutic efficacy in
tardive dyskinesia (TD) and other neuropsychiatric disorders is
generally believed to be no higher than 1000 ng/mL and generally
not less than 300 ng/mL, as the doses used in the successful
treatment of TD by the inventor have been between 2 and 4 grams
daily.
[0157] In the dog study described herein, the subject animals
typically weighing around 10 kg received a simulated GR dose of 324
mg with release proportional to the square root of time over 8
hours--100% of the drug delivered 7.5 hours after the start of the
experiment. In this study the average time the concentration was
above 2000 ng/mL after 8.3 hours. In view of the--(1) linearity of
pharmacokinetics; (2) validity of extrapolating dosage on a mg/kg
basis; (3) validity of simulated GR as a predictor of the function
of an actual GR formulation; and (4) humans weighing 70 kg--the
concentration of acamprosate above a therapeutic threshold of 500
ng/mL could be attained for 8 hours with a dose of GR acamprosate
of (7*324)/4=567 mg.
[0158] While there can be inter-individual variability in body
weight and the precise pharmacokinetic profile, a blood level above
a therapeutic threshold for a human neuropsychiatric disorder can
be maintained for eight hours after a single dose of GR acamprosate
of less than one gram.
[0159] Thus, in some embodiments, a threshold value can an amount
of a 300 ng/mL to 1000 ng/mL (or any amount of sub range there
between) over a 4-8 hour period, preferable for about 5-7 hours,
more preferably for a period of about 6 hours. For example, the
threshold value that the acamprosate formulation can meet can be
about 500-600 ng/mL for about 6 hours.
[0160] Some embodiments relate to acamprosate formulations and uses
of the same where several hours of exposure--typically between 4
and 8 hours--to an adequate level of acamprosate can produce
therapeutic effects on CNS function lasting for hours after the
level of acamprosate falls--and often for the remainder of a 24
hour day. Thus, a single dose of GR acamprosate pill designed to
release the drug over a 4-8 hour period can be sufficient to give a
24 hour therapeutic effect. Controlled release technology also can
be utilized to ensure that a sufficient amount of acamprosate is
released and available during a given time so as to keep the
amount, concentration or level of acamprosate in the patient above
the threshold.
[0161] Gastric retention in the fed state typically lasts about 4
hours. Thus, at the lower end of the controlled release interval of
some embodiments of the technology (4 hours), the controlled
release can take place almost entirely within the stomach. At the
upper end of the interval the release can take place partly in the
duodenum and possibly the upper jejunum. This may entail a partial
loss of bioavailability, but only for the quantity of drug not yet
released after 4 or more hours, it will apply to less than 50% of
the total dose.
[0162] Those skilled in the art having the benefit of this
application will appreciate that for treating a specific
neuropsychiatric condition, the clinical response of a population
can be optimized by selecting twice a day rather than once a day
dosage, or by reducing the release time from 8 hours to 6 hours or
4 hours, for example. When a shorter exposure to the therapeutic
level of acamprosate suffices for persistent efficacy, individual
doses can be smaller, or, alternatively, the same dose can suffice
for treating a condition that might otherwise require a higher dose
if the release were over 8 hours, for example.
[0163] To attain the benefits of the GR formulation of acamprosate
described in some of the present embodiments, the specific
formulation preferably can release 90% or more of the acamprosate
within 8 hours. On the other hand, at least 50% of the acamprosate
is released within 3-4 hours, the typical time the pill (or other
dosage form) will remain in the stomach if it is administered in
the fed state. The latter criterion ensures that the GR preparation
will be more bioavailable than enteric-coated acamprosate, and that
it will approach the increased bioavailability seen with
immediate-release acamprosate delivered directly to the
stomach.
[0164] One of skill in the art also can titrate dosing to achieve a
maintenance above a therapeutic threshold for a given patient. For
example, a physician can titrate the dosage upward until a
concentration greater than 50% of C.sub.max for 4-8 hours,
preferably about 6 hours.
[0165] The fact that therapeutic efficacy can be achieved using
acamprosate formulations of less than 1 gram daily with once or
twice daily administration is surprising and unexpected. That is
particularly true where the pK curve caused by the formulation
maintains a steady concentration for only part of (generally for
only 4-8 hours) a 24 hour period.
Example 11
Induction of Fed Mode Using Alpha-Lipoic Acid
[0166] In this example, alpha-lipoic acid is incorporated into a
tablet for the purpose of increasing gastric retention time.
