Con-cret® – Creatine Micro-Dosing® Dietary Supplement 2017-08-16T14:29:06-04:00

Con-cret® – Creatine Micro-Dosing® Dietary Supplement

Based on Patented “Creatine Hydrochloride”

Prepared by

Donald W. Miller, Ph.D.
Professor
Department of Pharmacology and Therapeutics
University of Manitoba

April 2011

Introduction

Creatine is a nutrient found in meat products and produced de novo in the liver. Nutritional supplements containing creatine have been used to increase muscle mass and muscle performance in athletes (Kreider et al., 1998; Casey et al., 1996). Due to the beneficial effects of creatine supplementation in the athletic market, there is increased interest in the use of creatine supplements for augmenting and complementing the treatment of therapeutic conditions in which muscle performance is compromised (Persky and Brazeau, 2001). However, it is estimated that as little as 9% of creatine monohydrate, the standard form of creatine used in dietary supplements, reaches the bloodstream following oral administration. As a result of the poor gastro-intestinal (GI) absorption of creatine monohydrate, current dosage forms require the consumption of up to 10-30 grams per day to obtain the desired effects of creatine on muscle performance. Furthermore, the formulation options are limited with creatine monohydrate as the large amounts required are not suitable for conventional oral dosage units such as tablets, capsules or liquid elixirs, not to mention inclusion in potential sports bars or drinks. Indeed, many of the undesired side-effects observed with creatine supplements including gastric distress, bloating, cramping and diarrhea, may be attributable to the large volumes of liquid required for most of the creatine monohydrate formulations. Thus, the inconvenience and inefficiencies of currently available creatine products and dosage forms limit both the performance-based and therapeutic-based applications for the general population. One way to impact on the effectiveness of creatine based dietary supplements would be through increasing the oral bioavailability of creatine (i.e. the amount of creatine that actually makes it from the gastrointestinal tract into the bloodstream). Such a creatine based dietary supplement with improved oral bioavailability would deliver the desired biological responses at lower required doses (i.e. 1-5 gram per day or less) would provide a substantial improvement in terms of side-effect profile, safety and convenience to the consumer, while providing a wider range of product applications for supplement suppliers.

CON-CRET® technology platform

There are two over-riding factors that determine the bioavailability of a compound, aqueous solubility (how well the compound dissolves in water) and cellular permeability (how well the compound moves across cellular, lipid-based membranes). Indeed, based on just these two properties, it is possible to establish a classification system to predict oral absorption of a compound (See Figure 1). Such a classification system is commonly used by the pharmaceutical industry and regulatory agencies such as the Food and Drug Administration to make informed decisions concerning oral absorption of drugs (Wu and Benet, 2005). Class 1 compounds have both high solubility and high permeability and are completely or near completely absorbed (i.e. 100% bioavailablity). Class 2 compounds have low solubility and high permeability and while bioavailability is not as great as class 1 compounds, it is still substantial (30% and greater). Class 3 compounds have high solubility and low permeability and class 4 compounds have both low solubility and permeability. Class 3 compounds typically have limited bioavailability (i.e. less than 25%) and class 4 compounds have little if any appreciable oral absorption. Within this classification system, a high solubility compound is one in which the highest administered dose is soluble in 250 ml of water while a high permeability compound is considered to be one with greater than 90% oral absorption (Wu and Benet, 2005). Under this system, creatine monohydrate, the most commonly used creatine supplement would be considered to be both a low permeability and low solubility (class 4) compound requiring ingestion of relatively large amounts to produce the desired biological effects. CON-CRET® is the result of a systematic search for creatine salts with improved aqueous solubility. The rationale being that improving the aqueous solubility of creatine would result in a creatine supplement with improved oral bioavailability. Studies described below, performed at University laboratories and private testing facilities support the contention that CON-CRET® is indeed a new form of creatine with enhanced solubility and improved oral bioavailability while maintaining the inherent safety of a creatine salt form.

Figure 1: Bioclassification system for determining oral bioavailability (Wu and Benet 2005).

Enhanced Aqueous Solubility of CON-CRET®

The aqueous solubility of several different creatine salt forms were evaluated to determine which ones would make suitable candidates for development as creatine-based dietary supplement. The analysis focused on both newly synthesized salt forms created in the laboratory of Dr. J. Vennerstrom (University of Nebraska) as well as commercially available creatine salt forms present within the consumer market (Gufford et al., 2010). These studies identified two particular salt forms, the hydrochloride and mesylate salts of creatine as having substantially higher solubility properties compared to commercially available creatine supplements (Table 1). The increases in solubility observed were approximately 30-40-fold greater than that detected for creatine monohydrate. Both the hydrochloride and mesylate salts were examined for both solid-state and solution stability. Of the two, creatine hydrochloride possessed stability properties that were as good (in the case of solid-state) or better (in the case of aqueous solution) than that of creatine monohydrate. Based on this, creatine hydrochloride (CON-CRET®) was selected for further study and development (mesylate being less stable and more expensive to produce).

