Creatyl-L-glutamine

Creatyl-L-Glutamine

1. Identity and Chemical Characterization

Chemical Names and Structure

Creatyl-L-glutamine (abbreviated CLG) is a synthetic dipeptide compound in which the carboxylic acid group of creatine is covalently linked via an amide bond to the amino group of L-glutamine. In this way, a dipeptide creatyl-L-glutamine is obtained from glutamine. It belongs to a broader class of molecules described in the scientific and patent literature as amide-protected creatine species or creatyl-amide species. The subject invention provides stable aqueous compositions of at least one amide-protected, biologically-active form of creatine (creatyl-amide) molecule, wherein the carboxylic acid group of creatine is linked to, for example, an amino group of an amine, an amino acid or a peptide, thereby forming an amide bond.

This invention provides amide-protected creatine molecules, wherein creatine is stabilized by protecting its carboxylic acid group. The parent molecule, creatine (N-aminoiminomethyl-N-methylglycine), is a sarcosine derivative present in the muscle tissue of many vertebrates, including man, while L-glutamine is a conditionally essential amino acid abundant in human plasma and skeletal muscle. The combination of these two molecules into a single covalently bonded dipeptide constitutes creatyl-L-glutamine.

Creatyl-L-leucine or creatyl-L-glutamine are synthetic dipeptides of creatine. Creatyl-L-glutamine is closely related to—and part of the same patent family as—creatyl-L-leucine (CLL), the two being the most commercially prominent members of this compound class. The synthesis of creatyl-amide species, such as creatyl-L-leucine, creatyl-L-carnosine, creatyl-1-methylhistidine, and creatyl-beta-alanyl-1-methylhistidine, can be achieved in a similar manner, except that different amino acids or peptides are used as starting materials.

Natural Occurrence

Creatine and leucine are not known to naturally form bonds with one another endogenously in humans or in nature; creatyl-L-leucine is synthesized by subjecting L-leucine to a series of chemical processes, resulting in leucine and creatine connected by a covalent bond, and thus is a novel ingredient. The same applies to creatyl-L-glutamine: it does not occur naturally in foods, plants, or the human body, and is produced exclusively through chemical synthesis. It therefore has no botanical source and no history of natural isolation from biological material.

Common Forms and Preparations

The compositions of the subject invention comprise stable aqueous solutions with a pH of about 1.5 to about 6.5, and contain creatyl-L-glutamine, creatyl-L-leucine, creatyl-L-carnosine, creatyl-1-methylhistidine, and/or creatyl-beta-alanyl-1-methylhistidine. Creatyl-L-glutamine has been incorporated primarily into aqueous (liquid) dosage forms, reflecting the key technological rationale for its creation: stability in water. To prepare a composition according to one embodiment of this invention, a desired amount of creatyl-L-glutamine can be added to a selected volume of water, and sufficient stirring is effected to cause dissolution of the creatyl-L-glutamine to create an aqueous composition.

This may allow creatyl-L-glutamine to be provided in products such as ready-to-drink water-based beverages such as sports drinks, and beverages for preventing muscle wasting and improving or stabilizing brain health in persons confined to a hospital, and in a multitude of different medical applications such as IV drips and injectable delivery systems. In commercial practice, creatyl-L-glutamine has appeared as an ingredient in ready-to-drink energy and sports beverages. It is labelled in some commercial products under trade-name designations such as mTORC1™ Molecule.

2. Historical and Traditional Use

Creatyl-L-glutamine has no historical or traditional use. As a fully synthetic, novel chemical entity that does not occur in nature and was first described in a patent application filed in 2010 (U.S. Patent No. 8,445,466, granted 2013), it has no record of use in any traditional medical system, folk medicine, herbal tradition, or cultural dietary practice. To the knowledge of researchers in this field, no formal toxicological, pharmacokinetic, or human studies on the combined compound had been published prior to recent investigations. Its development is entirely a product of modern pharmaceutical and sports-nutrition chemistry, motivated by the limitations of conventional creatine monohydrate in aqueous formulations.

The parent molecules—creatine and glutamine—do have independent histories of use. Creatine supplementation emerged in mainstream sports science in the early 1990s following landmark work demonstrating its ergogenic effects; glutamine has been studied as a clinical nutritional support agent since at least the 1980s. However, neither of these histories transfers to creatyl-L-glutamine, which is a chemically distinct synthetic molecule.

