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.

Application of Central Composite Design in Optimization of Valsartan Nanosuspension to Enhance its Solubility and Stability.

The objective of the present research is to prepare stable nano suspensions of Valsartan (VAL) with high solubility and dissolution. VAL is an orally administered anti-hypertensive drug with lower bio-availability of 25%, this is attributed to its lower aqueous solubility (0.082 mg/ml). VAL nano suspensions were prepared by using a bottom-up precipitation technique using five level full factorial central composite design (CCD). The optimized nano formulations NS21, NS22, NS23 showed the particle size of 268.42±8.99, 288.3±11.32, 293.46±6.92 nm, zeta potential of 20.89±0.79, 26.01 ±1.02, 21.34±0.43 mVs and the dissolution efficiency of 93.10±1.459, 91.84±1.419, 89.47±0.644 % respectively. SEM & AFM studies represent the formation of fine irregularly shaped particles with smooth surfaces on nanosization. X-rd studies confirmed the physical state conversion of crystalline drug into amorphous form. Drug excipient compatibility was studied using differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). The investigation pragmatic the solubility and dissolution efficiency of VAL in nanosuspension was significantly higher when compared with its pure form. Finally, it is concluded that, nanosuspension approach could be an ideal, promising approach to increase the solubility and dissolution of BCS-II drugs like Valsartan.

Formulation of unidirectional release buccal patches of carbamazepine and study of permeation through porcine buccal mucosa.

OBJECTIVE: To achieve transbuccal release of carbamazepine by loading in unidirectional release mucoadhesive buccal patches. METHODS: Buccal patches of carbamazepine with unidirectional drug release were prepared using hydroxypropyl methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone and ethyl cellulose by solvent casting method. Water impermeable backing layer (Pidilite® Biaxially-oriented polypropylene film) of patches provided unidirectional drug release. They were evaluated for thickness, mass uniformity, surface pH and folding endurance. Six formulations FA2, FA8, FA10, FB1, FB14 and FB16 (folding endurance above 250) were evaluated further for swelling studies, ex vivo mucoadhesive strength, ex vivo mucoadhesion time, In vitro drug release, ex vivo permeation, accelerated stability studies and FTIR and XRD spectral studies. RESULTS: The ex vivo mucoadhesion time of patches ranged between 109 min (FA10) to 126 min (FB14). The ex vivo mucoadhesive force was in the range of 0.278 to 0.479 kg/m/s. The In vitro drug release studies revealed that formulation FA8 released 84% and FB16 released 99.01% of drug in 140 min. CONCLUSIONS: The prepared unidirectional buccal patches of carbamazepine provided a maximum drug release within specified mucoadhesion period and it indicates a potential alternative drug delivery system for systemic delivery of carbamazepine.

Design and evaluation of polymeric coated minitablets as multiple unit gastroretentive floating drug delivery systems for furosemide.

A gastro retentive floating drug delivery system with multiple-unit minitablets based on gas formation technique was developed for furosemide. The system consists of core units (solid dispersion of furosemide:povidone and other excipients), prepared by direct compression process, which are coated with two successive layers, one of which is an effervescent (sodium bicarbonate) layer and other one an outer polymeric layer of polymethacrylates. The formulations were evaluated for pharmacopoeial quality control tests and all the physical parameters evaluated were within the acceptable limits. Only the system using Eudragit RL30D and combination of them as polymeric layer could float within acceptable time. The time to float decreased as amount of the effervescent agent increased and, when the coating level of polymeric layer decreased. The drug release was controlled and linear with the square root of time. By increasing coating level of polymeric layer decreased the drug release. The rapid floating and the controlled release properties were achieved in this present study. The stability samples showed no significant change in dissolution profiles (f(2) = 81). The in vivo gastric residence time was examined by radiograms and it was observed that the units remained in the stomach for about 6 h.

Preparation of a matrix type multiple-unit gastro retentive floating drug delivery system for captopril based on gas formation technique: in vitro evaluation.

A gastro retentive floating drug delivery system with multiple-unit minitab's based on gas formation technique was developed in order to prolong the gastric residence time and to increase the overall bioavailability of the drug. The system consists of the drug-containing core units prepared by direct compression process, which are coated with three successive layers of an inner seal coat, effervescent layer (sodium bicarbonate) and an outer gas-entrapped polymeric membrane of an polymethacrylates (Eudragit RL30D, RS30D, and combinations of them). Only the system using Eudragit RL30D and combination of them as a gas-entrapped polymeric membrane could float. The time to float decreased as amount of the effervescent agent increased and coating level of gas-entrapped polymeric membrane decreased. The optimum system floated completely within 3 min and maintained the buoyancy over a period of 12 h. The drug release was controlled and linear with the square root of time. Increasing coating level of gas-entrapped polymeric membrane decreased the drug release. Both the rapid floating and the controlled release properties were achieved in the multiple-unit floating drug delivery system developed in this present study. The analysis of the parameter dissolution data after storage at 40 degrees C and 75% RH for 3 months showed, no significant change indicating the two dissolution profiles were considered to be similar (f2 value is more than 50).