US20120029082A1 - Nutritional or therapeutic compositions to increase bodily glutathione levels - Google Patents

Nutritional or therapeutic compositions to increase bodily glutathione levels Download PDF

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US20120029082A1
US20120029082A1 US13/184,041 US201113184041A US2012029082A1 US 20120029082 A1 US20120029082 A1 US 20120029082A1 US 201113184041 A US201113184041 A US 201113184041A US 2012029082 A1 US2012029082 A1 US 2012029082A1
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selenium
glutathione
anhydride
ester
salt
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Albert Crum
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
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    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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    • A23L33/175—Amino acids
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
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    • A61P19/00—Drugs for skeletal disorders
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    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • This invention relates to nutritional or therapeutic compositions useful for treating mammals to increase their body content of glutathione above a pretreatment level thereby to enhance the immune activity of the treated mammal. More specifically, it relates to compositions containing a selenium compound together with a glutathione precursor which is a mixture of glutamic acid, cystine and glycine.
  • Glutathione is a tripeptide and a major reducing agent in the mammalian body. Its chemical structure is:
  • ROS reactive oxygen species
  • RNS reactive nitrogen species
  • Mammalian cells have numerous mechanisms to eliminate these damaging free radicals and reactive species.
  • One such mechanism includes the glutathione system, which plays a major role in direct destruction of reactive oxygen compounds and also plays a role in the body's defense against infection.
  • glutathione One of the most important contributions of glutathione to mammalian health is its participation in the proper functioning of the immune system to respond to infection or other types of trauma. It is known that weakening of the immune system caused by infection or other traumas occurs concurrently with depletion of glutathione in body tissues. It is known, also, that such weakening can be reversed by replenishing the supply of glutathione. It is believed that glutathione accomplishes its salutary effects by protecting immune cells against the ravages of oxidizing agents and free radicals.
  • compositions and methods to aid in elimination of damaging free radicals and reactive oxygen and nitrogen species.
  • One possible mechanism for achieving this may be through enhancement of glutathione levels in patients utilizing precursors for glutathione synthesis.
  • the mucous membrane is the membrane which lines those body passages which communicate directly or indirectly with the exterior.
  • the important parts of the mucous membrane are those portions which line the oral passage, the nose, the anus and the vagina since the compositions are intended for sublingual, buccal, nasal, anal and or vaginal delivery.
  • Oral delivery by sublingual or buccal routes is much preferred because of its convenience. Such delivery may be, for example, in the form of pills, lozenges and tablets which may be retained in the mouth until dissolved. In rare instances, parenteral delivery may be utilized, but this is normally not necessary.
  • compositions of this invention are:
  • the separate components serve as precursors for the metabolic formation of glutathione after they have been transported across the mucous membrane.
  • compositions may be used alone but, normally they will be employed in association with one or more non-toxic pharmaceutically acceptable carriers appropriate to the method of administration.
  • compositions will be utilized to increase the formation of glutathione and thus to enhance the immune activity of a mammal in need of such treatment.
  • the effect of the treatment is such that after the treatment, the mammal will be more resistant to microbial infection or other trauma adversely affecting immune activity than before such treatment.
  • compositions are useful to treat a wide variety of diseases associated with the presence of excess free radical or reactive oxygen or nitrogen species. These include, for example, cancer, Alzheimer's disease, arteriosclerosis, rheumatoid arthritis and other autoimmune diseases, cachexia, coronary artery disease, chronic fatigue syndrome, AIDS and others as will be apparent to the skilled artisan.
  • compositions described and claimed herein will contain components suitable for the anabolic production of glutathione once they have been transported through the mucous membrane.
  • the precursors of glutathione are glutamic acid, cystine and glycine.
  • the proposed components are amphoteric and therefore may be employed as non-toxic metal salts or acid addition salts.
  • the salts are alkalic or alkaline earth metal salts, preferably sodium, potassium or calcium sails.
  • Suitable acid addition salts include salts of hydrochloric, phosphoric and citric acid.
  • amino acids may also be employed in the form of certain of their derivatives including esters and anhydrides which before or after transport through the mucous membrane will be modified into the form in which they will be joined together to form glutathione.
  • glutamic acid cystine, glycine
  • the sulfur containing amino acid in the compositions of this invention is cystine.
