WO2024052700A1 - Compositions pour augmenter les taux de glutathion et leurs procédés de fabrication - Google Patents

Compositions pour augmenter les taux de glutathion et leurs procédés de fabrication Download PDF

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Publication number
WO2024052700A1
WO2024052700A1 PCT/GB2023/052336 GB2023052336W WO2024052700A1 WO 2024052700 A1 WO2024052700 A1 WO 2024052700A1 GB 2023052336 W GB2023052336 W GB 2023052336W WO 2024052700 A1 WO2024052700 A1 WO 2024052700A1
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WIPO (PCT)
Prior art keywords
selenium
cystine
glycine
microns
glutamine
Prior art date
Application number
PCT/GB2023/052336
Other languages
English (en)
Inventor
Albert Crum
Alberta CRUM
Joseph Fortunak
Original Assignee
The Proimmune Company, Llc
Tollett, Ian
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Proimmune Company, Llc, Tollett, Ian filed Critical The Proimmune Company, Llc
Publication of WO2024052700A1 publication Critical patent/WO2024052700A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • 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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds

Definitions

  • This invention relates to nutritional or therapeutic compositions and processes for making the same 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 or glutamine, cystine and glycine and processes to make the same.
  • Glutathione is a tripeptide and a major reducing agent in the mammalian body. Its chemical structure is: or, more simply GLU-CYS-GLY.
  • 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 intracellularly.
  • 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. There is a need for compositions and methods to aid in elimination of damaging free radicals and reactive oxygen and nitrogen species.
  • glutathione levels may be through enhancement of glutathione levels in patients utilizing precursors for glutathione synthesis.
  • 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.
  • 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.
  • Amino acid compositions of glutamine, cystine, and glycine have been demonstrated to increase intracellular levels of glutathione when taken as a nutritional composition. This effect is maximized when the availability of these amino acids is in the ratio of approximately 1.0:0.5: 1.0.
  • the use of catalytic amounts of selenium and preferably in the forms of L- selenomethionine or selenocystine is also further beneficial to this use. A method of manufacturing a homogeneous, stable composition for such a purpose is not readily available or apparent, however.
  • the NHANES III national survey reported that the mean dietary intake of selenium for adults in the US ranges between 100.5 and 158.5 mg/day. It is therefore readily apparent that for the purpose of catalyzing intracellular glutathione synthesis, the desired amount of selenium to be delivered should be sufficient to be effective but should not exceed the RDA. Thus, the target amount of elemental selenium to be delivered to an individual in compositions in the prior art (e.g., in US patent reissue numbers RE 39,374 and RE 42,645, both incorporated by reference in their entirety, it is between approximately 1 mg and 7.5 mg/day).
  • a problem to be addressed in the process for manufacturing such a product therefore is a reliable, reproducible means of manufacturing a homogeneous composition containing the desired doses of amino acids and selenium.
  • the difficulty of ensuring the homogeneity of the very low concentration of selenium present in the composition, so that an individual will not exceed the RDA of selenium intake, will be evident to one of skill in the art.
  • a product must contain very low amounts of selenium distributed evenly throughout the composition.
  • Example 2 of US RE 42, 645 E calls for 5 micrograms of selenium methionine to be evenly dispersed in 976 milligrams of amino acids and other ingredients to arrive at the desired composition.
  • composition The importance of stability of the composition will also be evident to one of skill in the art. This is important in terms of the uniformity of selenium content in the composition over time. It is further important in terms of the uniformity and stability of the amino acids contained in the composition over the lifetime of the product.
  • Compounded powders are known to be prone to segregation during mixing and upon storage.
  • Amino acids are also known to react with themselves (dimerization), or with excipients (e.g., the Maillard reaction between amino acid residues and reducing sugars), to yield degradation products over time.
  • a third problem to be solved in preparing such a pharmaceutical composition is convenience of administration. Large doses of a composition to be administered orally to a human are inconvenient. The likelihood of compliance with a recommended dose for a composition is inversely correlated with the size of the dose. Thus, the amounts of inactive ingredients (commonly called excipients) in a composition are minimized for high-dose materials to enhance compliance with the recommended dose.
  • a method for the preparation of a homogeneous nutritional or therapeutic composition comprising glutamine, cystine, glycine and a selenium source comprising the steps of
