U.S. patent application number 12/667272 was filed with the patent office on 2010-10-07 for method for decreasing symptoms of alcohol consumption.
This patent application is currently assigned to ALCOBRA LTD.. Invention is credited to Shimon Amselem, Yaron Ilan, Dalia Megiddo, Gur Megiddo, Rina Yamin.
Application Number | 20100256198 12/667272 |
Document ID | / |
Family ID | 40226624 |
Filed Date | 2010-10-07 |
United States Patent
Application |
20100256198 |
Kind Code |
A1 |
Megiddo; Gur ; et
al. |
October 7, 2010 |
METHOD FOR DECREASING SYMPTOMS OF ALCOHOL CONSUMPTION
Abstract
The present invention relates to methods and compositions of
metadoxine and physiologically compatible active derivatives
thereof, and their use for decreasing symptoms of alcohol
consumption as well as in the prevention of alcohol consumption
related symptoms in subjects in need thereof.
Inventors: |
Megiddo; Gur; (M.P. Judean
Hills, IL) ; Megiddo; Dalia; (M.P. Judean Hills,
IL) ; Yamin; Rina; (Rehovot, IL) ; Ilan;
Yaron; (Jerusalem, IL) ; Amselem; Shimon;
(Rehovot, IL) |
Correspondence
Address: |
ROPES & GRAY LLP
PATENT DOCKETING 39/361, 1211 AVENUE OF THE AMERICAS
NEW YORK
NY
10036-8704
US
|
Assignee: |
ALCOBRA LTD.
Givatayim
IL
|
Family ID: |
40226624 |
Appl. No.: |
12/667272 |
Filed: |
July 3, 2008 |
PCT Filed: |
July 3, 2008 |
PCT NO: |
PCT/IL08/00917 |
371 Date: |
June 23, 2010 |
Current U.S.
Class: |
514/343 ;
514/345; 546/278.4; 546/301 |
Current CPC
Class: |
A61K 9/2054 20130101;
A61K 9/1652 20130101; A61P 39/00 20180101; A61K 31/44 20130101;
A61K 31/455 20130101; A61P 1/16 20180101; A61K 9/0095 20130101;
A61K 9/1635 20130101; A61K 47/38 20130101; A61P 25/30 20180101;
A61K 31/4015 20130101; A61K 9/5026 20130101; A61K 31/4415 20130101;
A61P 25/00 20180101; A61P 25/32 20180101; A61K 9/7061 20130101;
A61K 47/32 20130101; A61P 39/02 20180101; A61P 3/00 20180101; A61K
9/0007 20130101; A61K 31/4415 20130101; A61K 31/4015 20130101 |
Class at
Publication: |
514/343 ;
514/345; 546/278.4; 546/301 |
International
Class: |
A61K 31/44 20060101
A61K031/44; A61K 31/4439 20060101 A61K031/4439; C07D 401/02
20060101 C07D401/02; C07D 213/67 20060101 C07D213/67; A61P 1/16
20060101 A61P001/16; A61P 39/00 20060101 A61P039/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 3, 2007 |
IL |
184389 |
Nov 5, 2007 |
IL |
187159 |
Claims
1. A method for decreasing or preventing symptoms or effects of
alcohol consumption in a subject in need thereof, wherein said
subject has not reached intoxication, comprising non-chronic
administration of a composition comprising metadoxine.
2. A method for preventing alcohol intoxication in a subject in
need thereof, wherein said subject has not reached intoxication,
comprising administering a composition comprising metadoxine.
3. A method for reducing or eliminating blood alcohol levels in a
subject in need thereof, wherein said subject has not reached
intoxication, comprising administering a composition comprising
metadoxine.
4. The method according to claim 2 or 3, wherein said composition
is administered by non-chronic administration.
5. The method according to claim 1, wherein said subject is or will
be social drinking, session drinking or binge drinking.
6. The method according to claim 1, wherein said composition is
administered in a single dosage form or portion thereof.
7. The method of claim 1, wherein the mode of administration is
oral, sublingual, buccal, nasal, transdermal, transmucosal, rectal
or subcutaneous administration.
8. A composition comprising metadoxine formulated for sustained or
controlled release upon administration to a subject.
9. A composition comprising metadoxine, wherein a portion of the
metadoxine is formulated for sustained release and a portion of the
metadoxine is formulated for immediate release upon administration
to a subject.
10. The composition according to claim 8, wherein the relative
proportion of sustained release metadoxine to immediate release
metadoxine is in a range of from 1-to-99 to 99-to-1, in whole
integers.
11. The composition according to claim 8, selected from a
pharmaceutical composition, a dietary supplement, a food and a
beverage.
12. The composition according to claim 8, wherein said metadoxine
is a physiologically compatible derivative.
13. The composition according to claim 8, wherein said composition
is formulated for non-chronic administration.
14. The composition according to claim 13, wherein said composition
is administered in a single dosage form or portion thereof.
15. The composition according to claim 8, wherein said composition
is formulated to release not less than 50% of the total metadoxine
within 8 hours.
16. The composition according to claim 8, wherein said composition
is formulated to release not less than 50% of the total metadoxine
within 6 hours.
17. The composition according to claim 8, wherein said composition
has a t.sub.max of metadoxine in the blood greater than about 1
hour.
18. The composition according to claim 17, wherein said composition
has a t.sub.max of metadoxine in the blood that is about 2-fold
greater than in an immediate release composition.
19. The composition according to claim 8, wherein said composition
is formulated to deliver up to 3000 mg of metadoxine in a single
dose administration or portion thereof.
20. The composition according to claim 8, wherein said composition
further comprises a polymeric material.
21. The composition according to claim 8, wherein said composition
further comprises an absorption enhancer.
22. The composition according to claim 8, wherein said composition
further comprises an acceptable excipient.
23. The composition according to claim 8, wherein said composition
comprises or consists essentially of Formula 1.
24. The composition according to claim 8, wherein said composition
comprises or consists essentially of Formula 2.
25. The composition according to claim 8, wherein said composition
comprises or consists essentially of Formula 3.
26. The composition according to claim 8, wherein said sustained
release is controlled release.
27. A method for increasing the mean t.sub.max of metadoxine in the
blood of a subject in need thereof comprising administering a
composition according to claim 8.
28. The method according to claim 27, wherein said composition has
a t.sub.max of metadoxine in the blood that is about 2-fold greater
than in an immediate release composition.
29. The method according to claim 1, wherein said composition is a
composition according to claim 8.
30. The method according to claim 28, wherein said subject is or
will be social drinking, session drinking or binge drinking.
31. The method according to claim 28, wherein said composition is
administered by non-chronic administration.
32. The method according to claim 31, wherein said composition is
administered in a single dosage form or portion thereof.
33. The method of claim 28, wherein said mode of administration is
oral, nasal, rectal, subcutaneous, transmucosal, sublingual, buccal
or transdermal administration.
34-37. (canceled)
38. A drug delivery device comprising a metadoxine composition
according to claim 8.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to methods and compositions of
metadoxine and functional, physiologically compatible derivatives
thereof, and their use in decreasing symptoms of alcohol
consumption as well as in the prevention of alcohol consumption
related symptoms in subjects in need thereof.
BACKGROUND OF THE INVENTION
[0002] Social drinking (the consumption of alcohol without becoming
intoxicated) is a social norm in many cultures and has long been
considered an acceptable practice which allows people to socialize
more freely and easily together. Drinking is relaxing for many
people, and drinking before and during parties, at bars or
restaurants, with meals and with family and friends are all acts
considered to be within the realm of social drinking, when alcohol
consumption is maintained so that intoxication is not reached.
[0003] More excessive or serious forms of drinking, often chronic,
may be potentially harmful to the drinker and to others affected by
the drinker. For example, drinking with the intent to get drunk or
intoxicated, drinking and driving while under the influence of
alcohol, loss of psychomotor coordination and speech, blackouts,
vomiting, alcohol poisoning and associated deaths are considered
among the harmful symptoms and effects of drinking that falls
outside the scope of social drinking. It would be desirable to
avoid these and other effects or consequences of excessive alcohol
consumption.
[0004] Alcohol abuse, moreover, is a common problem in the general
population all over the world. Alcohol abuse and alcoholism are
responsible for a wide variety of medical problems, which are
considered part of the new-age epidemics, among them the most
recognized being alcohol-induced liver disease, primary and
secondary malnutrition, and neuron damage, often leading to
death.
[0005] The pharmaco-therapeutic aspect of alcoholism includes the
use of drugs, with different actions and objectives. Metadoxine is
a pyridoxine-pyrrolidone carboxylate (also known as pyridoxol
L,2-pyrrolidon-5 carboxylate or pyridoxine
5-oxo-2-pyrrolidon-carboxylate) with significant alcohol scavenging
properties which has been used to treat acute alcohol intoxication,
poisoning, and certain acute alcohol syndromes (reviewed in
Addolorato et al., Int. J. Immunopathol. Pharmacol. (2003)
16:207-214). Long term data show that metadoxine is safe for use by
humans.
[0006] Metadoxine is capable of accelerating the elimination of
alcohol from the blood and tissues, helping restore the functional
structure of the liver and relieve neuro-psychological disorders
associated with chronic alcohol intoxication and associated
syndromes. In animal studies, metadoxine increased plasma clearance
and urinary excretion of ethanol, inhibited the increased
production of fatty acid esters in the liver during chronic alcohol
intake, reduced oxidative stress and prevented glutathione
depletion in hepatic tissues (Antonelli et al., Pharmacol. Res.
Commun. (1984) 16:189-197). In the brain, metadoxine increased the
level of GABA and acetylcholine in the frontoparietal cortex of
guinea pigs.
[0007] Metadoxine is an ion-pair between pyrrolidone carboxylate
(PCA) and pyridoxine (vitamin B6) with the two compounds linked in
a single product by salification. The pairing with PCA
synergistically increases the pharmacological activity of
pyridoxine (see, e.g., U.S. Pat. No. 4,313,952). Metadoxine is
freely soluble in water and in gastric fluid. Oral absorption of
the drug is fast with high bioavailability (60-80%). The half life
of metadoxine in human serum is short (40-60 minutes) without
appreciable differences between oral and intravenous administration
(Addolorato et al., supra; Lu Yuan et al., Chin. Med. J. 2007
120(2) 160-168).