3. Synthesis Route

The synthesis of creatyl-L-glutamine follows a multi-step organic chemical process documented in U.S. Patent No. 8,445,466. First, L-glutamine as the starting material is reacted with 2-chloroacetyl chloride to obtain N-chloroacetyl-L-glutamine. This intermediate is converted to sarcosyl-L-glutamine in aqueous methylamine solution. Sarcosyl-L-glutamine is further treated to obtain creatyl-L-glutamine. In this way, a dipeptide creatyl-L-glutamine is obtained from glutamine.

4. Key Constituents and Proposed Mechanisms of Action

Structural Rationale

The central design principle of creatyl-L-glutamine is the amide protection of the creatine carboxyl group. Amide-protection of the creatine carboxylic group prevents the carboxylic group and guanidine group of creatine from reacting and dehydrating to produce creatinine. Creatinine is the inactive, renally excreted metabolite of creatine and provides no ergogenic or physiological benefit. Although creatine solubility may be increased at lower pH and higher temperatures — lower pH being common in drink formulations and higher temperatures being used for processing and packaging — under those conditions it also rapidly degrades by self-cyclizing into creatinine. The amide bond in creatyl-L-glutamine is intended to prevent this cyclization.

Glutamine also has low solubility and rapidly converts to undesirable glutamic acid when combined with water; likewise, creatine converts to creatinine over time when combined with water. Both glutamine and creatine can be delivered in a stable and soluble form as the creatyl dipeptide creatyl-L-glutamine; consequently, creatyl-L-glutamine may provide the benefits of enhanced aqueous stability of both creatine and of glutamine.

Proposed Hydrolytic Release of Creatine and Glutamine

The working hypothesis proposed in the patent literature is that after oral ingestion, digestive enzymes cleave the amide bond to release free creatine and free L-glutamine. A further advantage of the present invention is that the amide bond of creatyl-amide species can be hydrolyzed in the digestive system by enzymes to release pure creatine and useful amino acids such as glutamine. However, as discussed in the Scientific Evidence section below, this hydrolytic claim has not been confirmed in published peer-reviewed research and is, in fact, contradicted by available experimental data.

Creatine's Established Biochemical Role (Parent Compound)

The proposed bioactivity of creatyl-L-glutamine derives entirely from the biochemistry of its two constituent molecules, both of which have well-established independent roles. Creatine is an important energy metabolite that is concentrated in tissues such as the muscles and brain; it is reversibly converted to creatine phosphate through a reaction with ATP or ADP, which is catalyzed by the enzyme creatine kinase.

Once creatine is taken up into the blood, approximately 95% is stored in skeletal muscle, of which about 67% is converted to phosphocreatine (PCr) and about 33% remains as free creatine. Phosphocreatine combines with adenosine diphosphate (ADP) and is catabolized by creatine kinase to rapidly resynthesize adenosine triphosphate (ATP). This reaction is reversible during periods of rest or light activity. Muscle stores of PCr may split and release energy for rapid resynthesis of ATP, although the supply of PCr is limited, with the combined total ATP and PCr capable of sustaining all-out maximal effort exercise lasting up to 5 to 10 seconds.

Dietary supplementation with relatively large amounts of creatine monohydrate has been proven as an effective sports supplement that can enhance athletic performance during acute high-energy demand physical activity. Some side effects have been reported with creatine monohydrate supplementation, which have stimulated research into new potential molecules that could be used as supplements to potentially provide bioavailable creatine.

5. Scientific Evidence by Area of Use

5.1 Aqueous Stability

The stability claim for creatyl-L-glutamine in aqueous solution is supported by data presented within the originating patent (U.S. 8,445,466), which is an industry-funded document and not an independent peer-reviewed study. The results reported in the patent show that creatyl-L-glutamine aqueous solutions remain stable for more than 90 days at room temperature (25°C) and refrigerator temperature (4°C), and that the composition is also stable for more than 30 days at elevated temperature (40°C), which is stated to be suitable for shipping in hot weather trucks and overseas containers.

The amide-protected creatine molecules such as creatyl-L-glutamine and creatyl-L-leucine are stated to be substantially stable in aqueous media, and the covalent amide bond formed between creatine and the protecting group exhibits unexpectedly improved hydrolysis-stability. These stability data come from the patent disclosure itself. Independent, peer-reviewed validation of these stability claims in published scientific literature was not identified in the available sources.

Evidence strength: Preliminary; based on patent-reported data. No independent peer-reviewed confirmation found.

