الفهرس 
General IntroductionOnly 14 pages are availabe for public view
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Abstract
Schizophrenia is a challenging and common psychotic disorder that greatly affects the quality of life of the affected patients. Patient compliance is among the major obstacles throughout treatment journey emerging the need to novel drug delivery techniques to maximize clinical outcomes. Transdermal drug delivery of antipsychotics is such a way to improve medication adherence and decrease multiple dosing thus enhancing patient compliance. Second generation antipsychotics (SGAs) have proven more efficiency and efficacy in management of schizophrenic patients. SGAs are used at lower doses when used transdermally and hence, reduction of unwanted side effects is achieved. Nevertheless, nano based formulations offered several advantages and higher efficacy than conventional systems.
Asenapine maleate (ASPM) is a new second-generation antipsychotic, received FDA-approval on August 13, 2009 with label indications for the acute treatment of schizophrenia in adults. Asenapine acts on various receptors with special high affinity to serotonin receptor (5-HT2A) and less affinity to D2 receptor leading to a great reduction in extrapyramidal side effects. The absolute oral bioavailability of asenapine is low (<2% with an oral tablet formulation) due to extensive hepatic metabolism. Sublingual administration raised its bioavailability up to 35% but is still greatly affected by food and water intake.
Hence, the purpose of this study was to formulate and to evaluate ASPM-loaded lipidic nanocarriers such as lipid nanocapsules (LNCs) and invasomes followed by an assessment of the optimized formulations for their in vivo pharmacokinetics via transdermal route compared to intravenous and oral routes.
Blank and ASPM loaded LNCs were successfully prepared based on the phase inversion method. They consisted of pegylated macrogols surfactants as the main ingredient having PEG moieties influencing both LNC formation and its stealth properties. Different oils were employed as the oily phase which was additionally stabilized by lecithin (Phospholipon 90G®). Moreover, the aqueous phase including sodium chloride (NaCl) greatly affected LNCs formation. The LNCs were optimized using one factor at a time study where the influence of three formulation variables was studied, namely; oily core type, surfactant type and oil: surfactant ratio. The prepared LNCs were characterized in terms of the mean particle size (PS), polydispersity index (PDI), zeta potential (ZP) and ex-vivo skin permeation. The selected ASPM formulation was further characterized by HR-TEM and FTIR studies.
The results demonstrated that the physical properties of LNCs were greatly affected by the oily core type. Labrafil® M1944CS and lavender oils displayed smaller particle size of LNCs than Labrafac® and Miglyol 812®. Increasing the oil: surfactant ratio led to the formation of larger LNCs due to the reduced emulsifying power of the surfactant. LNCs containing the lowest oil: surfactant ratio were smaller and homogenously distributed particles. Skin permeation experiment revealed the superiority of lavender oil based LNCs over Labrafil® based ones.
ASPM loaded LNCs showed sufficient stability over 6 months with minor changes in terms of their size particle and PDI. The optimized LNC formulation using lavender oil and kolliphor HS 15 with ratio 2:1 was selected as the optimized formulation for further analysis and in vivo studies. TEM and FTIR showed spherical discrete particles and indicated the complete drug encapsulation.
In the second chapter of this work, ASPM-loaded invasomes were successfully prepared by the thin film hydration technique incorporating lecithin (Phospholipon 90G®), terpenes (limonene and cineole) and ethanol. The penetration enhancing effect of terpenes was compared to hydromiscible cosolvent (Transcutol®). The optimization of invasomes followed one factor at a time study where the effect of types and concentrations of penetration enhancers were studied. The observed dependent variables were the mean particle size (PS), polydispersity index (PDI), zeta potential (ZP) and ex-vivo skin permeation experiments.
The results revealed that invasomes containing transcutol displayed smaller particle sizes than limonene and cineole. The lipophilicity of the penetration enhancers greatly affected the entrapment efficiency of the invasomes. Invasomes containing terpenes showed higher efficiency to encapsulate asenapine than soft vesicles containing Transcutol. Ex vivo skin permeation revealed that invasomes with hydrocarbon terpenes are more efficient than ketone terpenes for the transdermal delivery of hydrophobic drugs. The effect of storage on the stability (PS, PDI and ZP) of loaded invasomes showed optimum stability over 6 months.
The optimized invasomal formulation employed 1% limonene was selected as the optimized formulation for further analysis and in vivo studies. The selected ASPM formulation was characterized by HR-TEM and FTIR studies. Transmission electron microscopy showed uniform spherical vesicles with intense outline and lighter core. FTIR study emphasized that ASPM was completely incorporated within the invasomes.
Finally, in vivo studies for the selected formulations were carried out to evaluate their ability to deliver asenapine maleate transdermally in comparison to the intravenous and the oral routes.
The in vivo results confirmed that the oral bioavailability (BAV) of asenapine is very low due to extensive hepatic metabolism. Transdermally applied formulations increased the rate and extent of absorption of asenapine. Transdermal LNCs and invasomes achieved 4 folds and 2 folds higher Cmax compared to oral suspension and delayed the Tmax from 1.5h to around 4h respectively. The bioavailability of asenapine loaded LNCs and invasomes after transdermal application was above 50% exceeding the bioavailability of sublingual tablets currently available in the market and exhibited sustained release kinetics over 72h which permits reduction of dosing frequency to increase patient adherence to medication. The drug plasma concentration was almost constant during 72 hours upon transdermal application, an effect that was even more pronounced in case of invasomes.
Histological examination of treated skin 24 hours post application were compared to control specimen and did not show any signs for inflammation or irritation of the skin.
To this end, the transdermal application of the investigated lipidic nanoparticles showed promising results as successful nanocarriers for asenapine maleate. They achieved higher bioavailability than the marketed dosage form and their extended release over 3days could have positive impact on medication adherence and compliance of schizophrenic patients.