Application of Statistical Tooling Techniques for Designing of Carvedilol Nanolipid Transferosomes and its Dermatopharmacokinetic and Pharmacodynamic Studies.

BACKGROUND: The hypothesis is to augment the bioavailability and therapeutic potential of low bioavailable Carvedilol (25-35%) through Nanostructured Lipid Carrier (NLC) loaded Transdermal patch (Nanolipid Transferosomes). METHODS: Box-Behnken design was designed to formulate NLC through a hot homogenization technique. About 17 formulations (C1-C17) were formulated by varying the critical material attribute and critical process parameter. Optimization was done based on its critical quality attributes like particle size, zeta potential and entrapment efficiency. Selected NLC (C16) has been fabricated into a transdermal patch through solvent evaporation technique and estimated for thickness, weight variation, moisture content, folding endurance, drug content, in vitro drug release, ex vivo skin permeation studies 48 hrs, in vitro drug release kinetic studies and skin irritation studies. In vivo pharmacokinetics and pharmacodynamic study parameters were compared between carvedilol loaded NLC transdermal patch and a conventional formulation (Coreg CR). RESULTS: NLC (C16) was selected as the best formulation based on desirable, less particle size (201.1 ± 2.02 nm), more zeta potential (-37.2 ± 1.84mV) and maximum entrapment efficiency (87.54 ± 1.84%). Experimental investigations of in vivo dermatopharmacokinetic data shown statistically significant changes (p<0.05) in the parameter (increased AUC0-α, MRT with decreased Cmax, Tmax) when administered through the transdermal patch and on compared to the conventional dosage form. It was observed that there was a significant change with p<0.05 among the pharmacokinetic factors of conventional Carvedilol formulation, Carvedilol NLC and Carvedilol NLC loaded Transdermal patch with a maximum time of peak plasma concentration (Tmax) of 4 hrs, 8 hrs and 8 hrs; maximum peak plasma concentration (Cmax) of 0.258 µg/ml, 0.208 µg/ml and 0.108 µg/ml. Area Under Curve (AUC0-α) was established to be 125.127 µg/ml/h, 132.576 µg/ml.h and 841.032 µg/ml.h. Mean Residence Time (MRT0- α) of the drug was established to be 17 hrs, 19 hrs and 82 hrs, respectively. This data reveals the impact of NLC on the enhancement of bioavailability through a transdermal patch. In vivo pharmacodynamic studies confirm that NLC loaded transdermal patch (Nanolipid Transferosomes) shows a significant control in blood pressure for 48 hrs when compared to the conventional dosage form. CONCLUSION: This research data concludes that NLC loaded transdermal patch (Nanolipid Transferosomes) was a suitable candidate to enhance the bioavailability of low bioavailable drug-like Carvedilol. Lay Summary: It was inferred from the literature that NLC filled transdermal patches were a novel strategy to increase the solubility and permeability of Carvedilol, which has less bioavailability. It reveals that there was no reproducible preparation for the NLC. It also reveals that the option of formulation and process parameters for the formation of NLC is not clearly justified. On account of this, an uniquely validated and optimized formulation technique was developed for NLC with low soluble and poorly bioavailable carvedilol, tested in Albino wistar rats for enhancement of bioavailability, the same study has been performed and proved.

Application of computational tools for the designing of Oleuropein loaded nanostructured lipid carrier for brain targeting through nasal route.

PURPOSE: Meningitis is an inflammation of meninges encircled the brain and spinal cord. Currently it can be treated with second generation cephalosporins which were ended up with an unresolvable problem called Multi Drug Resistance (MDR). Hence, there is a need to develop a better herbal molecule to conflict the MDR. METHODS: Hot Blanching technique followed by ultra sound assisted extraction using bio-solvent aqueous glycerol was used to extract OLE from olive leaves. QbD tool was applied to predict the interactions between Critical Material Attributes (Ratio of solid Lipid X1, Concentration of Surfactant X2) and Critical Process Parameters (Homogenization Time X3) on Critical Quality Attributes (CQA, Particle Size Y1, Zeta Potential Y2, and Entrapment Efficiency Y3). Particulate characteristics were evaluated and Invivo pharmacokinetic study was done in albino Wistar rats by IV and IN route of administration. RESULTS: Thermal studies reflect the formation of low ordered crystalline structure of lipid matrix which offers higher encapsulation of drug in NLC than physical mixture. CMA and CPP show significant effect on CQA and method operable design range was developed. Histo-pathological studies confirms that there is no signs of toxicity and in-vitro drug release studies reveals a rapid release of a drug initially followed by prolonged release of oleuropein upto 24 h. The absolute bioavailability of drug loaded NLC in brain was higher in IN route compared to NLC administered by IV route. CONCLUSIONS: In a nutshell, challenges offered by the hydrophilic OLE for brain targeting can be minimized through lipidic nature of NLC. Graphical Abstract.