Paclitaxel-loaded micro or nano transfersome formulation into novel tablets for pulmonary drug delivery via nebulization

Abstract

A simplistic approach was conducted to manufacture novel paclitaxel (PTX) loaded protransfersome tablet formulations for pulmonary drug delivery. Large surface area presented by pulmonary system offer better target using anti-cancer drug deposition for localized effect in the lungs. Protransfersomes are dry powder formulations, whereas transfersomes are liquid dispersions containing vesicles generated from protransfersomes upon hydration. Protransfersome powder formulations (F1-F27) (referred as Micro formulations based on transfersomes vesicles size post hydration) were prepared by employing phospholipid (Soya phosphatidylcholine (SPC)), three different carbohydrate carriers (Lactose monohydrate, LMH; Microcrystalline cellulose, MCC; and Starch), three surfactants (i.e. Span 80, Span 20 and Tween 80) in three different lipid phase to carrier ratios (i.e. 1:05, 1:15 and 1:25 w/w), with the incorporation of PTX as a model drug. Hydrophobic chain of SPC may enhance PTX solubility as well as its accommodation to improve entrapment and delivery via transfersome vesicles to the target site. Out of the 27 Micro protransfersome formulations, PTX-loaded LMH powder formulations F3, F6 and F9 (i.e. 1:25 w/w lipid phase to carrier ratio) exhibited an excellent powder flowability via angle of repose (AOR) and good compressibility index due to the smaller and uniform particle size and shape of LMH. Following hydration, these formulations also showed smaller volume median diameter (VMD) in micrometres (5.65 ± 0.85-6.76 ± 0.61 µm) and PTX entrapment of 93-96%. Hydrated transfersome formulations (F3, F6 and F9) were converted into Nano size via probe sonication and referred as Nano formulations. These Nano formulations were converted into dry powder via spray drying (SD) (F3NSD, F6NSD and F9NSD) or freeze drying (FD) (F3NFD, F6NFD and F9NFD). Post manufacture of protransfersome tablets (i.e. 9 formulations), quality control tests were conducted in accordance to British Pharmacopeia (BP). Only Micro formulations protransfersome tablets (i.e. F3, F6 and F9) passed the uniformity of weight test, exhibited high crushing strength and tablet thickness when compared to SD or FD protransfersome tablets. Micro protransfersome formulations (i.e. F3, F6 and F9) into tablets demonstrated shorter nebulization time and high output rate using Ultrasonic nebulizer as compared to Vibrating mesh nebulizer (i.e. Omron NE U22). Based on formulations, characterizations and nebulizer performance; Micro protransfersome tablet formulations F3, F6 and F9 (i.e. 1:25 w/w) and Ultrasonic nebulizer was found to be a superior combination with enhanced output efficiency. Moreover, PTX-loaded F3, F6 and F9 tablet formulations (10%) were identified as toxic (60, 68 and 67% cell viability) to cancer MRC-5 SV2 (i.e. immortalized human lung cells) while safe to MRC-5 (normal lung fibroblast cells) cell lines.

Novel Micro- and Nanocellulose-Based Delivery Systems for Liposoluble Compounds

“…Several commercial forms of MCC, such as Avicel ® , Pharmacel ® , Ceolus ® , Celphere™, and Ethispheres ® in a variety of grades are now available [87][88][89][90]. Avicel ® and MCC spheres, such as Celphere™ and Ethispheres ® , have been the most used in liposoluble compound delivery studies [91][92][93][94].…”

“…Although the surface of MCC has a slight negative charge due to hydroxyl groups, this charge is confined to a relatively small surface area on a large mass of insoluble MCC, and would not likely adsorb or bind significant amounts of bioactives [18]. Therefore, aiming to improve its encapsulating and delivery properties, MCC is usually conjugated with lipidic systems [91][92][93], other polymers [94], or even chemically modified [83].…”

“…The authors concluded that the MCC retained high contents of bioactive compounds, i.e., showing potential to be used as a phytopharmaceutical active ingredient in nutraceutical, cosmeceutical, and/or veterinary formulations. Khan et al developed paclitaxel loaded protransfersome powder formulations using a phospholipid (soya phosphatidylcholine), cholesterol, a carbohydrate carrier (MCC, lactose monohydrate or starch), and a surfactant (Span 80, Span 20 or Tween 80) via a slurry-based method, followed by compression into novel paclitaxel-loaded protransfersome tablets [92]. The MCC systems were successful in paclitaxel encapsulation, exhibiting EE of 92-98%, depending on the formulation.…”

Improved Bioavailability of Ebastine through Development of Transfersomal Oral Films

“…Nevertheless, transfersomes in aqueous dispersion may create problems in the handling and storage of incorporated drugs. Fusion, leakage, hydrolysis and aggregation may limit the benefits of transfersomes as carriers [ 19 ]. However, stability can be provided to transfersomes by converting them into solid state.…”

Microencapsulated Chitosan-Based Nanocapsules: A New Platform for Pulmonary Gene Delivery

“…This was expected taking into account the direct relationship between the D g and the theoretical D aer (see formula in Section 2.9 .). To achieve an adequate pulmonary delivery, the MS must have approximately an aerodynamic diameter between 1–5 µm [ 39 , 68 , 69 , 70 ]. If they are smaller than 1 µm, the particles will be expelled with the air, but if they are greater than 5 µm, they will remain in the upper respiratory tract [ 66 , 69 ].…”