  • the sulfur containing amino acid moiety in glutathione is cysteine.
  • the latter contains a sulfhydryl group. In the former molecule, two cysteine molecules are joined via a disulfide bond.
  • cystine is used in the compositions of this invention. Upon reductive cleavage of the disulfide bridge, two molecules of cysteine are formed. Thus each molecule of cystine is capable of forming two molecules, of cysteine, each of which will join with glutamic acid and glycine to form two molecules of glutathione.
  • the only component in the novel compositions of this invention which may be toxic is selenium. Accordingly, in providing dosage units for mammalian administration by any selected route, the limiting factor is to avoid treatment either with single or multiple dosage units at such levels that the total delivery of selenium is close to its toxic limit.
  • the recommended daily dosage for humans therefore ranges from 10 to 75 ⁇ g per day.
  • the range may be generally higher but will, of course, depend upon the animal and its size.
  • compositions of this invention for daily delivery and the duration of the period of such delivery will depend upon the professional judgment of the physician or veterinarian in attendance. Numerous factors will be involved in that judgment such as age, body weight, physical condition of the patient or animal and the ailment or disorder being treated.
  • Selenium is one of numerous trace metals found in many foods.
  • selenium may be employed as one of several non-toxic, water soluble organic or inorganic selenium compounds capable of being absorbed through the mucosal membrane.
  • the presently preferred inorganic selenium compounds are aliphatic metal salts containing selenium in the form of selenite or selenate anions.
  • organic selenium compounds are more preferred because they are normally less toxic than inorganic compounds.
  • Other selenium compounds which may be mentioned by way of example include selenium cystine, selenium methionine, mono- and di-seleno carboxylic acids with about seven to eleven carbon atoms in the chain.
  • Seleno Amino acid chelates are also useful. Any of these selenium compounds may be considered for use in the present invention as selenium precursors.
  • selenium as employed in the composition be capable of transport through the mucosal membrane of the patient under treatment. For this reason, water insoluble selenium compounds are not generally useful.
  • selenium is sometimes used hereinafter to include any of the various water soluble selenium products which can be transported through the mucosal membrane in the practice of this invention. It will be understood, however, that the particular forms of selenium compounds set forth herein are not to be considered limitative. Other selenium compounds, which exhibit the desired activity and are compatible with the other components in the mixture and are non-toxic, can be used in the practice of the invention. Many of them are available commercially.
  • the amount of selenium precursor employed in the novel compositions is only enough to provide a catalytic quantity of the element to activate the glutathione system.
  • the catalytic quantity of selenium precursor utilized in the compositions of this invention is such that it will produce either in one dosage unit or in multiple dosage units sufficient elemental selenium to promote the production and activation of glutathione. Typically, this will be at or near the recommended daily allowance of selenium for the individual mammal under treatment. This amount will be well below the toxicity limit for elemental selenium.
  • a representative range of catalytic quantities of selenium precursors is set forth in the present application in paragraph [0026] on page 6, as shown to be effective based on the age of the individual.
  • the presently preferred method of transdermal delivery for the novel compositions is oral, either sublingual or buccal. It is convenient to provide dosage units for such delivery in the form of pills, lozenges or tablets such as gelled tablets which will slowly dissolve in the mouth.
  • Nasal delivery will typically be accomplished by sprays or drops. Suppositories will be useful for rectal or vaginal delivery.
  • compositions used in the method of the invention comprise a therapeutically effective amount of combined glutamic acid, cystine, glycine and a selenium precursor in a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable means one that is generally recognized as safe, approved by a regulatory agency of the federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the active compounds are administered.
  • compositions which may be provided in bulk or dosage unit form are prepared in accordance with standard pharmaceutical practice and may contain excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • Sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil may also be useful.
  • the composition if desired, can also contain
  • Buffering agents are sometimes used in the compositions of the invention to maintain a relatively constant hydrogen ion concentration in the mouth (pH about 7.5) or other point of entry.
  • An appropriate buffering agent may be selected from numerous known reagents including, for example phosphate, carbonate and bicarbonate systems.
  • Alpha-lactalbumin is useful because of its buffering properties. Additionally, it is non-toxic, water soluble and contains appreciable amounts of the required amino acids.
