Thesis (Ph.D)-Cairo University, 2024.

Bibliography: pages 9-11.

Nanotechnology has gained much attention in the previous years in the improvement of drug delivery to the central nervous system (CNS). It has proven its effectiveness in the treatment of neurological diseases; such as Parkinson’s disease (PD), Alzheimer’s disease, stroke and brain tumors. This was greatly achieved through the design and development of nanocarriers that are capable of targeting the CNS crossing the blood brain barrier (BBB). Those nanocarriers are characterized by their small size facilitating the drug solubility and bioavailability. Also, they could be administered through various routes of administration; such as the intranasal, transdermal, ocular, buccal and vaginal routes. Examples of nanocarrier platforms that have been extensively studied include polymeric nanoparticles, liposomes, polymeric micelles, carbon nanotubes, dendrimers, solid lipid nanoparticles and others. A class of nanoparticles that are characterized by their high flexibility and ability to penetrate the biological membranes are the ultradeformable nanovesicles.
A brief review was introduced discussing different ultradeformable nanovesicles. This was considered a unique characteristic for certain nanovesicles that are administered through the transdermal route. It also explained the different preparation techniques, highlighting various studies that explained and proved the superiority of the mentioned vesicles in delivering different drugs through the transdermal route. The review succeeded in differentiating between the different ultradeformable nanovesicles through mentioning the composition of each one of them. The successfulness of the ultradeformable vesicles was reflected through the availability of market products that were prepared on the concept of ultraflexibility.
Rasagiline mesylate (RSM), a selective and irreversible monoamine oxidase (MAO)-inhibitor, is used for the treatment of Parkinson’s disease (PD). In order to exert its action, it should be delivered to the CNS in sufficient concentration without being hurdled by the blood brain barrier (BBB). Moreover, the hydrophilic nature of RSM and its susceptibility to extensive hepatic first pass metabolism markedly reduce its bioavailability (36%). The abovementioned drawbacks were addressed and resolved in our current study through the fabrication of two different drug delivery systems capable of carrying the hydrophilic drug in their core and their administration through two different routes of administration.
As for the first study, RSM was directly delivered to the CNS through its incorporation in transferosomes that were furtherly transformed to an in situ gel structure and administered through the intranasal route. Transferosomes were prepared using thin film hydration technique. DesignExpert® software was adopted for the selection of the optimum formulation, varying the type of edge activator (EA), in the presence/absence of cholesterol. The optimum formulation composed of phosphatidylcholine, EA; sodium deoxycholate in the ratio 5:1 w/w, in the absence of cholesterol. It possessed vesicular size (VS; 198.63 ± 34.98 nm), and percentage entrapment efficiency (%EE; 95.73 ± 0.09%). The selected optimized formulation was characterized adopting Fourier transform infrared spectroscopy (FTIR) to detect any possible interaction, and transmission electron microscopy (TEM) for morphological illustration of the formed vesicles. The optimized RSM-loaded transferosomes were furtherly incorporated into an in situ gel structure for the sustainment of drug release and enhanced residence time on the nasal mucosa. The optimized gel formulation was composed of 0.5% pectin, 15% Pluronic® F-127, and 5% Pluronic® F-68. Finally, the optimized gel formulation was tested against intravenous aqueous solution in rats for the assessment of the systemic as well as the brain kinetics. The obtained results showed enhanced brain bioavailability (131.17%) and direct nose-to-brain targeting with drug targeting efficiency and direct transport percentage indices (304.53% and 67.16%, respectively), in addition to the safety and biocompatibility of the prepared RSM-loaded transferosomal in situ gel formulation on the nasal mucosa.
Regarding terpene-assisted novasomal gel preparation administered through the transdermal route. Novasomes were created utilizing ethanol injection method, with terpenes serving to enhance skin penetration. Varying the amount cholesterol, type of terpene, and surface active agents (SAA): free fatty acid (FFA) were applied using Design Expert® software. The optmimum novasomal formulation composed of 60 mg cholesterol, SAA:FFA ratio 1:1 in the presence of eugenol. VS was 265.90 ± 2.40 nm, and %EE was 83.09 ± 0.42%. The optimized formulation was characterized using differential scanning calorimetry (DSC) and transmission electron microscopy (TEM). The novasomal gel formulations were prepared using 2% hydroxypropyl methylcellulose (HPMC) and 2% carboxymethyl cellulose (CMC). The in vivo study demonstrated the gel's potential in mitigating PD symptoms through behavioral, biochemical, and histopathological assessments in rats with PD induced by rotenone. Notable elevation was observed in the number of crossovers, grooming score, frequency of rearing, gripe strength, as well as dopamine levels in the brain, coupled with decreased interleukin-17 and NLRP-3 inflammasome levels, in comparison to the positive control group. Furthermore, no brain tissue damage was observed in the treated rats. The findings indicate that the RSM-loaded novasomal gel is a promising method for the transdermal administration of water-soluble medications such as RSM.
The abovementioned studies revealed the successful development of nanovesicular systems that are capable of carrying the hydrophilic drug, RSM, and its delivery to the CNS bypassing the hepatic first pass metabolism with marked enhancement in the bioavailability. It also highlighted the possibility of nose-to-brain direct delivery of the CNS drugs when administered through the intranasal route via the olfactory and trigeminal pathways offering a promising approach for further future studies.

على توصيل العقار إلي الجهاز العصبي المركزي مرورا بطبقات الجلد المختلفة. . تم إجراء دراسة اختراق للطبقات الجلدية بوضع الصيغة المثلى للهلام المحمل بالنوفازومات علي سطح الجلد، و ذلك باستخدام نموذج الفئران المصابة بالباركنسون الناجم عن حقن مادة الروتينون. و قد تم فحص الأنسجة الجلدية المختلفة، و كذلك التغيرات النسيجية في أقسام المخ بعد إجراء الدراسات. و قد تبين من نتائج الفحوصات، أن صيغة الهلام المحمل بالنوفازومات حافظ علي سلامة الأنسجة الجلدية و لم يحدث أي تغيرات سلبية في أنسجة أقسام المخ المختلفة. و قد أجريت دراسة أخري لتقييم التغيرات السلوكية والكيميائية الحيوية للفئران، و جاءت نتائجها إيجابية من حيث تخفيف اضطرابات الحركة؛ وتثبيط تدهور الدوبامين، وإفراز IL-17، وتنشيط مجموعة الالتهاب NLRP3مما يؤكد فاعلية العقار في علاج الأعراض المختلفة المصاحبة لمرض باكنسون و كون عقار راساغيلين الميسيلات ناقل واعد لتوصيل العقار عبر الجلد.

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