[0008] Metadoxine is marketed in several countries as a
prescription drug in the form of 500 mg tablets and 300 mg
injections. Tablets contain 500 mg of metadoxine, microcrystalline
cellulose and magnesium stearate. Ampoules contain 300 mg of
metadoxine, sodium metabisulfite, EDTA sodium,
methyl-p-hydroxybenzoate and water.
[0009] Maximal levels of ethanol appear in the blood stream 30-60
minutes after drinking. Due to the fast absorption of ethanol,
stomach wash is ineffective against ethanol overdose. Because
ethanol is miscible in water, it will be targeted to water-rich
tissues, such as the brain, where it will cause the familiar
symptoms. An average drink increases blood ethanol level to about
20 mg/dl, which can typically be metabolized and cleared in about
one hour. Up-regulation of alcohol-dehydrogenase (ADH) in heavy
drinkers may increase the ethanol clearance to about 30 mg/dl per
hour.
[0010] There is thus a need for methods and compositions that are
capable of quickly reducing alcohol levels and providing quick
restoration of sobriety following alcohol consumption in any type
of drinking, or that reduce or prevent symptoms of alcohol
consumption, particularly in subjects that have not reached
intoxication levels or who do not exhibit symptoms of chronic
alcoholic related syndromes. It would be desirable, for example, to
have a treatment which could be administered during or shortly
after social drinking of any amount of alcohol that would enable
the drinker to quickly become sober enough to legally drive. There
is also a need for better treatment and prevention of acute and
chronic alcohol intoxications and related diseases, such as
alcoholism.
SUMMARY OF THE INVENTION
[0011] The present invention solves one or more of the problems
referred to above by providing various methods for reducing or
preventing effects of alcohol consumption by administering a
metadoxine composition. Metadoxine compositions formulated for
sustained or controlled release, optionally also including an
immediate release component, and methods for using such sustained
or controlled release metadoxine formulations of the invention, are
also provided.
[0012] Accordingly, in certain aspects, the invention provides a
method for decreasing or preventing symptoms or effects of alcohol
consumption in a subject in need thereof, preferably wherein the
subject has not reached intoxication, comprising administering a
composition comprising metadoxine.
[0013] In certain aspects, the invention provides a method for
preventing alcohol intoxication in a subject in need thereof,
comprising administering a composition comprising metadoxine.
[0014] In certain aspects, the invention provides a method for
reducing or eliminating blood alcohol levels in a subject in need
thereof, preferably wherein the subject has not reached
intoxication, comprising administering a composition comprising
metadoxine.
[0015] In certain other aspects, the invention provides a
composition comprising metadoxine formulated for sustained release
or controlled release. In some aspects, the invention provides a
composition comprising metadoxine, wherein a portion of the
metadoxine is formulated for sustained or controlled release and a
portion of the metadoxine is formulated for immediate release.
[0016] Accordingly, in any of the various embodiments of the
methods of the invention described above, the composition may
comprise metadoxine formulated for immediate release, sustained
release, controlled release, or a combination of any of the
foregoing. In any of the various embodiments of the above described
methods, the administration is non-chronic administration.
Moreover, the metadoxine may consist of or comprise a
physiologically compatible metadoxine derivative as described
herein.
[0017] In certain other aspects, the invention provides a method
for increasing the mean t.sub.max of metadoxine in the blood of a
subject in need thereof comprising administering a metadoxine
composition of the invention formulated for sustained release or
controlled release, optionally including a portion of the
metadoxine formulated for immediate release.
[0018] In certain aspects, the invention provides a use of any one
of the compositions of the invention in the manufacture of a
therapeutic composition useful for practicing each of the methods
of the invention as described herein, e.g., for reducing or
preventing symptoms or effects of alcohol consumption; for
preventing alcohol intoxication; for reducing or eliminating blood
alcohol levels in a subject, or for increasing the mean t.sub.max
of metadoxine in the blood of a subject, among others.
[0019] In any of the various embodiments of metadoxine compositions
described herein (e.g., metadoxine formulated for immediate
release, sustained release, controlled release, or a combination of
any of the foregoing), the metadoxine may consist of or comprise a
physiologically compatible metadoxine derivative, as described
herein. In certain embodiments, metadoxine compositions are
formulated for non-chronic administration, and preferably for
non-invasive administration.
[0020] The present invention also provides delivery devices and
kits comprising a metadoxine composition of the invention, and
methods for their use in the treatment or prevention of alcohol
consumption related symptoms. Kits may optionally include means for
measuring or monitoring blood alcohol concentration (BAC) levels
before, during or after administration of a metadoxine
composition.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIG. 1 shows a graph of the rate of release of certain
metadoxine compositions of the present invention as described in
Examples 2-3. The graph illustrates the difference between an
immediate release formulation and a slow release formulation of
metadoxine. Metadoxine (%) released vs. time (hours).
[0022] FIG. 2 illustrates exemplary dissolution rates of various
slow release metadoxine formulations prepared using different
polymers as describes in Examples 4-6. Metadoxine (%) released vs.
time (hours).
[0023] FIG. 3 illustrates metadoxine mean serum levels in 3 pigs
after administration of immediate release and slow release
formulations as described in Example 13. Metadoxine mean serum
levels (micrograms (mcg)/ml) vs. time (hours).
[0024] FIG. 4 illustrates metadoxine mean serum levels in 3 pigs
after administration of a slow release metadoxine formulation (250
mg) and double dose (500 mg) slow release metadoxine formulations
as described in Example 13. Metadoxine mean serum levels (mcg/ml)
vs. time (hours).
DESCRIPTION OF THE INVENTION
Definitions
[0025] For convenience, certain terms employed in the
specification, examples, and appended embodiments, are collected
here. Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs.
[0026] The articles "a" and "an" are used herein to refer to one or
to more than one (i.e., to at least one) of the grammatical object
of the article. By way of example, "an element" means one element
or more than one element.
[0027] The term "including" is used herein to mean, and is used
interchangeably with, the phrase "including but not limited
to".
[0028] The term "or" is used herein to mean, and is used
interchangeably with, the term "and/or," unless context clearly
indicates otherwise.
[0029] The term "such as" is used herein to mean, and is used
interchangeably, with the phrase "such as but not limited to".
[0030] The term "prophylactic" or "therapeutic" treatment refers to
administration to a subject of one or more of the compositions of
the invention. If it is administered prior to clinical
manifestation of the unwanted condition (e.g., disease or other
unwanted state of the host animal) then the treatment is
prophylactic, i.e., it contributes to prevention of, i.e.,
protection of the subject against developing an unwanted condition,
whereas if administered after manifestation of an unwanted
condition, the treatment is therapeutic (i.e., it is intended to
diminish, ameliorate or prevent progression of the unwanted
condition or side effects therefrom).
[0031] The term "therapeutic effect" refers to a local or systemic
effect in animals, particularly mammals, and more particularly
humans, caused by a pharmacologically active substance or
substances. The term thus means any substance intended for use in
diagnosis, cure, mitigation, treatment or prevention of disease or
in the enhancement of desirable physical or mental development and
conditions in an animal or human. The term "therapeutically
effective amount" means that amount of such a substance that
produces some desired local or systemic effect at a reasonable
benefit/risk ratio applicable to any treatment. In certain
embodiments, a therapeutically-effective amount of a compound or
composition will depend on its therapeutic index, solubility, and
the like. For example, certain metadoxine formulations of the
present invention may be administered in a sufficient amount to
produce a reasonable benefit/risk ratio applicable to a selected
treatment, as may be determined by the skilled artisan.
[0032] The term "effective amount" refers to the amount of a
therapeutic reagent that when administered to a subject in an
appropriate dose and regimen produces at least one desired
result.
[0033] A "subject" or "patient" to be treated by a method of the
invention may mean either a human or non-human animal, preferably a
mammal.
[0034] Throughout this specification, the word "comprise" or
variations such as "comprises" or "comprising" will be understood
to imply the inclusion of a stated integer or groups of integers
but not the exclusion of any other integer or group of
integers.
[0035] The term "bioavailable" means that at least some amount of a
particular compound is present in the systemic circulation. Formal
calculations of oral bioavailability are described in terms of an F
value ("Fundamentals of Clinical Pharmacokinetics," John G. Wegner,
Drug Intelligence Publications; Hamilton, Ill. 1975). F values are
derived from the ratio of the concentration of the parent drug in
the systemic circulation (e.g., plasma) following intravenous
administration to the concentration of the parent drug in the
systemic circulation after administration by a non-intravenous
route (e.g., oral). Therefore, oral bioavailability within the
scope of the present invention contemplates the ratio or F value of
the amount of parent drug detectable in the plasma after oral
administration compared to intravenous administration.
[0036] The term "treating" or "treatment" refers to mitigating or
alleviating at least on symptom of a condition, disease or disorder
in a mammal, such as a human, or the improvement of an
ascertainable measurement associated with a condition, disease or
disorder.
[0037] The term "metadoxine" as used herein refers to the currently
known and available form of metadoxine, which is an ion-pair
between pyrrolidone carboxylate (PCA) and pyridoxine (vitamin B6)
with the two compounds linked in a single product by salification.
The term "metadoxine" as used herein is also intended to refer to
and encompass any other active form of pyrrolidone carboxylate
(PCA) in stable association with pyridoxine (vitamin B6). Stable
association between the PCA and pyridoxine may be non-covalent,
such as through a salt link, or other hydrostatic or electrostatic
forces. Stable association, in other cases, may be accomplished by
covalent bonding, e.g., by means of a linker or other chemical bond
between the PCA and pyridoxine in which metadoxine activity is
retained. The skilled artisan will be able to test the biological
activity of any such complexes in standard metadoxine assays.