  • compositions may also contain mucous membrane penetration enhancers such as sodium lauryl sulphate, sodium dodecyl sulphate, cationic surfactants such as palmitoyl DL carnitine chloride, cetylpyridinium chloride, non-ionic surfactants such as polysorbale 80, polyoxyethylene 9-lauryl either, glyceryl monolaurate, polyoxyalkylenes, polyoxyethylene 20 cetyl ether, lipids such as oleic acid, bile salts such as sodium glycocholate, sodium taurocholate and related compounds.
  • mucous membrane penetration enhancers such as sodium lauryl sulphate, sodium dodecyl sulphate, cationic surfactants such as palmitoyl DL carnitine chloride, cetylpyridinium chloride, non-ionic surfactants such as polysorbale 80, polyoxyethylene 9-lauryl either, glyceryl monolaurate, polyoxyalky
  • compositions of the invention are most conveniently utilized in dosage units for oral administration. They may be used alone but are preferably provided as tablets, suitably sublingual tablets. Such tablets may be prepared in one a day form or for intermittent use throughout the day, for example every three hours.
  • the tablets will typically weigh from about 0.5 to 5 grams and will contain a therapeutically effective amount of the essential ingredients together with the selected vehicle.
  • “Therapeutically effective” as used herein means the amount of the composition which is sufficient to achieve the desired result, i.e., enhancement of the immune system. It means that the immune system is more effective in combating infection after treatment than it was before treatment.
  • compositions of the invention can be provided in a number of different forms and at dosage levels appropriate to the individual mammal being treated.
  • tablets, elixers, solutions, emulsions, powders, capsules and other forms can be provided for one a day treatment or successive treatments on the same day for animals or humans whether male or female, whether infant, adolescent or adult.
  • the defining feature of this advantage is the amount of selenium precursor utilized since the other components are essentially non-toxic.
  • tablets and other forms of the immunoenhancing compositions can be prepared to provide any quantity of elemental selenium from less than 1 to 7.5 ⁇ g.
  • a tablet containing 10 ⁇ g of selenium methionine is capable of delivering 4 ⁇ g of elemental selenium
  • 7.5 ⁇ g of selenium methionine is capable of delivering 3 ⁇ g of selenium. Tablets may be given several times per day to achieve the desired immune enhancing effect.
  • a one a day tablet weighing two grams may contain 200 mg or more of the composition.
  • a similar tablet intended to be used every four hours may contain 50 mg to 100 mg or more of the therapeutically effective composition. Equivalent amounts of carrier and active components will be utilized in other compositions designed for other methods of administration.

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Abstract

Nutritional or therapeutic compositions containing glutamic acid, cystine, glycine and a selenium precursor and methods for their utilization to increase glutathione synthesis and thereby enhance the immune system are described.

Description

    STATEMENT OF PRIORITY
  • More than one application for the Reissue of U.S. Pat. No. 6,592,908 has been filed. The reissue applications are the present application, U.S. patent application Ser. No. 11/371,804, filed Mar. 9, 2006, and U.S. Ser. No. 11/181,001, filed Jul. 13, 2005, and issued as U.S. Pat. RE 39,734 on Jul. 17, 2007.
    • FIELD OF THE INVENTION
  • This invention relates to nutritional or therapeutic compositions useful for treating mammals to increase their body content of glutathione above a pretreatment level thereby to enhance the immune activity of the treated mammal. More specifically, it relates to compositions containing a selenium compound together with a glutathione precursor which is a mixture of glutamic acid, cystine and glycine.
    • BACKGROUND OF THE INVENTION
  • Glutathione is a tripeptide and a major reducing agent in the mammalian body. Its chemical structure is:
  • Figure US20120029082A1-20120202-C00001
  • or, more simply
  • GLU-CYS-GLY
  • Its chemical name is glutamyl-cysteinyl-glycine.
  • Like many other small peptides in the mammalian body, it is not synthesized by procedures involving DNA, RNA and ribosomes. Rather, it is synthesized from the amino acids available in the body by procedures utilizing enzymes and other body components such as adenosine triphosphate as an energy source.
  • It is generally recognized that many disease processes are attributed to the presence of elevated levels of free radicals, reactive oxygen species (ROS) and reactive nitrogen species (RNS), such as superoxide, hydrogen peroxide, singlet oxygen, peroxynitrite, hydroxyl radicals, hypochlorous acid (and other hypohalous acids) and nitric oxide.
