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Purpose <p>Oral delivery of proteins is limited by the acidic conditions of the stomach and low permeability due to low lipophilicity. In this study, hydrophobic ion pairing (HIP) and a self-nanoemulsifying drug delivery system (SNEDDS) were used to overcome these limitations.</p> Methods <p>HIP is a noncovalent strategy that enhances the lipophilicity of hydrophilic protein drugs. LEU (leuprolide acetate) was complexed with sodium dodecyl sulfate (SDS). The LEU concentration was 5&#xa0;mg/mL, and the reaction molar ratio with SDS was determined to be 1:2. HIP was characterized using scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). Precipitation efficiency and partitioning coefficients were measured. Capryol 90, Cremophor EL, and Transcutol HP were selected for the solubility and emulsification studies, respectively. The SNEDDS composition was optimized using Design-Expert software. The oil-to-surfactant ratio was set as a factor. Droplet size, transmittance, and degree of dissociation were set as the responses.</p> Results <p>No peaks were observed at 155℃ and 220℃, confirming that HIP was formed. Precipitation efficiency was 99.9%, and the partitioning coefficient of HIP was increased from − 1.85 to 1.14. The optimized HIP-SNEDDS formulation was characterized by a small droplet size, high transmittance, and low LEU dissolution. Free LEU achieved approximately 80% dissolution within 1&#xa0;h, whereas HIP and HIP-loaded SNEDDS exhibited much lower dissolution rates at 16.87% and 16.81%, respectively, at 1&#xa0;h. After 8&#xa0;h, free LEU reached almost 100% dissolution, whereas HIP showed a tendency to gradually decrease to 79.6%, and HIP-SNEDDS to 45.61%. The inhibitory concentration (IC50) of HIP against MDCK cells was 1.8 times greater than that of LEU due to the increased presence of SDS. The Papp value of HIP was approximately 1.04 times that of LEU, while that of HIP-loaded SNEDDS was approximately 1.50 times higher, indicating enhanced membrane permeability.</p> Conclusion <p>The SNEDDS is expected to protect LEU from degradation under acidic gastric conditions. The higher membrane permeabilities of HIP and SNEDDS indicated improved lipophilicity of LEU. Therefore, the HIP-loaded SNEDDS of LEU could be attributed to the potential for oral drug delivery of protein drugs.</p>

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Hydrophobic ion pairing–loaded SNEDDS for leuprolide acetate: in vitro feasibility for enhanced lipophilicity, acidic dissolution control, and MDCK permeability

  • 期刊论文

  • 发表日期：

    2025年12月17日

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  • Hyelim Yoo,
  • Young-Guk Na,
  • Minki Jin,
  • Suyeon Hwang,
  • Samuel Lee,
  • Young Ju Jo,
  • Ji Hyun Bang,
  • Hong-Ki Lee,
  • Cheong-Weon Cho

摘要

Purpose

Oral delivery of proteins is limited by the acidic conditions of the stomach and low permeability due to low lipophilicity. In this study, hydrophobic ion pairing (HIP) and a self-nanoemulsifying drug delivery system (SNEDDS) were used to overcome these limitations.

Methods

HIP is a noncovalent strategy that enhances the lipophilicity of hydrophilic protein drugs. LEU (leuprolide acetate) was complexed with sodium dodecyl sulfate (SDS). The LEU concentration was 5 mg/mL, and the reaction molar ratio with SDS was determined to be 1:2. HIP was characterized using scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). Precipitation efficiency and partitioning coefficients were measured. Capryol 90, Cremophor EL, and Transcutol HP were selected for the solubility and emulsification studies, respectively. The SNEDDS composition was optimized using Design-Expert software. The oil-to-surfactant ratio was set as a factor. Droplet size, transmittance, and degree of dissociation were set as the responses.

Results

No peaks were observed at 155℃ and 220℃, confirming that HIP was formed. Precipitation efficiency was 99.9%, and the partitioning coefficient of HIP was increased from − 1.85 to 1.14. The optimized HIP-SNEDDS formulation was characterized by a small droplet size, high transmittance, and low LEU dissolution. Free LEU achieved approximately 80% dissolution within 1 h, whereas HIP and HIP-loaded SNEDDS exhibited much lower dissolution rates at 16.87% and 16.81%, respectively, at 1 h. After 8 h, free LEU reached almost 100% dissolution, whereas HIP showed a tendency to gradually decrease to 79.6%, and HIP-SNEDDS to 45.61%. The inhibitory concentration (IC50) of HIP against MDCK cells was 1.8 times greater than that of LEU due to the increased presence of SDS. The Papp value of HIP was approximately 1.04 times that of LEU, while that of HIP-loaded SNEDDS was approximately 1.50 times higher, indicating enhanced membrane permeability.

Conclusion

The SNEDDS is expected to protect LEU from degradation under acidic gastric conditions. The higher membrane permeabilities of HIP and SNEDDS indicated improved lipophilicity of LEU. Therefore, the HIP-loaded SNEDDS of LEU could be attributed to the potential for oral drug delivery of protein drugs.