(M0930-07-41) Development and Evaluation of Buprenorphine Sublingual Formulation for the Treatment of Neonatal Opioid Withdrawal Syndrome

Purpose: The FDA and professional societies recommend that where possible pediatric drug formulations should not contain ethanol. A widely used buprenorphine formulation used in the treatment of neonatal opioid withdrawal syndrome (NOWS) contains 30% ethanol. We have developed an ethanol-free oral solutiuon of buprenorphine to assess the drug substance’s stability in an ethanol-free environment. A gel formulation has many advantages, it allows for precise dosing via administration of the drug substance as well as, gives the ability for flexible-dose regimens as it can be tailored per patient requirements. This formulation gives ease of administration, as gels are easier to apply to topical surfaces than other formulations. Using a gel sublingually, can increase the absorption through the sublingual mucosa and increase the bioavailability of the drug substance. Owing to the advantages of a gel formulation, an oral gel of buprenorphine was pursued using different polymers as gelling agents. Hydroxypropyl methylcellulose (HPMC) was determined to be the ideal candidate for this formulation. This formulation was characterized by establishing the stability and efficacy of the oral gel and exploring the potential clinical benefits and feasibility of implementing this formulation in neonatal care settings to improve outcomes for neonates affected by NOWS and pave the way for further advancements in pediatric formulations.

Methods: An ethanol-free oral solution as a non-gel formulation was developed first, by diluting commercial buprenorphine injection (0.3 mg/mL) to a final concentration of 0.75 mg/mL in water for irrigation. Aliquots of 1 mL were transferred to amber-colored oral syringes. For the stability studies, these syringes were kept at two different storage conditions (2-6^oC and 25^oC at 60% relative humidity). The syringes were evaluated for 60 days for pH, osmolarity, drug content, microbial growth, and visual appearance. An oral gel formulation was pursued with different polymers as gelling agents with buprenorphine after establishing an ethanol-free oral solution. Based on the evaluation of different polymers as gelling agents with buprenorphine, hydroxypropyl methylcellulose (HPMC) was determined to be the ideal candidate for this formulation. A short-term stability study was performed with this novel formulation by assessing physical and chemical parameters for 30 days. These parameters were evaluated at specified time intervals where pH was assessed using a pH microelectrode to measure the pH of the gel throughout the study. Viscosity was determined for the oral gel via a rheometer to ensure the gel formulation was suitable and there was an ease of administration. Liquid Chromatography-Mass Spectrometry (LC-MS) analysis was conducted using an LC-MS/QTOF to evaluate the novel oral gel formulation of buprenorphine. This was achieved by developing a robust and validated LC-MS method for quantifying buprenorphine in the oral gel by determining the drug’s stability, degradation products, drug concentration, degradation kinetics, and release profile under these storage conditions.

Results: Initially, an ethanol-free oral solution of buprenorphine was developed and evaluated. Afterward, an attempt to develop a novel oral gel formulation was pursued using different polymers as gelling agents in combination with the drug substance. After a thorough investigation, HPMC was selected as a suitable gelling agent for the desired formulation. A stability study was conducted for the novel formulation under different storage conditions. It was determined that the formulation with the drug substance showed consistent pH values indicating the compatibility the formulation has with the oral mucosa and preventing irritation or discomfort upon administration. The viscosity of the oral gel formulation showed consistent results indicating the ease of administration in the oral cavity. LC-MS analysis was performed to quantify buprenorphine in the novel oral gel formulation. The analytical method was developed, validated, and used to detect the drug substance in the formulation during the stability testing. Buprenorphine was found stable in this formulation as the drug substance could be detected by the analytical method, with minimal observations of degradants under the different storage conditions, and was determined to be stable for 30 days.

Conclusion: A 60-day stability study for an ethanol-free buprenorphine oral solution was performed and evaluated under both storage settings (2-6^oC and 25^oC with 60% relative humidity). The solution was clear, microbial growth was not detected and LC-MS analysis of the drug substance revealed that it was stable at the end of the 60-day study. A novel oral gel formulation was pursued using HPMC polymer which demonstrated stability, compatibility, and suitability for neonatal administration, and the formulation was determined to be stable for 30 days upon stability testing. Our research will contribute to improved outcomes for neonates affected by NOWS and open the door for more investigative research in the development of future pediatric formulations.

References: 1. Finnegan, L.P.; Connaughton, J.F.; Kron, R.E.; Emich, JP. Neonatal abstinence syndrome: assessment and management. Addict Dis. 1975, 2, (1-2):141-58.
2. Kraft, W.K. Buprenorphine in Neonatal Abstinence Syndrome. Clin. Pharmacol. Ther. 2018, 103, 1, 112-119.
3. Aiyer, R.; Gulati, A.; Gungor, S.; Bhatia A.; Mehta, N. Treatment of chronic pain with various buprenorphine formulations: A systematic review of clinical studies. Anesthesia Analgesia. 2018, 127, 2, 529-538.
4. Rochani, A.; Nguyen, V.; Becker, R.; Kraft, W.K.; Kaushal, G. Stability-indicating LC-MS Method for Determination of Stability of Extemporaneously Compounded Buprenorphine Oral Syringes for Neonatal Abstinence Syndrome. J. Pediatr. Pharmacol. Ther. 2021, 26, 4, 395-404.

Acknowledgements: We would like to thank the Department of Pharmacology, Physiology & Cancer Biology and the Department of Pharmaceutical Sciences, at Thomas Jefferson University for all their support throughout the project. This work was supported by the National Institutes of Health Institutional Training Grant [T32GM008562] and NICHD HELP for NOWS Subaward [3-312-0218259-67167L] Grant. There are no conflicts to disclose regarding the work of this project.

Assay of the Drug Substance Buprenorphine

Rheological Results of Novel Buprenorphine Oral Gel Formulation

Release Study Results of Novel Buprenorphine Oral Gel Formulation