Application of Sonanos™:
Solubilizer for Higher-Molecular-Weight Modalities

Sonanos™ DS (Solubility Enhancement Grade) dramatically enhances the solubility of poorly water‑soluble APIs, including higher-molecular-weight modalities such as peptides. Simple addition of the API powder to a Sonanos™ DS solution enables effective solubilization without the need for organic solvents.

Compared with conventional solubilizers, Sonanos™ DS offers three advantages:

• It can achieve solubilization with a smaller amount of excipient.
• It is applicable even to components that have traditionally been difficult to solubilize —such as large molecules with a molecular weight over 800 (e.g., poorly water‑soluble peptides or TPDs).
• It demonstrates a high level of safety.

Typical Formulation Composition

Below is a representative formulation using Sonanos™ DS with a dosing volume of 1 mL. The envisioned API dose ranges from approximately 4.5 to 18 mg per 1 mL, which corresponds to the typical maximum dosing volume for subcutaneous (SC) injection.

Solubility Enhancement of PROTACs

Sonanos™ DS is an effective solubilizer for bulky VHL‑ligand PROTACs. In some cases, we observed improved solubility compared with conventional solubilizers. In one example, GNE‑987, a VHL‑ligand PROTAC, was used as a model API. Sonanos™ was compared with hydroxypropyl‑β‑cyclodextrin (HP‑β‑CD) and other existing solubilizers for solubility enhancement. As a result, Sonanos™ demonstrated the greatest enhancement among the solubilizers tested. These findings suggest its potential applicability to VHL‑ligand PROTACs, for which oral delivery is often challenging and subcutaneous administration may offer a viable alternative.

Advantages in Subcutaneous PK Profiles for PROTAC Formulations (vs. Conventional Solubilizers)

The PK profile was evaluated using MZ‑1 as a model compound. Following subcutaneous administration in rats at an API dose of 5 mg/kg, clear differences were observed between the formulations. With the HP‑β‑CD–based formulation, a sharp increase in plasma concentration was observed shortly after dosing. In contrast, the Sonanos™ formulation showed a reduced initial burst, along with prolonged Tmax and mean residence time. Importantly, the overall exposure (AUC) was comparable between the two formulations, suggesting that Sonanos™ may provide a PK profile better suited for subcutaneous delivery.

Solubility Enhancement of Poorly Water-Soluble Peptides

Sonanos™ DS is an effective solubilizer for poorly water‑soluble peptides. For example, we evaluated its solubility‑enhancing effect using poorly water‑soluble cyclic peptide powders. Sonanos™ significantly improved peptide solubility without the use of organic solvents.
Although specific molecular structures are confidential, in one case (cyclic peptide A), a commercially available solubilizer (polysorbate 80) increased solubility by approximately 2,000‑fold compared with the API alone, whereas Sonanos™ DS (2.4%) achieved an improvement exceeding 70,000‑fold.

Note: moleular weight of cyclic peptide A and B is 2,201 and 1,036, respectively.

Effect of Sonanos™ DS on PK Profile of Cyclic Peptides

We also investigated the effect of Sonanos™ DS on the pharmacokinetic (PK) profile of a poorly water‑soluble peptide. Cyclosporin A (CyA) was used as a model drug, solubilized with Sonanos™ DS, and intravenously administered to Sprague–Dawley rats (SD rats).
Sonanos™ DS did not significantly alter the PK profile of CyA, indicating its suitability as a solubilizer. These results suggest that APIs encapsulated in Sonanos™ nanogel particles are rapidly released after entering systemic circulation.

• Animals: SD rats (Slc:SD), male, 6-7 weeks
• IV, N = 3, 2.5 mL/kg
• Concentration measurements: UHPLC

Solubility Enhancement of Small Molecule APIs

Sonanos™ DS can also function as an effective solubilizer for poorly water‑soluble small molecule APIs. To evaluate its solubilization capacity, poorly water‑soluble APIs were mixed with a Sonanos™ DS solution and subsequently filtered.
As shown below, Sonanos™ DS (0.1%) demonstrated a clear solubility‑enhancing effect for paclitaxel and itraconazole, which were used as model compounds.

Effect of Sonanos™ DS on PK Profile of Small Molecule APIs

The impact of Sonanos™ DS on the PK profile of a small‑molecule API was further evaluated using itraconazole (ITZ) as a model drug. ITZ was selected because its half‑life (~4 hours) is substantially shorter than that of Sonanos™ nanogel particles (~15 hours).
After intravenous administration of the ITZ formulation solubilized with Sonanos™ DS to Sprague–Dawley rats (SD rats), no significant changes in the PK profile were observed. This result further supports the suitability of Sonanos™ DS as a solubilizer and suggests rapid release of the encapsulated API following systemic administration.

• Animals: SD rats, male, 6-7 weeks
• IV, N = 4, 4.0 mL/kg
• Concentration measurements: HPLC

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