Title : Enhancing drug loading of Phenytoin into nanoemulsion via hydrophobic ion pairing and its potential to prevent in-vitro precipitation upon serial dilution at blood pH
Abstract:
Phenytoin was originally formulated in organic solvents at pH 12 and has been used via intravenous administration in treating epilepsy. However, due to its unfavorable pKa (8.3) with respect to physiological blood pH 7.4, it resulted in poor solubility and precipitation that caused phlebitis issues upon administration. The current study is focused on formulating nanoemulsions containing lipophilic ion-pair into oil to circumvent precipitation at physiological pH and potentially prevent phlebitis. A novel and atypical hydrophobic salt (1:1) was formed using a surfactant type counter ion Hexadecyl Trimethyl Ammonium Hydroxide (CTAH) and Phenytoin. Hydrophobic ion-pair (HIP) was found to be practically insoluble in water but led to 8-fold high Castor oil solubility compared to the Phenytoin itself, and expectedly demonstrated infinite log P value. Castor oil was selected after screening various oils to formulate the nanoemulsion. The hydrophobic ion pair dissolved in Castor oil was further solubilized with lecithin, and subsequently, the entire oily phase was emulsified with polysorbate 20 to formulate the nanoemulsion. Potential disproportionation and leaching of Phenytoin from CTAH counter ion were confirmed over increasing concentrations of Polysorbate 20 from the HIP alone and dissolved in Castor oil separately. This revealed the strong partitioning tendency of the hydrophobic ion-pair into Castor oil due to enhanced lipophilicity. Polysorbate 20 was found to be an effective emulsifier to formulate the nanoemulsion at ≤ 300 nm particle size, with a zeta potential of > 30+ mV. The positive charge of the emulsion contributed to the leaching of CTAH in the aqueous phase. The emulsion was found to be stable over a period of one month. A serial dilution study of the nanoemulsion was performed in PBS buffer, microscopic observations suggested no birefringence despite incubation for several hours. This result indicated that Phenytoin remained strongly partitioned within the dispersed oily phase whether ion-paired or not. The zeta potential was remarkably flipped to a negative charge when formulated alone with Phenytoin due to the lack of CTAH leaching into the continuous phase. The advantage of ion pairing was in fact a higher drug loading, at which it remained partitioned into the disperse phase and did not precipitate when diluted and incubated in PBS buffer for several hours. The higher drug load could enable a smaller volume slow bolus injection to meet 50 mg/min or lower delivery rate criteria for Phenytoin in the clinical setup.
Audience Take Away Notes:
By attending this presentation on enhancing drug loading of Phenytoin into nanoemulsion via hydrophobic ion pairing and its potential to prevent in-vitro precipitation upon serial dilution at blood pH, the audience will gain a deep understanding of the novel approach to use hydrophobic ion pairing to enhance drug delivery. The audience will learn about the process of nanoemulsion formation and how hydrophobic ion pairing can enhance the drug loading of (BCS Class II) poorly soluble drug. Additionally, the presentation will explain the significance of preventing in-vitro precipitation upon serial dilution at blood pH, which can increase drug efficacy and reduce the risk of side effects. Overall, attendees will acquire practical knowledge and insights into innovative drug delivery techniques that can lead to the development of more effective and efficient treatments.
This research will help audience in following ways:
- A deep understanding of the process of forming nanoemulsion and the role of hydrophobic ion pairing in drug loading can provide valuable insights for creating innovative drug delivery systems.
- Gaining knowledge of the physical characterization of nanoemulsion formulation can inform the development of drug delivery systems and improve their efficacy.
- Learning about the significance of preventing in-vitro precipitation at blood pH can aid in mitigating the phlebitis issue of the drug, thereby improving its therapeutic value.
- Acquiring knowledge of the challenges associated with drug loading and delivery can facilitate the evaluation of different excipients for enhancing drug loading, leading to the development of more effective drug delivery systems.
- Developing a deeper understanding of the scientific principles that underpin drug formulations can inform future research and innovation in the field and lead to the discovery of more effective treatments for patients.
- This research will be beneficial to other faculty members to expand their research in many ways:
- The techniques utilized in this research can be applied to explore the drug delivery options for other BCS Class II drugs that possess poor aqueous and oil solubility.
- The hydrophobic ion pairing approach has the potential to alter drug lipophilicity and improve drug loading for drugs with poor bioavailability.
- A comprehensive understanding of in vitro drug release studies, which involve the consideration of various parameters like dissolution media, temperature, and pH, could inspire future research on the use of hydrophobic ion pairing for drug loading and delivery of other drugs and conditions.
- The study provides a model for investigating the potential of other innovative drug delivery techniques, such as solid lipid nanoparticles, SEDDS, and liposomes, in preventing in-vitro precipitation upon serial dilution at blood pH.
- The research presents a new approach to drug loading and delivery that could be explored and expanded upon in future research and teaching, offering a promising avenue for the drug development.
- The research study outlines the challenges associated with the formulation of phenytoin drug and demonstrates the potential for improvement using hydrophobic ion pairing. The approach of hydrophobic ion pairing can help designers to understand the value and benefits of using this technique to enhance drug loading, which can improve drug efficacy and reduce the required dosage. The prevention of in-vitro precipitation upon serial dilution at blood pH can reduce the risk of side effects and ensure a more consistent drug effect. The use of nanoemulsion can enable targeted drug delivery to specific areas of the body, improving treatment effectiveness and minimizing unwanted effects in other areas. Overall, The findings of this research provide a basis for the unique drug delivery systems for other drugs and applications, which can simplify and improve the work of pharmaceutical designers.
- This research offers insights into the preparation of hydrophobic ion pairing to enhance drug lipophilicity, as well as an innovative approach using nanoemulsions to improve drug loading and reduce side effects associated with in vitro precipitation due to poor drug solubility. By using smaller and more targeted dosages, patient compliance can be increased, leading to better patient experiences and treatment adherence. The use of hydrophobic ion pairing can simplify the design and process of drug delivery systems, potentially reducing time and cost and simplifying regulatory requirements, as there is no modification of the drug involved.
- Hydrophobic Ion pairing presents several promising opportunities for drug delivery technologies, including nanoparticle-based drug delivery, modified drug release to increase circulation time, reducing side effects and toxicity, enhancing drug loading, preventing in vitro precipitation issues, and providing a straightforward and less stringent approach for regulatory approval.
