US20120264781A1 - Method for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition - Google Patents

Method for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition Download PDF

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US20120264781A1
US20120264781A1 US13/380,215 US201013380215A US2012264781A1 US 20120264781 A1 US20120264781 A1 US 20120264781A1 US 201013380215 A US201013380215 A US 201013380215A US 2012264781 A1 US2012264781 A1 US 2012264781A1
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metadoxine
disorder
cognitive
condition
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Rina Yamin
Dalia Megiddo
Yaron Ilan
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Arcturus Therapeutics Ltd
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Alcobra Ltd
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Assigned to ALCOBRA LTD. reassignment ALCOBRA LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: YAMIN, RINA, ILAN, YARON, MEGIDDO, DALIA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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Definitions

  • the present invention relates to methods of treating and/or relieving and/or improving and/or preventing a cognitive disease, disorder or condition in a subject in need thereof using metadoxine and derivatives thereof or compositions comprising thereof.
  • Alterations in cognitive function may lead to altered state of consciousness, or to altered cognitive function, and may manifest in memory impairment, or learning disabilities, or any type of altered function.
  • ADHD/ADD Attention deficit hyperactivity disorder
  • Amnesia is a condition which can be defined by loss of memory due to some disturbing or appalling psychological experience, brain injury or chain of emotional events. There are different reasons and causes of amnesia such as organic or functional reasons. Organic amnesia is caused due to damage to the brain by external factors which can be due to physical impacts like trauma or disease. Functional amnesia is due to psychological factors.
  • amnesia-like phenomena head injury, severe illness, high fever, seizures, emotional shock or hysteria, alcohol-related brain damage, drugs, stroke, Alzheimer's disease and brain surgery, any type of metabolic disease such as hepatic or uremic encephalopathy, any disease that altered blood flow in the brain, or altered neurotransmission in the brain, or is the result of increase or decrease in any type of metabolite in the brains, any disease associated with accumulation of amyloid in the brain, or with the alteration of electrical function, or metabolic function, or any type of altered mechanism in the brain.
  • metabolic disease such as hepatic or uremic encephalopathy
  • any disease that altered blood flow in the brain or altered neurotransmission in the brain
  • any disease associated with accumulation of amyloid in the brain or with the alteration of electrical function, or metabolic function, or any type of altered mechanism in the brain.
  • Fatigue is related to most lifestyle habits and mental health conditions.
  • the literature describes fatigue as a complex phenomenon that represents decreased ability to perform or accomplish mental or physical tasks or respond after extended activity as well as decreased motivation to perform tasks.
  • the level of fatigue experienced by an individual relates to past cumulative daily activity patterns and to periods of sleep and activity.
  • fatigue results from time spent on tasks, natural circadian factors, and inadequate sleep.
  • Alertness is the state of readiness and attentiveness achieved without artificial or natural enhancements.
  • Having difficulties with concentrating is a symptom that can arise from both physical and psychological or emotional problems. Symptoms of lack of or deficiency in concentration may or may not be associated with other memory-related symptoms such as forgetfulness.
  • Physical medical conditions that affect concentration include Lyme disease, whiplash, and various others.
  • Psychological conditions that may impair concentration include depression, certain anxiety disorders, and stress. Sleep disorders such as insomnia or sleep apnea can also impair concentration ability.
  • 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. Metadoxine has been used to treat acute alcohol intoxication, poisoning, and certain other 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.
  • 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).
  • metadoxine increased the level of GABA and acetylcholine in the frontoparietal cortex of guinea pigs.
  • Metadoxine is an ion-pair between pyrrolidone carboxylate (PCA) and pyridoxine (vitamin B6) with the two compounds linked in a single product by salification.
  • PCA pyrrolidone carboxylate
  • vitamin B6 pyridoxine
  • 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).
  • 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.
  • U.S. Pat. No. 6,541,043 describes a composition and method for treating Attention Deficit/Hyperactivity Disorder (ADHD), the composition comprising dimethylaminoethanol (DMAE), together with a variety of agents, inter alia vitamin B6, optionally with conventional drugs for treating ADHD.
  • DMAE dimethylaminoethanol
  • WO03/003981 discloses compositions for the structural/functional nutritional support for subjects with poor focus, concentration and/or memory, as well as subjects who subjectively experience transient mental fatigue or poor cognitive function. These compositions comprise, inter alia B-complex vitamins, including B6, and L-pyroglutamic acid, together with a large number of other ingredients.
  • WO09/004,629 describes a method for decreasing or preventing symptoms or effects of alcohol consumption comprising administration metadoxine.
  • US20070248696 describes a composition for improving neuromuscular facilitation, also known as “muscle memory,” and enhancing cognitive functions, such as memory and mental focus, in the form of a dietary supplement that comprises, amongst many ingredients, also vitamin B6.
  • US20090081179 discloses the use of polyunsaturated fatty acids and e.g. vitamin B6 amongst others, in treatment of patients suffering from Parkinson's disease, Huntington's chorea, epilepsy, schizophrenia, paranoia, depression, sleep disorders, impaired memory function, psychoses, dementia and ADHD.
  • EP 511943 describes pyroglutamic acid derivatives as enhancers of learning processes and memory. The effect of administration of metadoxine on memory recovery was tested on abstinent chronic alcoholic.
  • Vitamin B6 was administered to a control group of similar patients. It was found that metadoxine helps recovery of short-term memory after 1-2 months of abstinence, and that its effect was superior to that of vitamin B6 [Sinforiani et al., Clin. Trials J., 27(2): 103-111 (1990)].
  • WO2010/013242 discloses salt adducts comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring, optionally additionally substituted, methods of their preparation, and pharmaceutical compositions and medicaments comprising them for the treatment of diseases or disorders associated with or inflicted by alcohol consumption.
  • the present invention is intended at solving one or more of the problems referred to above, by providing various methods for improving cognitive performance by administering a composition comprising metadoxine or a derivative thereof to a subject in need.
  • Metadoxine and/or metadoxine derivatives compositions formulated for sustained or controlled release optionally also including an immediate release component or a metadoxine or a metadoxine derivative, and methods for using such sustained or controlled release or combined metadoxine or metadoxine derivatives formulations of the invention, are also provided.
  • the composition may comprise metadoxine or metadoxine derivative formulated for sustained release or controlled release.
  • the compositions comprising metadoxine or metadoxine derivatives may have a portion of the metadoxine or metadoxine derivatives formulated for sustained or control led release and a portion of the metadoxine or metadoxine derivatives formulated for immediate release.
  • the invention provides a method for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, condition or disorder, in a healthy subject or a patient in need, said method comprising administering to said subject an effective amount of metadoxine or a derivative thereof.
  • the invention provides a method for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition in a subject, said method comprising administering to said subject an effective amount of a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring, optionally additionally substituted.
  • the invention provides a method for the improvement of cognitive functions in a healthy subject, said method comprising administering to said subject an effective amount of a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring, optionally additionally substituted.