It is important to note that all the salt forms of creatine examined had similar permeability properties as reflected in the similar octanol-water coefficients. This was expected as all forms of creatine would pass across cellular membranes as the de-salted, free base form of creatine. However, to further confirm that that creatine hydrochloride (CON-CRET®) was as permeable as other commercially available creatine supplements, permeability studies were performed in Caco-2 cell monolayers (Figure 2). The Caco-2 cells are a widely used cell culture model for predicting and assessing human intestinal permeability (Mandagere et al., 2002). All permeability studies were performed under conditions where the creatine compounds were completely dissolved in aqueous buffer to remove the solubility influences that could affect permeability. In these studies, all the creatine compounds, creatine hydrochloride (CON-CRET®), creatine pyruvate and creatine citrate had similar permeability in Caco-2 monolayers (Figure 2). These findings confirm that permeability parameters are similar for all the creatine salt forms. Based on the classification system discussed earlier, supplements using creatine hydrochloride (CON-CRET®) would be considered to be class 3 compounds (i.e. high solubility / low permeability). Compared to the other creatine supplements examined, which fall under the class 4 category, use of creatine hydrochloride (CON-CRET®) would be expected to provide for superior dosage formulations and improved oral bioavailability.

Figure 2: Caco-2 monolayer permeability for various creatine salt forms. Creatine hydrochloride (CHCl), creatine monohydrate (CM), creatine citrate (CCit) and creatine pyruvate (CPyr) were examined for permeability across Caco-2 monolayers. Values represent the mean + SEM of 6 monolayers per treatment group. Data from Gufford et al., 2010.

Enhanced Oral Bioavailability of CON-CRET®

To quantitatively determine the improvements in oral bioavailability with creatine hydrochloride (CON-CRET®), the pharmacokinetic profile for CON-CRET® was compared with that of creatine monohydrate. The study design was a blinded, cross-over format in which 10 normal healthy volunteers were selected and given equivalent doses of CON-CRET® or of creatine monohydrate with a 6 oz glass of cold water. Blood samples were taken immediately prior to ingestion of creatine compounds and at 30, 60, 120, and 180 minutes after ingestion of the creatine supplements. After a two-week wash out period, the same volunteers returned and were administered the remaining creatine supplement and blood samples were obtained as described. The treatment order of administration of the creatine supplements was randomized and the volunteers were unaware of which supplement they were receiving. This format allowed for direct comparison of CON-CRET® with creatine monohydrate in the same individual and as such minimized inter-subject variability with regard to creatine absorption in the gastro-intestinal tract. Informed consent was obtained for all study participants.

Results of this study show that there is an increase in plasma creatine concentrations in the blood following ingestion of either creatine supplement (Figure 3). However, the creatine concentrations observed in the blood following CON-CRET® administration were greater compared to creatine monohydrate (Figure 3). The increase plasma concentrations of creatine following CON-CRET® administration resulted in significantly greater area under the plasma creatine concentration curve (AUC) for CON-CRET® (Figure 3). As the plasma AUC provides an index of the relative oral bioavailability of the two creatine supplements, it is readily apparent that CON-CRET® provides for better oral absorption compared to standard creatine monohydrate. Considering the differences in the molecular weight of the two creatine salt forms, there is an approximately 70% increase in oral bioavailability with CON-CRET® as compared to creatine monohydrate. Thus the increase in oral bioavailability predicted through the use of the more highly soluble creatine hydrochloride salt form was actually observed in human volunteers.

Summary

Standard forms of creatine supplements are limited in the oral bioavailability due to low aqueous solubility properties. As a result, relatively large amounts (10-30 g /day) of supplement must be consumed to provide the desired effects of creatine on muscle function. Our studies have identified a new salt form of creatine, creatine hydrochloride (CON-CRET®) that has far superior solubility properties in aqueous solutions. The more than 40-fold improvement in solubility results in enhanced oral absorption of creatine. Our in-house studies indicate improvements of 70% for oral absorption and bioavailability. This new salt form of creatine has several advantages. First, improved bioavailability means smaller (and therefore safer) doses of CON-CRET® can be used to obtain the desired biological effects of creatine supplementation. This means reduced chance of side-effects and better consumer compliance in regard to taking the supplement. In addition, the ability to “micro-dose” CON-CRET® provides a much wider formulational platform with powders, capsules, pills, power bars and power drinks containing CON-CRET® being able to actually result in biologically relevant amounts of creatine in the body. These advantages place CON-CRET® in a superior position in the creatine dietary supplement category.

Figure 3: Plasma creatine concentrations following oral ingestion of creatine monohydrate (dark circles) or CON-CRET (open circles) in human volunteers (Top panel). Plasma Area Under the Curve for creatine monohydrate (CM) and CON-CRET (CC) formulations (Bottom panel). * p < 0.05 compared to creatine mono; ** p < 0.001 compared to CM group.

References

Casey A, Constantin-Teodosiu D, Howell S, Hultman E, and Greenhaff PL. Creatine supplementation favorable: Affects performance and muscle metabolism during maximal exercise in humans. Am. J. Physiol. 271:E31-E37, 1996.

Gufford BT, Kamaraj S, Miller NJ, Miller DW, Gu X, Vennerstrom JL and Robinson DH. Physicochemical characterization of creatine N-methlyguanidinium salts. J. Dietary Suppl. 7:240-252, 2010.

Kreider RB, Ferreira M, Wilson M, Grindstaff P, Plisk S, Reinardy J, Cantler E, and Almada AL. Effects of creatine supplementation on body composition, strength, and sprint performance. Med. Sci. Sports Exerc. 30:73-82, 1998.

Mandagere AK, Thompson TN and Hwang KK. Graphical model for estimating oral bioavailability of drugs in humans and other species from their Caco-2 permeability and in vitro liver enzyme metabolic stability rates. J. Med. Chem. 45:304-311. 2002.

Persky AM, Brazeau GA. Clinical pharmacology of the dietary supplement creatine monohydrate. Pharmacol. Rev. 53:161-76, 2001.

Wu C-Y. and Benet LZ. Predicting drug disposition via application of BCS: Transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm. Res. 22:11-22, 2005.

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