Proteolysis targeting chimeras (PROTACs), heterobifunctional molecules that hijack the ubiquitin–proteasome system (UPS) to degrade specific proteins, hold great promise in treating diseases driven by traditionally “undruggable” targets. However, their large molecular weight, high hydrophobicity, and other physicochemical hurdles contribute to their limited bioavailability, suboptimal pharmacokinetics, and attenuated therapeutic efficacy. Consequently, diverse formulation innovations have been investigated to optimize PROTAC delivery. This review examines current challenges and advances in specialized drug delivery approaches designed to bolster PROTAC pharmacological performance. We first outline the fundamental limitations of PROTACs—their low aqueous solubility, poor cell permeability, rapid clearance, and concentration-dependent “hook effect”. We then discuss how various enabling formulations address these issues, including polymeric micelles, emulsions, amorphous solid dispersions, lipid-based nanoparticles, liposomes, and exosomes. Collectively, these delivery technologies substantially improve the therapeutic outcomes of PROTACs in preclinical cancer models. Future applications may extend beyond oncology to address other complex diseases using newly emerging heterobifunctional molecules. By integrating advanced formulation science with innovative degrader design, the field stands poised to unlock the clinical potential of PROTACs for protein degradation therapies.

Background/Objectives: The poor aqueous solubility of many therapeutic compounds remains a key barrier to achieving optimal oral bioavailability. While traditional formulation strategies—such as surfactant-based solubilization, nanocrystals, and amorphous solid dispersions—have yielded varying degrees of success, they are often limited by poor physical stability, high excipient loads, inconsistent absorption, and safety concerns associated with long-term surfactant exposure. To address these challenges, this review evaluates surfactant–particle hybrid drug delivery systems as a next-generation platform for enhancing the oral delivery of poorly water-soluble drugs. Methods: A comprehensive literature analysis was conducted to examine the mechanistic foundations, formulation techniques, and translational hurdles associated with these hybrid systems. Representative in vitro and in vivo case studies were critically reviewed to assess performance consistency, particularly with respect to dissolution enhancement, supersaturation stabilization, and permeability modulation. Consideration was also given to manufacturing feasibility, excipient safety, scalability, and regulatory constraints. Results: Findings indicate that surfactant–particle hybrids provide synergistic benefits by integrating solubilization and stabilization functions with tailored particle design. These systems have shown consistent improvements in pharmacokinetic profiles and drug absorption across diverse drug candidates. However, limitations remain, including challenges in long-term physical stability and excipient compatibility that must be addressed for broader application. Conclusions: Surfactant–particle hybrid systems offer a versatile and promising approach to overcoming the limitations of poorly soluble drugs. With careful attention to formulation optimization and regulatory compliance, they have the potential to serve as a transformative platform in future oral drug delivery strategies.

Dapagliflozin base and a commercial dapagliflozin propanediol hydrate cocrystal (DPF-PDHC) were highly hygroscopic and thermally unstable. In this study, to address this limitation, we prepared a novel dapagliflozin di-L-proline cocrystal (DPF-LPC) and evaluated its physicochemical characterization compared with DPF-PDHC. After the preparation of the DPF-LPC-loaded tablet, its dissolution, stability and bioequivalence in beagle dogs and mini-pigs were assessed. DPF-LPC was well prepared with a dapagliflozin base and L-proline in a molar ratio of 1:2. Similar to DPF-PDHC, DPF-LPC was highly lipophilic and crystalline in nature. However, these two cocrystals exhibited different melting points and crystalline structures, indicating their different cocrystal forms. Moreover, DPF-LPC exhibited less hygroscopicity and lower water content than DPF-PDHC. The DPF-LPC-loaded tablet composed of DPF-LPC, Comprecel M102, lactose monohydrate, crospovidone, magnesium stearate, and Opadry (coating) at a weight ratio of 15.6:104.4:100.0:8.0:2.0:7.0, was dissolution-equivalent to the commercial tablet. Moreover, it provided lower impurities than the commercial tablet, indicating its better stability. In the two animals, there were no significant differences in the plasma concentrations, AUC, C_max, and T_max values, suggesting that they were bioequivalent. Therefore, the novel DPF-LPC-loaded tablet with excellent stability and bioequivalence may be used as a potential alternative to the commercial DPF-PDHC-loaded tablet.

In this study, we developed a tamsulosin pellet-loaded orally disintegrating tablet (ODT) that is bioequivalent to commercially available products and has improved patient compliance using microcrystalline cellulose (MCC) and mannitol. Utilizing the fluid bed technique, the drug, sustained release (SR) layer, and enteric layer were sequentially prepared by coating MCC pellets with the drug, HPMC, Kollicoat, and a mixture of Eudragit L and Eudragit NE, respectively, resulting in the production of tamsulosin pellets. The tamsulosin pellet, composed of the MCC pellet, drug layer, SR layer, and enteric layer at a weight ratio of 20:0.8:4.95:6.41, was selected because its dissolution was equivalent to that of the commercial capsule. Tamsulosin pellet-loaded ODTs were prepared using tamsulosin pellets and various co-processed excipients. The tamsulosin pellet-loaded ODT composed of tamsulosin pellets, mannitol–MCC mixture, silicon dioxide, and magnesium stearate at a weight ratio of 32.16:161.84:4.0:2.0 gave the best protective effect on the coating process and a dissolution profile similar to that of the commercial capsule. Finally, no significant differences in beagle dogs were observed in pharmacokinetic parameters, suggesting that they were bioequivalent. In conclusion, tamsulosin pellet-loaded ODTs could be a potential alternative to commercial capsules, improving patient compliance.

This study aimed to improve the solubility of ezetimibe (EZT), which has low aqueous solubility, by preparing complexes using β-cyclodextrin (β-CD) derivatives. Phase solubility studies and Job’s plot confirmed a high apparent stability constant for EZT with β-CD and even higher constants with its derivatives, establishing a 1:1 stoichiometric ratio. The composites were prepared using spray drying over a range of molar ratios, and their physicochemical properties were evaluated using techniques such as scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FT-IR). Saturation solubility and in vitro dissolution tests revealed that solubility increased with higher CD molar ratios. EZT/RM-β-CD inclusion complexes (ICs) and EZT/DM-β-CD ICs exhibited a similar solubility, which was greater than that of EZT/HP-β-CD ICs and EZT/SBE-β-CD ICs (where RM, DM, HP, and SEB represent H, CH₃, -CH₂-CHOH-CH₃ and -(CH₂)₄-SO₃Na synthetic derivatives, respectively). Most complexes, except for EZT/SBE-β-CD at 1:2 or higher ratios, showed superior solubility compared with EZT powder and commercial products. Molecular docking simulations confirmed EZT inclusion within the CD, revealing hydrogen bonds and binding energies that aligned with solubility trends. These findings suggest that EZT complexes with β-CD derivatives significantly improve solubility, highlighting their potential for developing more effective oral solid formulations for hyperlipidemia treatment.