  • the ratio of glutamine, cystine and glycine in the composition is in a molar ratio of between about 0.9 to about 1.1 in glutamine; between about 0.3 to about 0.6 in cystine and between about 1 to about 2 in glycine.
  • the selenium source comprises between about 0.0001% and about 1% by weight of the composition.
  • the selenium source is a non-toxic water soluble organic or inorganic selenium compound.
  • the selenium source is selected from: sodium selenite, selenium methionine, selenium cysteine, selenium cystine, a mono-seleno amino acid with 6 to 12 carbon atoms in the chain or a di-seleno amino acid with 10 to 24 carbon atoms in the chain, including but not limited to, encapsulated forms of such sources of selenium.
  • the selenium source is Selenium Select 5000 (Sabinsa Corporation).
  • the molar ratio in the composition is about 1 in glutamine, about 0.5 in cystine and about 1 in glycine.
  • the particle size (D90) of the homogeneous mixture is between about 100 microns and about 200 microns.
  • the particle size of the homogeneous mixture is measured by a particle size analyzer and represents the volume-weighted distribution of the particles.
  • a method for the preparation of a homogeneous nutritional or therapeutic composition comprising glutamic acid, cystine, glycine and a selenium source comprising the steps of
  • the ratio of glutamic acid, cystine and glycine in the composition is in a molar ratio of between about 0.9 to about 1.1 in glutamic acid; between about 0.3 to about 0.6 in cystine and between about 1 to about 2 in glycine.
  • the selenium source comprises between about 0.0001% and about 1% by weight of the composition, such that the selenium source provides between about 4 micrograms and about 55 micrograms of selenium per daily dose.
  • the selenium source is a non-toxic, water soluble, organic or inorganic selenium compound
  • the selenium source is sodium selenite, selenium methionine, selenium cystine, a monosei eno amino acid with 6 to 12 carbon atoms in the chain or a di- seleno amino acid with 8 to 24 carbon atoms in the chain.
  • the selenium source is Selenium Select 5000.
  • the molar ratio in the composition is about 1 in glutamine, about 0.5 in cystine and about 1 in glycine.
  • the particle size (D90) of the homogeneous mixture is between about 100 microns and about 200 microns.
  • the particle size of the homogeneous mixture is measured by a particle size analyzer and represents a volume-weighted distribution.
  • a pharmaceutical composition prepared according to the methods above wherein the particle size of the homogeneous mixture (D90) is between about 25 (preferably 50) microns and about 300 microns. In another embodiment a pharmaceutical composition prepared according to the methods above, wherein the composition is stable for at least 24 months under normal storage conditions.
  • the manufacturing batch examples cited below provide approximate quantities to be charged in the manufacture of a single, 1,000kg batch of product and as represented in an illustrative master batch record. These approximate quantities are not meant to be in any way limiting to the actual relative content charged of amino acids or selenium source, provided that such amounts are within the safe recommended daily dose of ingredients used as dietary supplements (e.g., selenium) and determined by the USDA.
  • Blended is again temporarily stopped, and the remaining approximately 100 grams of dibasic calcium phosphate is added to the blender. Blending is resumed for a minimum of approximately twenty minutes.
  • the mixture is discharged from the blender and is stored appropriately for further use.
  • a sample of the blend may be tested by an appropriate method (e.g., atomic absorption) to ensure that the blend contains a uniform content of approximately 5,000 ppm (parts-per-million) of elemental selenium.
  • the selenium source of Example One and as used in subsequent examples may be optionally in the form of organic selenium (e.g. L-selenomethionine, selenocysteine, selenocystine, Se-Methyl-selenocystine), or inorganic selenium (e.g., sodium or potassium selenite or selenate).
  • organic selenium e.g. L-selenomethionine, selenocysteine, selenocystine, Se-Methyl-selenocystine
  • inorganic selenium e.g., sodium or potassium selenite or selenate
  • a sample of 1.013 kg of Selenium Select 5000TM (Sabinsa Corporation, containing 5,000 ppm of elemental Selenium) is weighed into a clean, dry container.
  • L-Glutamine 344.4 kg; 2,357 moles
  • glycine 342.6 kg; 4,564 moles
  • L-cystine 212.0 kg; 882 moles
  • Approximately 10 kilograms each of L-glutamine, L-cystine, and glycine are separately weighed and charged through a 16-mesh sieve into a container.
  • the full desired amount (1.013 kg) of Selenium Select 5000 is similarly charged through a 16-mesh sieve into the container.
  • a sample of 0.99 kg of Selenium Select 5000TM (Sabinsa Corporation, containing 5,000 ppm of elemental Selenium) is weighed into a clean, dry container.
  • L-Glutamine (386 kg; 2,640 moles), glycine (198 kg; 2,640 moles), and L-cystine (317.2 kg; 1,320 moles) are separately weighed and held in containers for subsequent use.
  • Approximately 10 kilograms each of L- glutamine, L-cystine, and glycine are separately weighed and charged through a 16-mesh sieve into a container.