  • Metadoxine is a salt of the corresponding anion of L-2-pyrrolidone-5-carboxylic acid (L-2-pyroglutamic acid) (1) and the protonated derivative of pyridoxine (vitamin B6) (2), having the following structures:
  • metaldoxine derivative it should be understood to encompass any other salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring, optionally additionally substituted.
  • said positively charged moiety is a compound of formula (I):
  • R 1 is straight or branched C 1 -C 6 alkyl
  • R 2 is selected from —OH, straight or branched C 1 -C 6 alkoxy, and straight or branched C 1 -C 6 alkoxycarbonyl
  • R 3 and R 4 are each independently selected from formyl, straight or branched C 1 -C 6 alkyl optionally substituted by at least one halogen, amine, hydroxy, C 1 -C 6 alkoxy, thiol and C 1 -C 6 alkoxycarbonyl.
  • R 6 is selected from H, straight or branched C 1 -C 6 alkyl optionally substituted by at least one halogen, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C 6 alkynyl, cycloalkyl, aryl and heteroaryl optionally substituted by a C 1 -C 6 alkyl;
  • R 7 , R 8 , R 9 , R 10 R 11 , R 12 , R 13 and R 14 are each independently selected from H, straight or branched C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, aryl and heteroaryl optionally substituted by at least one group selected from C 1 -C 6 alkyl, halogen, amino, cyano, nitro, thiol, C 1 -C 6 alkoxy, aminocarbonyl, C 1 -C 6 alkoxycarbonyl, C 1
  • ADHD/ADD Attention Deficit/Hyperactivity Disorder
  • Amnesia impaired memory
  • Amnesia impaired wakefulness
  • mental fatigue conditions including disease related fatigue
  • Shift Work Sleep Disorder Narcolepsy
  • Obstructive Sleep Apnea/Hypopnea Syndrome Depression
  • Substance dependence including for example addictive substances
  • Parkinson's disease Schizophrenia, Poor concentration, and Poor focus, or any combination thereof.
  • the invention provides a method for the treatment, alleviation of symptoms of, relieving, improving and preventing a neurobehavioral disorder, such as for example ADHD and/or ADD, in a patient in need or in a health subject experiencing symptoms associated with or connected to a permanent or temporary neurobehavioral disorder such as ADHD and/or ADD, said method comprising administering to said subject an effective amount of metadoxine or a derivative thereof.
  • a neurobehavioral disorder such as for example ADHD and/or ADD
  • ADD Attention Deficit Disorder
  • ADHD Attention Deficit Hyperactivity Disorder
  • Poor concentration Poor concentration
  • Poor focus or any combination or symptoms thereof.
  • the methods of the invention may further improve wakefulness in subjects (at any age, such as for example pediatric, adolescent or adult subjects) who experience excessive sleepiness due to one of the following non-limiting diagnosed sleep disorders: obstructive sleep apnea/hypopnea, shift work sleep disorder and narcolepsy.
  • a cognitive disease, disorder or condition alleviated, relieved, improved or prevented by a method of the invention may additionally include any condition associated with learning disabilities, impairment of memory, cognitive dysfunction, alteration of cognitive function, including Alzheimer's disease, or any type of encephalopathy, including uremic and hepatic encephalopathy.
  • a neurobehavioral disorder alleviated, relieved, improved or prevented by a method of the invention may additionally include any condition associated any symptoms associated or connected with a neurobehavioral disorder such as for example learning disabilities, impairment of memory, cognitive dysfunction, alteration of cognitive function, etc.
  • the composition may comprise metadoxine or metadoxine derivatives formulated for immediate release, sustained release, controlled release, or a combination of any of the foregoing.
  • a cognitive function When referring to a cognitive function it should be understood to encompass at least one of the following non-limiting list: temporary or long term learning disabilities, temporary or long term impairment of memory, temporary or long term cognitive dysfunction, temporary or long term alteration of cognitive function, temporary or long term concentration impairment, temporary or long term focus impairment, temporary or long term impaired wakefulness, temporary or long term mental fatigue conditions, temporary or long term Shift Work Sleep Disorder, or any combination thereof.
  • an improvement in the cognitive functions in a healthy subject it is meant to encompass any change (minor or significant) in the cognitive condition of a subject.
  • said improvement may be noticeable in at least one of the following non-limiting list of conditions: temporary or long term learning disabilities, temporary or long term impairment of memory, temporary or long term cognitive dysfunction, temporary or long term alteration of cognitive function, temporary or long term concentration impairment, temporary or long term focus impairment, temporary or long term impaired wakefulness, temporary or long term mental fatigue conditions, temporary or long term Shift Work Sleep Disorder, or any combination thereof.
  • the invention provides a method for increasing the mean t max of metadoxine or metadoxine derivatives in the blood of a subject comprising administering a metadoxine or metadoxine derivatives composition of the invention formulated for sustained release or controlled release, optionally including a portion of the metadoxine or metadoxine derivatives formulated for immediate release.
  • the invention provides a use of any one of the compositions of the invention for the manufacture of a therapeutic and/or pharmaceutical composition and/or medicament useful for practicing each of the methods of the invention as described herein, e.g., for treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition in healthy patients or patients suffering from Attention Deficit/Hyperactivity Disorder (ADHD/ADD), impaired memory (Amnesia), mental fatigue conditions, poor concentration, and poor focus.
  • ADHD/ADD Attention Deficit/Hyperactivity Disorder
  • Amnesia impaired memory
  • the subject may be a child, an adolescent, an adult or an elderly or aged person.
  • the invention also relates to any condition associated with learning disabilities, impairment of memory, any alteration of cognitive function, including Alzheimer's disease, related to alterations in blood flow, sclerosis, amyloid deposition, alteration of neurotransmitters in the brain, metabolic alterations such as the accumulation of ammonia, any type of encephalopathy, including uremic and hepatic encephalopathy, or any type of altered functions due to altered levels of any substance.
  • Alterations in cognitive function may lead to altered state of consciousness, or to altered cognitive function, and may manifest in memory impairment, or learning disabilities, or any type of altered function.
  • metadoxine or metadoxine derivatives compositions described herein e.g., metadoxine or metadoxine derivatives 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.
  • FIG. 1 shows a graph of the rate of release of certain metadoxine compositions of the present invention as described in Example 1.
  • the graph illustrates the difference between an immediate release formulation and a slow release formulation of metadoxine.
  • Metadoxine (%) released vs. time (hours).
  • FIG. 2 illustrates the rates of release of immediate-release formulation compared to release from slow-release tablets.
  • the invention provides a method for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition in a subject, said method comprising administering to said subject an effective amount of a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring, optionally additionally substituted.
  • the invention provides a method for the improvement of cognitive functions in a healthy subject, said method comprising administering to said subject an effective amount of a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring, optionally additionally substituted.