[0038] The term "acceptable derivative" with respect to metadoxine
refers to any salt, conjugate, ester, complex or other chemical
derivative of metadoxine or any of the moieties comprising the
same, which, upon administration to a subject, is capable of
providing (directly or indirectly) metadoxine or a metabolite or
functional residue thereof, or measurable metadoxine activity. The
term "physiologically compatible metadoxine derivative" may be used
interchangeably herein with the term "acceptable derivative" and
refers to a functional, active, pharmaceutically acceptable
derivative of metadoxine.
[0039] The term "excipient" refers to an inactive substance used as
a carrier for the active ingredient in a formulation.
[0040] The term "controlled release" refers to any formulation
which delivers an agent at a controlled rate for an extended time
and is designed to achieve a desired agent level profile.
[0041] The term "sustained release" is used in its conventional
sense to refer to a formulation that provides for gradual release
of an active material over an extended period of time, which in
certain embodiments may also further result in substantially
constant blood levels over an extended time period, i.e.,
controlled release.
[0042] The term "immediate release" is used in its conventional
sense to refer to a formulation that provides for non delayed or
controlled release of an active material upon administration.
[0043] The term "half-life" of a substance is the time it takes for
a substance to lose half of its pharmacologic, physiologic, or
other activity. Biological half-life is an important
pharmacokinetic parameter and is usually denoted by the
abbreviation t.sub.1/2.
[0044] The term "non-invasive" refers to modes of treatment which
do not puncture the skin.
[0045] The term "non-chronic administration" may be used
interchangeably herein with the term "acute administration" and
refers to giving a measured or non-measured quantity or portion of
a medication to a subject on a non-regular basis. Non-chronic
administration may be a single dose treatment or a multiple dose
treatment, and may optionally be given over time. Typically but not
always, a non-chronic administration is given to treat or prevent a
non-chronic condition. Certain chronic conditions may also benefit
from non-chronic administration of a metadoxine composition
described herein.
[0046] The term "chronic administration" refers to giving a
measured quantity of a medication on a regular basis to a subject.
In some embodiments, chronic administration is to treat or prevent
one or more chronic conditions or diseases. Chronic diseases have
one or more of the following characteristics: they are permanent,
leave residual disability, are caused by nonreversible pathological
alteration, require special training of the patient for
rehabilitation, or may be expected to require a long period of
supervision, observation, or care.
[0047] The term "single dose treatment" refers to giving a measured
quantity of a medication to be taken at one time. It is given to
treat non-chronic conditions on an irregular basis, depending on
personal need.
[0048] The term "alcoholism" refers to a primary chronic disease
known as alcohol dependence syndrome, the most severe stage of a
group of drinking problems. Alcoholism is considered a progressive
disease, meaning that the symptoms and effects of drinking alcohol
become increasingly more severe over time (Morse R. et al., JAMA
268(8):1012-4 (1992)).
[0049] The term "alcohol abuse" refers to repeated drinking despite
alcohol-related physical, social, psychological, or occupational
problems (The Diagnostic and Statistical Manual of Mental
Disorders, IV). When alcohol abuse reaches the alcohol dependence
stage, the person may also experience tolerance, withdrawal, and an
uncontrolled drive to drink.
[0050] Art-recognized symptoms of alcohol consumption include:
reduced activity in the central nervous system, loose muscle tone,
loss of fine motor coordination, a staggering "drunken" gait, eyes
appear "glossy," pupils may be slow to respond to stimulus, pupils
may become constricted, decreased heart rate, lower blood pressure
and respiration rate, decreased reflex responses, slower reaction
times, skin may be cool to the touch (but the user may feel warm),
profuse sweating, loss of fine motor coordination, or odor of
alcohol on the breath. Symptoms of alcohol consumption and
diagnostic criteria for alcohol intoxication include those
described in the Diagnostic and Statistical Manual of Mental
Disorders DSM-IV, e.g., section 303.00 Diagnostic Criteria for
Alcohol Intoxication.
[0051] The term "alcohol intoxication" as used herein refers to a
situation where the quantity of alcohol a person consumes exceeds
the individual's tolerance for alcohol and produces, either during
or shortly after drinking, clinically important psychological,
behavioral or physical abnormalities, such as inappropriate
aggression, and impaired judgment and social functioning. One or
more of the following signs or symptoms of alcohol intoxication
occur shortly after drinking: (1) slurred speech; (2) impaired
motor coordination; (3) unsteady gait; (4) nystagmus (involuntary,
irregular eye movement characterized by smooth pursuit of an object
in one direction and saccadic movement in the other direction); (5)
inattention and/or impaired memory; and (6) stupor or coma (see
Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition, (DSM-IV) 303.00).
[0052] Sobriety, intoxication, alcohol abuse, alcohol-related
aggression or alcoholism may be measured according to one or more
art recognized tests, such as psychomotor texts, serum alcohol
level tests, for example accepted inhalation tests, Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition, (DSM-IV),
Alcohol Abstinence Self-Efficacy Scale (AASE; DiClemente,
Carbonari, Montgomery, and Hughes, 1994), Barratt Impulsiveness
Scale-11 (BIS-11; Barratt, 1994), State-Trait Anger Expression
Inventory-2 (STAXI-2; Spielberger, 1999), Conflict Resolution,
Impulsivity and Aggression Questionnaire (CRIAQ; Honess, Maguire,
and Vanstone, 2001), Social Problem-Solving Inventory-Revised
(SPSI-R; D'Zurilla, Nezu, and Maydeu-Olivares, 2002),
Alcohol-Related Aggression Questionnaire (ARAQ; McMurran, Egan,
Austin, and Charlesworth, under review), or The Alcohol Use
Disorders Identification Test (AUDIT; Saunders, Aasland, Babor, et
al., 1993). Levels of alcohol in the body may be measured in urine,
blood, breath or saliva.
[0053] There is a wide range of variability in blood alcohol levels
that different individuals can tolerate without becoming
intoxicated. The range may be as great as from 0.3 to 1.5 mg/ml,
although most states in the U.S. set the sobriety level for legally
driving at 0.8 mg/ml (DSM-IV, 303.00; supra). Some users may
develop significant behavioral changes or become intoxicated at a
much lower Blood Alcohol Concentration (BAC) than the legal limit.
This condition is known as "Alcohol Idiosyncratic Intoxication" or
"Pathological Intoxication" (DSM-IV, 291.9) In general, however,
the following symptoms are associated with increasing BAC levels:
[0054] 0.02-0.03 BAC: No loss of coordination, slight euphoria and
loss of shyness. Depressant effects are not apparent. [0055]
0.04-0.06 BAC: Feeling of well-being, relaxation, lower
inhibitions, sensation of warmth. Euphoria. Some minor impairment
of reasoning and memory, lowering of caution. [0056] 0.07-0.09 BAC:
Slight impairment of balance, speech, vision, reaction time, and
hearing. Euphoria. Judgment and self-control are reduced, and
caution, reason and memory are impaired. [0057] 0.10-0.125 BAC:
Significant impairment of motor coordination and loss of good
judgment. Speech may be slurred; balance, vision, reaction time and
hearing will be impaired. Euphoria. It is illegal to operate a
motor vehicle at this level of intoxication. [0058] 0.13-0.15 BAC:
Gross motor impairment and lack of physical control. Blurred vision
and major loss of balance. Euphoria is reduced and dysphoria
(anxiety, restlessness) is beginning to appear. [0059] 0.16-0.20
BAC: Dysphoria predominates, nausea may appear. The drinker has the
appearance of a "sloppy drunk." [0060] 0.25 BAC: The drinker needs
assistance in walking; total mental confusion. Dysphoria with
nausea and some vomiting. [0061] 0.30 BAC: Loss of consciousness.
[0062] 0.40 BAC and up: Onset of coma, possible death due to
respiratory arrest.
[0063] The term "social drinking" refers to the consumption of
alcohol in a safe, legal and socially acceptable manner usually
without the intent of reaching the point of becoming intoxicated
(i.e., to achieve alcohol intoxication). Although the amount of
blood alcohol which leads to intoxication varies widely between
individuals, three or fewer measured drinks (or a blood alcohol
level of up to 0.05%) is generally considered to be within the
social drinking range.
[0064] The term "session drinking" refers to drinking in large
quantities over a single period of time, or session, without the
intention of getting heavily intoxicated. The focus is on the
social aspects of the occasion.
[0065] The term "binge drinking" refers to drinking alcohol solely
for the purpose of intoxication, although it is quite common for
binge drinking to apply to a social situation, creating some
overlap in social and binge drinking. In certain embodiments, binge
drinking refers to a woman consuming four drinks and a man
consuming five drinks on a single drinking occasion. Because
drinking occasions can last up to five or seven hours, many such
bingers never become intoxicated.
[0066] The term "t.sub.max" refers to the time to peak
concentration. Calculation of time at which maximum concentration
occurs after a single dose administration is performed according to
the formula:
t max = 2.303 .lamda. a - .lamda. z log .lamda. a .lamda. z
##EQU00001##
[0067] where .lamda..sub.a and .lamda..sub.z are the apparent
absorption and elimination rate constants, respectively.
Methods of Treatment and Prevention Using Metadoxine
Compositions
[0068] In certain embodiments, the present invention provides a
method for decreasing or preventing symptoms or effects of alcohol
consumption in a subject in need thereof, especially wherein the
subject has not reached intoxication, comprising administering a
composition comprising metadoxine or a physiologically acceptable
derivative thereof. In certain such embodiments, the method
comprises non-chronic administration of a composition comprising
metadoxine or a physiologically acceptable derivative thereof.
[0069] In certain embodiments, the present invention provides a
method for preventing alcohol intoxication in a subject in need
thereof, comprising administering a composition comprising
metadoxine or a physiologically acceptable derivative thereof. In
certain such embodiments, the method comprises non-chronic
administration of a composition comprising metadoxine or a
physiologically acceptable derivative thereof. In certain
embodiments, methods for preventing intoxication include treatment
of a subject with a composition comprising metadoxine or a
physiologically acceptable derivative thereof, wherein the subject
has previously reached intoxication and has subsequently sobered to
a level that is below intoxication during a single drinking
session.
[0070] In certain embodiments, the present invention provides a
method for preventing alcoholism in a subject in need thereof,
especially when the subject is not an acute alcoholic, comprising
administering a composition comprising metadoxine or a
physiologically acceptable derivative thereof.
