Controlled temozolomide release with HPMC modified montmorillonite

This study examines the potential applications of montmorillonite (Mt) clay, both in its natural and as a suitable candidate for controlled drug release when modified with hydroxypropyl methylcellulose (HPMC). The main focus of the research specifically revolves around temozolomide (TMZ), which is a critical element for the treatment of glioblastoma. Inorganic composite such as mesoporous silica supported clay nanomaterials offer suitable solutions due to their large surface areas and precisely defined pore structures. It is known that Mt clay, obtained by enriching bentonite, stands out with its high adsorption capacity and biocompatibility and has a promising position as a drug carrier. HPMC is a hydrophilic cellulose derivative widely used in the pharmaceutical industry, increasing the potential of Mt clay for controlled-release drug formulations. TMZ chemotherapy, which is frequently used in the treatment of glioblastoma, is usually applied together with standard treatment protocols including maximal surgical resection. TMZ is also can be used for breast cancer, melanoma and non-small-cell (NSCL). It is known to be widely used in other types of cancer, such as lung cancer (for example, NSCL), but it may or may not be associated with glioblastoma. Although it improves the survival rates of cancer patients, TMZ is known to be limited by rapid clearance, low solubility, and undesirable side effects. Therefore, the main aim of this study was investigating the controlled release of TMZ through HPMC-modified Mt clay. The purification process of Mt clay involves mineral enrichment techniques, allowing the material to be checked for quality and suitability for pharmaceutical applications. The enrichment process was carried out by purifying Mt clay from non-clay minerals by sedimentation method and aimed to separate clay particles with sizes below 3-5 micrometers. After enrichment, raw and purified Mt samples were comprehensively characterized using various analytical techniques. X-ray diffraction (XRD) technique was used to analyze the crystal structure, X-ray fluorescence (XRF) spectroscopy to determine the elemental composition, scanning electron microscopy (SEM) for surface imaging, and transmission electron microscopy (TEM) to examine the morphological structure. Surface areas of clay mineral samples were determined using the BET (Brunauer- Emmett-Teller) N2 sorption technique. Zeta potential and particle size analyzes were also performed to evaluate surface charge and particle size distribution. Loading TMZ ingredient into enriched Mt was performed as described follow. First, 150 mL of TMZ solution was added to various Mt and HPMC compositions to prepare six different drug formulations. Each formulation was incubated on a magnetic stirrer at 37°C for 24 hours, then dried at 37-40°C. The dried mixtures were then turned into powder form using a agate mortar. To determine the concentration of TMZ in solutions, TMZ solutions of different concentrations were prepared. Spectra within the wavelength range 200-400 nm were then recorded and the wavelength at which the TMZ exhibited the most prominent absorbance peak was determined as 289 nm. Formulation's TMZ release profiles were evaluated in simulated gastric fluid. For this, each capsule from each formulation was added into dialysis bags containing simulated gastric fluids, and then each dialysis bag was placed in release media. While the stirring process was continuing by magnetic stirrer, samples were taken from the aqueous media at certain time intervals and TMZ concentration measurements were made with a UV spectrophotometer at 289 nm wavelength, and thus TMZ release amounts were determined against time. According to the data obtained from TMZ release profiles, a rapid release started in the first 15 minutes in all drug formulations except F1 and this rapid release continued for 45-60 minutes. Thus, at the end of 60 minutes, approximately 60-70% cumulative TMZ release was achieved. In the F1 formulation, rapid release continued for 90 minutes and cumulative TMZ release reached approximately 92%. The reason for the faster release in the F1 formulation is that the drug carrier system consists only of Mt clay, that is, there is no HPMC in the formulation. It has thus been proven that HPMC molecules cause delayed release because they cover the surface of TMZ-loaded Mt clay. Again, it was determined that the F4 formulation exhibited a rapid release of TMZ since it did not contain HPMC. It was determined that TMZ release was slower as the HPMC ratio increased in the formulations. Another result obtained from the release profiles is that the carrier system and TMZ composition ratio change the release kinetics. It was determined that the release was slower in formulations with a TMZ/carrier system ratio of 1/5 compared to those with a 1/10 ratio. This can be explained by the fact that in 1/5 ratio formulations, the TMZ ratio is higher than the carrier system, which causes a higher driving force. Namely, it can be said that as the adsorbate (TMZ) concentration increases, the mass transfer between the clay layers becomes more intense and stronger. Thus, when the TMZ concentration is less than the amount of clay, adsorption mostly occurs on clay surfaces, while as the concentration increases, adsorption occurs on the surface and at the same time, intense adsorption occurs between the clay layers. During the drug release process, TMZ molecules accumulated between clay layers show slower release kinetics than molecules accumulated on the surfaces. According to the release profiles, it was seen that as the HPMC ratio increased, the cumulative TMZ release amount decreased slightly. As a result, it was determined that the F6 formulation showed the best controlled release kinetics. The F6 formulation exhibited rapid TMZ release of 50% levels in the first 45 minutes. In the following period, the release occurred more slowly for 360 minutes and reached approximately 90%.