  • the invention provides, a use of a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring, optionally additionally substituted, for the preparation of a medicament for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition in a subject.
  • the invention provides, a use of a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring, optionally additionally, for the preparation of a medicament for the improvement of cognitive functions in a healthy subject.
  • R 1 is straight or branched C 1 -C 6 alkyl
  • R 2 is selected from —OH, straight or branched C 1 -C 6 alkoxy, and straight or branched C 1 -C 6 alkoxycarbonyl
  • R 3 and R 4 are each independently selected from formyl, straight or branched C 1 -C 6 alkyl optionally substituted by at least one halogen, amine, hydroxy, C 1 -C 6 alkoxy, thiol and C 1 -C 6 alkoxycarbonyl.
  • said carboxylated lactam ring is selected from the group consisting of:
  • R 6 is selected from H, straight or branched C 1 -C 6 alkyl optionally substituted by at least one halogen, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C 6 alkynyl, cycloalkyl, aryl and heteroaryl optionally substituted by a C 1 -C 6 alkyl;
  • R 7 , R 8 , R 9 , R 10 R 11 , R 12 , R 13 and R 14 are each independently selected from H, straight or branched C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, aryl and heteroaryl optionally substituted by at least one group selected from C 1 -C 6 alkyl, halogen, amino, cyano, nitro, thiol, C 1 -C 6 alkoxy, aminocarbonyl, C 1 -C 6 alkoxycarbonyl, C 1
  • said carboxylated lactam ring is a compound of formula (II):
  • R 6 , R 7 , R 8 , R 9 and R 10 are as defined above.
  • said carboxylated lactam ring is compound (1):
  • R 1 , R 2 , R 3 and R 4 are as defined above.
  • R 1 is a C 1 -C 6 alkyl and R 2 , R 3 and R 4 are as defined above.
  • R 2 is selected from —OH and C 1 -C 6 alkoxy; and R 1 , R 3 and R 4 are as defined above.
  • R 3 is —CH 2 R 15 , wherein R 15 is selected from —C 1 -C 6 alkoxy, —OH and —NH 3 + ; and R 1 , R 2 and R 4 are as defined above.
  • R 4 is selected from formyl and —CH 2 R 16 , wherein R 16 is selected from —C 1 -C 6 alkoxy and —OH; and R 1 , R 2 and R 3 are as defined above.
  • R 1 is —CH 3
  • R 2 is —OH
  • R 3 and R 4 are both —CH 2 OH.
  • said carboxylated lactam ring is a compound of formula (II):
  • R 6 , R 7 , R 8 , R 9 and R 10 are as defined above.
  • R 6 is C 1 -C 6 alkyl.
  • R 9 is C 1 -C 6 alkyl.
  • said carboxylated lactam ring is a compound of formula (III):
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are as defined above.
  • said carboxylated lactam ring is a compound of formula (IV):
  • said positively charged moiety is compound (2):
  • said salt adduct is selected from the following:
  • said cognitive disease, disorder or condition is selected from Attention Deficit/Hyperactivity Disorder (ADHD/ADD), impaired memory (Amnesia), impaired wakefulness, mental fatigue conditions, Shift Work Sleep Disorder, Narcolepsy, Obstructive Sleep Apnea/Hypopnea Syndrome, poor concentration, and poor focus or any combination thereof.
  • ADHD/ADD Attention Deficit/Hyperactivity Disorder
  • Amnesia impaired memory
  • impaired wakefulness mental fatigue conditions
  • Shift Work Sleep Disorder Narcolepsy
  • Obstructive Sleep Apnea/Hypopnea Syndrome poor concentration, and poor focus or any combination thereof.
  • said cognitive disease, disorder or condition is selected from learning disabilities, impairment of memory, cognitive dysfunction, alteration of cognitive function, including Alzheimer's disease, or any type of encephalopathy, including uremic and hepatic encephalopathy.
  • said cognitive disease, disorder or condition is a neurobehavioral disease, disorder or condition.
  • said neurobehavioral disease, disorder or condition is selected from Attention Deficit Hyperactivity Disorder (ADHD), Attention Deficit Disorder (ADD), impaired memory, poor concentration, and poor focus.
  • ADHD Attention Deficit Hyperactivity Disorder
  • ADD Attention Deficit Disorder
  • impaired memory poor concentration, and poor focus.
  • said cognitive disease, disorder or condition is selected from Attention Deficit Disorder (ADD) or Hyperactivity Disorder (ADHD/ADD), impaired memory (Amnesia), impaired wakefulness, mental fatigue conditions, Shift Work Sleep Disorder, Narcolepsy, Obstructive Sleep Apnea/Hypopnea Syndrome, poor concentration, and poor focus or any combination thereof.
  • ADHD Attention Deficit Disorder
  • ADHD/ADD Hyperactivity Disorder
  • Amnesia impaired memory
  • Amnesia impaired wakefulness
  • mental fatigue conditions Shift Work Sleep Disorder
  • Narcolepsy Narcolepsy
  • Obstructive Sleep Apnea/Hypopnea Syndrome poor concentration, and poor focus or any combination thereof.
  • said cognitive function selected from temporary or long term learning disabilities, temporary or long term impairment of memory, temporary or long term cognitive dysfunction, temporary or long term alteration of cognitive function, temporary or long term concentration impairment, temporary or long term focus impairment, temporary or long term impaired wakefulness, temporary or long term mental fatigue conditions, temporary or long term Shift Work Sleep Disorder, or any combination thereof.
  • said subject is a child, an adolescent, an adult, or an elderly person.
  • said salt adduct is formulated in a sustained-, delayed or controlled-release dosage form.
  • said salt adduct is formulated in a sustained-, delayed or controlled-release dosage form combined with a salt adduct formulated in an immediate or burst effect dosage form.
  • said salt adduct is formulated to deliver up to 0.1-1000 mg/kg body weight/day of said salt adduct, preferably 1-400 mg/kg body weight of said salt adduct, in a single dose administration or portion thereof. In other embodiments said salt adduct is formulated to deliver up to 100-700 mg/kg body weight/day of said salt adduct.
  • said salt adduct is formulated together with at least one additional pharmaceutically active agent.
  • a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring, optionally additionally substituted, for use in the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition in a subject.
  • a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring, optionally additionally, for use in the improvement of cognitive functions in a healthy subject.
  • an element means one element or more than one element.
  • 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., clinical 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 there from).
  • the unwanted condition e.g., clinical or other unwanted state of the host animal
  • 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.
  • 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.
  • a therapeutically-effective amount of a compound or composition will depend on its therapeutic index, solubility, and the like.
  • certain metadoxine or metadoxine derivatives 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.
  • an 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.
  • 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.
  • the term “subject” as used herein may refer to a healthy individual, or a subject suffering any cognitive problems.