[0071] In certain embodiments, the present invention provides a
method for slowing the progression of alcoholism in a subject in
need thereof, especially when the subject is not an acute
alcoholic, comprising administering a composition comprising
metadoxine or a physiologically acceptable derivative thereof.
[0072] In certain embodiments, the present invention provides a
method for reducing or eliminating blood alcohol levels in a
subject in need thereof, especially wherein the subject has not
reached intoxication, comprising administering a composition
comprising metadoxine or a physiologically acceptable derivative
thereof. In certain such embodiments, the method comprises
non-chronic administration of a composition comprising metadoxine
or a physiologically acceptable derivative thereof.
[0073] In certain embodiments, the present invention provides a
method for increasing the mean t.sub.max of metadoxine in the blood
of a subject in need thereof comprising administering a composition
comprising metadoxine or a physiologically acceptable derivative
thereof, and especially wherein the composition comprises
metadoxine or a physiologically acceptable derivative thereof
formulated in whole or in part for sustained or controlled release.
In certain such embodiments, the method comprises non-chronic
administration of a composition comprising metadoxine or a
physiologically acceptable derivative thereof formulated in whole
or in part for sustained or controlled release. In certain
embodiments of the invention, the mean t.sub.max of metadoxine in
the blood of a subject is increased by 50%, 100%, 150%, 200%, 300%,
400% 500% or greater than 500%.
[0074] In certain embodiments, the application provides a method
for increasing the half-life (t.sub.1/2) of metadoxine in the blood
or serum of a subject in need thereof comprising administering a
composition comprising metadoxine or a physiologically acceptable
derivative thereof, and especially wherein the composition
comprises metadoxine or a physiologically acceptable derivative
thereof formulated in whole or in part for sustained release or
controlled release, optionally including a portion of the
metadoxine formulated for immediate release. In certain embodiments
of the invention, the t.sub.1/2 of metadoxine in the blood or serum
of a subject is increased by 50%, 100%, 150%, 200%, 300%, 400% 500%
or greater than 500%.
[0075] In certain embodiments of the invention, metadoxine or a
physiologically acceptable derivative thereof is used for immediate
relief of drunkenness and regaining of sobriety in a subject in
need thereof. In some embodiments, the subject has not reached
alcohol intoxication levels. Such immediate relief has a great
value in preventing various hazards, particularly motor vehicle
accidents and other personal injuries. In certain such embodiments,
the method comprises non-chronic administration of a composition
comprising metadoxine or a physiologically acceptable derivative
thereof, and may optionally be formulated in whole or in part for
sustained or controlled release.
[0076] In certain embodiments, metadoxine or a physiologically
acceptable derivative thereof is used for prolonged relief of
drunkenness and regaining of sobriety in a subject in need thereof.
In some embodiments, the subject has not reached alcohol
intoxication levels. As above, such prolonged relief has a great
value in preventing various hazards, particularly motor vehicle
accidents and other personal injuries and also has a value in
preventing and treating various symptoms and conditions associated
with prolonged or frequent alcohol consumption. In certain such
embodiments, the method comprises non-chronic administration of a
composition comprising metadoxine or a physiologically acceptable
derivative thereof, and may be optionally formulated in whole or in
part for sustained or controlled release.
[0077] In certain embodiments, methods of the present invention may
be used to treat a subject that has consumed alcohol but is not
intoxicated. In certain embodiments, the methods of the invention
may be used to treat a subject that has consumed alcohol but has
not had an increase in psychomotor excitation and aggression. The
methods of the present invention are intended for use in a variety
of subjects before, during or after a variety of types of alcohol
consumption of any amount. As each subject will present with
different symptoms of alcohol consumption, blood alcohol
concentrations alone are often useful but insufficient taken alone
to describe subjects that will benefit from the compositions and
methods of the present invention.
[0078] In certain embodiments, metadoxine compositions of the
invention, e.g., formulated in whole or in part for sustained or
controlled release, enable more efficient use of metadoxine in the
treatment or prevention of non-chronic or chronic alcohol
intoxications and syndromes and conditions related thereto.
[0079] In certain embodiments, the methods of the present invention
may be used to prevent alcohol consumption related symptoms. In
certain embodiments, subjects are treated before any alcohol
consumption. In certain embodiments, subjects are treated after
alcohol consumption, but before symptoms occur. In certain
embodiments, subjects are treated after alcohol consumption, but
before subjects are intoxicated. These embodiments are not mutually
exclusive and may be combined in any desired combination.
[0080] In certain embodiments, the methods of the invention may
prevent symptoms of alcohol consumption related to drinking one
drink or a portion thereof. In certain embodiments, the methods of
the invention may prevent symptoms of alcohol consumption related
to drinking 2, 3, 4, 5 or more drinks.
[0081] In a yet further embodiment, the invention provides a method
for the rapid or immediate restoration of sobriety following
alcohol consumption in a subject in need of such treatment,
comprising administering to said subject a composition comprising
metadoxine or a physiologically acceptable derivative thereof. In
certain embodiments, the subject has not reached alcohol
intoxication levels. In certain embodiments, the administration is
a non-chronic administration.
[0082] Furthermore, the invention provides a method of treatment
and/or prevention of alcohol intoxication in a subject in need of
such treatment, comprising administering to said subject a
composition comprising metadoxine or a physiologically acceptable
derivative thereof. In certain embodiments, the subject has not
reached alcohol intoxication levels. In certain embodiments, the
administration is a non-chronic administration.
[0083] Still further, the invention relates to a method of reducing
alcohol blood, serum or tissue levels (e.g., muscle and other
non-adipose tissues) in a subject in need of such treatment,
comprising administering to said subject a composition comprising
metadoxine or a physiologically acceptable derivative thereof. In
certain embodiments, the subject has not reached alcohol
intoxication levels. In certain embodiments, the administration is
a non-chronic administration.
[0084] In certain embodiments, the invention provides a method of
reducing or preventing an increase in BAC in a subject who is or
has been consuming alcohol. In certain embodiments, the methods of
the present invention may decrease or prevent an increase in BAC so
that the subject has a BAC that is legally low enough to permit the
subject to operate a motor vehicle. In certain embodiments, the
compositions of the invention may prevent an increase in BAC beyond
1, 2, 3, or more levels as described in the definitions above. In
certain embodiments, the compositions of the present invention may
decrease BAC. In certain embodiments, the methods of the present
invention may decrease BAC to a level where operating a motor
vehicle is legally permitted. In certain embodiments, the
compositions of the invention may decrease BAC by 1, 2, 3 or more
levels as described in the definitions above.
[0085] In certain of the above described methods of the invention,
the metadoxine or acceptable derivative thereof may be formulated
for immediate release upon administration to the subject. In
certain of the above described methods of the invention, the
metadoxine or acceptable derivative thereof may be formulated for
sustained and/or controlled release, and may optionally be
formulated to have both immediate release and sustained and/or
controlled release characteristics upon administration to the
subject. In certain embodiments, metadoxine or a physiologically
acceptable derivative thereof is formulated for non-chronic
administration. Metadoxine formulations of the invention are
described in more detail below.
Metadoxine Formulations and Administration Regimens
[0086] In certain embodiments, the present invention provides a
composition comprising metadoxine or a physiologically acceptable
derivative thereof formulated for sustained and/or controlled
release when administered to a subject.
[0087] In certain embodiments, the present invention provides a
composition comprising metadoxine or a physiologically acceptable
derivative thereof wherein a portion of the metadoxine or
derivative is formulated for sustained and/or controlled release
and a portion of the metadoxine or derivative is formulated for
immediate release when administered to a subject.
[0088] In certain embodiments, a metadoxine composition may
decrease symptoms of alcohol consumption related to drinking one
drink or a portion thereof. In certain embodiments, a metadoxine
composition may decrease symptoms of alcohol consumption related to
drinking 2, 3, 4, 5 or more drinks.
[0089] In certain embodiments, a metadoxine composition may be
delivered in a single dose form, such as in a single dose drink. In
certain embodiments, the compositions of the invention may be
delivered in a single dose per drinking session. In certain
embodiments, a metadoxine composition may be delivered in a single
dose per binge drinking session. In certain embodiments, a
metadoxine composition may be delivered in a single dose per acute
alcohol related condition or potential condition. In certain
embodiments, a metadoxine composition may be delivered in a single
dose form per intoxication or potential intoxication. A potential
condition or intoxication may be a state that would lead to the
condition or intoxication without intervention. In certain
embodiments, a single dose may be a partial dose, i.e., a portion
of a single dosage form.
[0090] In certain embodiments, metadoxine compositions may be
administered 24 hours, 12 hours, 8 hours, 4 hours, 2 hours, one
hour, 55 minutes, 50 minutes, 45 minutes, 40 minutes, 35 minutes,
30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 5
minutes or immediately before alcohol consumption.
[0091] In certain embodiments, metadoxine compositions may be
administered 24 hours, 12 hours, 8 hours, 4 hours, 2 hours, one
hour, 55 minutes, 50 minutes, 45 minutes, 40 minutes, 35 minutes,
30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 5
minutes or immediately before alcohol related symptoms occur.
[0092] In certain embodiments, metadoxine compositions may be
administered 24 hours, 12 hours, 8 hours, 4 hours, 2 hours, one
hour, 55 minutes, 50 minutes, 45 minutes, 40 minutes, 35 minutes,
30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 5
minutes or immediately after alcohol consumption.
[0093] In certain embodiments, metadoxine compositions may be
administered 24 hours, 12 hours, 8 hours, 4 hours, 2 hours, one
hour, 55 minutes, 50 minutes, 45 minutes, 40 minutes, 35 minutes,
30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 5
minutes or immediately after alcohol related symptoms occur.
[0094] In certain embodiments, metadoxine compositions may be
administered hourly, daily, weekly, monthly, yearly (e.g., in a
time release form) or as a one-time delivery. The administration
may be chronic or non-chronic. In certain embodiments, the delivery
is not continuous. In certain embodiments, a metadoxine composition
may be delivered in a single dose. In certain embodiments, the
administration is once, twice, three times or more within a 12- to
24-hour period at which time the treatment is discontinued. In
certain embodiments, the administration is once, twice, three times
or more within a 24- to 48-hour period at which time the treatment
is discontinued. In certain embodiments, the mode of delivery is
non-invasive. In certain embodiments, the delivery is not
intravenous.