[0167] In a dog model, 125 mg of alpha-lipoic acid is administered
15 minutes before administration of swellable tablets containing
acamprosate and labeled with barium sulfate. The treatment is
performed largely as described in U.S. Pat. No. 7,405,238, the
content of which is incorporated herein by reference in its
entirety. The retention in the stomach of an 800 mg swellable
tablet of maximum dimension 19.05 mm in four beagle dogs (weight 6
kg to 10 kg) is compared with the retention of such a tablet in
either the fasting state or after a 50 gram meal. The results of
the test with alpha-lipoic acid are summarized in the following
table:
TABLE-US-00013 TABLE 13 Minimum gastric Average gastric Maximum
gastric retention time retention time retention time Condition
(hours) (hours) (hours) Fasting 0.5 0.9 1.7 After 125 mg 1.5 2.8 5
alpha-lipoic acid After 50 g meal 3 4.1 4.5
[0168] The data from this small sample of dogs support the notion
that alpha-lipoic acid can significantly influence gastric
retention time of an acamprosate-containing tablet, at dosages of
alpha-lipoic acid that are small enough to be practicably
incorporated into a tablet for consumption by a human patient, or
to be incorporated into a coating for such a tablet.
Example 12
Human Administration of Acamprosate and Alpha-Lipoic Acid
[0169] In this example, alpha-lipoic acid is utilized as an
immediate-release coating of a gastric-retentive tablet containing
acamprosate as its active pharmaceutical ingredient.
[0170] A patient suffering from TD receives an effective but
inconvenient treatment regimen of 3330 mg acamprosate daily, in the
form of 10 enteric-coated tablets divided into three doses taken
without food. This regimen is replaced by one of two tablets taken
each morning on awakening or alternatively at bedtime, in either
case on an empty stomach, each comprising 350 mg acamprosate in a
GR formulation coated with 150 mg of an immediate-release
formulation of R alpha-lipoic acid (it should be understood that
the use of "R" alpha lipoic is not to be limiting; racemic alpha
lipoic acid can also be used or any other form of the alpha lipoic
acid as well). Almost all of the R alpha-lipoic acid passes through
the duodenum before most of the acamprosate reaches the duodenum.
The patient experiences adequate relief of TD symptoms compared to
his normal regimen of enteric coated acamprosate (i.e., without
gastric retentive formulation), and greatly improved convenience
and treatment regimen adherence.
Example 13
In Vitro Demonstration of Persistent Effect of Acamprosate Exposure
on Neuronal Response to Glutamatergic Stimulation
[0171] The study is designed to test whether pre-treatment with
acamprosate can have long-term neuronal protective effects against
glutamate neurotoxicity. The study uses an in vitro organotypic
hippocampal slice model. The study assesses whether less than 24
hours per day of exposure to a sufficient level of acamprosate can
offer 24-hour therapeutic actions in neuropsychiatric disorders.
The study demonstrates the persistent effect of exposure to
acamprosate in protecting cultured rat hippocampus neurons from
challenge with a toxic level of a glutamate agonist drug. This
supports, among other things, the therapeutic use of acamprosate in
neuropsychiatric disorders because the latter are related to the
effect of acamprosate to decrease glutamate effects at NMDA and
metabotropic glutamate receptors. The rat study shows that
acamprosate has a persistent effect on some of the post-synaptic
effects of glutamate agonists even after acamprosate has been
removed from the culture medium for up to eight hours.
[0172] Hippocampal slices derived from 8-day-old Sprague Dawley
rats are plated and subsequently exposed to a relatively acute (8
hour) or more chronic (5 day) acamprosate treatment. The slices are
then removed from the medium containing acamprosate and returned to
control medium for either 1 or 8 hours. The slices will then be
challenged with either NMDA (50 uM) or a selective mGLuR1 or mGluR5
agent for 1 hr. The slices are then placed in normal medium with
propidium iodide for 24 hr and assessed for
neurotoxicity/neuroprotection as described below.
Methodology:
[0173] Preparing an Organotypic Hippocampal Slice Culture
(OHSC):
[0174] Eight-day old Sprague-Dawley rat pups are used in all
organotypic hippocampal slice experiments (OHSC) experiments. Pups
are sacrificed (3 males/3 females per litter) via rapid
decapitation, brains are then aseptically removed and transferred
to ice-cold dissecting media. Following removal of the meninges,
hippocampi are removed, sliced coronally at 200 .mu.m and plated in
triplicate onto 0.4 .mu.m Biopore membranes. Membranes are
suspended in 1 ml culture media using six-well plates. Plates are
then incubated at 37.degree. C. in a 5% CO.sub.2/21% O.sub.2/74%
N.sub.2 medical grade gas composition for 5 days in vitro (DIV) to
allow affixture to the Teflon.RTM. membrane. Typically, 14-18
slices can be derived from each pup.
