CORE Metadata, citation and similar papers at core.ac.uk Provided by CLoK Article A Facile and Novel Approach to Manufacture Paclitaxel-Loaded Proliposome Tablet Formulations of Micro or Nano Vesicles for Nebulization Khan, Iftikhar, Lau, Katie, Bnyan, Ruba, Houacine, Chahinez, Roberts, Matthew, Isreb, Abdullah, Elhissi, Abdelbary and Yousaf, Sakib Available at http://clok.uclan.ac.uk/33622/ Khan, Iftikhar, Lau, Katie, Bnyan, Ruba, Houacine, Chahinez, Roberts, Matthew, Isreb, Abdullah ORCID: 0000-0001-9939-6161, Elhissi, Abdelbary and Yousaf, Sakib (2020) A Facile and Novel Approach to Manufacture Paclitaxel-Loaded Proliposome Tablet Formulations of Micro or Nano Vesicles for Nebulization. Pharmaceutical Research, 37 (116). 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Terms and conditions for use of this material are defined in the http://clok.uclan.ac.uk/policies/ CLoK Central Lancashire online Knowledge www.clok.uclan.ac.uk Pharm Res (2020) 37:116 https://doi.org/10.1007/s11095-020-02840-w RESEARCH PAPER A Facile and Novel Approach to Manufacture Paclitaxel-Loaded Proliposome Tablet Formulations of Micro or Nano Vesicles for Nebulization Iftikhar Khan1 & Katie Lau 1 & Ruba Bnyan 1 & Chahinez Houacine 2 & Matthew Roberts2 & Abdullah Isreb2 & Abdelbary Elhissi3 & Sakib Yousaf2 Received: 30 August 2019 /Accepted: 13 May 2020 # The Author(s) 2020 ABSTRACT by spray drying (SD) to get a dry powder of these formulations Purpose The aim of this study was to develop novel as F3SDN, F6SDN and F9SDN, and gave high yield (>53%) paclitaxel-loaded proliposome tablet formulations for pulmo- and exhibited poor to very poor compressibility index values via nary drug delivery. Carr’s Index. Post tablet manufacturing, F3 tablets formula- Method Proliposome powder formulations (i.e. F1 – F27) tion showed uniform weight uniformity (129.40 ± 3.85 mg), were prepared employing Lactose monohydrate (LMH), good crushing strength (14.08 ± 1.95 N), precise tablet thick- Microcrystalline cellulose (MCC) or Starch as a carbohydrate ness (2.33 ± 0.51 mm) and a short disintegration time of carriers and Soya phosphatidylcholine (SPC), Hydrogenated 14.35 ± 0.56 min, passing all quality control tests in accor- soya phosphatidylcholine (HSPC) or Dimyristoly phosphati- dance with British Pharmacopeia (BP). Upon nebulization of dylcholine (DMPC) as a phospholipid. Proliposome powder F3 tablets formulation, Ultrasonic nebulizer showed better formulations were prepared in 1:5, 1:15 or 1:25 w/w lipid nebulization time (8.75 ± 0.86 min) and high output rate phase to carrier ratio (lipid phase; comprising of phospholipid (421.06 ± 7.19 mg/min) when compared to Vibrating mesh and cholesterol in 1:1 M ratio) and Paclitaxel (PTX) was used nebulizer. PTX-loaded F3 tablet formulations were identified as model anticancer drug. as toxic (60% cell viability) to cancer MRC-5 SV2 cell lines Results Based on flowability studies, out of 27 formulations; while safe to normal MRC-5 cell lines. F3, F6, and F9 formulations were selected as they exhibited an Conclusion Overall, in this study LMH was identified as a excellent angle of repose (AOR) (17.24 ± 0.43, 16.41 ± 0.52 superior carbohydrate carrier for proliposome tablet manu- and 15.16 ± 0.72°), comparatively lower size of vesicles (i.e. facturing in a 1:25 w/w lipid to carrier ratio for in-vitro nebu- 5.35 ± 0.76, 6.27 ± 0.59 and 5.43 ± 0.68 μm) and good com- lization via Ultrasonic nebulizer. pressibility index (14.81 ± 0.36, 15.01 ± 0.35 and 14.56 ± 0.14) via Carr’s index. The selected formulations were re- KEY WORDS nebulizer . paclitaxel . proliposome . quality duced into Nano (N) vesicles via probe sonication, followed control testing . tablets Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11095-020-02840-w) contains supplementary material, which is available to authorized users. * Iftikhar Khan ABBREVIATION [email protected]; [email protected] AOR Angle of repose * Sakib Yousaf DPMC Dimyristoly phosphatidylcholine [email protected] F Formulation FD Freeze dried 1 School of Pharmacy and Biomolecular Sciences, Liverpool John Moores FDM Freeze dried Micro University, Liverpool L3 3AF,UK FDN Freeze dried Nano 2 School of Pharmacy and Biomedical Sciences, University of Central HSPC Hydrogenated soya phosphatidylcholine Lancashire, Preston PR1 2HE, UK LMH Lactose monohydrate 3 Pharmaceutical Sciences Section, College of Pharmacy, Qatar University, MCC Microcrystalline cellulose P.O. Box 2713, Doha, Qatar