5.2 Bioavailability and Creatine Delivery

The fundamental question regarding creatyl-L-glutamine — whether it is effectively hydrolyzed in the digestive system to release bioavailable creatine — has been addressed in only a small body of published research, all of which concerns its closely related analog creatyl-L-leucine (CLL). Unpublished data directly addressing CLG are referenced in the peer-reviewed literature, and the findings are unfavorable.

Unpublished data suggested creatyl-L-glutamine was only 27% hydrolyzed to creatine in an in vitro model of digestion. This figure is cited in a 2022 peer-reviewed article published in the journal Nutrients (da Silva RP, 2022) as prior unpublished work by Owoc and Li (2014). The hydrolysis rate of 27% is described in the context of explaining why the related compound CLL was expected to have poor bioavailability, and the authors use it as a point of comparison.

For creatyl-L-leucine (the most studied analog), it was found that CLL supplementation in the diet did not increase plasma, muscle, or brain creatine levels after 7 days of supplementation. In comparison, creatine monohydrate (CrM) supplementation significantly increased creatine levels in plasma and muscle while brain creatine content displayed a trend toward an increase.

The observation that portal venous plasma creatine concentration from CLL-supplemented rats was not different from control rats indicates that CLL is not converted to creatine in the intestine during digestion. The authors reasoned that peptide bonds are normally stable under physiological conditions, only hydrolyzed by protease or peptidase enzymes; however, the chemical structure of CLL is not likely to be recognized by the active sites of a protease or peptidase given the very different structure of creatine when compared to amino acid residues in a peptide. Thus, it is highly unlikely that a peptidase enzyme or other enzyme would bind to CLL to catalyze hydrolysis to creatine and leucine. The same structural reasoning applies to creatyl-L-glutamine, since both share the same amide bond architecture involving the creatine moiety.

The most directly relevant human clinical evidence concerns creatyl-L-leucine. Twenty-nine healthy men (n = 17) and women (n = 12) consumed 5 g/day of either creatine monohydrate, CLL, or placebo for 14 days in a randomized, double-blind design, completing three bouts of supervised resistance exercise per week, with muscle biopsies collected before and after the intervention for quantification of muscle creatine. The results demonstrated that 2 weeks of supplementation with CLL did not statistically significantly increase muscle creatine, while creatine monohydrate supplementation significantly increased muscle creatine content. This trial was published in the International Journal of Sport Nutrition and Exercise Metabolism in 2022 (Askow et al., PMID 36007881). No equivalent human trial has been published specifically on creatyl-L-glutamine.

Despite previous studies demonstrating that many putative forms of creatine fail to improve on the ergogenic effects of CrM and augment muscle creatine content, novel supplements continue to be introduced to the market.

Evidence strength: For creatyl-L-glutamine specifically — only unpublished in vitro data exist (27% hydrolysis). For the closely analogous creatyl-L-leucine — one human RCT and one animal feeding study, both finding no significant bioavailability of creatine from the compound. The available evidence does not support the claim that creatyl-L-glutamine is an effective vehicle for delivering creatine to muscle tissue.

5.3 Athletic Performance and Muscle Creatine Accumulation

No published peer-reviewed human clinical trial specifically examining creatyl-L-glutamine's effects on athletic performance, muscle strength, lean body mass, or exercise capacity was identified in the literature. The evidence base for these outcomes as applied to CLL (the studied analog) also fails to demonstrate efficacy: when compared to the control and the creatine monohydrate-supplemented diet, creatyl-L-leucine supplementation resulted in no bioaccumulation of either creatyl-L-leucine or creatine in tissue.

Evidence strength: Absent for creatyl-L-glutamine directly. Evidence from the structurally analogous CLL is negative (no muscle creatine accumulation). No human performance outcomes data are available for CLG.

5.4 Brain Health and Neurological Applications

The patent and associated commercial materials suggest creatyl-L-glutamine might support brain health, consistent with the known role of creatine in cerebral energy metabolism. This may allow creatyl-L-glutamine to be provided in products such as ready-to-drink water-based beverages for preventing muscle wasting and improving or stabilizing brain health in persons confined to a hospital, and in a multitude of different medical applications. However, these statements originate from patent documentation rather than from clinical or preclinical research. For CLL, animal data found no accumulation of creatine in brain tissue following supplementation. No published studies specifically examining CLG's neurological effects were identified.

Evidence strength: No published evidence. Speculative based on parent-compound (creatine) physiology and commercial claims.

