# Steering the Clinical Translation of Delivery Systems for Drugs and Health Products
## 3 Poster Presentations
### Strategies to Improve the Solubility of Poorly Soluble Drugs by Soluplus(r) Nanomicelles  
[PERSON], [PERSON], [PERSON] and [PERSON] *  
Department of Drug Sciences, University of Catania, 95125 Catania, Italy  
* Correspondence: [EMAIL_ADDRESS](r) (Figure 20) is a graft amphipathic copolymer consisting of polyvinyl caprolactam (57%), polyvinyl acetate (30%), and polyethylene glycol (13%) produced by BASF [78]. Soluplus(r) exhibits amphipathic properties due to its hydrophilic and hydrophobic residues and it spontaneously forms spherical micelles in aqueous solution above a CMC of 7.6 mg/L. Compared to conventional surfactants, Soluplus(r) produces smaller spherical micelles (70-100 nm), with a hydrophobic core-hydrophilic shell structure that can help solubilizing poorly soluble compounds. The spherical structure of these nanomicelles reduces the free energy of the system and can aid for the production of highly water-soluble formulations [79; 80; 81; 82; 83]. The aim of this study was to prepare Soluplus(r) micelles to enhance the solubility of three model APIs belonging to class II of the Biopharmaceutics Classification System (BCS), i.e., characterized by a poor solubility and a good permeability profile: ibuprofen (Ib), idebenone (Id) and miconazole (Mc). Nanomicelles were produced by two alternative methods, namely direct dissolution of the drug in a 1.5 mM aqueous solution of Soluplus(r) (dd) or by solvent evaporation-thin film hydration method (tf), in which the polymer and the drug were co-dissolved in acetone and evaporated to dryness, after which water was added under stirring at r.t., to produce the micelles at the wished polymer concentration. The obtained nanomicelle suspensions were transparent, slightly opalescent when compared to water. No differences were observed between loaded and unloaded micelles in terms of mean size (Z-ave). Blank Soluplus(r) micelles had an average size of \(61.78\pm 1.61\) nm and a polydispersity index (PDI) of \(0.068\pm 0.022\); the micelles loaded with the three APIs showed analogous values (Table 2). Solubility of the tested APIs increased linearly with the concentration of Soluplus(r), up to 290-fold for idebenone (Figure 21). \begin{table}
\begin{tabular}{c c c c c c} \hline \hline \multirow{2}{*}{**Formulation**} & \multicolumn{4}{c}{**Size Analysis**} & \multirow{2}{*}{**PDI**} & \multirow{2}{*}{**ZP**} \\ \cline{2-2} \cline{4-5}  & **Z-Ave** & & & **PK1** & & **Area \%** \\ \hline
**SNM-Id(tm)** & \(59.00\pm 1.028\) & \(63.06\pm 1.145\) & \(100\) & \(0.053\pm 0.011\) & \(-2.98\) \\
**SNM-Id(tm)** & \(60.60\pm 1.385\) & \(65.25\pm 3.108\) & \(100\) & \(0.056\pm 0.038\) & \(-1.23\) \\
**SNM-Ib(tm)** & \(50.20\pm 0.1450\) & \(54.22\pm 1.095\) & \(99.5\) & \(0.164\pm 0.022\) & \(-2.43\) \\
**SNM-Ib(tm)** & \(59.05\pm 0.9603\) & \(64.00\pm 0.6731\) & \(100\) & \(0.100\pm 0.053\) & \(-4.12\) \\
**SNM-Mc(tm)** & \(55.62\pm 0.0396\) & \(63.45\pm 3.265\) & \(98.8\) & \(0.189\pm 0.008\) & \(0.481\) \\
**SNM-Mc(tm)** & \(56.42\pm 3.5370\) & \(55.77\pm 4.956\) & \(99.9\) & \(0.156\pm 0.030\) & \(0.7896\) \\ \hline \hline \end{tabular}
\end{table} 
Table 2: Size analysis (Z-Ave), polydispersity index (PDI) and Zeta potential (ZP) values of drug-loaded Soluplus® nanomicelles produced by the direct dissolution method (dd) or by thin film hydration (tf). Figure 20: Structure of Soluplus®. Reological studies (Figure 22) indicated that Soluplus(r) micelles are suitable for ocular application, with a viscosity lower than 100 cP up to a 2 mM concentration, while at 35 \({}^{\circ}\)C (i.e., the temperature of corneal surface), they tend to become more viscous and bioadhesive. In terms of Z-ave and PDI, the SNM-Id batches were stable at 4, 25 and 37 \({}^{\circ}\)C up to 6 months; SNM-Ib and SNM-Mc were stable for up to 3 months. The drug-loaded nanomicelles can be easily sterilized by filtration through either PES or PTFE 0.22-\(\upmu\)m membranes, without significant changes in the mean particle size.