  • cognitive or “cognitive function” or “cognitive problems” or cognitive disorders” or “cognitive malfunction” or “cognitive disease, disorder or condition” and the like, may be used herein interchangeably and as used herein may be taken to mean any function of cognition, including but not limited to Attention Deficit/Hyperactivity Disorder (ADHD/ADD), impaired memory (Amnesia), mental fatigue conditions, poor concentration, poor focus, as well as in any condition associated with learning disabilities, impairment of memory, any alteration of cognitive function, including Alzheimer's disease, related to alterations in blood flow, sclerosis, amyloid deposition, alteration of neurotransmitters in the brain, metabolic alterations such as the accumulation of ammonia, any type of encephalopathy, including uremic and hepatic encephalopathy, or any type of altered functions due to altered levels of any substance.
  • ADHD/ADD Attention Deficit/Hyperactivity Disorder
  • Amnesia impaired memory
  • cognitive function including Alzheimer's disease, related to alterations in blood flow, s
  • cognitive dysfunction includes any conditions resulting from, inter alia, altered blood flow to whole or part of the brain such as in stroke; altered acid base balance; altered in electrolytes; alteration (increase or decrease) of the level of any metabolite, e.g.
  • urea or ammonia deposition of any substrate such as amyloid in any part of the brain such as in Alzheimer Disease or Parkinson's Disease; alteration in any part of the immune system whether peripheral or central, that affect the brain, such as in multiple sclerosis or different types of lupus erythematosus; changes in level or function of any cytokine or chemokine; effect/s of drug/s directed towards or targeted to the brain, or affecting the brain in a indirect manner; alterations in neurotransmitters; and any alterations of nerves or synapses in the brain.
  • neurorobehavioral or “neurobehavioral function” or “neurobehavioral problems” or “neurobehavioral disorders” or “neurobehavioral malfunction” and the like, may be used herein interchangeably and as used herein may be taken to mean any function of cognition, including but not limited to Attention Deficit/Hyperactivity Disorder (ADHD/ADD), impaired memory, poor concentration, poor focus, as well as in any condition associated with learning disabilities, impairment of memory, or any symptoms associated or connected there from such as for example poor performance in social (home, community, etc.), educational (class, playground, etc.) environments.
  • ADHD/ADD Attention Deficit/Hyperactivity Disorder
  • ADHD/ADD Attention Deficit/Hyperactivity Disorder
  • impaired memory poor concentration
  • poor focus as well as in any condition associated with learning disabilities, impairment of memory, or any symptoms associated or connected there from such as for example poor performance in social (home, community, etc.), educational (class, playground, etc.) environments.
  • the present invention relates to any of the known ADHD subtypes:
  • Predominantly hyperactive-impulsive for which most symptoms are in the hyperactivity-impulsivity categories, and some symptoms of inattention are present, although inattention may still be present to some degree
  • Predominantly inattentive the majority of symptoms are in the inattention category and fewer symptoms of hyperactivity-impulsivity are present, although hyperactivity-impulsivity may still be present to some degree; Children with this subtype are less likely to act out or have difficulties getting along with other children. They may sit quietly, but they are not paying attention to what they are doing. Therefore, the child may be overlooked, and parents and teachers may not notice symptoms of ADHD.
  • Combined hyperactive-impulsive and inattentive some of the symptoms of inattention and some symptoms of hyperactivity-impulsivity are present.
  • Inattentive type symptoms may include:
  • Predominantly hyperactive-impulsive type symptoms include:
  • Additional manifestations of primarily impulsivity may include:
  • salt adduct is meant to encompass a salt product of a direct addition of two or more distinct ions, wherein the overall charge of the salt adduct is zero.
  • the salt adduct comprises one positively charged moiety having a single positive charge functional group (i.e., the positively charged moiety is charged with +1 net charge) and one negatively charged moiety having a single negative charge functional group (i.e., the negatively charged moiety is charged with ⁇ 1 net charge).
  • the salt adduct comprises one positively charged moiety having two positively charged functional groups, which may be the same or different (i.e., the positively charged moiety is charged with +2 net charge) and two negatively charged moieties, which may be the same or different, and each having a single negative charged functional group (i.e., each negatively charged moiety is charged with ⁇ 1 net charge).
  • the salt adduct comprises two positively charged moieties, which may be the same or different, having each one positively charged functional group (i.e., each positively charged moiety is charged with +1 net charge) and one negatively charged moiety, having two negatively charged functional groups, being the same or different (i.e., the negatively charged moiety is charged with ⁇ 2 net charge).
  • the salt adduct comprises a positively charged moiety charged with +n net charge (originating from one or more positively charged functional groups, which may be the same or different), and a negatively charge moiety having ⁇ n (originating from one or more negatively charged functional groups, which may be the same or different) net charge, wherein n is an integer which may be equal to 1, 2, 3, 4, 5 or 6.
  • a “positively charged moiety of a salt adduct” of the invention is the corresponding acid of pyridoxine, or any derivative thereof.
  • the positive charge of the positively charged moiety stems from the protonated basic nitrogen atom of pyridoxine (as for example in compound (2)) or any derivative thereof (such as for example compounds of formula (I)).
  • the positively charged pyridoxine derivative is substituted with a positively charged functional group such as for example —NH 3 + , —CH 2 NH 3 + , —NH 2 R + , —NHR 2 + (wherein each R is independently a C 1 -C 6 alkyl), which may, in some embodiments, be present in addition to the positively charged protonated basic aromatic nitrogen atom in the pyridine ring.
  • a positively charged functional group such as for example —NH 3 + , —CH 2 NH 3 + , —NH 2 R + , —NHR 2 + (wherein each R is independently a C 1 -C 6 alkyl), which may, in some embodiments, be present in addition to the positively charged protonated basic aromatic nitrogen atom in the pyridine ring.
  • a “carboxylated 5- to 7-membered lactam ring” of a salt adduct of the invention is meant to encompass a ⁇ -lactam, ⁇ -lactam or ⁇ -lactam rings, having a negatively charged carboxylate group (—COO ⁇ ) substituted thereto.
  • said carboxylate group is substituted at the lactam ring carbon atom adjacent to the amide nitrogen.
  • said carboxylated lactam ring is a L-2-pyrrolidone-5-carboxylate (compound (1)).
  • said carboxylate group is substituted on any position of the lactam ring.
  • said carboxylated 5- to 7-membered lactam ring may be substituted by another substituent at any position on the lactam ring.
  • halogen as used herein means F, Cl, Br or I.
  • C 1 -C 6 alkyl represents a saturated, branched or straight hydrocarbon chain having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • Typical C 1-6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and the like.
  • C 2 -C 6 alkenyl represents a branched or straight hydrocarbon chain having 2, 3, 4, 5 or 6 carbon atoms and at least one double bond positioned between any two carbons of the chain.
  • Examples of such groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl and the like.
  • C 2 -C 6 alkynyl represents a branched or straight hydrocarbon chain having 2, 3, 4, 5 or 6 carbon atoms and at least one triple bond positioned between any two carbons of the chain.
