Alsaiwed, Omar Ahmed; (2025) Development of optimal topical formulations of Asenapine Maleate. Masters thesis (M.Phil), UCL (University College London).

Preview

Text Alsaiwed_10204128_thesis.pdf Download (1MB) | Preview

Abstract

The skin, that forms up the integumentary system, is the largest and most apparent organ in the human body. It constitutes around 10% of the body's total mass and is the main defence against environmental dangers. Schizophrenia, a psychiatric condition that impacts around 1% of the population as a whole, presents with symptoms such as delusions, hallucinations, and cognitive deficits in thought organisation. Reduced emotional expressiveness, decreased engagement with others, and decreased interest are some mild symptoms. Asenapine maleate (ASM) was approved by the United States Food and Drug Administration (FDA) in 2009 for the treatment of bipolar I disorder and schizophrenia. Given its significant hepatic metabolism, the sublingual route became the most suitable form of administration, even though some patients may find hard to follow this regimen. While sublingual administration provides ideal bioavailability, it may be challenging for some due to the need for dietary modifications, potential adverse effects (such as tongue numbness), and the requirement for precise sublingual placement of the medication. The purpose of this study is to evaluate pre-formulation parameters through the following main goals: (i) performing in-vitro permeation and mass balance studies with methylparaben (MP) as a model compound to improve experimental methods (ii) characterising the thermal properties of ASM using thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC); (iii) developing and validating a novel High-Performance Liquid Chromatography (HPLC) method for ASM analysis; and (iv) carrying out solubility studies with propylene glycol monolaurate (PGML), Transcutol®, polyethylene glycol (PEG 400), polyethylene glycol (PEG 600), isopropyl myristate (IPM), isopropyl palmitate (IPP), and methanol. Furthermore, the study will involve evaluations of the stability of ASM in methanol, Transcutol, PEG 400, and phosphate buffered saline (PBS)/BrijTM. A novel method of HPLC was carefully designed and validated for the accurate analysis of ASM in compliance with the guidelines set out by the International Council for Harmonisation (ICH). Permeation studies were conducted utilising PDMS membranes in Franz cells to study the passage of MP over time. The results showed a gradual and consistent rise in MP permeability. The investigation revealed that permeability commenced after around five minutes, demonstrating a clear and direct relationship between time and permeation. This observation validates the use of PDMS membranes as a dependable platform for assessing the diffusion of MP, in accordance with Fick's first law. The mass balance experiment found that a substantial portion of MP remained adhered to the membrane surface, whereas a significant amount entered the receptor phase. The recovery rate of 97.10% ± 1.95% falls within the acceptable range recommended by the OECD for non-volatile compounds, demonstrating the efficacy and accuracy of the experimental design. In relation to ASM, the investigation employed UV spectroscopy to analyse its characteristics, and it was observed that the UV spectra of ASM dissolved in ethanol displayed the highest level of absorption at approximately 231 nm. This discovery is essential for the investigation and description of ASM. The discrepancies in maximal UV absorption wavelengths reported in the literature can be attributed to differences in measurement instruments, solvents, and experimental conditions. ASM was found to stay stable in several solvents over the course of 72 hours at 32 ± 1°C. The PBS solution with 6% Brij™ exhibited the highest stability, whereas the methanol solution showed the lowest stability. The thermal properties of ASM were analysed using TGA and DSC. The TGA demonstrated that ASM decomposes at a precise temperature of 234.63°C, yielding important insights into its thermal stability. The melting point of ASM was determined to be 141.72°C using the DSC, which exhibited an endothermic peak. The little differences in melting point readings, in comparison to the values found in literature, may be ascribed to variances in experimental circumstances, sample purity, and equipment calibration. An innovative HPLC technique has been developed and confirmed to be accurate for identifying and measuring ASM. This approach demonstrated exceptional linearity, accuracy, precision, resilience, and appropriateness for ASM analysis. Based on solubility experiments, methanol was shown to be the most appropriate solvent for ASM. However, Transcutol® also exhibited notable solubility capabilities. The stability assessments confirmed the durability of ASM in all investigated solvents for a duration of 72 hours at a temperature of 32°C. Future research will prioritise the examination of different solvents that could potentially transport ASM, assess the effectiveness of ASM model formulations through laboratory studies on skin penetration, and determine prototype formulations that meet the requirements for advancing to subsequent phases of clinical development. The objective of these initiatives is to improve the efficiency and compliance of treatments based on antipsychotic medications (ASM), ultimately leading to more efficient management of schizophrenia and bipolar I disorder. Further research will investigate the interactions between solvents and ASM, with the goal of developing novel formulation techniques to enhance the stability and effectiveness of ASM formulations for topical administration.

Downloads since deposit

Loading...

0Downloads

Download activity - last month

Export as JSONXMLCSV

Loading...

Download activity - last 12 months

Export as JSONXMLCSV

Loading...

Downloads by country - last 12 months

Export as JSONCSVXML

Loading...

Archive Staff Only

View Item