Dry Powder Inhaler of a Cytotoxic Agent, a New Avenue as Drug Delivery for the Lung Cancer

Abstract

Introduction and Rationale: Dry powder inhalation (DPI) systems are localized drug delivery systems with improved drug delivery at reduced dose and systemic toxicity due to non-invasive technique of drug administration higher localized concentration, reduced loss of drug and overall cost of treatment.

Liposomal drug delivery system offers advantages such as biocompatibility, biodegradability and low toxicity due to the formulation components as well as particle size giving larger surface area and deep lung deposition.

Lung cancer, one of the most fatal among all the types of cancer due to late diagnosis and untoward effects of chemotherapeutic agents on the normal cells has led to drug targeting actively or passively. Inhalational systems have been under study since many years for anticancer agents such as doxorubicin, 9-nitrocamptothecin, cisplatin, etc.

Docetaxel BCS class II drug have been extensively researched for cancer targeting via carrier- based systems. But research has not yet been directed towards development of dry powder inhalation system for localized delivery. Hence, the present research work focuses on development of biocompatible liposomal DPI of Docetaxel, as a novel approach for targeting lung cancer.

Aim and Objective: To develop and evaluate liposomal dry powder inhalation of Docetaxel Trihydrate.

Methodology:
a. Preparation of Liposomes: Liposomal formulation of docetaxel was developed using hydrogenated soyaphosphatidyl choline (HSPC) and di- stearoyl phosphatidyl glycerol- sodium salt (DSPG- Na) and cholesterol in the ratio of 1:0.25:0.25 by weight by ethanol injection method.
b. Preparation of liposomal DPI: Prepared liposomes were lyophilized using trehalose as cryoprotectant and dried formulation was further optimized to improve in-vitro drug deposition characteristics. The process of lyophilization was optimized for amount of cryoprotectant.
c. Evaluation: Developed liposomes were evaluated for particle size, particle size distribution, zeta potential, drug release study, SEM analysis and in vitro anticancer study whereas liposomal DPI was evaluated for in- vitro drug deposition study using twin stage impinger and flow characteristics.

Results and Discussion: The results for liposomal dispersion revealed mean particle size of 135.0 ± 0.289 nm, PDI 0.249 ± 0.093 and zeta potential - 10.5 ± 0.86 mV. Release profile of the dispersion through the dialysis membrane in the alcoholic phosphate buffer saline, pH 7.4 indicated that formulation follows Higuchi type release kinetics with Fickian diffusion. In-vitro anticancer study against A549 lung cancer cell lines revealed IC50 of 188.67 mcg/ ml, which was lower than the pure drug. Results of wound scratch assay and colony formation assay showed 0% wound closure as well as very few colonies formation respectively at the concentration equal to IC50 and IC20.

Results for optimization of cryoprotectant revealed that the Trehalose is the better choice as cryoprotectant in the ratio of 1:5 lipid to cryoprotectant. It was further modified with fine grade lactose as secondary carrier to obtain desired in vitro drug deposition. The evaluation showed the effective index of 43.30 and % FPF 18.06 indicating better in- vitro drug deposition study.

Conclusion: Thus, the localized drug delivery system for an anticancer agent via carrier- based formulation was successfully developed.

Keywords: Dry Powder Inhalation, Docetaxel, Liposome