  • Examples of such groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl and the like.
  • C 1 -C 6 alkoxy refers to the radical —O—C 1-6 alkyl, wherein C 1-6 alkyl is as defined above.
  • Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
  • C 1 -C 6 alkylthio refers to the radical —S—C 1-6 alkyl, wherein C 1-6 alkyl is as defined above. Representative examples are methylthio, ethylthio, isopropylthio, n-propylthio, butylthio, pentylthio and the like.
  • cycloalkyl as used herein represents a monocyclic, carbocyclic group having 3, 4, 5, 6, 7 or 8 carbon atoms, but may also include heteroatoms such as N, O and/or S. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • aryl as used herein is intended to include carbocyclic aromatic ring systems such as phenyl, biphenylyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl and the like.
  • Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and the like.
  • heteroaryl refers to ring systems in which at least one ring is an aromatic ring in which at least one atom is a non-carbon atom, either substituted or non-substituted, where the non-carbon atom may be, for example, a nitrogen, sulfur or oxygen atom.
  • C 1 -C 6 alkoxycarbonyl refers to the radical —C(O)O—C 1-6 alkyl, wherein C 1-6 alkyl is as defined above.
  • C 1 -C 6 alkoxy and “C 1 -C 6 alkylthio” as used herein refers to the radicals C 1-6 —O— and C 1-6 —S—, respectively, wherein C 1-6 alkyl is as defined above.
  • hydroxyl refers to the radical —OH.
  • thiol refers to the radical —SH.
  • formyl refers to the radical —COH.
  • cyano refers to the radical —CN.
  • nitro refers to the radical —NO 2 .
  • amine refers to —NH 3 or any primary (—NH 2 R), secondary (—NHR 2 ), tertiary (—NR 3 ) or quarternary amines (—NR 4 + ), wherein each R may be the same or different and independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl as defined herein above.
  • C 1 -C 6 carboxyalkyl refers to the radical —CO—(C 1 -C 6 alkyl), wherein C 1-6 alkyl is as defined above.
  • aminocarbonyl refers to the radical —CONR 2 , wherein each of groups R is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl as defined herein above.
  • alkoxycarbonylalkyl refers to the radical —OCO—(C 1 -C 6 alkyl), wherein C 1-6 alkyl is as defined above.
  • amino refers to the radical —C( ⁇ NH)—NH 2 .
  • Such substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, an alkylthio, an acyloxy, a phosphoryl, a phosphate, a phosphonate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aryl or heteroaryl moiety.
  • moieties of a salt adduct of the invention may contain each at least one chiral center, and thus may exist in, and be isolated as, any stereoisomer thereof including, enantiomers, diastereomers or any mixtures thereod including, but not limited to racemic mixtures.
  • the present invention includes any possible stereoisomer (e.g. enantiomers, diastereomers), any mixtures thereof including, but not limited to, racemic mixtures, of any of the individual moieties of a salt adduct of the invention.
  • each of the moieties of a salt adduct of the invention may be separated by conventional techniques, such as preparative chromatography.
  • the moieties of a salt adduct of the invention may be each prepared in any mixture of possible stereoisomers thereof, including but not limited to racemic mixtures thereof, or individual stereoisomers (e.g. enantiomers, diastereomers) may be prepared either by enantiospecific synthesis or by chiral chromatographic separation of a racemate.
  • the invention should be understood to encompass natural and non-natural amino acids or any derivative thereof.
  • non-natural amino acid refers herein to amino acids, or any derivative thereof, that are not among the amino acids which are the building blocks of proteins having L as well as D-configurations, while “natural amino acids”, refer to amino acids or any derivative thereof, which are the building blocks of proteins, having L as well as D-configurations.
  • Table 1 depicts several examples of salt adducts of the present invention.
  • bio-available 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.
  • treating refers to mitigating, improving, relieving 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. Treatment as used herein also encompasses treatment of healthy individuals.
  • metadoxine or metadoxine derivatives 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.
  • 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.
  • excipient refers to an inactive substance used as a carrier for the active ingredient in a formulation.
  • 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.
  • 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.
  • 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.
  • 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 in .
  • non-invasive refers to modes of treatment which do not puncture the skin.
  • 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 or metadoxine derivatives composition described herein.
  • chronic administration refers to giving a measured quantity of a medication on a regular basis to a subject.
  • chronic administration is to treat or prevent one or more chronic conditions, problems 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.
  • 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.
  • t 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:
  • ⁇ ⁇ and ⁇ z are the apparent absorption and elimination rate constants, respectively.
  • the present invention provides a method for improvement of cognitive function and/or behavior in healthy patients or patients suffering from Attention Deficit/Hyperactivity Disorder (ADHD/ADD), impaired memory (Amnesia), mental fatigue conditions, poor concentration, and poor focus comprising administering a composition comprising metadoxine or a derivative thereof.
  • the method comprises non-chronic administration of a composition comprising metadoxine or a derivative thereof.
  • the present invention provides a method for increasing the mean t max of metadoxine or metadoxine derivatives in the blood of a subject for improving or treating cognitive condition as herein defined, comprising administering a composition comprising metadoxine or a derivative thereof, and especially wherein the composition comprises metadoxine or a derivative thereof formulated in whole or in part for sustained or controlled release.
  • the method comprises non-chronic administration of a composition comprising metadoxine or a derivative thereof formulated in whole or in part for sustained or controlled release.
  • the mean t max of metadoxine or metadoxine derivative in the blood of a subject is increased by 50%, 100%, 150%, 200%, 300%, 400%, 500% or greater than 500%.
  • the application provides a method for increasing the half-life (t 1/2 ) of metadoxine or a metadoxine derivative in the blood or serum of a subject, for improving or treating cognitive condition as herein defined, comprising administering a composition comprising metadoxine or a derivative thereof, and especially wherein the composition comprises metadoxine or a derivative thereof formulated in whole or in part for sustained release or controlled release, optionally including a portion of the metadoxine or a metadoxine derivative formulated for immediate release.
  • the t 1/2 of metadoxine or metadoxine derivative in the blood or serum of a subject is increased by 50%, 100%, 150%, 200%, 300%, 400%, 500% or greater than 500%.
  • the metadoxine or 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 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 derivative thereof is formulated for non-chronic administration. Metadoxine or metadoxine derivative formulations used by the invention are described in more detail below.
  • the present invention provides a composition comprising metadoxine or a derivative thereof formulated for sustained and/or controlled release when administered to a subject for improving or treating cognitive condition as herein defined for improving or treating cognitive condition as herein defined.
  • the present invention provides a composition comprising metadoxine or a 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 for improving or treating cognitive condition as herein defined.
  • effective serum levels of the active ingredient are achieved within from about 10 to about 20 or 30 or 40 or 50 or 60, 90 minutes, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h following metadoxine or metadoxine derivative administration. In certain embodiments, effective serum levels of the active ingredient in said subject are achieved within from about 5 to about 20 or 30 or 40 or 50 or 60, 90 minutes, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h following metadoxine or metadoxine derivative administration.