  • the full desired amount (0.99 kg) of Selenium Select 5000 is similarly charged through a 16-mesh sieve into the container.
  • L-Glutamine 344.4 kg; 2,357 moles
  • glycine 342.6 kg; 4,564 moles
  • L-cystine 212.0 kg; 882 moles
  • Approximately 10 kilograms each of L-glutamine, L-cystine, and glycine are separately weighed and charged through a 16-mesh sieve into a container.
  • L-sel enomethionine/dicalcium phosphate blend is similarly charged through a 16-mesh sieve into the container.
  • Approximately 10 kilograms each of L- glutamine, L-cystine, and glycine are again separately weighed and charged through a 16- mesh sieve into the same container.
  • the contents of the container are transferred to a clean, twin-cone blender and are blended for a minimum of approximately five minutes. This blended material is discharged into an appropriate container for subsequent use. All of the remaining L-glutamine, L-cystine, and glycine are passed through a 16-mesh sieve into appropriate and separate containers.
  • L-Glutamine (428 kg; 2,929 moles), glycine (220 kg; 2,930 moles), and L-cystine (352 kg; 1,465 moles) are separately weighed and held in containers for subsequent use.
  • Approximately 10 kilograms each of L-glutamine, L-cystine, and glycine are separately weighed and charged through a 16-mesh sieve into a container.
  • L-selenocy stine in dicalcium phosphate is similarly charged through a 16-mesh sieve into the container.
  • Approximately 10 kilograms each of L-glutamine, L-cystine, and glycine are again separately weighed and charged through a 16-mesh sieve into the same container.
  • the contents of the container are transferred to a clean, twin-cone blender and are blended for a minimum of approximately five minutes. This blended material is discharged into an appropriate container for subsequent use. All of the remaining L-glutamine, L-cystine, and glycine are passed through a 16-mesh sieve into appropriate and separate containers.
  • L-Glutamine (428 kg; 2,929 moles), glycine (220 kg; 2,930 moles), and L-cystine (352 kg; 1,465 moles) are separately weighed and held in containers for subsequent use.
  • Approximately 10 kilograms each of L-glutamine, L-cystine, and glycine are separately weighed and charged through a 16-mesh sieve into a container.
  • L-selenocy stine The full desired amount (1.11 kg) of L-selenocy stine is similarly charged through a 16-mesh sieve into the container. Approximately 10 kilograms each of L-glutamine, L-cystine, and glycine are again separately weighed and charged through a 16-mesh sieve into the same container. The contents of the container are transferred to a clean, twin-cone blender and are blended for a minimum of approximately five minutes. This blended material is discharged into an appropriate container for subsequent use. All of the remaining L-glutamine, L-cystine, and glycine are passed through a 16-mesh sieve into appropriate and separate containers.
  • a sample of approximately 1.11 kg of Selenium Select 5000TM (Sabinsa Corporation, containing 5,000 ppm of elemental Selenium) is weighed into a clean, dry container.
  • L- Glutamine (428 kg; 2,929 moles), glycine (220 kg; 2,930 moles), L-cystine (352 kg; 1,465 moles), and magnesium ascorbate (307 kg; 820 moles) are separately weighed and held in containers for subsequent use.
  • Approximately 10 kilograms each of L-glutamine, L-cystine, glycine, and magnesium ascorbate are separately weighed and charged through a 16-mesh sieve into a container.
  • the full desired amount (1.013 kg) of Selenium Select 5000TM is similarly charged through a 16-mesh sieve into the same container.
  • Approximately 10 kilograms each of L-glutamine, L-cystine, glycine, and magnesium ascorbate are again separately weighed and charged through a 16-mesh sieve into the same container.
  • the contents of the container are transferred to a clean, twin-cone blender and are blended for a minimum of approximately five minutes. This blended material is discharged into an appropriate container for subsequent use.
  • the remaining L-glutamine, L-cystine, and glycine are passed through a 16-mesh sieve into appropriate and separate containers.
  • the selenium content in each of the samples tested was found to be both uniform across samples taken from the same batch at the same time, and stable with respect to samples taken at different times of storage. All samples tested were within the limits expected in consideration of the Relative Standard Deviation of the test method and in consideration of expected variability of content uniformity.
  • the sample results for selenium were within ⁇ 5% for all samples tested. The results obtained at 12 months from samples tested using HPLC coupled with ICP-MS averaged 5.78 ppm (102.3% of expected value). Further, the results of sample testing indicated an average value of 5.58 ppm (98.8% of expected value) at 24 months when tested using Atomic Absorption (AA). These results indicate that the product is stable and homogeneous for selenium content.
  • Example Nine Stability of the Composition. Amino Acids Content
  • HPLC High-Performance Liquid Chromatography
  • the samples may be tested using, for example, official methods in the US and International Pharmacopeia for the determination of amino acids as specifically discussed in the relevant sections of these Pharmacopeia.