M Micro 116 Page 2 of 19 Pharm Res (2020) 37:116 N Nano pulmonary administration of PTX has been reported to en- PS Probe sonication hance drug accumulation within the lung and reduce systemic PTX Paclitaxel distribution, which in turn exhibited reduced systemic toxicity SEM Scanning electron microscope (10). Similarly, an in-vitro study demonstrated complete tu- SD Spray dried mour remission and reduced systemic toxicity post nebuliza- SDM Spray dried Micro tion of PTX delivered using solid lipid nanoparticles (11). SDN Spray dried Nano Likewise, transfersome/protransfersome is an another lipid- SPC Soya phosphatidylcholine based drug delivery system designed to suit different situations TEM Transmission electron microscope and delivery scenarios, however unlike liposome and solid TSI Two Stage Impinge lipid nanoparticles incorporate a surfactant as the primary PDI Polydispersity index component, imbibing transfersome with elasticity in terms of their structure enhancing delivery performance, also demon- strated cytotoxic activity against cancer cells (12). A compari- INTRODUCTION son between PTX liposome formulation as aerosol and the intravenous administration of two commercial formulations The usage of Paclitaxel (PTX) as an anticancer agent in the was conducted by Joshi, Shirsath (13). The study demonstrat- treatment of a plethora of cancers (e.g. lung, breast and neck) ed no pulmonary toxicity following aerosol treatment with is well documented (1). PTX appears as needle or fine white to 75% more enhanced metastases inhibition, in comparison to off-white crystalline powder with a molecular weight of parenteral administration (13). 853.91 g/mol (chemical structure of PTX in supplementary The biocompatibility and biodegradability of liposomes data (Fig. a)). PTX storage temperature is 0°C for short term (lipid vesicles) are well-established properties (14). Being struc- and − 20°C for long term in desiccator. A number of physi- turally similar to biological membranes, unlike poly- cochemical properties, like; size, size distribution, entrapment oxyethylated castor oil, are not associated with hypersensitiv- efficiency and zeta potential are critical parameters for PTX- ity reactions (15,16). Hydrophobic compounds are commonly loaded formulations. PTX is associated with a number of entrapped within the concentric bilayers of the vesicles, physicochemical limitations, two significant issues include; whereas hydrophilic molecules position into the central aque- lower aqueous solubility and cellular permeability (2,3). A ous core (17). A number of studies have demonstrated that number of approaches have been employed to overcome PTX can be entrapped into liposomes bilayers without these drawbacks, including the use of cyclodextrins, which PEGylation (18–22). Additionally, PTX entrapment and sta- significantly improve PTX water solubility without altering bility in bilayers may be affected by a number of factors (e.g. its cytostatic activity (4). A commercially available parenteral presence of saturated and unsaturated hydrocarbon chains of formulation under the name of Taxol® is available on the lipids, PEGylation, fusion or aggregation, and the presence or market, which has addressed the compounds poor solubility absence of triglycerides (23)). PEGylation coating of liposomes by formulation with poly-oxyethylated castor oil and ethanol may also prolong retention time, reduce recognition and up- in a 50:50 v/v ratio followed by 5–20 times dilution. However, take by phagocytic cells, offer protection from opsonin binding there are established side-effects associated with poly- in plasma (24–26), thus improving pharmacokinetic and oxyethylated castor oil, namely, laboured breathing and hy- pharmacodynamics properties (27) (i.e. long circulating lipo- persensitivity reactions (5). Thus, there is a clear need for a somes) (28). As formulations, drug-loaded liposomes delivered biocompatible formulation, which enhances cellular perme- to the lungs via nebulization have been associated with a lower ability and water solubility. Previous research has addressed incidence of system side-effects and improved therapeutic ef- this need through formulation of PTX loaded onto albumin fect (29). Arikace® is a liposome formulation containing ami- nanoparticles, under the product Abraxane® (currently under kacin for the treatment of cystic fibrosis via nebulization is clinical trial). Whilst this has been observed to improve