[0095] In certain embodiment, the delivery may be continuous
delivery for a period of time, e.g., intravenous delivery. In one
embodiment of the methods described herein, the metadoxine
composition is administered at least once per hour. In one
embodiment of the methods described herein, the metadoxine
composition is administered hourly. In one embodiment of the
methods described herein, the metadoxine composition is
administered at least once per day. In one embodiment, the
metadoxine composition is administered daily. In one embodiment,
the metadoxine composition is administered every other day. In one
embodiment, the metadoxine composition is administered every 6 to 8
days, or more specifically, weekly.
[0096] In certain embodiments, effective serum levels of the active
ingredient are achieved within from about 10 to about 20 or 30 or
40 or 50 or 60 minutes following metadoxine administration. In
certain embodiments, effective serum levels of the active
ingredient are achieved within from about 5 to about 20 or 30 or 40
or 50 or 60 minutes following metadoxine administration. In certain
embodiments, effective serum levels of the active ingredient are
achieved within from about 20 to about 20 or 30 or 40 or 50 or 60
minutes following metadoxine administration. In certain
embodiments, effective serum levels of the active ingredient are
achieved within about 5, 10, 15, 20, 30, 40, 50 or 60 minutes.
[0097] In certain embodiments, relief or decrease or prevention of
alcohol related symptoms are achieved within from about 5 to about
20 or 30 or 40 or 50 or 60 minutes following metadoxine
administration. In certain embodiments, relief or decrease or
prevention of alcohol related symptoms are achieved within from
about 10 to about 20 or 30 or 40 or 50 or 60 minutes following
metadoxine administration. In certain embodiments, relief or
decrease or prevention of alcohol related symptoms are achieved
within from about 15 to about 20 or 30 or 40 or 50 or 60 minutes
following metadoxine administration.
[0098] In certain embodiments, relief or decrease or prevention of
alcohol related symptoms are achieved within from about one hour to
about 2, 3, 4, 5, 6, 7 or 8 hours following metadoxine
administration. In certain embodiments, relief or decrease or
prevention of alcohol related symptoms are achieved within from
about 2 hours to about 3, 4, 5, 6, 7 or 8 hours following
metadoxine administration. In certain embodiments, relief or
decrease or prevention of alcohol related symptoms are achieved
within from about 3 hours to about 4, 5, 6, 7 or 8 hours following
metadoxine administration. In certain embodiments, relief or
decrease or prevention of alcohol related symptoms are achieved
within from about 4 hours to about 5, 6, 7 or 8 hours following
metadoxine administration. In certain embodiments, relief or
decrease or prevention of alcohol related symptoms are achieved
within from about 5 hours to about 6, 7 or 8 hours following
metadoxine administration. In certain embodiments, relief or
decrease or prevention of alcohol related symptoms are achieved
within from about 6 hours to about 7 or 8 hours following
metadoxine administration. In certain embodiments, relief or
decrease or prevention of alcohol related symptoms are achieved
within from about 7 to about 8 hours following metadoxine
administration.
[0099] In certain embodiments, relief or decrease or prevention of
alcohol related symptoms are achieved within about 5, 10, 15, 20,
30, 40, 50 or 60 minutes following metadoxine administration. In
certain embodiments, relief or decrease or prevention of alcohol
related symptoms are achieved within about 2, 3, 4, 5, 6, 7 or 8
hours following metadoxine administration.
[0100] In certain embodiments, the therapeutic effective amount, or
dosage, may be dependent on the amount of alcohol consumed or to be
consumed, state of intoxication, severity and responsiveness of the
subject, or whether there is to be chronic or acute treatment. The
course of metadoxine treatment may last from a few minutes to
several days to several months, or until a cure is effected or a
diminution of the symptom, condition or disease state is achieved.
The treatment regimen selected may be chronic or non-chronic.
Optimal dosing schedules may be calculated from measurements of
drug accumulation in the body of the patient. Persons of ordinary
skill can easily determine optimum dosages, dosing methodologies
and repetition rates. In general, dosage is calculated according to
body weight, and may be given once or more daily, weekly, monthly
or yearly, or even once every 2 to 20 years. Persons of ordinary
skill in the art can easily estimate repetition rates for dosing
based on measured residence times and concentrations of the
combined composition of the invention in bodily fluids or tissues.
Following successful treatment, it may be desirable to have the
patient undergo maintenance therapy to prevent the recurrence of
the disease state, wherein the combined composition of the
invention is administered in maintenance doses, once or more
daily.
[0101] The present inventors have developed innovative approaches
for the administration of metadoxine based on enteral (via the
digestive tract) and/or parenteral (other routes than digestive
tract) routes. These approaches provide for a rational design of
delivery systems with desired properties based on the meticulous
selection of the carrier, e.g. appropriate
surfactants/co-surfactants composition or micro/nano particles
(such as liposomes or nano-liposomes) entrapping the active
ingredients, or other additives or excipients, for the delivery
system of interest.
[0102] The enteral delivery systems may be designed for oral
administration (tablets, sachets, lozenges, capsules, gelcaps,
drops, or other palatable form) or rectal administration
(suppository or (mini) enema form).
[0103] In addition, the delivery system of interest may be in
liquid form, for example a drop solution, syrup. Furthermore, the
delivery system of interest may be in form of a beverage or food
article. Thus, the active ingredient/s used by the invention may be
comprised in a beverage, particularly soft drinks like juices,
nectars, water, sparkling water and other sparkling drinks, shakes,
milk shakes and other milk-based drinks, and the like. Liquid
preparations may also be in the form of concentrated syrups, for
diluting with water or sparkling water. Alternatively, the active
ingredient/s may be comprised in food articles, such as snack bars,
health bars, biscuits, cookies, sweets, confectionery products, ice
creams, ice lollies, and the like.
[0104] Still further, the invention relates to a food or beverage
article comprising a physiologically active pyridoxine derivative,
particularly pyridoxol L,2-pyrrolidon-5 carboxylate (metadoxine),
for fast restoration of sobriety following alcohol consumption in a
subject in need thereof, especially wherein the subject has not
reached intoxication. In certain embodiments, consumption of the
food or beverage article of the invention may lead to achievement
of serum levels of the active ingredient within from about 10 to
about 40-60 minutes following consumption thereof.
[0105] The parenteral ways include subcutaneous, transdermal
(diffusion through the intact skin), transmucosal (diffusion
through a mucous membrane), sublingual, buccal (absorbed through
cheek near gumline) administration, or administration by
inhalation. In certain embodiments, the compositions of the
invention are not administered by invasive modes of treatment
(i.e., are non-invasive). In certain embodiments, the metadoxine
compositions are not administered by intravenous injection.
[0106] In certain embodiments, compositions of the invention are
delivered as a microcrystalline powder or a solution suitable for
nebulization; for intravaginal or intrarectal administration,
pessaries, suppositories, creams or foams. A preferred formulation
is a formulation for oral administration. Another preferred
formulation is for topical administration. Another preferred
formulation is for transmucosal administration, sublingual, buccal
(absorbed through cheek near gumline) administration,
administration by inhalation or ocular administration, e.g., in eye
drops.
[0107] Administration of metadoxine for medical uses requires safe
and efficient delivery systems. The present invention provides
delivery systems for safe delivery of a variety of substances due
to their special physico-chemical features, particularly direct
absorption, by non-invasive means, and consequent avoidance of side
effects. The delivery systems significantly enhance efficiency and
quality of metadoxine absorption based on its unique
physicochemical features, which enables lower concentrations or
amounts of active substance to be delivered to a subject in a
biologically active form. The delivery systems of the invention
provide for the direct access of the active substance to the
tissues and thus provide immediate or near-immediate effects of
metadoxine to the subject in need thereof.
[0108] Accordingly, in certain embodiments, the present invention
provides a non-invasive pharmaceutical delivery system for the
improved administration of a physiologically active pyridoxine,
particularly pyridoxol L,2-pyrrolidon-5 carboxylate (metadoxine),
or a physiologically acceptable derivative thereof, comprising as
the active ingredient said physiologically active pyridoxine in a
suitable carrier for fast restoration of sobriety following alcohol
consumption in a subject in need thereof, particularly wherein the
subject has not reached intoxication. In certain embodiments, serum
levels of the active ingredient are achieved within from about 10
to about 40-60 minutes following administration.
[0109] In another embodiment, the invention provides a non-invasive
pharmaceutical delivery system for the improved administration of a
physiologically active pyridoxine derivative, particularly
pyridoxol L,2-pyrrolidon-5 carboxylate (metadoxine), for use in
preventing or treating chronic and/or acute alcohol intoxication in
a subject in need thereof, comprising as the active ingredient said
pyridoxine derivative, in a suitable carrier. In certain
embodiments, serum levels of said active ingredient are achieved
within from about 10 to about 40-60 minutes following
administration.
[0110] In certain embodiments, the drug delivery systems of the
invention may be designed for oral, nasal, ocular, rectal,
subcutaneous, transdermal, transmucosal, sublingual, buccal or
inhalation administration. The drug delivery systems may provide
the active substance in a controlled release mode. In certain
embodiments, the drug delivery systems of the invention may further
comprise at least one additional pharmaceutically active agent.
[0111] The delivery systems of the invention may generally comprise
a buffering agent, an agent which adjusts the osmolarity thereof,
and optionally, one or more pharmaceutically acceptable carriers,
excipients and/or additives as known in the art. Supplementary
pharmaceutically acceptable active ingredients can also be
incorporated into the compositions. The carrier can be solvent or
dispersion medium containing, for example, water, ethanol, polyol
(for example, glycerol, propylene glycol, and liquid polyethylene
glycol, and the like), suitable mixtures thereof, and vegetable
oils. The proper fluidity can be maintained, for example, by the
use of a coating, such as lecithin, by the maintenance of the
required particle size in the case of dispersion and by the use of
surfactants.