  • Mammalian cells have numerous mechanisms to eliminate these damaging free radicals and reactive species. One such mechanism includes the glutathione system, which plays a major role in direct destruction of reactive oxygen compounds and also plays a role in the body's defense against infection.
  • It is known that insufficient levels of glutathione may result in the onset of numerous diseases. Diseases of aging appear to be associated with a drop in glutathione levels. Moreover, since there is no evidence of transport of glutathione into cells, glutathione must be produced intra cellularly.
  • One of the most important contributions of glutathione to mammalian health is its participation in the proper functioning of the immune system to respond to infection or other types of trauma. It is known that weakening of the immune system caused by infection or other traumas occurs concurrently with depletion of glutathione in body tissues. It is known, also, that such weakening can be reversed by replenishing the supply of glutathione. It is believed that glutathione accomplishes its salutary effects by protecting immune cells against the ravages of oxidizing agents and free radicals.
  • There is a need for compositions and methods to aid in elimination of damaging free radicals and reactive oxygen and nitrogen species. One possible mechanism for achieving this may be through enhancement of glutathione levels in patients utilizing precursors for glutathione synthesis.
  • There is some question as to whether orally ingested glutathione is available to enhance the immune system. Since it is a tripeptide, conventional wisdom suggests that it would be hydrolyzed in the intestinal system to release the free amino acids. Even if some of the tripeptide gets through the gastrointestinal wall intact, it is questionable whether it can be absorbed as such into the individual cell, rather than being synthesized intracellularly. Some experts are of the opinion that glutathione resists hydrolysis when taken orally. In any event, it is generally acknowledged that an increase in tissue and cellular concentrations of glutathione facilitates resistance to infective agents by enhancing the immune system.
  • The mucous membrane is the membrane which lines those body passages which communicate directly or indirectly with the exterior. For purposes of this invention, the important parts of the mucous membrane are those portions which line the oral passage, the nose, the anus and the vagina since the compositions are intended for sublingual, buccal, nasal, anal and or vaginal delivery. Oral delivery by sublingual or buccal routes is much preferred because of its convenience. Such delivery may be, for example, in the form of pills, lozenges and tablets which may be retained in the mouth until dissolved. In rare instances, parenteral delivery may be utilized, but this is normally not necessary.
    • BRIEF SUMMARY OF THE INVENTION
  • The essential components of the compositions of this invention are:
  • 1. A selenium precursor together with
  • 2. Glutamic acid, cystine and glycine.
  • The separate components serve as precursors for the metabolic formation of glutathione after they have been transported across the mucous membrane.
  • The compositions may be used alone but, normally they will be employed in association with one or more non-toxic pharmaceutically acceptable carriers appropriate to the method of administration.
  • The compositions will be utilized to increase the formation of glutathione and thus to enhance the immune activity of a mammal in need of such treatment. The effect of the treatment is such that after the treatment, the mammal will be more resistant to microbial infection or other trauma adversely affecting immune activity than before such treatment.
  • Because of their ability to increase production of glutathione, the compositions are useful to treat a wide variety of diseases associated with the presence of excess free radical or reactive oxygen or nitrogen species. These include, for example, cancer, Alzheimer's disease, arteriosclerosis, rheumatoid arthritis and other autoimmune diseases, cachexia, coronary artery disease, chronic fatigue syndrome, AIDS and others as will be apparent to the skilled artisan.
    • DETAILED DESCRIPTION OF THE INVENTION
  • In accordance with the present invention, the compositions described and claimed herein will contain components suitable for the anabolic production of glutathione once they have been transported through the mucous membrane. As presently conceived, the precursors of glutathione are glutamic acid, cystine and glycine.
  • It will be appreciated by the skilled artisan that the proposed components are amphoteric and therefore may be employed as non-toxic metal salts or acid addition salts. Typically, the salts are alkalic or alkaline earth metal salts, preferably sodium, potassium or calcium sails. Suitable acid addition salts include salts of hydrochloric, phosphoric and citric acid.
  • The amino acids may also be employed in the form of certain of their derivatives including esters and anhydrides which before or after transport through the mucous membrane will be modified into the form in which they will be joined together to form glutathione.
