Application of Statistical Tooling Techniques for Designing of Carvedilol Nanolipid Transferosomes and its Dermatopharmacokinetic and Pharmacodynamic Studies
Authors: Selvaraj Brito R. , Sridhar Seshaiah K. , Kesavan Bhaskar R. , Palagati Sucharitha 
Published: September 2020

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.