[0112] As used herein "pharmaceutically acceptable carrier"
includes any and all solvents, dispersion media, coatings,
antibacterial and antifungal agents and the like. The use of such
media and agents for pharmaceutical active substances is well known
in the art. Except as any conventional media or agent is
incompatible with the active ingredient, its use in the therapeutic
composition is contemplated. It is contemplated that the active
agent can be delivered by any pharmaceutically acceptable route and
in any pharmaceutically acceptable dosage form.
[0113] Oral forms include, but are not limited to, tablets,
capsules, pills, sachets, lozenges, drops, powders, granules,
elixirs, tinctures, suspensions, syrups, and emulsions. Also
included are oral rapid-release, time controlled-release, and
delayed-release pharmaceutical dosage forms. The active drug
components can be administered in a mixture with suitable
pharmaceutical diluents, excipients or carriers (collectively
referred to herein as "carrier"), materials suitably selected with
respect to the intended form of administration.
[0114] Where the delivery system is for oral administration and is
in the form of a tablet or capsule or the like, the active drug
components can be combined with a non-toxic pharmaceutically
acceptable inert carrier such as lactose, starch, sucrose, glucose,
modified sugars, modified starches, methylcellulose and its
derivatives, dicalcium phosphate, calcium sulfate, mannitol,
sorbitol, and other reducing and non-reducing sugars, magnesium
stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate,
calcium stearate and the like. For oral administration in liquid
form, the active drug components can be combined with non-toxic
pharmaceutically acceptable inert carriers such as ethanol,
glycerol, water and the like. When desired or required, suitable
binders, lubricants, disintegrating agents and coloring and
flavoring agents can also be incorporated into the mixture.
Stabilizing agents such as antioxidants, propyl gallate, sodium
ascorbate, citric acid, calcium metabisulphite, hydroquinone, and
7-hydroxycoumarin can also be added to stabilize the dosage forms.
Other suitable compounds can include gelatin, sweeteners, natural
and synthetic gums such as acacia, tragacanth, or alginates,
carboxymethylcellulose, polyethylene, glycol, waxes and the
like.
[0115] Additional suitable pharmaceutically acceptable carriers
that may be used in these pharmaceutical compositions include, but
are not limited to, ion exchangers, alumina, aluminum stearate,
magnesium stearate, lecithin, serum proteins, such as human serum
albumin, buffer substances such as phosphates, glycine, sorbic
acid, potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids, water, salts or electrolytes, such as
protamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based substances,
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates,
waxes, polyethylene-polyoxypropylene-block polymers, polyethylene
glycol and wool fat. In some embodiments, the pharmaceutically
acceptable carrier is magnesium stearate. Additional pharmaceutical
excipients commonly accepted and used are found in, for example,
Remington's Pharmaceutical Sciences (Gennaro, A., ed., Mack Pub.,
1990).
[0116] For purposes of parenteral administration, solutions in
suitable oil such as sesame or peanut oil or in aqueous propylene
glycol can be employed, as well as sterile aqueous solutions of the
corresponding water-soluble salts. Such aqueous solutions may be
suitably buffered, if necessary, and the liquid diluent first
rendered isotonic with sufficient saline or glucose. These aqueous
solutions are especially suitable for intravenous, intramuscular,
subcutaneous and intraperitoneal injection purposes. In this
connection, the sterile aqueous media employed are all readily
obtainable by standard techniques well-known to those skilled in
the art. Methods of preparing various pharmaceutical compositions
with a certain amount of active ingredient are known, or will be
apparent in light of this disclosure, to those skilled in this
art.
[0117] The half-life of metadoxine in human serum is very short. Lu
Yuan et al. (Chin. Med. J. 2007 120(2) 160-168) shows a mean half
life of about 0.8 hour. A way of prolonging serum levels of active
moiety is by administering the material in a sustained-release
formulation. Because metadoxine is freely soluble in water and in
various biological fluids (see Example 1), it is difficult to
sustain its release and prolong its' absorption time. Therefore, it
was unexpected that sustained release could be achieved. A control
release dosage form of metadoxine may be based on a predetermined
gradual release of the active ingredient in the biological fluids,
resulting in a sustained action with small fluctuations of the
plasma level over a prolonged period of time.
[0118] In certain embodiments, the delivery system of this
invention may be administered in controlled release formulations.
In certain embodiments, the method of administration will be
determined by the attending physician or other person skilled in
the art after an evaluation of the subject's condition and
requirements. An embodiment of the method of the present invention
is to administer the therapeutic compound described herein in a
sustained release form. Any controlled or sustained release method
known to those of ordinary skill in the art may be used with the
compositions and methods of the invention such as those described
in Langer, Science 249(4976):1527-33 (1990). Such method comprises
administering a sustained-release composition, a suppository, or a
coated implantable medical device so that a therapeutically
effective dose of the composition of the invention is continuously
delivered to a subject of such a method. Sustained release may also
be achieved using a patch designed and formulated for the purpose.
The composition of the invention may be delivered via a capsule
which allows sustained-release of the agent over a period of time.
Controlled or sustained-release compositions include formulation in
lipophilic depots (e.g., fatty acids, waxes, oils). Also
comprehended by the invention are particulate compositions coated
with polymers (e.g., poloxamers or poloxamines). Sustained release
formulae or devices, or any topical formulations, may additionally
contain compositions to stabilize the composition or permeate
physiological barrier such as skin or mucous membrane. Exemplary
additional components may include any physiologically acceptable
detergent, or solvent such as, for example, dimethylsulfoxide
(DMSO).
[0119] In certain embodiments, the metadoxine in compositions of
the invention may be formulated for sustained or controlled release
over a period of at least 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or
12 hours. In certain embodiments, the metadoxine in compositions of
the invention may be formulated for sustained or controlled release
over a period of about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12
hours. In certain embodiments, the metadoxine in compositions of
the invention may be formulated for sustained or controlled release
over a period of between about 0.5 or 1 or 2 or 3 or 4 hours and
about 5, 6, 7, 8, 9, 10, 11 or 12 hours. In certain embodiments,
the metadoxine in compositions of the invention may be formulated
for sustained or controlled release over a period of between about
5 or 6 or 7 or 8 hours and about 9, 10, 11 or 12 hours.
[0120] In certain embodiments, the metadoxine in compositions of
the invention may be in immediate, fast of burst release form.
[0121] In certain embodiments, the metadoxine in compositions of
the invention may be formulated to release up to 5, 10, 15, 20, 25,
30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99, 99.5 or
100% of the total metadoxine in about 0.5, 1, 2, 3, 4, 5, 6, 7 or 8
hours. In certain embodiments, the metadoxine in compositions of
the invention may be formulated to release not less than 5, 10, 15,
20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99,
99.5 or 100% of the total metadoxine in about 0.5, 1, 2, 3, 4, 5,
6, 7 or 8 hours.
[0122] In certain embodiments, the metadoxine in compositions of
the invention may be in a combination of sustained or slow release
and immediate or fast release forms. In certain embodiments, the
relative proportion of sustained or slow release metadoxine to
immediate or fast release metadoxine is, e.g., 1 to 99, 5 to 95, 10
to 90, 15 to 85, 20 to 80, 25 to 75, 30 to 70, 35 to 65, 40 to 60,
45 to 55, 50 to 50, 55 to 45, 60 to 40, 65 to 35, 70 to 30, 75 to
25, 80 to 20, 85 to 15, 90 to 10, 95 to 5, or 99 to 1.
[0123] In certain embodiments, a polymeric material is used to
sustain or control release of metadoxine. In certain embodiments,
the type of polymeric material and the amount of which is used,
have a strong influence on the rate of release of metadoxine from
the product of the present invention. Examples of polymers include
both hydrophobic and hydrophilic polymers. Examples of hydrophobic
polymers include, but are not limited to, ethyl cellulose and other
cellulose derivatives, fats such as glycerol palmito-stereate,
beeswax, glycowax, castorwax, carnaubawax, glycerol monostereate or
stearyl alcohol, hydrophobic polyacrylamide derivatives and
hydrophobic methacrylic acid derivatives, as well as mixtures of
these polymers. Hydrophilic polymers include, but are not limited
to, hydrophilic cellulose derivatives such as methyl cellulose,
hydroxypropylmethyl cellulose, hydroxyethylcellulose, hydroxypropyl
cellulose, carboxymethyl cellulose, sodium carboxymethylcellulose
and hydroxyethyl methylcellulose polyvinyl alcohol, polyethylene,
polypropylene, polystyrene, polyacrylamide, ethylene vinyl acetate
copolymer, polyacrylate, polyurethane, polyvinylpyrrolidone,
polymethylmethacrylate, polyvinyl acetate, polyhydroxyethyl
methacrylate, as well as mixtures of these polymers. Furthermore,
any mixture of one or more hydrophobic polymer and one or more
hydrophilic polymer could optionally be used.
[0124] In certain embodiments, a polymeric material to be used in
compositions of the invention is microcrystalline cellulose such as
"Avicel PH 101" manufactured by FMC BioPolymer's.
[0125] In certain embodiments, a polymeric material to be used in
compositions of the invention is Hydroxypropyl Methylcellulose such
as "Metholose" produced by Shin-Etsu Chemical Co.
[0126] In certain embodiments, a polymeric material to be used in
compositions of the invention is Ethyl cellulose such as
"Ethocel.TM." manufactured by The Dow Chemical Company.
[0127] In certain embodiments, a polymeric material to be used in
compositions of the invention is an acrylic polymer such as
"Eudragit RS.TM." produced by Rohm GmbH.
[0128] In certain embodiments, a polymeric material to be used in
compositions of the invention is a colloidal silicone dioxide such
as "Aerosil.TM." manufactured by Degussa.
[0129] In certain embodiments, a polymeric material to be used in
compositions of the invention is a Poly (Vinyl Acetate) such as
"Kollicoat SR" manufactured by BASF.
[0130] In certain embodiments, a polymeric material to be used in
compositions of the invention is an Ethyl Acetate and Vinyl Acetate
solution such as "Duro-Tak" manufactured by Delasco Dermatologic
Lab & Supply, Inc.