5.5 Glutamine-Related Health Effects

Because creatyl-L-glutamine hypothetically releases L-glutamine upon hydrolysis, the patent literature implies it could confer the physiological benefits associated with glutamine supplementation. Glutamine is the most abundant free amino acid in human plasma and skeletal muscle and plays roles in nitrogen transport, gut mucosal integrity, immune function, and as a conditionally essential amino acid under physiological stress. However, given that the compound is only partially hydrolyzed (27% in the available in vitro model), the degree to which intact creatyl-L-glutamine delivers functionally meaningful quantities of free glutamine is unknown and has not been investigated in published clinical studies.

Evidence strength: No published evidence for creatyl-L-glutamine as a glutamine delivery vehicle.

6. Body Systems and Health Areas Associated with Creatyl-L-Glutamine

• Skeletal Muscle / Musculoskeletal System: The primary rationale for the compound's development is as an alternative creatine delivery vehicle for muscle energy metabolism. Phosphocreatine helps provide ATP during short bursts of high-intensity exercise, and the depletion of phosphocreatine has been associated with the onset of fatigue; the phosphocreatine pool in skeletal muscle is expandable, which has led to oral supplementation of creatine and phosphocreatine to increase these components in muscle, thereby enhancing exercise performance.
• Central Nervous System / Brain: Creatine is an important energy metabolite that is concentrated in tissues such as the muscles and brain. Creatyl-L-glutamine has been proposed in patent literature for potential brain-health applications, though no published evidence supports this for CLG specifically.
• Gastrointestinal System: The digestive system is the site at which the amide bond would need to be cleaved for either creatine or glutamine to become bioavailable. The limited hydrolytic efficiency documented in available data bears directly on gastrointestinal processing.
• Immune and Metabolic Systems: To the extent that glutamine plays known roles in immune cell fuel supply and nitrogen metabolism, CLG has been proposed as a vehicle to deliver glutamine for these purposes, but without supporting published data.

7. Dosage Forms and Reported Dosages

Creatyl-L-glutamine does not have established clinical dosages supported by peer-reviewed human trials. The compound appears in commercial products at quantities that have been subject to legal scrutiny. A survey presented in litigation found about one-in-five cans of Bang sold would go to Monster beverages if super creatine was removed or if Bang buyers were more informed about the amount of super creatine — 25 mg — in the product. This 25 mg figure represents a commercially available dose substantially lower than the multi-gram doses typical of creatine monohydrate supplementation research.

The patent specifies concentration ranges for formulations: the total concentration of creatyl-L-glutamine species in an aqueous solution may be any amount between about 0.1% and about 25% by weight. For its closely studied analog CLL, the human randomized controlled trial by Askow et al. (2022) used 5 g/day for 14 days — equivalent to the standard creatine monohydrate comparison dose — with no significant effect on muscle creatine content.

In the animal toxicological studies conducted on CLL (the closest analog with published safety data), doses ranged from 1,250 to 5,000 mg/kg body weight per day. No equivalent published dose-finding or pharmacokinetic study exists for creatyl-L-glutamine in humans or animals.

8. Safety Considerations

No Published Formal Toxicology for Creatyl-L-Glutamine

While individually, creatine and leucine (and by analogy, creatine and glutamine) have been studied and used extensively by humans with few serious adverse side effects; to the knowledge of researchers in this field, no formal toxicological, pharmacokinetic, or human studies on the combined creatyl compound had been published at the time of recent writing. This statement from a 2018 peer-reviewed toxicology journal article specifically flags the gap in safety data for these novel synthetic creatyl dipeptides.

Toxicological Data on the Analog Creatyl-L-Leucine

Formal toxicology has been conducted on the structural analog CLL, and by extension these data provide the most relevant safety context for the CLG compound class. A battery of toxicological studies was conducted to investigate the genotoxicity and repeated-dose oral toxicity of creatyl-L-leucine in rats in accordance with internationally accepted guidelines. There was no evidence of mutagenicity in a bacterial reverse mutation test and in an in vitro mammalian chromosomal aberration test. There was no genotoxic activity observed in an in vivo mammalian micronucleus test at concentrations up to the limit dose of 2,000 mg/kg bw/day. Creatyl-L-leucine did not cause mortality or toxic effects in Hsd.Han Wistar rats in a 90-day repeated-dose oral (gavage) toxicity study at doses of 1,250, 2,500, and 5,000 mg/kg bw/d. The no observed adverse effect level (NOAEL) from the 90-day study was determined to be 5,000 mg/kg bw/d, the highest dose tested, for both male and female rats.

These CLL toxicology data were published in the International Journal of Toxicology in 2018 (Reddeman et al.). These findings provide some indirect reassurance about the compound class, but they cannot be directly extrapolated to creatyl-L-glutamine, which has a different amino acid component with its own distinct metabolic handling.