  • All of this will be readily appreciated by those skilled in the art. Accordingly, when the terms glutamic acid, cystine, glycine are employed both in the specification and claims they will be understood to mean not only the products themselves, but also those derivatives which can be converted to a unit of the glutathione molecule.
  • The sulfur containing amino acid in the compositions of this invention is cystine. The sulfur containing amino acid moiety in glutathione is cysteine. The latter contains a sulfhydryl group. In the former molecule, two cysteine molecules are joined via a disulfide bond.
  • However, it is not possible to utilize cysteine in compositions for mammals because it is somewhat toxic. Accordingly, in the compositions of this invention, cystine is used. Upon reductive cleavage of the disulfide bridge, two molecules of cysteine are formed. Thus each molecule of cystine is capable of forming two molecules, of cysteine, each of which will join with glutamic acid and glycine to form two molecules of glutathione.
  • Of course all amino acids employed in this invention, except glycine which does not form optical isomers, are in the natural or L-form.
  • Although wide variations are possible, it will be apparent that the optimum ratio of glutamic acid to cystine to glycine in the novel compositions described herein is 1:0.5:1. If an excess of any acid is used, it will presumably be of nutritional value or may simply be metabolized.
  • As will be apparent to the skilled artisan, the only component in the novel compositions of this invention which may be toxic is selenium. Accordingly, in providing dosage units for mammalian administration by any selected route, the limiting factor is to avoid treatment either with single or multiple dosage units at such levels that the total delivery of selenium is close to its toxic limit.
  • The recommended daily allowances for elemental selenium as reported in The Pharmacological Basis of Therapeutics, Ninth Edition, page 1540, The McGraw-Hill Companies, 1996 are as follows:
  • Years ug
    Infants 0.0-0.5 10
    0.5-1.0 15
    Children 1-3 20
    4-6 20
     7-10 30
    Males 11-14 40
    15-18 50
    19-24 70
    25-50 70
    51+ 70
    Females 11-14 45
    15-18 50
    19-24 55
    25-50 55
    50+ 55
    Pregnant — 65
    Lactating 1st six months 75
    2nd six months 75
  • The recommended daily dosage for humans therefore ranges from 10 to 75 μg per day. For animals the range may be generally higher but will, of course, depend upon the animal and its size.
  • The precise amount of the therapeutically useful compositions of this invention for daily delivery and the duration of the period of such delivery will depend upon the professional judgment of the physician or veterinarian in attendance. Numerous factors will be involved in that judgment such as age, body weight, physical condition of the patient or animal and the ailment or disorder being treated.
  • Selenium is one of numerous trace metals found in many foods. In the compositions of this invention, selenium may be employed as one of several non-toxic, water soluble organic or inorganic selenium compounds capable of being absorbed through the mucosal membrane. The presently preferred inorganic selenium compounds are aliphatic metal salts containing selenium in the form of selenite or selenate anions. However, organic selenium compounds are more preferred because they are normally less toxic than inorganic compounds. Other selenium compounds which may be mentioned by way of example include selenium cystine, selenium methionine, mono- and di-seleno carboxylic acids with about seven to eleven carbon atoms in the chain. Seleno Amino acid chelates are also useful. Any of these selenium compounds may be considered for use in the present invention as selenium precursors.
  • It is important for the practice of this invention that the selenium as employed in the composition be capable of transport through the mucosal membrane of the patient under treatment. For this reason, water insoluble selenium compounds are not generally useful.
  • For convenience, the term “selenium” is sometimes used hereinafter to include any of the various water soluble selenium products which can be transported through the mucosal membrane in the practice of this invention. It will be understood, however, that the particular forms of selenium compounds set forth herein are not to be considered limitative. Other selenium compounds, which exhibit the desired activity and are compatible with the other components in the mixture and are non-toxic, can be used in the practice of the invention. Many of them are available commercially.
  • In fact, the amount of selenium precursor employed in the novel compositions is only enough to provide a catalytic quantity of the element to activate the glutathione system. The catalytic quantity of selenium precursor utilized in the compositions of this invention is such that it will produce either in one dosage unit or in multiple dosage units sufficient elemental selenium to promote the production and activation of glutathione. Typically, this will be at or near the recommended daily allowance of selenium for the individual mammal under treatment. This amount will be well below the toxicity limit for elemental selenium. By way of non-limiting examples, a representative range of catalytic quantities of selenium precursors is set forth in the present application in paragraph [0026] on page 6, as shown to be effective based on the age of the individual.