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  • Health & Medical Sciences (AREA)
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  • Engineering & Computer Science (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • Nutrition Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Procédé de préparation d'une composition nutritionnelle ou thérapeutique homogène comprenant de la glutamine ou de l'acide glutamique, de la cystine, de la glycine et une source de sélénium, comprenant les étapes a) de dilution en série de la source de sélénium, b) de broyage et/ou de tamisage de la glutamine ou de l'acide glutamique, de la cystine et de la glycine individuellement pour donner une taille de particule (D90) comprise entre environ 50 micromètres et environ 300 micromètres, c) de mélange de la source de sélénium, de la glutamine ou de l'acide glutamique, de la cystine et de la glycine pour produire un mélange homogène ayant une taille de particule (D90) comprise entre environ 25 micromètres et environ 300 micromètres. L'invention concerne également des compositions fabriquées selon le procédé.
PCT/GB2023/052336 2022-09-08 2023-09-08 Compositions pour augmenter les taux de glutathion et leurs procédés de fabrication WO2024052700A1 (fr)

Applications Claiming Priority (2)

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US202263404808P 2022-09-08 2022-09-08
US63/404,808 2022-09-08

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE39374E1 (en) 1999-08-06 2006-11-07 Ricoh Company, Ltd. Constant voltage power supply with normal and standby modes
USRE42645E1 (en) 2002-09-23 2011-08-23 Albert Crum Nutritional or therapeutic compositions and methods to increase bodily glutathione levels
CN103535721A (zh) * 2013-09-27 2014-01-29 美国东方生物技术（香港）有限公司 提高人体内谷胱甘肽浓度的组合物及其制备方法和应用
WO2021263206A1 (fr) * 2020-06-26 2021-12-30 Prothione, Llc Compositions et méthodes de traitement de la covid-19

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE39374E1 (en) 1999-08-06 2006-11-07 Ricoh Company, Ltd. Constant voltage power supply with normal and standby modes
USRE42645E1 (en) 2002-09-23 2011-08-23 Albert Crum Nutritional or therapeutic compositions and methods to increase bodily glutathione levels
CN103535721A (zh) * 2013-09-27 2014-01-29 美国东方生物技术（香港）有限公司 提高人体内谷胱甘肽浓度的组合物及其制备方法和应用
WO2021263206A1 (fr) * 2020-06-26 2021-12-30 Prothione, Llc Compositions et méthodes de traitement de la covid-19

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