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EP-4739140-A2 - FORMULATIONS AND METHODS FOR INCREASING CREATININE LEVELS IN PLASMA, EXTRACELLULAR FLUID AND/OR INTRACELLULAR COMPARTMENTS

EP4739140A2EP 4739140 A2EP4739140 A2EP 4739140A2EP-4739140-A2

Abstract

Formulations and methods that increase creatinine levels in plasma, extracellular fluid and/or intracellular compartments in an animal and delivery methods therefor. In particular, the present disclosure is directed to creatinine pronutrients, formulations including the creatinine pronutrients, and methods of administering the formulations to increase creatinine levels in plasma, extracellular fluid and/or intracellular compartments.

Inventors

  • FAULKNER, Mark, C.
  • MILLER, DONALD, W.

Assignees

  • VIREO Systems, Inc.

Dates

Publication Date
20260513
Application Date
20240705

Claims (20)

  1. 1. A method for increasing extracellular creatinine levels in an animal, the method comprising: providing a formulation, the formulation comprising a therapeutically effective dose of at least one creatinine pronutrient; and administering a therapeutically effective dose of the formulation to the animal.
  2. 2. The method of claim 1, wherein the creatinine pronutrient comprises ethyl (a - guanido - methyl) ethanoate, creatine alkyl ester, creatine amide alkyl ester, creatine cyclohexyl ester, or salts, or derivatives or combinations thereof.
  3. 3. The method of claim 1, wherein the creatinine pronutrient comprises ethyl (a - guanido - methyl) ethanoate, creatine ethyl ester hydrochloride, creatine isopentyl ester hydrochloride, or derivatives or combinations thereof.
  4. 4. The method of claim 1, wherein the creatinine pronutrient comprises creatine isopentyl ester hydrochloride, or derivatives or combinations thereof.
  5. 5. The method of claim 1, wherein the formulation comprises about 30 to about 100 weight percent of the creatinine pronutrient.
  6. 6. The method of claim 1, wherein the creatinine pronutrient is present in the formulation at a concentration of about 0.1 mM to about 10 mM.
  7. 7. A method for increasing intracellular creatinine levels in an animal, the method comprising: providing a formulation, the formulation comprising at least one creatinine pronutrient; and administering a therapeutically effective dose of the formulation to the animal.
  8. 8. The method of claim 7, wherein the creatinine pronutrient comprises creatine tert-butyl ester hydrochloride or derivatives thereof.
  9. 9. The method of claim 7, wherein the formulation comprises about 30 to about 100 weight percent of the creatinine pronutrient.
  10. 10. The method of claim 7, wherein the creatinine pronutrient is present in the formulation at a concentration of about 0.1 mM to about 10 mM.
  11. 11. An oral supplement comprising a formulation comprising a creatinine pronutrient suitable for increasing creatinine levels in an animal, wherein the creatinine pronutrient comprises creatine alkyl ester, creatine amide alkyl ester, creatine cyclohexyl ester and salts, derivatives, or combinations thereof, and wherein the creatinine pronutrient is present in the formulation at a concentration of about 0.1 mM to about 10 mM.
  12. 12. The oral supplement of claim 11, wherein the formulation further comprises a creatine derivative.
  13. 13. The oral supplement of claim 11, wherein the creatinine pronutrient has a bioavailability that is at least 2 times the bioavailability of creatinine.
  14. 14. The oral supplement of claim 11, wherein the creatinine pronutrient comprises ethyl (a - guanido - methyl) ethanoate, creatine ethyl ester hydrochloride, creatine isopentyl ester hydrochloride, creatine tert-butyl ester hydrochloride, or derivatives or combinations thereof.
  15. 15. The oral supplement of claim 14, wherein the creatinine pronutrient comprises creatine isopentyl ester hydrochloride or derivatives thereof.
  16. 16. The oral supplement of claim 14, wherein the creatinine pronutrient comprises creatine tert-butyl ester hydrochloride or derivatives thereof.
  17. 17. A method for reducing permeability increases across the blood-brain barrier in an animal due to bradykinin release, the method comprising: providing a formulation, the formulation comprising at least one creatinine pronutrient at a concentration of about 0.1 mM to about 10 mM; and administering a therapeutically effective dose of the formulation to the animal.
  18. 18. The method of claim 17, wherein the creatinine pronutrient comprises ethyl (a - guanido - methyl) ethanoate, creatine ethyl ester hydrochloride, creatine isopentyl ester hydrochloride, creatine tert-butyl ester hydrochloride, or derivatives or combinations thereof.
  19. 19. The method of claim 18, wherein the creatinine pronutrient comprises creatine isopentyl ester hydrochloride or derivatives thereof.
  20. 20. The method of claim 18, wherein the creatinine pronutrient comprises creatine tert-butyl ester hydrochloride or derivatives thereof.