  • As indicated above, the presently preferred method of transdermal delivery for the novel compositions is oral, either sublingual or buccal. It is convenient to provide dosage units for such delivery in the form of pills, lozenges or tablets such as gelled tablets which will slowly dissolve in the mouth.
  • Nasal delivery will typically be accomplished by sprays or drops. Suppositories will be useful for rectal or vaginal delivery.
  • This invention provides pharmaceutical compositions used in the method of the invention. Such compositions comprise a therapeutically effective amount of combined glutamic acid, cystine, glycine and a selenium precursor in a pharmaceutically acceptable carrier. In a particular embodiment, the term “pharmaceutically acceptable” means one that is generally recognized as safe, approved by a regulatory agency of the federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the active compounds are administered.
  • The compositions which may be provided in bulk or dosage unit form are prepared in accordance with standard pharmaceutical practice and may contain excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil may also be useful. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, coloring agents or buffering agents.
  • Buffering agents are sometimes used in the compositions of the invention to maintain a relatively constant hydrogen ion concentration in the mouth (pH about 7.5) or other point of entry. An appropriate buffering agent may be selected from numerous known reagents including, for example phosphate, carbonate and bicarbonate systems. Alpha-lactalbumin is useful because of its buffering properties. Additionally, it is non-toxic, water soluble and contains appreciable amounts of the required amino acids.
  • The compositions may also contain mucous membrane penetration enhancers such as sodium lauryl sulphate, sodium dodecyl sulphate, cationic surfactants such as palmitoyl DL carnitine chloride, cetylpyridinium chloride, non-ionic surfactants such as polysorbale 80, polyoxyethylene 9-lauryl either, glyceryl monolaurate, polyoxyalkylenes, polyoxyethylene 20 cetyl ether, lipids such as oleic acid, bile salts such as sodium glycocholate, sodium taurocholate and related compounds.
  • Examples of these suitable carriers are described in Remington's Pharmaceutical Sciences, Nineteenth Edition (1990), Mack Publishing Company, Easton, Pa. in Handbook of Pharmaceutical Excipients, published by The American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (1986) and the Handbook of Water-Soluble Gums and Resins, ed. By R. L. Davidson, McGraw-Hill Book Co., New York, N.Y. (1980). Compositions and methods of manufacturing compositions capable of absorption through the mucosal tissues are taught in U.S. Pat. No. 5,288,497. These publications are incorporated by reference herein in their entirety. They can be readily employed by the skilled artisan to devise methods of delivery other than those specifically described in this disclosure.
  • The compositions of the invention are most conveniently utilized in dosage units for oral administration. They may be used alone but are preferably provided as tablets, suitably sublingual tablets. Such tablets may be prepared in one a day form or for intermittent use throughout the day, for example every three hours.
  • The tablets will typically weigh from about 0.5 to 5 grams and will contain a therapeutically effective amount of the essential ingredients together with the selected vehicle. “Therapeutically effective” as used herein means the amount of the composition which is sufficient to achieve the desired result, i.e., enhancement of the immune system. It means that the immune system is more effective in combating infection after treatment than it was before treatment.
  • A particular advantage of the compositions of the invention is that they can be provided in a number of different forms and at dosage levels appropriate to the individual mammal being treated. For example, tablets, elixers, solutions, emulsions, powders, capsules and other forms can be provided for one a day treatment or successive treatments on the same day for animals or humans whether male or female, whether infant, adolescent or adult. The defining feature of this advantage is the amount of selenium precursor utilized since the other components are essentially non-toxic.
  • Referring to the table above, tablets and other forms of the immunoenhancing compositions can be prepared to provide any quantity of elemental selenium from less than 1 to 7.5 μg. For example, a tablet containing 10 μg of selenium methionine is capable of delivering 4 μg of elemental selenium, and 7.5 μg of selenium methionine is capable of delivering 3 μg of selenium. Tablets may be given several times per day to achieve the desired immune enhancing effect.
  • A one a day tablet weighing two grams may contain 200 mg or more of the composition. A similar tablet intended to be used every four hours may contain 50 mg to 100 mg or more of the therapeutically effective composition. Equivalent amounts of carrier and active components will be utilized in other compositions designed for other methods of administration.