[0131] In certain embodiments, the composition of the invention
comprises or consists essentially of Formula 1. Formula 1 comprises
or consists essentially of 100-3000 mg metadoxine and 5-20,000 mg
metholose.
[0132] In certain embodiments, the composition of the invention
comprises or consists essentially of Formula 2. Formula 2 comprises
or consists essentially of 100-3000 mg metadoxine and 5-7000 mg
Ethocel E10.TM..
[0133] In certain embodiments, the composition of the invention
comprises or consists essentially of Formula 3. Formula 3 comprises
or consists essentially of 100-3000 mg metadoxine and 5-20,000 mg
Eudragit RS.TM..
[0134] In certain embodiments, the compositions of the invention
comprise or consist essentially of about 250, 300, 400, 500, 600,
700, 800, or 900 mg to about 1000, 1500, 2000, 2500 or 3000 mg
metadoxine. In certain embodiments, the compositions of the
invention comprise or consist essentially of about 5, 100, 500, or
1000 mg to about 2000, 4000, 10,000, 15,000, or 20,000 mg Avicel PH
101.TM.. In certain embodiments, the compositions of the invention
comprise or consist essentially of about 25, 50, 100, 150, 200,
250, 300, 350, 400, 450, 500, 550 or 600 mg to about 650, 700, 750,
800, 850, 900, 950, 1000, 5000, 10,000, 15,000 or 20,000 mg of a
polymeric material. In certain embodiments, the polymeric material
is metholose, Ethocel E10.TM. or Eudragit RS.TM.. In certain
embodiments, metholose comprises or consists essentially of between
1 and 90% of the formulation, preferably between 5 and 70%. In
certain embodiments, Ethocel.TM. comprises or consists essentially
of between 1 and 30% of the formulation, preferably between 2 and
20%. In certain embodiments, Eudragit.TM. comprises or consists
essentially of between 1 and 90% of the formulation, preferably
between 5 and 70%.
[0135] In certain embodiments, delivery systems of the invention
comprise delivery devices. In certain embodiments, the compositions
of the invention are delivered by an osmotic process at a
controlled rate such as by an osmotic pump. The system may be
constructed by coating an osmotically active agent with a rate
controlling semipermeable membrane. This membrane may contain an
orifice of critical size through which agent is delivered. The
dosage form after coming into contact with aqueous fluids, imbibes
water at a rate determined by the fluid permeability of the
membrane and osmotic pressure of the core formulation. This osmotic
imbibitions of water result in formation of a saturated solution of
active material with in the core, which is dispensed at controlled
rate from the delivery orifice in the membrane.
[0136] In certain embodiments, the compositions of the invention
are delivered using biodegradable microparticles. In certain
embodiment, the system to prepare microparticles consists of an
organic phase comprised of a volatile solvent with dissolved
polymer and the material to be encapsulated, emulsified in an
aqueous phase. In certain embodiments, the biodegradable polymers
that can be used for the microparticle matrix, comprises polylactic
acid (PLA) or the copolymer of lactic and glycolic acid (PLAGA).
The PLAGA polymer degrades hydrolytically over time to its
monomeric components, which are easily removed from the body
through natural life processes.
[0137] The preparation may also contain an absorption enhancer and
other optional components. Examples of absorption enhancers
include, but are not limited to, are cyclodextrins, phospholipids,
chitosan, DMSO, Tween, Brij, glycocholate, saponin, fusidate and
energy based enhancing absorption equipment.
[0138] Optional components present in the dosage forms include, but
are not limited to, diluents, binders, lubricants, surfactants,
coloring agents, flavors, buffering agents, preservatives,
stabilizing agents and the like.
[0139] Diluents, also termed "fillers" include, for example,
dicalcium phosphate dihydrate, calcium sulfate, lactose, cellulose,
kaolin, mannitol, sodium chloride, dry starch, hydrolyzed starches,
silicon dioxide, colloidal silica, titanium oxide, alumina, talc,
microcrystalline cellulose, and powdered sugar. For administration
in liquid form, the diluents include, for example, ethanol,
sorbitol, glycerol, water and the like.
[0140] Binders are used to impart cohesive qualities to the
formulation. Suitable binder materials include, but are not limited
to, starch (including corn starch and pregelatinzed starch),
gelatin, sugars (including sucrose, glucose, dextrose, lactose and
sorbitol), polyethylene glycol, waxes, natural and synthetic gums,
e.g., acacia, tragacanth, sodium alginate, celluloses, and Veegum,
and synthetic polymers such as polymethacrylates and
polyvinylpyrrolidone.
[0141] Lubricants are used to facilitate manufacture; examples of
suitable lubricants include, for example, magnesium stearate,
calcium stearate, stearic acid, glyceryl behenate, and polyethylene
glycol.
[0142] Surfactants may be anionic, cationic, amphoteric or nonionic
surface active agents, with anionic surfactants preferred. Suitable
anionic surfactants include, but are not limited to, those
containing carboxylate, sulfonate and sulfate ions, associated with
cations such as sodium, potassium and ammonium ions. Particularly
preferred surfactants include, but are not limited to: long alkyl
chain sulfonates and alkyl aryl sulfonates such as sodium
dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as
sodium bis-(2-ethylhexyl)-sulfosuccinate; and alkyl sulfates such
as sodium lauryl sulfate.
[0143] Stabilizing agents such as antioxidants, include, but are
not limited to, propyl gallate, sodium ascorbate, citric acid,
calcium metabisulphite, hydroquinone, and 7-hydroxycoumarin.
[0144] If desired, the present compositions may also contain minor
amounts of nontoxic auxiliary substances such as wetting or
emulsifying agents, preservatives, and the like.
[0145] Any of the compositions of the invention may be used alone
or in combination with one or more additional therapeutic agents,
for the treatment of alcohol consumption related symptoms. For
examples of additional therapeutic agents see U.S. Patent
Application Publication Nos. 2005/0271739, 2004/0162270 and
2002/0192303, herein incorporated by reference in their
entirety.
[0146] The amount of both the compound and the additional
therapeutic agent that may be combined with the carrier materials
to produce a single dosage form will vary depending upon the host
treated and the particular mode of administration. Preferably, the
compositions of this invention should be formulated so that a
dosage of between 0.1-1 g/kg body weight/day, preferably 0.1-300
mg/kg body weight, can be administered. The dose of the compound
depends on the condition and the illness of the patient, and the
desired daily dose. In human therapy, the oral daily dose is
preferably 10-3000 mg. These doses are administered in unit dosage
forms, which may be divided into 2-3 smaller doses for each day in
certain cases, especially in oral treatment.
[0147] In certain embodiments, the compositions of the present
invention may act synergistically in combination with each other
and may further act synergistically in the presence of an
additional therapeutic agent. Therefore, the amount of compound(s)
and additional therapeutic agent(s) in such compositions will be
less than that required in a monotherapy utilizing only that
therapeutic agent. In such compositions a dosage of between 0.1-1
g/kg bodyweight/day of the additional therapeutic agent can be
administered.
Use of Metadoxine to Prepare Therapeutic Compositions
[0148] In certain embodiments, the present invention provides a use
of metadoxine (or a functional, physiologically acceptable
derivative of metadoxine) in the manufacture of a therapeutic
composition useful for administering to a subject in need thereof
according to any one of the methods of the invention as described
herein. In certain embodiments, the present invention provides a
use of metadoxine (or a functional, physiologically acceptable
derivative of metadoxine) in the manufacture of a therapeutic
composition useful for administering to a subject in need thereof
according to any one of the compositions of the invention as
described herein.
Kits and Delivery Devices
[0149] The present invention also provides delivery devices and
kits comprising a metadoxine composition of the invention, and
methods for their use. Delivery devices and kits of the invention
may be used for practicing each of the methods of the invention as
described herein, e.g., for reducing or preventing symptoms or
effects of alcohol consumption; for preventing alcohol
intoxication; for reducing or eliminating blood alcohol levels in a
subject, or for increasing the mean t.sub.max of metadoxine in the
blood of a subject, among others.
[0150] In certain embodiments of this invention, kits and delivery
devices of this invention may be included in a container, package
or dispenser alone or as part of a kit with labels and instructions
for administration. In certain embodiments of this invention,
components for performing methods of this invention may be included
in a container, package or dispenser alone or as part of a kit with
labels and instructions for administration. In certain embodiments,
the components may include means for measuring or monitoring BAC
levels before, during or after administration of a metadoxine
composition. Measuring or monitoring BAC levels is performed by
conventional means known to one of ordinary skill in the art.
[0151] Delivery devices for use with the compositions and methods
of the invention may include any devices for drug delivery known to
one of ordinary skill in the art. In certain embodiments, delivery
devices are used to maintain sustained or controlled release of the
compositions of the invention.
EXAMPLES
[0152] The following examples are intended to be illustrative of
the disclosed invention. The examples are non-limiting, and the
skilled artisan will recognize that other embodiments are within
the scope of the present invention. Where not otherwise noted,
methods were performed using techniques that would be understood by
one of ordinary skill in the art.
Example 1
Solubility Testing of Metadoxine
[0153] 200 mg of metadoxine powder were weighted into 4 test tubes.
For each test tube 2 g of one aqueous medium was added. Media
tested were Dulbecco's PBS pH 7.2, simulated gastric fluid without
pepsin USP (SGF pH 1.2), phosphate buffer 10 mM pH 4.5 and
simulated intestinal fluid without pancreatin USP (SIF pH 6.8). The
material was fully dissolved in all four aqueous media. Additional
amount of metadoxine powder was added in 200 mg portions until
maximal weight of 1.4 g was achieved.
Results:
[0154] Metadoxine (1.4 g) was dissolved in 2 g of each medium. The
final concentration (w/w) was 70%.
Conclusion:
[0155] Metadoxine is freely soluble in various biological
fluids.
Example 2
Immediate Release Tablets of Metadoxine
[0156] 500 mg tablets were prepared using the same ingredients as
the commercial product: microcrystalline cellulose and magnesium
stearate.