Description

FORMULATIONS AND METHODS FOR INCREASING CREATININE LEVELS IN PLASMA, EXTRACELLULAR FLUID AND/OR INTRACELLULAR COMPARTMENTS FIELD OF THE INVENTION The present disclosure describes formulations and methods that increase extracellular and/or intracellular creatinine levels and delivery methods therefor. In this aspect, the present disclosure is directed to creatinine pronutrients, formulations including the creatinine pronutrients, and methods of administering the formulations to increase creatinine levels in plasma, extracellular fluid, and/or intracellular compartments, which, in turn, reduces or inhibits Bradykinin receptor activation, reduces or prevents loss of blood-brain barrier integrity, and/or reduces or inhibits activation of the inflammatory pathway. BACKGROUND OF THE INVENTION Bradykinin (BK) is a pro-inflammatory nonapeptide that acts through it receptors and activates several second messenger systems to regulate blood-brain barrier permeability, pain perception, and nitric oxide production, among other things. Indeed, BK is released in pathological conditions such as trauma and inflammation and then binds to its kinin receptors Bl and B2. As a result, while expression of Bl is minimal under normal circumstances, it is expressed as a result of tissue injury and its signaling promotes local tissue inflammation by recruiting neutrophils, dilating capillaries, and constricting venous outflow. In addition, Bradykinin receptors induce the overexpression of a number of cytokines, including TNF-a, IL- 10, IL-6, IL- 10, IL-8 and IL-2 that are implicated in inflammation, respiratory, gastrointestinal, cardiac, neuronal, ophthalmologic and dermatological problems. It has been suggested that the BK receptor activation that occurs in neuroinflammatory diseases may contribute to both the inflammation and loss of blood-brain barrier integrity that is characteristic of these diseases (Mugisho 00, Robilliard LD, Nicholson LFB, Graham ES, O'Carroll SJ. Bradykinin receptor- 1 activation induces inflammation and increases the permeability of human brain microvascular endothelial cells. Cell Biol Int. 2020 Jan;44(l):343- 351). In sum, BK release leads to activation of Bl and B2 receptors, which, in turn, increases permeability of brain endothelial cells, and activates inflammatory pathways in the brain. Creatine is an organic acid that is synthesized in the liver and kidneys from arginine, glycine, and methionine (Brosnan J T et al., Ann Rev Nutr 27: 241-261 (2007); Greenhaff P, J Nutr Biochem 8: 610-618 (1997); Wallimann et al., Amino Acids 40: 1271-1296 (2011)). In the body, creatine is non-enzymatically converted into creatinine (Wyss M et al., Physiol Rev 80: 1107-1213 (2000); Santos R V, et al. Life Sci 75: 1917-1924 (2004)). The structure of creatinine is as follows: While creatinine has been considered an inert metabolic end product of creatine, studies have found that creatinine (and its derivatives such as creatinine HC1) possesses biological activity. Indeed, one study by Madan et al. (1979) indicates that creatinine acts as an antiinflammatory agent against acute and chronic inflammation in rats. Another study by Leland et al. (Int Immunopharm 11 : 1341-1347 (2011)) suggested that creatinine may have the ability to dampen the innate immune response. In addition, a 2011 study demonstrated several downstream metabolites of creatinine and their reactive oxygen species scavenging effects (Drug Discoveries & Therapeutics 5(4): 162-175 (2011)). In yet another study, the ability of creatinine and creatinine HC1 to suppress bacterial replication was demonstrated (McDonald T L et al., J Antibiot (Tokyo) 65: 153-156 (2012)). In a subsequent study, it was shown that creatinine HC1 does not affect the growth of fungi, which was then used to demonstrate that creatinine HC1 could be used as a novel additive in fungal growth media to permit fungi to grow efficiently without bacterial contamination (Smithee et al., J Microbiol Meth 105: 155-161 (2014)). U.S. Patent No. 11,058,655 describes the use of creatinine and creatinine salts as anti-inflammatory immunomodulators useful for treating an inflammatory condition or an autoimmune disease and/or inducing an immunomodulatory response. Creatinine levels can vary depending on age, race, gender, and body mass. Blood creatinine levels of 50 pM to 100 pM is generally considered normal (Brosnan J T et al., Ann Rev Nutr 27: 241-261 (2007); McDonald T L et al., J Antibiot (Tokyo) 65: 153-156 (2012)). In fact, while fluctuation is normal, the average level for a healthy adult male should be between about 0.6 to 1.2 mg/deciliter, and for females, it should be between 0.5 to 1.1 mg/deciliter. Most in the medical community believe that low creatinine levels are relatively benign. Indeed, it is largely accepted that certain populations have below-normal blood creatinine levels, e.g., pregnant women, vegetarians, and those with low muscle mass due to age, chronic illness, and maln