(T0930-12-83) Co-micelle Technology by Hyaluronic Acid (HA) Nanogel (trade name Sonanos^TM) Solubilize as much of a Poorly Water-Soluble Drug as Possible with as Little as Possible

Purpose: In recent years, 80% of drug candidate compounds have been classified as poorly water-soluble, making great preparations for the development of new drugs¹. Many approaches have been explored with the aim of enhancing solubility of poorly water-soluble drug. For instance, modifying the structure of the API to improve the solubility, or using salt formation and surfactants is commonly used. However, it is difficult to use a large amount of solubilizer (ex. Tween-80) from the viewpoint of side effects including toxicity and anaphylactic shock. In our group, cholesterol-modified hyaluronic acid (CHHA), forming nano-sized hydrogel (Sonanos^TM) in water, having versatile encapsulation property of small-sized molecules, middle-sized molecules, peptide including cyclic peptides, and proteins, have been developed (Figure 1)². Hyaluronic acid (HA) nanogel (trade name Sonanos^TM) has hyaluronic acid in the main chain, a hydrophilic, biocompatible material with low toxicity, and a hydrophobic group in the side chain². A nano-ordered gel is spontaneously formed, due to its hydrophilic-hydrophobic interactions, in which it is possible to load small molecules, peptides, and proteins. So far, Sonanos^TM can dissolve poorly water-soluble drug overwhelmingly more than conventional solubilize³. Herein, we introduce “Co-micelle” technology that utilizes a new DDS base material to maximize the solubilization effect as much as possible in organic solvent free.

Methods: Co-Micellization: Various surfactants were added to Sonanos^TM, and the changes in the peaks of the Sonanos^TM were confirmed through SEC analysis. Solubilization of water-insoluble API with Sonanos^TM: The API powder was added to 0.461~0.600mL of CHHA solution (36mg/mL) in water and then added to the solution of cosolvent (Tween-80, Poloxamer 188, Chol-PEG600) in water. To encapsulate the API, the mixture was stirred with CHHA at 20 ℃ for 24 hours ([CHHA] = 16.6~21.6 mg/mL, [CyA] = 5 mg/mL or [Temsirolimus] = 10 mg/mL). Then, the solution was filtered using a 0.45μm PES syringe filter to remove precipitated API. Finally, the API concentration was quantified by HPLC method.

Results: The addition of various surfactants to Sonanos^TM resulted in a significant increase in the peaks of Sonanos^TM in SEC analysis, providing evidence for the formation of co-micelles between Sonanos^TM and the surfactants. API solubilization study was performed with model peptide (cyclosporin A) and middle-molecule (Temsirolimus). As a result, the saturated solubility of a poorly soluble cyclosporin in CHHA only was 0.64mg/mL, but it was improved to 3.96~4.86mg/mL by adding a small amount of surfactant (Tween-80, Poloxamer 188, Chol-PEG600) (Figure 2-1, 2-2). In the same manner, Temsirolims was also examined, and the addition of a small amount of Chol-PEG600 increased the solubility of API by more than 10 times (Figure 3). (Figure 4). The peptide or middle-molecule containing Sonanos^TM formulation was sterile filterable and easily passed through a 30 G needle.

Conclusion: From the above results, we have concluded that Co-micelle technology containing Sonanos^TM formulation have enormous potential to enhance the solubility in water without organic solvent (DMSO, EtOH etc.). We believe Sonanos^TM can dramatically dissolve your APIs and avoid potential risk associated with other solubilizing excipients.

References: 1. Bhalani, D.V et al. Biomedicines 2022, 10, 2055.
2. T. Nakai et al. Macromol. Biosci. 2012, 12. 475.