TABLE-US-00001 Metadoxine 500 milligrams Avicel PH 101 .TM. 100
milligrams Magnesium stearate 14 milligrams
[0157] Materials were mixed together and compressed into tablets.
Dissolution was tested using USP apparatus 2 (paddles), 50 rpm, 500
ml intestinal fluid pH=6.8, 37.degree. C. Tablets dissolved
immediately reaching 100% after 30 minutes (see FIG. 1).
Example 3
Slow Release Tablets of Metadoxine
[0158] 500 mg tablets were prepared using same ingredients as the
commercial product plus matrix forming polymer. Polymer selection
is important to achieving slow release of this highly soluble
molecule. This polymer swallows in aqueous media and forms a
viscous gel which releases the active material slowly.
TABLE-US-00002 Metadoxine 500 milligrams Avicel PH 101 .TM. 72
milligrams Metholose 90SH 250 milligrams Magnesium stearate 21
milligrams
[0159] Materials were mixed together and compressed into tablets.
Dissolution was tested using USP apparatus 2 (paddles), 50 rpm, 500
ml intestinal fluid pH=6.8, 37.degree. C. Tablets dissolved slowly
reaching 74% after 6 hours (see FIG. 1).
Example 4
Slow Release Capsules of Metadoxine
[0160] Granules were prepared using high shear granulation and
vacuum drying. The choice of granulation solvent is important since
it has to dissolve the polymer and not the active material.
TABLE-US-00003 Metadoxine 250 milligrams per capsule Avicel PH 101
.TM. 51.5 milligrams per capsule Metholose 90SH 125 milligrams per
capsule
[0161] Materials were mixed together and granulated with the aid of
ethanol. Granules were filled inside gelatin capsules. Dissolution
was tested using USP apparatus 2 (paddles), 50 rpm, 500 ml
intestinal fluid pH=6.8, 37.degree. C. Granules dissolved slowly
reaching 75% after 4 hours (see FIG. 2).
Example 5
Slow Release Capsules of Metadoxine
[0162] Granules were prepared using high shear granulation and
vacuum drying. The dissolution of this composition is by
diffusion.
TABLE-US-00004 Metadoxine 250 milligrams per capsule Avicel PH 101
.TM. 83.5 milligrams per capsule Ethocel E10 .TM. 36.5 milligrams
per capsule
[0163] Materials were mixed together and granulated with the aid of
ethanol. Granules were filled inside gelatin capsules. Dissolution
was tested using USP apparatus 2 (paddles), 50 rpm, 500 ml
intestinal fluid pH=6.8, 37.degree. C. Granules dissolved slowly
reaching 85% after 4 hours (see FIG. 2).
Example 6
Slow Release Capsules of Metadoxine
[0164] Granules were prepared using high shear granulation and
vacuum drying. This is an example of an acrylic hydrophobic polymer
as a polymeric material.
TABLE-US-00005 Metadoxine 250 milligrams per capsule Avicel PH 101
.TM. 90 milligrams per capsule Eudragit RS .TM. 46 milligrams per
capsule
[0165] Materials were mixed together and granulated with the
solution of Eudragit RS.TM. solution in ethanol. Granules were
filled inside gelatin capsules. Dissolution was tested using USP
apparatus 2 (paddles), 50 rpm, 500 ml intestinal fluid pH=6.8,
37.degree. C. Granules dissolved slowly reaching 100% after 2 hours
(see FIG. 2).
Example 7
Controlled Release Syrup of Metadoxine
[0166] Syrup is prepared using an overhead rotary mixer.
TABLE-US-00006 Metadoxine granules 950 milligrams per 5 milliliters
Strawberry Flavor 20 milligrams per 5 milliliters Sorbitol 70%
Solution to complete volume of 5 milliliters
[0167] Metadoxine slow release granules (from Example 5) are mixed
in Sorbitol 70% solution. Strawberry Flavor is added.
Example 8
Ready to Swallow Sachets of Metadoxine
[0168] Two granulations are performed in a mixer granulator:
Granules No 1:
TABLE-US-00007 [0169] Metadoxine 600 milligrams Cyclodextrine 500
milligrams
Granules No 2:
TABLE-US-00008 [0170] Metadoxine 800 milligrams Metholose 90SH 200
milligrams Ethocel E10 .TM. 50 milligrams Final Mix: Magnesium
Stearate 10 milligrams Aerosil 200 .TM. 10 milligrams
[0171] Granules No 1 (enhanced absorption formula) and Granules No
2 (slow release formula) are mixed together with other ingredients
and filled inside sachets.
Example 9
Metadoxine Ice Cream
[0172] Micro granules (pellets) are prepared using extrusion
technology:
TABLE-US-00009 Metadoxine 2500 milligrams Mannitol 200 milligrams
Ethocel E10 .TM. 50 milligrams Pellets are coated in a Wurster
Fluidized Bed Dryer. Kollicoat SR 30D 200 milligrams
[0173] Pellets are mixed with ice cream and delivered as chocolate
coated ice cream cubes.
Example 10
Dermal Patch of Metadoxine
[0174] Materials (below) are mixed together to form a clear gel.
The gel is coated onto a backing membrane by using coating
equipment. The laminate is dried and a polyester release liner is
laminated onto the dried metadoxine gel. The sheet is cut into
patches and stored in a cool place.
TABLE-US-00010 Metadoxine 2300 milligrams Durotak 387-2287 200
milligrams Ethanol 10 milliliters Water 5 milliliters
Example 11
Metadoxine Chocolate Bar
[0175] Micro granules (pellets) are prepared using extrusion
technology:
TABLE-US-00011 Metadoxine 2000 milligrams Ethocel E10 .TM. 70
milligrams Pellets are mixed with 1000 milligrams Metadoxine
[0176] The mixture is incorporated inside melt chocolate bar.
Example 12
Metadoxine Effervescent Candy
[0177] Micro granules (pellets) are prepared using extrusion
technology:
TABLE-US-00012 Metadoxine 70 milligrams Metholose 90SH 35
milligrams Pellets are mixed with 60 milligrams Metadoxine Sodium
bicarbonate 60 milligrams Citric acid 100 milligrams Sucralose 20
milligrams Cherry flavor 10 milligrams
[0178] The mixture is filled inside Sachets.
Example 13
Pharmacokinetic Study in Pigs
[0179] A three-way crossover bioavailability test after a single
oral administration to three fasting healthy pigs was performed.
One arm of the study involves 250 mg immediate release capsules--as
a study control (same as current marketed formulation). The second
arm of the study involves 250 mg slow-release capsules--test
formulation. The third arm of the study involves intake of two 250
mg slow-release capsules (500 mg)--test formulation. The aim of
this arm was to establish the optimal dose for the slow-release
delivery. Usually, slow-release formulations contain higher dose
than immediate release formulations and are given less
frequently.
[0180] A total of 3 commercial pigs, 15-18 kg body-weight were
treated. The pigs fasted 36 hours before the experiment excluding
liquid food 24 hours before the experiment. The animals received
the drugs orally according to the treatment arms. 3 ml of Blood
were drawn into EDTA tubes before treatment and at 20', 40' 1 hr, 2
hr, 4 hr, 8 hr and 24 hr after drug administration. Blood was
centrifuged, serum collected and frozen. Serum was analyzed for
metadoxine content using a sensitive specific HPLC method.
[0181] The results show that time to peak (t.sub.max) of the
slow-release formulation is delayed (about 2 hours compared to
about 1 hour of the immediate release formulation) (FIG. 3; Table
1). Area under the curve (AUC) of both formulations are similar
(Table 1). When a double dose was given the t.sub.max is delayed to
the same extent as the slow-release single dose, however, AUC was
doubled (FIG. 4; Table 1).
TABLE-US-00013 TABLE 1 AUC Cmax Tmax Formulation (.mu.g/h * ml)
(.mu.g/ml) (h) Immediate 32.8 8.7 1 release Slow release 34.9 8.9 2
Slow release x2 69.0 18.2 2
Example 14
Pharmacokinetic Study in Human Subjects
[0182] A randomized three-way crossover comparative bioavailability
study, with 9 healthy fasting subjects receiving single doses of
metadoxine formulations on three occasions separated by at least 3
days washout period is performed. One arm of the study involves 500
mg immediate release tablets--as a study control (same as current
marketed formulation). The second arm of the study involves 500 mg
slow-release tablets--test formulation. The third arm of the study
involves intake of two 500 mg slow-release tablets (1000 mg)--test
formulation. Blood samples are collected following a predetermined
time schedule in each period in order to characterise drug
absorption and elimination.
[0183] Subjects arrive in the morning, after an overnight fasting
(at least 10 hours). Each subject is assigned a subject number,
which is used for allocation to treatment groups. A baseline (time
0) blood specimen is obtained by aseptic venipuncture. Then each
subject ingests a single dose of metadoxine, either a test or a
reference product as outlined above, with 200 ml tap water. Venous
blood (6 ml each) is then drawn (anticoagulated with EDTA) at 0.5,
0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post
dosing (total of 15 in each period). Each blood specimen is
identified by a label specifying the study number, subject #,
period and sample #. Blood samples are immediately handled and
separated by centrifugation and the plasma aliquoted into 3 sets of
test tubes and frozen at -75.degree. C. (nominal) for analysis of
metadoxine concentrations. Following at least a 3 day washout
between periods, the procedure is repeated with each subject being
dispensed an alternate product.
[0184] Human results are expected to be similar to the pigs'
results of Example 13. t.sub.max of the slow-release formulation is
delayed and AUC of both formulations are similar. When a double
dose is given the t.sub.max is delayed to the same extent as the
slow-release single dose, however, AUC is doubled.
[0185] While some embodiments of the invention have been described
by way of illustration, it will be apparent that the invention can
be put into practice with many modifications, variations and
adaptations, and with the use of numerous equivalents or
alternative solutions that are within the scope of persons skilled
in the art, without departing from the spirit of the invention or
exceeding the scope of the claims.
[0186] All publications, patents and patent applications are herein
incorporated by reference in their entirety to the same extent as
if each individual publication, patent or patent application was
specifically and individually indicated to be incorporated by
reference in its entirety.
* * * * *