[0175] Acamprosate Pretreatment:
[0176] On the fifth day in vitro the plates are treated with new
culture medium, with half exposed to 200 .mu.M calcium acamprosate
and half to normal medium for either 8 hr or 5 days. At this time,
the plates are placed into fresh control medium for either 1 hr or
8 hr.
[0177] Glutamatergic Challenge:
[0178] At this time, the plates are placed either in fresh medium,
medium with NMDA (50 uM) or a metabotropic glutamate receptor
agonist for 1 hour.
[0179] Neurotoxicity/Neuroprotection Assessment:
[0180] For the final medium change, the plates are moved into
normal media containing propidium iodide (PI) added to each well
for 24 hours. PI only penetrates cell membranes of damaged or
potentially dying cells, binding to DNA to produce a bright,
intensified red fluorescence at 630 nm. The slices are visualized
with SPOT Advanced version 4.0.2 software for Windows at a 5.times.
objective with a Leica DMIRB microscope that is fitted for
fluorescent detection using blue-green light, and connected to a
personal computer through a SPOT 7.2 color mosaic. The emission
wavelength of PI is 620 nm in the visual range; PI has a peak
excitation wavelength of 536 nm. PI is excited using a band-pass
filter exciting wavelengths between 510 and 560 nm. Intensity of
the PI fluorescence is analyzed by densitometry using Image J and
the pictures are quantified by detecting optical intensity of the
CA1 pyramidal cell layer, CA3 pyramidal cell layer, and dentate
gyrus granule cell layer of the hippocampus following background
subtraction. Fluorescence is recorded in arbitrary units, then
converted to percent of control, facilitating comparison across
multiple cultures and controlling for variation between litters. PI
uptake has been shown to correlate well with other measures of
cellular injury and cellular death.
Example 14
[0181] Acamprosate is tested using a rat model of tardive
dyskinesia looking at abnormal chewing movements produced in rats
by exposing them for several weeks to haloperidol, a potent
first-generation neuroleptic. First, acamprosate is tested and
shows a steadily-maintained blood level will reduce or eliminate
the abnormal movements. Rats then are dosed with acamprosate in a
way that matches the therapeutic blood level for no more than 12
hours out of 24, to confirm that this reduces the involuntary
movements.
Example 15
[0182] Acamprosate is tested in transgenic mouse models with
movement disorders [(Per2(Brdm1) deletion or ENT1(-/-) mice or
other mouse models] and hyperglutamatergic states. First,
acamprosate is tested and shows a steadily-maintained blood level
will reduce or eliminate the abnormal movements. Mice then are
dosed with acamprosate in a way that matches the therapeutic blood
level for no more than 12 hours out of 24, to confirm that this
reduces the involuntary movements.
Example 16
[0183] The pharmacokinetic properties of the specific
gastric-retentive (GR) preparation of acamprosate described in
EXAMPLE 5 is tested in human subjects in two studies. In the first,
subjects receive, 30 minutes after a standard high-fat meal, a
single dose of 400 mg of GR acamprosate, of 800 mg of GR
acamprosate, or of 666 mg of enteric-coated acamprosate. Plasma
concentrations of acamprosate are determined at 1, 2, 4, 6, 8, 12,
24, and 48 hours afterwards and pharmacokinetic parameters are
calculated.
[0184] In at least some subjects (a) C.sub.max and AUC are
proportional to dosage for the 400 and 800 mg GR dosages, and (b)
with respect to the 666 enteric-coated dosage, the GR formulations
have higher bioavailability and a shorter T.sub.max.
[0185] In the second study subjects receive 400 mg of GR
acamprosate in the fasting state, in the fed state, and in the
fasting state preceded (e.g., at least 10-15 minutes earlier) by
600 mg of R alpha lipoic acid.
[0186] In at least some subjects the pharmacokinetic curve (and the
parameters AUC, C.sub.max and T.sub.max) are similar for 400 mg of
GR acamprosate in the fed state and for 400 of GR acamprosate in
the fasting state preceded by R alpha lipoic acid; 400 mg of GR
acamprosate in the fasting state without alpha lipoic acid shows a
significantly lower AUC and lower C.sub.max than either of the
other two conditions.