  • effective serum levels of the active ingredient are achieved within from about 20 to about 20 or 30 or 40 or 50 or 60, 90 minutes, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h following metadoxine or metadoxine derivative administration. In certain embodiments, effective serum levels of the active ingredient are achieved within about 5, 10, 15, 20, 30, 40, 50 or 60, 90 minutes, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h.
  • the present inventors have developed innovative approaches for the administration of metadoxine or metadoxine derivative based on enteral (via the digestive tract) and/or parenteral (other routes than digestive tract) routes (WO2009/004629). 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.
  • 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.
  • 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).
  • the delivery system of interest may be in liquid form, for example a drop solution, syrup.
  • the delivery system of interest may be in form of a beverage or food article.
  • 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.
  • 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.
  • the delivery system may be a food or beverage article comprising a physiologically active pyridoxine derivative, particularly pyridoxol L,2-pyrrolidon-5 carboxylate (metadoxine).
  • a physiologically active pyridoxine derivative particularly pyridoxol L,2-pyrrolidon-5 carboxylate (metadoxine).
  • 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. Examples may be sweets, chocolate, candies and candy bars, energy bars, ice creams, pastry products and the like.
  • parenteral ways of administration include subcutaneous, transferal (diffusion through the intact skin), transmucosal (diffusion through a mucous membrane), sublingual, buccal (absorbed through cheek near gumline) administration, or administration by inhalation.
  • the compositions used by the invention are not administered by invasive modes of treatment (i.e., are non-invasive).
  • the metadoxine or metadoxine derivative compositions are not administered by intravenous injection.
  • compositions used by 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.
  • 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 or metadoxine derivative 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 or metadoxine derivative to the treated subject.
  • the present invention uses 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.
  • a physiologically active pyridoxine particularly pyridoxol L,2-pyrrolidon-5 carboxylate (metadoxine)
  • metaldoxine pyridoxol L,2-pyrrolidon-5 carboxylate
  • serum levels of the active ingredient are achieved within from about 10 to about 40-60 minutes following administration.
  • the invention employs 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 improvement of cognitive behavior in a subject in need thereof, comprising as the active ingredient said pyridoxine derivative, in a suitable carrier.
  • a physiologically active pyridoxine derivative particularly pyridoxol L,2-pyrrolidon-5 carboxylate (metadoxine)
  • metaldoxine pyridoxol L,2-pyrrolidon-5 carboxylate
  • serum levels of said active ingredient are achieved within from about 10 to about 40-60 minutes following administration.
  • the drug delivery systems employed by the invention may be designed for oral, nasal, ocular, rectal, subcutaneous, transferal, transmucosal, sublingual, buccal or inhalation administration.
  • the drug delivery systems may provide the active substance in a controlled release mode.
  • the drug delivery systems of the invention may further comprise at least one additional pharmaceutically active agent.
  • the delivery systems used by the invention may generally comprise a buffering agent, an agent that 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.
  • 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 pharmaceutically active substances is well known in the art.
  • the active agent can be delivered by any pharmaceutically acceptable route and in any pharmaceutically acceptable dosage form.
  • 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 single dosage form or in separate dosage forms to be administered together or independently.
  • 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.
  • 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.
  • a non-toxic pharmaceutically acceptable inert carriers such as ethanol, glycerol, water and the like.
  • 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.
  • 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.
  • the pharmaceutically acceptable carrier is magnesium stearate. Additional pharmaceutical excipients commonly accepted and used are found in, for example, Remington's Pharmaceutical Sciences (Genn):
  • 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.
  • aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes.
  • 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.
  • metadoxine in human serum is very short. Lu Yuan et al. ( Chin. Med. J 2007 120(2) 160-168), showed 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, 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 or metadoxine derivative 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.
  • the delivery system used by this invention may be administered in controlled release formulations.
  • 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).
  • 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).
  • compositions comprising a salt adduct as defined by the invention formulated as a single dose.
  • Said single dose formulation may be an immediate release formulation, a burst formulation, a prolonged release formulation, a sustained release formulation or any other controlled release formulation known to a person skilled in the art.
  • a composition comprising a salt adduct defined by the invention may be a combined dosage formualtion, wherein different types of formulations are administered to a subject, i.e. any combination of an immediate release formulation, a burst formulation, a prolonged release formulation, a sustained release formulation or any other controlled release formulation known to a person skilled in the art, given either in a single dose or in separate doses given seperately, concomitantly or sequentially wherein the gap of time between administration of separate dosages is defined based on the condition and severity of disease or disorder of a subject or the physical condition of said subject.
  • a composition used by the methods of the invention are formulated as combined dosage forms, wherein at least one dosage from of a suit adduct defined by the invention is in an immediate release form and at least one doage form of a salt adduct defined by the invention (being the same or different from the salt adduct formulated in the immediate release formulation) is formulated as a controlled (slow and/or sustained) release formulation.
  • the weight ratio of a salt adduct as defined by the invention comprised in said at least one immediate release formulation and at least one controlled release formulation may be 1:1, 1:2, 2:1, 3:2, 2:3, 1:3, 3:1, 4:1, 1:4, 5:2, 2:5, 1:5, 5:1.
  • said at least one immediate release form and at least one controlled release form of a salt adduct defined above may be administered to a subject seperately, concomitantly, sequentially, concurrently, consequetively and so forth.
  • said at least one immediate release form is administered initially.
  • said at least one controlled release formulation is administered initially.
  • the metadoxine or metadoxine derivative 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 or metadoxine derivative in compositions used by 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 or metadoxine derivative in compositions used by 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 or metadoxine derivative in compositions used by 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.
  • the metadoxine or metadoxine derivative in compositions used by the invention may be in immediate, fast of burst release form.
  • the metadoxine or metadoxine derivative in compositions used by 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 or metadoxine derivative in about 0.5, 1, 2, 3, 4, 5, 6, 7 or 8 hours.
  • the metadoxine or metadoxine derivative in compositions used by 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 or metadoxine derivative in about 0.5, 1, 2, 3, 4, 5, 6, 7 or 8 hours.
  • the metadoxine or metadoxine derivative in compositions used by the invention may be in a combination of sustained or slow release and immediate or fast release forms.
  • the relative proportion of sustained or slow release metadoxine or metadoxine derivative to immediate or fast release metadoxine or metadoxine derivative 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.
  • a polymeric material is used to sustain or control the release of metadoxine or metadoxine derivative.
  • the type of polymeric material and the amount of which is used has a strong influence on the rate of release of metadoxine or metadoxine derivative from the product of the present invention.
  • polymers include both hydrophobic and hydrophilic polymers.
  • 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 methyl-cellulose polyvinyl alcohol, polyethylene, polypropylene, polystyrene, polyacrylamide, ethylene vinyl acetate copolymer, polyacrylate, poly-urethane, 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.
