COMPOSITIONS AND METHODS FOR PROMOTING NITRIC OXIDE PRODUCTION THROUGH AN ORAL DELIVERY SYSTEM

• US 20160151428A1
• Filed: 05/05/2014
• Published: 06/02/2016
• Est. Priority Date: 05/04/2013
• Status: Active Grant

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Bryan, Nathan S.
• Granted Patent: US 10,471,109 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 35/74 Bacteria therapeutic use of a bacterial protein A61K38/00
• CPC Class Codes: A61K 35/741 Probiotics probiotic yeast, e.g. saccharomyces A61K36/06
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system

Abstract

Probiotic compositions, particularly oral compositions, comprising one or more bacteria that are capable of producing nitrite and/or nitric oxide in a subject are provided. Some compositions further comprise nitrate/nitrate, such as a botanical source of nitrate. Some compositions further comprise botanical sources of nitrate reductase. Also, provided are methods of improving the oral and/or vascular health of a subject by orally administering a composition comprising one or more bacteria capable of producing nitric oxide. Methods of repopulating the nitric oxide producing microflora and bacterial environment in the oral cavity of a subject are also provided.

Claims

1. A method of establishing or enhancing a bacteria population in the oral cavity comprising administering a probiotic composition, where the probiotic composition comprises bacteria selected from a group consisting essentially of Neisseria, Veillonella, Haemophilus, Actinomyces, Granulicatella, Prevotella, Leptotrichia, Brevibacillus, Porphyromonas, Fusobacterium, and clade Gemellaceae, where the composition is configured to release at least a portion of the bacteria in the oral cavity.

2. The method of claim 1, wherein the bacteria are selected from a group consisting essentially of Granulicatella, Neisseria, Prevotella, Haemophilus, Fusobacterium, Brevibacillus, and clade Gemellaceae.

3. The method of claim 1, wherein the bacteria comprise one or more of the following:

Granulicatella adiacens, Haemophilus parainfluenzae, Actinomyces odontolyticus, Actinomyces viscosus, Actinomyces oris, Neisseria flavescens, Neisseria mucosa, Neisseria sicca, Neisseria subflava, Prevotella melaninogenica, Prevotella salivae, Veillonella dispar, Veillonella parvula, Veillonella atypical, Fusobacterium nucleatum, and Brevibacillus brevis.

4. The method of claim 1, wherein the bacteria consists essentially of nitrite-accumulating bacteria, where the nitrite-accumulating bacteria are bacteria that allow nitrite levels in a bacteria culture to increase and nitrate levels to decrease when the bacteria culture comprises bacteria isolate or mixture consisting essentially of the nitrite-accumulating bacteria.

5. The method of claim 1, wherein the bacteria consists essentially of strains that contain nitrate-reductase encoding genes and do not contain nitrite-reductase encoding genes.

6. The method of claim 1, wherein the bacteria consists essentially of strains that express one or more of the following nitrate reductase genes:

narG, narL, narJ, narQ, narI, napC, napB, napH, napD, napA, napG, and napF.

7. The method of claim 1, wherein the isolated bacteria consists essentially of strains that do not express the following nitrite reductase genes:

nirK, nirB, nirD, nrfF, nrfA, and nrfH.

8. The method of claim 1, wherein the bacteria consists essentially of strains that do not express nitric oxide reductase.

9. The method of claim 1, wherein the bacteria consists essentially of weak acid or non-acid producing bacterial strains.

10. The method of claim 1, wherein a dosage of the composition comprises 1 mg to 100 g of the bacteria.

11. The method of claim 1, where a dosage of the composition comprise an activity of 5 billion to 20 billion colony forming units.

13. The method of claim 1, wherein the probiotic composition is stored at or below 45°

C. or wherein the bacteria are freeze-dried.

15. The method of claim 1, wherein the bacteria are genetically-modified or recombinant bacteria, where a gene encoding nitric oxide reductase is suppressed.

16. The method of claim 1, wherein the probiotic composition further comprises nitrate.

17. The method of claim 1, wherein the probiotic composition further comprises a botanical source of nitrate and the botanical source of nitrate comprises one or more of beet root, kale, artichoke, holy basil, gymnema sylvestre, ashwagandha root, salvia, St. John wort, broccoli, stevia, spinach, gingko, kelp, tribulus, eleuthero, epimedium, eucommia, hawthorn berry, rhodiola, green tea, codonopsys, panax ginseng, astragalus, pine bark, dodder seed, Schisandra, cordyceps, and mixtures thereof.

19. The method of claim 1, the probiotic composition further comprises the one or more excipients, wherein the one or more excipients comprises a substance having a pH buffering capacity, wherein the pH buffering substance is selected form the group consisting of bicarbonates, carbamides, phosphates, proteins, salts, and combinations of two or more thereof.

40. The method of claim 1, wherein the composition is administered to subjects suffering from one or more of cardiovascular disease, atherosclerosis, stroke, ischemic injury, peripheral artery disease, congestive heart failure, hypertension, pulmonary arterial hypertension, hypertension associated with urea cycle disorders and pre-eclampsia, vascular dementia, Alzheimer'"'"'s Disease, metabolic syndrome, and type 2 diabetes.

12. (canceled)

14. (canceled)

18. (canceled)

20. (canceled)

21. A probiotic composition comprising:

an effective amount of nitrate and

a bacteria isolate or mixture that comprises one or more of Neisseria, Veillonella, Haemophilus, Actinomyces, Granulicatella, Prevotella, Leptotrichia, Brevibacillus, Porphyromonas, Fusobacterium, and oral bacteria of the Gemellaceae family,

wherein the composition does not contain a contaminating amount of Lactobacillus.

22. The probiotic composition of claim 21, wherein the bacteria are selected from a group consisting essentially of Granulicatella, Neisseria, Prevotella, Haemophilus, Fusobacterium, Brevibacillus and clade Gemellaceae.

23-39. -39. (canceled)

41-45. -45. (canceled)

46. A method of enhancing nitrate reduction in the oral cavity comprising administering a probiotic composition,

where the probiotic composition comprises a bacteria isolate or mixture that comprises one or more of Neisseria, Veillonella, Haemophilus, Actinomyces, Granulicatella, Prevotella, Leptotrichia, Brevibacillus, Porphyromonas, Fusobacterium, and clade Gemellaceae,

wherein the composition does not contain a contaminating amount of Lactobacillus.

47-66. -66. (canceled)