  • The following examples are given by way of illustration only and are not to be considered a limitation since many apparent variations are possible without departing from the spirit or scope of the invention.
    • EXAMPLE 1 Tablet
  • Ingredients:
    89 mg cystine
    75 mg glycine
    147 mg glutamic acid
    22.5 μg polyvinylpynolidone
    61.25 mg lactose
    4.5 ml alcohol SD3A-200 proof
    9 mg stearic acid
    42.3 mg corn starch
    10 μg selenium methionine
  • Blend the cystine, glycine, glutamic acid, polyvinylpyrolidone and lactose together and pass through a 40 mesh screen. Add the alcohol slowly and knead well. Screen the wet mesh through a 4 mesh screen. Dry the granulation at 50 degrees centigrade for 10 hours. Pass the mixture of stearic acid, corn starch and selenium compound through a 60 mesh screen and tumble with the granulation until all the ingredients are well mixed. Compress using a 7/16 inch standard concave punch.
    • EXAMPLE 2
  • Tablet
  • Ingredients:
    178 mg cystine
    150 mg glycine
    294 mg glutamic acid
    5 μg selenium methionine
    126 mg lactose
    78 mg potato starch
    96 mg ethyl cellulose
    54 mg stearic acid
  • Thoroughly mix the ingredients in a blender, dry, put through a 12 mesh screen and compress into tablet using a 13/32 inch concave punch.

Claims (19)

1-12. (canceled)
13. A composition for increasing the level of glutathione in a mammal consisting essentially of:
(A) an anabolic precursor of glutathione, consisting of glutamic acid or a salt, an ester, or an anhydride thereof, cystine or a salt, an ester, or an anhydride thereof and glycine or a salt, an ester, or an anhydride thereof, which collectively convert to glutathione; and
(B) a source of selenium, in an amount that is non-toxic to the mammal on a daily total unit dosage delivery basis; wherein said source of selenium is selenium methionine, selenium cystine, a mono-seleno carboxylic acid with seven to eleven carbon atoms in a chain, or a di-seleno carboxylic acid with seven to eleven carbon atoms in a chain.
14. The composition according to claim 13 in unit dosage form.
15. The composition according to claim 13 in bulk form.
16. The composition according to claim 14 wherein the dosage unit is for oral administration.
17. The composition according to claim 14 wherein the dosage unit is for nasal administration.
18. The composition according to claim 14 wherein the dosage unit is for sublingual administration.
19. The composition according to claim 14 wherein the dosage unit is for buccal administration.
20. The composition according to claim 14 wherein the dosage unit is for anal or vaginal administration.
21. The composition of claim 13 wherein the mammal is a human.
22. The composition of claim 13 wherein one or more of said glutamic acid, cystine, and glycine are in the form of a salt, an ester, or an anhydride thereof.
23. The composition of claim 13 wherein the glutamic acid is in the form of a salt, an ester, or an anhydride thereof.
24. The composition of claim 13 wherein the cystine is in the form of a salt, an ester, or an anhydride thereof.
25. The composition of claim 13 wherein the glycine is in the form of a salt, an ester or an anhydride thereof.
26. A method of increasing the level of glutathione in a mammal comprising administering to said mammal an effective amount of a composition consisting essentially of:
(A) an anabolic precursor of glutathione, consisting of glutamic acid or a salt, an ester, or an anhydride thereof, cystine or a salt, an ester, or an anhydride thereof and glycine or a salt, an ester or an anhydride thereof, which collectively convert to glutathione; and
(B) a source of selenium, in an amount that is non-toxic to the mammal on a daily total unit dosage delivery basis; wherein said source of selenium is selenium methionine, selenium cystine, a mono-seleno carboxylic acid with seven to eleven carbon atoms in a chain, or a di-seleno carboxylic acid with seven to eleven carbon atoms in a chain.
27. The method of claim 26 wherein cystine converts to cysteine in the intracellular formation of glutathione.
28. The method of claim 26 wherein the source of selenium provides a unit dosage on an elemental basis of from 1 μg to 7.5 μg of selenium.
29. The method of claim 26, wherein the source of selenium is in a mucosal-membrane transportable form.
30. The method of claim 26, wherein the composition of for oral administration.
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