  • a polymeric material to be used in compositions of or used by the invention is microcrystalline cellulose such as “Avicel PH 101” manufactured by FMC BioPolymer's.
  • a polymeric material to be used in compositions of or used by the invention is hydroxypropyl methyl-cellulose such as “Metholose”, produced by Shin-Etsu Chemical Co.
  • a polymeric material to be used in compositions of or used by the invention is ethyl cellulose such as “EthocelTM”, manufactured by The Dow Chemical Company.
  • a polymeric material to be used in compositions of or used by the invention is an acrylic polymer such as “Eudragit RSTM”, produced by Rohm GmbH.
  • a polymeric material to be used in compositions of or used by the invention is a colloidal silicone dioxide such as “AerosilTM”, manufactured by Degussa.
  • a polymeric material to be used in compositions of or used by the invention is a poly(vinyl acetate) such as “Kollicoat SR”, manufactured by BASF.
  • a polymeric material to be used in compositions of or used by the invention is an ethyl acetate and vinyl acetate solution such as “Duro-Tak”, manufactured by Delasco Dermatologic Lab & Supply, Inc.
  • composition of or used by the invention comprises or consists essentially of Formula 1.
  • Formula 1 comprises or consists essentially of 100-3000 mg metadoxine or metadoxine derivative and 5-20,000 mg Metholose.
  • composition of or used by the invention comprises or consists essentially of Formula 2.
  • Formula 2 comprises or consists essentially of 100-3000 mg metadoxine or metadoxine derivative and 5-7000 mg Ethocel E10TM.
  • composition of or used by the invention comprises or consists essentially of Formula 3.
  • Formula 3 comprises or consists essentially of 100-3000 mg metadoxine or metadoxine derivative and 5-20,000 mg Eudragit RSTM
  • compositions of or used by 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 or metadoxine derivative. In certain embodiments, the compositions of or used by 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 101TM.
  • the compositions of or used by 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.
  • the polymeric material is Metholose, Ethocel E10TM or Eudragit RSTM.
  • Metholose comprises or consists essentially of between 1 and 90% of the formulation, preferably between 5 and 70%.
  • EthocelTM comprises or consists essentially of between 1 and 30% of the formulation, preferably between 2 and 20%.
  • EudragitTM comprises or consists essentially of between 1 and 90% of the formulation, preferably between 5 and 70%.
  • delivery systems of or used by the invention comprise delivery devices.
  • the compositions of or used by 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 imbibition of water results in formation of a saturated solution of active material within the core, which is dispensed at controlled rate from the delivery orifice in the membrane.
  • the compositions of or used by the invention are delivered using biodegradable microparticles.
  • 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.
  • the biodegradable polymers that can be used for the microparticle matrix comprises polylactic acid (PLA) or the copolymer of lactic and glycolic acid (PLAGA).
  • PLAGA polylactic acid
  • PLAGA copolymer of lactic and glycolic acid
  • the preparation of or used by the present invention may also contain an absorption enhancer and other optional components.
  • absorption enhancers include, but are not limited to, cyclodextrins, phospholipids, chitosan, DMSO, Tween, Brij, glycocholate, saponin, fusidate and energy based enhancing absorption equipment.
  • 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.
  • 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.
  • the diluents include, for example, ethanol, sorbitol, glycerol, water and the like.
  • 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.
  • Lubricants are used to facilitate manufacture; examples of suitable lubricants include, for example, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, and polyethylene glycol.
  • 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.
  • Stabilizing agents such as antioxidants, include, but are not limited to, propyl gallate, sodium ascorbate, citric acid, calcium metabisulphite, hydroquinone, and 7-hydroxycoumarin.
  • compositions of or used by the invention may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, preservatives, and the like.
  • compositions of or used by the invention may be used alone or in combination with one or more additional therapeutic agents, for the improvement of cognitive behavior.
  • additional therapeutic agents are: amphetamines, methylphenidate HCl, dexmethylphenidate hydrochloride, atomoxetine, reboxetine, fluoxatine, sertraline, paroxetine, fluoroxamine, citalopram, venlafaxine, bupropion, nefazodone and mirtazapine.
  • 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.
  • 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.
  • 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.
  • the present invention provides a use of metadoxine or metadoxine derivative (including a functional, physiologically acceptable derivative of metadoxine) in the manufacture of a therapeutic composition useful for administering to a subject for improvement of cognitive function or treatment and/or prevention of cognitive disorders or malfunction according to any one of the methods of the invention as described herein.
  • Metadoxine was formulated at various ratios of immediate release and slow release according to Table 1:
  • FIG. 1 shows that Metadoxine reaches maximal concentration immediately after about 0.5 hour and may remain in the blood for up to about 7 hours. After singe administration in healthy Caucasian subjects, dose-linearity was demonstrated for C max and AUC over the dose range of 700 to 2100 mg.
  • the total dose of metadoxine administered was 1400 mg, in dual (combined immediate and slow) release formulation.
  • Tests at inclusion included selection of patients, and included clinical diagnosis by DSM IV, psychiatric examination, WURS & ASRS questionnaires, TOVA (Test of Variables of Attention) score, Wechsler (Wechsler Adult Intelligence Scale) subtests, BDI (Beck Depression Inventory) and STAI (State-Trait Anxiety Inventory) questionnaire. More than one week after the inclusion, the participants were given a single dose of Metadoxine SR (1400 mg) and after 90 minutes performed again the Wechsler subtests and the TOVA test.
  • the TOVA is a computerized test developed to assess attention and impulsivity in normal and clinical populations.
  • Main outcome measures for the TOVA are the Omission Standard Score (SS; inattention measure) the Commission Standard Score (SS; measure of impulse control), the Response Time (RT) SS, the Variability in RT SS, and overall ADHD SS (a composite score of the previous submeasures).
  • the Primary outcome measure was the ADHD Score, TOVA Omission, TOVA Commission, TOVA RT and TOVA Variability analysed as Standard Score in % compared to the patient's prior performance of the TOVA test at baseline. Secondary outcome measures were Subtests from Weschler: Digit span, Symbol Search, Digit symbol.
  • the results of the TOVA test indicate statistically significant improvement in all TOVA parameters those related to inattention (number of omissions, greater stability in Response Time and decrease in overall ADHD score) and those related to impulsivity (number of commissions).
  • a single tablet was administered to each patient comprising 1400 mg dose of DER Metadoxine.
  • the total dose of metadoxine administered was 1400 mg, in dual extended release formulation.
  • Metadoxine DER (1400 mg) and perfomed the TOVA test after the following time periods: 90 minutes, 4 hours and 7 hours.
  • the TOVA is a computerized test developed to assess attention and impulsivity in normal and clinical populations.
  • Main outcome measures for the TOVA are the Omission Standard Score (SS; inattention measure) the Commission Standard Score (SS; measure of impulse control), the Response Time (RT) SS, the Variability in RT SS, and overall ADHD SS (a composite score of the previous submeasures).