Safety of Component Molecules

In humans, results from several studies in which healthy adult male and female subjects received oral supplemental L-glutamine at daily doses ranging from 3 to 45 g for up to 10 weeks did not reveal any compound-related adverse effects. A review of the safety of L-glutamine concluded that there is strong evidence in humans supporting an absence of adverse effects associated with the supplemental consumption of up to 14 g L-glutamine/day.

L-glutamine showed no mutagenic activity in a bacterial reverse mutation assay and did not induce chromosomal aberrations in Chinese hamster lung fibroblast cells in an in vitro chromosomal aberration assay. The safety profiles of the individual components (creatine and L-glutamine) are well-characterized; however, the covalently bonded dipeptide creatyl-L-glutamine must be considered a distinct chemical entity for regulatory and safety purposes.

Novel Ingredient Status and Regulatory Context

Creatyl-L-leucine is synthesized by subjecting L-leucine to a series of chemical processes, resulting in leucine and creatine connected by a covalent bond; thus, CLL is a novel ingredient. The same classification applies to creatyl-L-glutamine. As novel synthetic ingredients, these compounds do not have a history of use prior to their patent filing in 2010, and their regulatory status as dietary supplement ingredients in the United States is subject to New Dietary Ingredient (NDI) provisions under DSHEA. No GRAS (Generally Recognized as Safe) designation or published regulatory approval by major bodies (FDA, EFSA, EMA) for creatyl-L-glutamine was identified in the available sources.

Litigation and Advertising Claims

Claims around "Super Creatine," first introduced by Bang in 2015, were at the heart of a concluded lawsuit filed by Bang's chief rival Monster Energy. Lawyers for Monster successfully argued that Bang misled consumers by touting the ingredient as being shelf-stable and water-soluble — rather than regular creatine, which is not dissolvable in water — and effective for increasing the levels of creatine in the bloodstream. This legal outcome underscores the gap between marketing claims and the available scientific evidence for the compound class. A jury ruled that certain advertising claims about "Super Creatine" (CLL) constituted false advertising.

Unknown Metabolic Fate

An unpublished simulated gastric digestion study on creatyl-L-glutamine indicated that only 27% of the compound was hydrolyzed; however, no digestion or pharmacokinetic data were located regarding CLL. This means that for creatyl-L-glutamine specifically, the fate of the remaining approximately 73% of unhydrolyzed compound after ingestion is unknown. It is not established whether the intact dipeptide is absorbed, excreted, or undergoes further metabolism. The long-term consequences of exposure to unhydrolyzed creatyl-L-glutamine have not been formally studied in humans.

9. Summary of Evidence Assessment

Creatyl-L-glutamine is a fully synthetic novel dietary ingredient with a clear and rational chemical design rationale: to stabilize both creatine and glutamine in aqueous solution by forming a covalently bonded dipeptide. The aqueous stability advantage, as reported in its originating patent, addresses a genuine limitation of conventional creatine and glutamine supplementation in liquid formats. However, the central bioavailability hypothesis — that the compound will be enzymatically cleaved in the gut to release therapeutically meaningful quantities of free creatine and glutamine — is not supported by published independent peer-reviewed evidence.

The only published digestion data for CLG, though unpublished and derived from an in vitro model, indicate only 27% hydrolysis. Data from its structural analog creatyl-L-leucine — assessed in both animal feeding studies and one human randomized controlled trial — consistently show no meaningful creatine delivery to muscle, plasma, or brain. The compound has no demonstrated ergogenic effects, no established clinical dosing protocols supported by peer-reviewed literature, and no formal published human safety studies. Toxicological studies on the structural analog CLL suggest low acute and subchronic toxicity at high doses in rodents, but these findings cannot be directly extrapolated to creatyl-L-glutamine.

Overall, the current state of publicly available evidence for creatyl-L-glutamine is insufficient to support efficacy claims related to muscle creatine loading, athletic performance, or any other health outcome. The compound remains in the category of novel, incompletely characterized synthetic dietary ingredients.

References

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• Askow AT et al. "Creatine Monohydrate Supplementation, but not Creatyl-L-Leucine, Increased Muscle Creatine Content in Healthy Young Adults: A Double-Blind Randomized Controlled Trial." International Journal of Sport Nutrition and Exercise Metabolism, 2022;32(6):446–452. Human Kinetics.
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• Monster Energy Company v. Vital Pharmaceuticals Inc. Civil Minutes, U.S. District Court, April 2022.