(M1230-05-29) Formulation Development of Extemporaneously Prepared Mucoadhesive In Situ Forming Gels for Oral Mucositis Pain Control

Purpose: It is reported that over 80% of the patients undergoing chemotherapy and radiation for head and neck cancer suffer from a mild to severe form of oral mucositis which is characterized by ulceration and uncontrolled pain. Current commercial therapies for pain management include a lidocaine mouth wash and opioids (oral tablets or transdermal patches). However, these approaches have major limitations such as insufficient contact time between the oral mouth wash and the mucosa as well as the short half-life of lidocaine (less than 30 min) and the case of oral tablets and transdermal patches, the risk of addiction associated with opioid use. Consequently, a novel sprayable mucoadhesive in situ forming oral gel (containing the local anesthetic Bupivacaine HCl) is proposed to accomplish prolonged pain control for cancer patients suffering from mild to severe oral mucositis. This innovative strategy overcomes the numerous shortfalls associated with the current therapies. Bupivacaine HCl has a high lipid solubility which favours drug diffusion through the lipid-rich neural membranes resulting in prolonged anaesthetic action when compared to lidocaine.Moreover, the incorporation of mucoadhesive polymer further enhances oral mucosa contact time resulting in extended pain control over a selected area in the oral cavity. Extemporaneous formulations prepared by a pharmacist are exceedingly being used as a cost effective strategy during clinical trials to accelerate the development and regulatory approval of novel dosage forms. Accordingly, this study utilizes a pre-commercialized Bupivacaine HCl injection for formulation development. Different concentrations/viscosities of sodium CMC (mucoadhesive polymer) and Pluronics^® (thermosensitive polymers) were investigated to understand the impact of different excipients on the critical quality attributes (CQAs, i.e., ex vivo mucoadhesion, gelling temperature, and in vitro drug release) of the oral gels.

Methods: Different formulations comprising of medium viscosity sodium CMC (ranging from 0% to 1.75% w/v) were prepared using Bupivacaine HCl injection (0.75% w/v, Fresenius Kabi) diluted to 0.25% w/v Bupivacaine HCl using purified water. The concentration of Pluronics^® (Pluronic^® F127- 19.5% w/v and Pluronic^® F68- 1.5% w/v) was kept constant during the initial optimization study. The formulations were characterized using ex vivo mucoadhesion (using excised porcine buccal mucosa and a texture analyzer) and gelling temperature (via tube inversion method). The oral gel formulation showing optimum mucoadhesion and gelling temperature was selected for further optimization trials. The previously selected sodium CMC (medium viscosity) concentration was utilized for further formulation development, i.e., to optimize the concentration of Pluronics^® (Pluronic^® F127- 19.5% w/v, 20% w/v, and 20.5% w/v). The formulation optimization process with the compositions of different formulations is described in Fig. 1A.

Results: It was observed that an initial increase in the concentration of sodium CMC led to an increase in the ex vivomucoadhesion and formulation gelation temperature. At lower concentrations ( < 1.25% w/v), these interactions lead to hinderance to the arrangements of micellar liquid crystals and an increase in the hydrogen bonding and interpenetration between sodium CMC and mucus layer thereby increasing the gelling temperature and mucoadhesion. However, formulations with sodium CMC above 1.25% w/v, showed a decrease in ex vivo mucoadhesion and gelling temperature with an increasing concentration of sodium CMC as a result of increased interactions and crosslinking bridges formed between sodium CMC polymers in the formulations. (Fig. 1B). The formulation with 1.25% w/v sodium CMC was sprayable at room temperature and showed the highest mucoadhesion and an optimum gelation temperature, and therefore was selected for further optimization, i.e., optimization of the concentration of Pluronics^®. It was observed that an increase in the concentration of Pluronic^®F127 led to a decrease in the gelling temperature (Fig. 2A). All the formulations had a similar drug loading (Fig. 2B). Interestingly, the formulations recorded a slight decrease in the ex vivomucoadhesion with an increase in the concentration of Pluronic^® F127 (Fig. 2C). This maybe as a result of lesser interactions between the polymers and the mucus layer due to an increase in formulation viscosity and a decrease in the aqueous content. All formulations showed similar in vitro release profiles, that followed first order release kinetics.  Formulation 3 containing 20.5% w/v of Pluronic^® F127 (Fig. 2D) had a slightly slower release rate.

Conclusion: Mucoadhesive in situ forming oral gels are capable of prolonging drug residence time in the oral cavity and provide better patient compliance compared to existing therapies for oral mucositis. Extemporaneous preparation of oral gels using a pre-commercialized Bupivacaine HCl injection is an efficient strategy to accelerate the regulatory approval of mucoadhesive in situ forming oral gels. The current research highlights the importance of optimization of formulation composition for achieving desirable clinical performance. It should be noted that slight variations in the concentrations of mucoadhesive polymer and thermogelling polymer (Pluronic^® F127) can have a significant impact on the in vitroperformance. Thus, it is imperative that these factors are considered during formulation development and evaluation for successful translation from bench to clinic.

References: Radha Kulkarni et.al; Mucoadhesive drug delivery systems: a promising non-invasive approach to bioavailability enhancement. Part I: biophysical considerations, Expert Opinion on Drug Delivery; Feb 2023.
Radha Kulkarni et.al.;Mucoadhesive drug delivery systems: a promising noninvasive approach to bioavailability enhancement. Part II: formulation considerations, Expert Opinion on Drug Delivery, Feb 2023.

Acknowledgements: This work was supported by the University of Connecticut, Pfizer Distinguished Chair in Pharmaceutical Technology funds, UConn SPARK Technology Commercialization Fund, and the International Association for Dental Research (Innovation in Oral Care award fund).

Fig. 1A) Formulation optimization trials; and B) ex vivo mucoadhesion and gelling temperatures for formulations containing 19.5% w/v Pluronic F127, 1.5% w/v Pluronic F68, each containing different concentrations of sodium CMC (0% w/v-1.75%w/v) (mean ±SD, n=3).

Fig. 2A) Gelling temperatures of formulations containing different concentrations of Pluronic® F127 (mean ±SD, n=3); B) % drug loading of the in situ gelling formulations (mean ±SD, n=3); C) ex vivo mucoadhesion study of mucoadhesive in situ forming oral gels (mean ±SD, n=3); and D) in vitro release study of mucoadhesive in situ forming oral gels (mean ±SD, n=3).