  • the Primary outcome measure was the ADHD Score, TOVA Omission, TOVA Commission, TOVA RT and TOVA Variability analysed as Standard Score in % compared to the patient's prior performance of the TOVA test at baseline. Secondary outcome measures were Subtests from Weschler: Digit span, Symbol Search, Digit symbol.
  • the double-blind study compared the cognitive performance of 14 healthy adults (ages 18-40) using cognitive tasks following a 24-hour period of total sleep deprivation (TSD).
  • TSD total sleep deprivation
  • Standardized neuropsychological testing was conducted in cognitive domains which have previously been shown to be affected by sleep and/or sleep deprivation, such as processing speed, attention, and inhibition.
  • Each participant was administered with one of two counterbalanced treatment conditions: (1) Composition of the invention (single dose 1400 mg DER Metadoxine) or (2) Placebo.
  • An actigraph is a small, light device ( ⁇ size of a wrist watch), placed on the subject's non-dominant wrist, which contains a movement sensor (accelerometer) that collects physical movement data sampled several times per second and stored in 1-minute epochs. Sleep/wake patterns were monitored using actigraphy, which has been validated against polysomnography, resulting in high correlations on sleep measures. Participants continuously wear an actigraph starting one week before the experimental phase until the end of the active protocol. Actigraphs are waterproof and durable and attached using non-removable wristbands, to ensure they are worn continuously.
  • Digit Symbol Substitution Test (DSST) (WAIS-III) is a paper-and-pencil processing speed task that measures visual-motor coordination and processing speed. It consists of nine digit-symbol pairs followed by a list of digits. Under each digit the subject is asked to write down the corresponding symbol as quickly as possible. The number of correct symbols within the allowed time (120 seconds) is measured.
  • CPT Connors' Continuous Performance Task
  • Digit Span (WA IS-III) is a test of attention, concentration, and working memory. Subjects are given sets of digits to repeat initially forwards then backwards. The task takes approximately 5 minutes to complete.
  • Paced Auditory Serial Addition Task—3rd Edition is a computerized task that measures auditory information processing speed and flexibility, as well as working memory. Single digits are presented either every 3 seconds (trial 1) or every 2 seconds (trial 2), and the patient must add each new digit to the one immediately prior to it.
  • the PASAT is presented on compact disk to control the rate of stimulus presentation.
  • the test score is the total number of correct sums given (out of 60 possible) in each trial. This task takes approximately 8 minutes to complete.
  • the tests were performed by a trained staff and took approximately 45 minutes to complete.
  • KSS Karolinska Sleepiness Scale
  • Likert scales asking about motivation to perform well, ability to concentrate, amount of effort required to perform the task, and perceived task difficulty.
  • the Likert questions are useful in examining whether performance is related to subjective effort, task difficulty, or sleepiness.
  • MC1 mild cognitive impairment
  • test 1 Twenty five patients of 60-79 years suffering from mild cognitive impairment (MC1) perform computerized neuropsychological test (Mindstreams) at the beginning of the study—(control 1), following 1 week administration of 350 mg metadoxine formulation twice a day (test 1), following 1 week wash-out period (control 2) and following 1 week administration of placebo formulation (test 2).
  • control 1 Twenty five patients of 60-79 years suffering from mild cognitive impairment (MC1) perform computerized neuropsychological test (Mindstreams) at the beginning of the study—(control 1), following 1 week administration of 350 mg metadoxine formulation twice a day (test 1), following 1 week wash-out period (control 2) and following 1 week administration of placebo formulation (test 2).
  • test 2 Twenty five patients of 60-79 years suffering from mild cognitive impairment (MC1) perform computerized neuropsychological test (Mindstreams) at the beginning of the study—(control 1), following 1 week administration of 350 mg metadoxine formulation twice a day (test 1), following 1 week wash-out period (control 2) and following 1 week administration
  • results are analyzed for differences between control and test. An improvement in some parameters like: digit recall, pattern recall with drug compared to placebo is expected.
  • Immediate release tablets were prepared using high shear wet granulation technology according to the following composition:
  • Metadoxine 500 milligrams Avicel PH 101 TM 72 milligrams PVP K-30 28 milligrams Magnesium stearate 5 milligrams
  • Metadoxine 455 milligrams Metholose 90SH 152 milligrams Ethocel E10 TM 25 miligrams Aerosil 200 5 milligrams Magnesium stearate 7 milligrams
  • the immediate release formulation released more than 90% in 0.5 hour, while slow release tablets released about 70% over 8 hours.
  • Granules were prepared using high shear granulation and vacuum drying. This is an example of an acrylic hydrophobic polymer as a polymeric material.
  • Metadoxine 350 milligrams per capsule Calcium carbonate 45 milligrams per capsule Eudragit RS TM 60 milligrams per capsule
  • Syrup is prepared using an overhead rotary mixer.
  • Metadoxine slow release granules (from Example 8) are mixed in xylitol solution. Cherry flavor is added.
  • Granules No. 1 Metadoxine 500 milligrams PVP K-25 10 milligrams Granules No 2: Metadoxine 800 milligrams Metholose 90SH 200 milligrams Ethocel E10 TM 50 milligrams Final Mix: Magnesium stearate 10 milligrams Aerosil 200 TM 5 milligrams Strawberry flavor 10 milligrams
  • Granules No 1 immediate absorption formula
  • Granules No 2 slow release formula
  • Metadoxine 2500 milligrams Durotak 387-2287 200 milligrams Ethanol 10 milliliters Water 5 milliliters
  • Micro granules are prepared using extrusion technology:

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US20100256198A1 (en) * 2007-07-03 2010-10-07 Alcobra Ltd. Method for decreasing symptoms of alcohol consumption
US8476304B2 (en) 2007-07-03 2013-07-02 Alcobra Ltd. Method for decreasing symptoms of alcohol consumption
US9808446B2 (en) 2007-07-03 2017-11-07 Alcobra Ltd. Method for decreasing symptoms of alcohol consumption
US8889715B2 (en) 2008-07-29 2014-11-18 Alcobra Ltd. Substituted pyridoxine-lactam carboxylate salts
US9428458B2 (en) 2008-07-29 2016-08-30 Alcobra Ltd. Substituted pyridoxine-lactam carboxylate-salts
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JP5770173B2 (ja) 2015-08-26
EP2445498A1 (en) 2012-05-02
EA023758B1 (ru) 2016-07-29
MX2011013775A (es) 2012-04-20
WO2010150261A1 (en) 2010-12-29
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HK1171370A1 (zh) 2013-03-28
BRPI1015231A2 (pt) 2018-02-20
JP2012531402A (ja) 2012-12-10
NZ597319A (en) 2014-06-27
AU2010264074A1 (en) 2012-01-19
CA2766107A1 (en) 2010-12-29
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AU2010264074B2 (en) 2014-08-07

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