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EP-4082552-B1 - LIQUIDS RICH IN NOBLE GAS AND METHODS OF THEIR PREPARATION AND USE

EP4082552B1EP 4082552 B1EP4082552 B1EP 4082552B1EP-4082552-B1

Inventors

  • HUANG, Shao-ling
  • MCPHERSON, DAVID
  • GENG, YONG-JIAN
  • YIN, Xing
  • KIM, Hyunggun
  • KLEGERMAN, Melvin
  • PENG, TAO

Dates

Publication Date
20260506
Application Date
20140317

Claims (14)

  1. A composition for use in a method of treating or preventing a neurological disease or neurological injury in a subject, the method comprising orally administering an effective amount of the composition, the composition comprising a dissolved Noble gas xenon.
  2. The composition for use of claim 1, wherein the neurological disease is Alzheimer's disease, optionally wherein beta-amyloid levels are to be reduced in the subject.
  3. The composition for use of claim 1, wherein the neurological disease is Alzheimer's disease, optionally wherein the progression of Alzheimer's disease is to be treated or prevented in the subject.
  4. The composition for use of claim 1, wherein the subject has or is at risk for thrombotic stroke, ischemic stroke, or hemorrhage stroke.
  5. The composition for use of claim 1, wherein the subject has a high risk of stroke.
  6. The composition for use of any one of claims 1-5, wherein the composition comprises: (i) an aqueous component comprising a dissolved Noble gas, wherein a portion of the Noble gas xenon is encapsulated with a water-soluble polymer; and/or (ii) an oil component comprising a dissolved Noble gas.
  7. The composition for use of claim 6, wherein the water-soluble polymer is a cyclodextrin.
  8. The composition for use of claim 7, wherein the cyclodextrin is α-, β-, or γ-cyclodextrin.
  9. The composition for use of claim 7, wherein the cyclodextrin is a mixture of α-, β-, or γ-cyclodextrin.
  10. The composition for use of claim 6, wherein the oil component: (a) comprises polyunsaturated fatty acids (PUFA); (b) is saturated with xenon gas or argon gas; (c) comprises soluble xenon gas; (d) is essentially free of oxygen; (e) comprises canola oil, flaxseed oil, rapeseed oil, soybean oil, walnut oil, fish oil, safflower oil, chia seed oil, sunflower seed oil, sesame seed oil, seaweed oil, corn oil, cotton seed oil, peanut oil, palm oil, avocado oil, coconut oil, or olive oil; or (f) comprises omega-3 fatty acids, omega-6 fatty acids, or omega-9 fatty acids.
  11. The composition for use of claim 6, wherein the oil component is comprised in an emulsion.
  12. The composition for use of claim 11, wherein the emulsion comprises: (a) 25% to 50% by volume of a Noble gas-saturated oil and 30% to 75% by volume of an aqueous solution; or (b) 15% to 75% by volume of a Noble gas-saturated oil and 25% to 85% by volume of an aqueous solution.
  13. The composition for use of claim 6, further comprising phospholipid, detergent, or protein components.
  14. The composition for use of claim 13, wherein: (a) the detergent is a plant surfactant, a synthetic detergent or a bile acid; (b) wherein the detergent is lithocholic acid, deoxycholic acid, taurocholic acid, glycocholic acid, chenodeoxycholic acid, or cholic acid; (c) the phospholipid is egg phosphocholine (egg PC), soybean PC, DPPC or DOPC; or (d) the protein is milk protein, whey protein, soy protein isolate, or bovine serum albumin.

Description

This application claims the benefit of United States Provisional Patent Application Nos. 61/788,808, filed March 15, 2013, and 61/889,901, filed October 11, 2013. The invention was made with government support under Grant Nos. NS067454, HL074002, and HL059586 awarded by the National Institutes of Health. BACKGROUND OF THE INVENTION 1. Field of the Invention The present disclosure relates generally to the fields of molecular biology, medicine and nutraceuticals. More particularly, it concerns methods for oral delivery of inert gas compositions, such as Xenon or Argon, for the treatment and prevention of disease. 2. Description of Related Art Both Xenon (Xe) and Argon (Ar) are, pleiotypic cytoprotective gases, which have unique advantages that include rapid diffusion across biological barriers such as the blood-brain barrier (BBB) and complete passage across cell membranes due to its low blood-gas partition coefficient. In animal models, Xe given as a continuous gas inhalation has demonstrated potent neuroprotective and myocardical protective effects. Xe protects against oxygen and glucose deprivation (OGD) and protects against hypoxia/ischemia by alteration of molecules involved in neuronal ischemic tolerance. Xe helps to induce transcription of several pro-survival genes including brain-derived neurotrophic factor (BDNF) and pro-survival proteins such as Bcl2 which promote cell tolerance to ischemic injury. Xe interacts with the human immune system by modulating inflammatory cytokines such as TNF-α and IL-6 in monocytes. Xe helps to sustain release of hypoxia inducible factor 1 alpha (HIF-1α) and other proteins. All these pathways are implicated in organ protection. WO02/45721 discloses intravenous composition for anaesthesia comprising aqueous liquid and encapsulation of Xenon in cyclodextrin. US 2005/238726 concerns neurological deficits in patients who have undergone cardiopulmonary bypass (CPB) by administering xenon. Intravenous administration and administration by inhalation are envisaged. Britton et al. (Circulation 122(16), 2010, pages 1578-1587) discloses xenon-loaded liposomes for intravenous administration for neuroprotection. DE19933704 discloses an oil in water emulsion comprising xenon for use in neuroprotection and neuroregeneration. The emulsion is administered intravenously. Current methods for gas delivery involve inhalation and administration of a gas donor. However, Xe or Ar inhalation cannot be practically given in many situations as the required high Xe or Ar concentration for inhalation limits the fraction of inspired oxygen necessary for cell survival. In addition, there is the difficulty of developing a continuous inhalation strategy for patients as daily use. Improved methods of delivery of Xe or Ar are greatly needed. SUMMARY OF THE INVENTION The present invention relates to a composition for use in a method of treating or preventing a neurological disease or neurological injury in a subject, the method comprising orally administering an effective amount of the composition, the composition comprising a dissolved Noble gas xenon. Any references in the description to methods of treatment refer to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy (or for diagnosis). Embodiments of the present disclosure relates generally to treatment methods, pharmaceuticals and nutraceuticals (a portmanteau of the words "nutrition" and "pharmaceutical", which is a food or food product with health and medical benefits, including the prevention and treatment of disease). More particularly, it concerns a composition for use in methods for primarily oral delivery of inert gas compositions to the gastrointestinal tract (GI), comprising the Noble gas Xenon. The noble gas according to the invention is xenon. Such gases can be delivered as part of a method for the prevention and/or treatment of diseases in the heart and brain, including but not limited to atherosclerosis-associated ischemic heart disease, stroke and other neuron degenerative condition, such as dementia (e.g., Alzheimer disease). In certain aspects, compositions comprising Noble gases provide reduction in one or more marker of inflammation or general improvement in well-being. Disclosed is a liquid (or semi-liquid, e.g., pastes or gels) formulation having an enhanced concentration of encapsulated Noble gas (e.g., the gas may be encapsulated to achieve a specified concentration) for use in a method of treating or preventing according to the invention. The Noble gas according to the present invention is Xenon. As used herein the encapsulated Noble gas can be provided as a gas dissolved in a lipid and emulsified, encapsulated in a liposome formulation and/or encapsulated in a water soluble molecule (e.g., cyclodextrin). In general the encapsulation allows the composition to achieve a higher gas content than can be achieved in an equal am