[0187] The herein described subject matter sometimes illustrates
different methods, compositions and/or components contained within,
or combined with, different other methods, compositions and/or
components. It is to be understood that the various described
methods, compositions, components and combinations of the same are
merely provided as non-limiting examples, and that in fact many
others can be implemented which achieve the same purposes and/or
functionality.
[0188] With respect to the use of substantially any plural and/or
singular terms herein, those having skill in the art can translate
from the plural to the singular and/or from the singular to the
plural as is appropriate to the context and/or application. The
various singular/plural permutations may be expressly set forth
herein for sake of clarity.
[0189] It will be understood by those within the art that, in
general, terms used herein, and especially in the appended claims
(e.g., bodies of the appended claims) are generally intended as
"open" terms (e.g., the term "including" should be interpreted as
"including but not limited to," the term "having" should be
interpreted as "having at least," the term "includes" should be
interpreted as "includes but is not limited to," etc.). It will be
further understood by those within the art that if a specific
number of an introduced claim recitation is intended, such an
intent will be explicitly recited in the claim, and in the absence
of such recitation no such intent is present. For example, as an
aid to understanding, the following appended claims may contain
usage of the introductory phrases "at least one" and "one or more"
to introduce claim recitations. However, the use of such phrases
should not be construed to imply that the introduction of a claim
recitation by the indefinite articles "a" or "an" limits any
particular claim containing such introduced claim recitation to
embodiments containing only one such recitation, even when the same
claim includes the introductory phrases "one or more" or "at least
one" and indefinite articles such as "a" or "an" (e.g., "a" and/or
"an" should typically be interpreted to mean "at least one" or "one
or more"); the same holds true for the use of definite articles
used to introduce claim recitations. In addition, even if a
specific number of an introduced claim recitation is explicitly
recited, those skilled in the art will recognize that such
recitation should typically be interpreted to mean at least the
recited number (e.g., the bare recitation of "two recitations,"
without other modifiers, typically means at least two recitations,
or two or more recitations). Furthermore, in those instances where
a convention analogous to "at least one of A, B, and C, etc." is
used, in general such a construction is intended in the sense one
having skill in the art would understand the convention (e.g., "a
system having at least one of A, B, and C" would include but not be
limited to systems that have A alone, B alone, C alone, A and B
together, A and C together, B and C together, and/or A, B, and C
together, etc.). In those instances where a convention analogous to
"at least one of A, B, or C, etc." is used, in general such a
construction is intended in the sense one having skill in the art
would understand the convention (e.g., "a system having at least
one of A, B, or C" would include but not be limited to systems that
have A alone, B alone, C alone, A and B together, A and C together,
B and C together, and/or A, B, and C together, etc.). It will be
further understood by those within the art that virtually any
disjunctive word and/or phrase presenting two or more alternative
terms, whether in the description, claims, or drawings, should be
understood to contemplate the possibilities of including one of the
terms, either of the terms, or both terms. For example, the phrase
"A or B" will be understood to include the possibilities of "A" or
"B" or "A and B."
[0190] Where a range of values is provided, it is understood that
each intervening value, to the tenth of the unit of the lower limit
unless the context clearly dictates otherwise, between the upper
and lower limits of that range is also specifically disclosed. Each
smaller range between any stated value or intervening value in a
stated range and any other stated or intervening value in that
stated range is encompassed within the invention. The upper and
lower limits of these smaller ranges may independently be included
or excluded in the range, and each range where either, neither or
both limits are included in the smaller ranges is also encompassed
within the invention, subject to any specifically excluded limit in
the stated range. Where the stated range includes one or both of
the limits, ranges excluding either or both of those included
limits are also included in the embodiments of the technology.
[0191] The publications discussed herein are provided solely for
their disclosure prior to the filing date of the present
application. Nothing herein is to be construed as an admission that
the present embodiments are not entitled to antedate such
publication by virtue of prior invention. Further, the dates of
publication provided may be different from the actual publication
dates which may need to be independently confirmed. The subject
matter disclosed in the publications, including any methods,
compositions, excipients (including ranges and dosages of the
same), etc., are incorporated herein by reference in their
entireties.
[0192] Many modifications and variations of the embodiments
described herein may be made without departing from the scope, as
is apparent to those skilled in the art. Also, while various
aspects and embodiments have been disclosed herein, other aspects
and embodiments will be apparent to those skilled in the art. The
various aspects and embodiments disclosed herein are for purposes
of illustration and are not intended to be limiting, with the true
scope and spirit being indicated by the following claims.
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