Paclitaxel-loaded Micro or Nano Transfersome Formulation into Novel Tablets for Pulmonary Drug Delivery via Nebulization

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

The Cytotoxic effect of an Ethanol extract of Momordica Charantia, Kuguacin-J and Cisplatin on healthy MCF-10A and MCF-7 and MDAMB-231 breast cancer cell lines employing In Vitro assays

Traditional medicines, derived from plants, could present alternative treatment strategy for cancer therapy. One such plant is Momordica charantia (MC) which possesses anti-carcinogenic properties. This study investigated the anticancer effect of an ethanol extract of MC fruit, Kuguacin-J (K-J), an isolated compound from the leaves of MC and cisplatin, either alone or combination on healthy MCF-10A mammary cells and compared with breast cancer MCF-7 and MDAMB-231 cell lines. Cell viability was tested using 8 μg/mL and 80 μg/mL doses of MC extract, K-J and cisplatin individually or combined for 24 and 48 hours. Caspase-3- activity was measured in MCF-7 and MDA-MB-231 cells using established methods. The results revealed that MC extract and K-J had no effect on healthy MCF-10A cell viability as compared to cisplatin which induced dose and time-dependent cell death. Similarly, treatment of MCF-7 cells with cisplatin induced cell death at high concentration at both the time points, while MC extract and K-J only induce MCF-7 cell death at high dose after 48 hours only. During combination therapy, both doses of cisplatin enhanced MCF-7 cell death when combined with MC extract or K-J after 24 and 48 hours. In MDAMB-231 cells, the three drugs, either alone or combined, evoked significant cell death at both the doses and time points. All three drugs, at high dose, elicited significant increase in caspase-3- activity in MCF-7 and MDA-MB-231 cells as compared to untreated cells. The results revealed that either MC extract or K-J alone or combined with cisplatin, can elicit significant increase in cell death and caspase–3-activity in MCF-7 and MDA-MB-231cells as compared to untreated cell

Anticancer drug delivery: Investigating the impacts of viscosity on lipid-based formulations for pulmonary targeting

Pulmonary drug delivery via aerosolization is a non-intrusive method for achieving localized and systemic effects. The aim of this study was to establish the impact of viscosity as a novel aspect (i.e., low, medium and high) using various lipid-based formulations (including liposomes (F1-F3), transfersomes (F4-F6), micelles (F7-F9) and nanostructured lipid carriers (NLCs; F10-F12)) as well as to investigate their impact on in-vitro nebulization performance using Trans-resveratrol (TRES) as a model anticancer drug. Based on the physicochemical properties, micelles (F7-F9) elicited the smallest particle size (12–174 nm); additionally, all formulations tested exhibited high entrapment efficiency (>89 %). Through measurement using capillary viscometers, NLC formulations exhibited the highest viscosity (3.35–10.04 m2/sec). Upon using a rotational rheometer, formulations exhibited shear-thinning (non-Newtonian) behaviour. Air jet and vibrating mesh nebulizers were subsequently employed to assess nebulization performance using an in-vitro model. Higher viscosity formulations elicited a prolonged nebulization time. The vibrating mesh nebulizer exhibited significantly higher emitted dose (ED), fine particle fraction (FPF) and fine particle dose (FPD) (up to 97 %, 90 % and 64 µg). Moreover, the in-vitro release of TRES was higher at pH 5, demonstrating an alignment of the release profile with the Korsmeyer-Peppas model. Thus, formulations with higher viscosity paired with a vibrating mesh nebulizer were an ideal combination for delivering and targeting peripheral lungs

Generation of High Dose Inhalable Effervescent Dispersions against Pseudomonas aeruginosa Biofilms

Purpose: Novel particle engineering approach was used in this study to generate high dose inhalable effervescent particles with synergistic effects against Pseudomonas aeruginosa biofilms. Methods: Spray dried co-amorphous salt of ciprofloxacin (CFX) and tartaric acid (TA) was prepared and coated with external layer of sodium bicarbonate and silica coated silver nanobeads. Design of experiments (DOE) was used to optimize physicochemical properties of particles for enhanced lung deposition. Results: Generated particles were co-amorphous CFX/TA showing that CFX lost its zwitterionic form and exhibiting distinct properties to CFX/HCl as assessed by FTIR and thermal analysis. Particles exhibited mass mean aerodynamic diameter (MMAD) of 3.3 μm, emitted dose of 78% and fine particle dose of 85%. Particles were further evaluated via antimicrobial assessment of minimum inhibitory concentrations (MIC) and minimum biofilm eradication concentration (MBEC). MIC and MBEC results showed that the hybrid particles were around 3–5 times more effective when compared to CFX signifying that synergistic effect was achieved. Diffusing wave spectroscopy results showed that the silver containing particles had a disruptive effect on rheological properties as opposed to silver free particles. Conclusions: Overall, these results showed the potential to use particle engineering to generate particles that are highly disruptive of bacterial biofilms

A Current Review from Recent Literature on Novel Sars-cov-2 Outbreak

The outbreak of a novel coronavirus 2019 was traced back in China in late 2019, followed by their worldwide transmission as a pandemic. From January to August 2020, a total of 1,724 papers were published, where 125 were only published in August 2020, demonstrating the importance and need for current awareness and research to overcome this deleterious virus. This paper briefly highlighted the major characteristics of the SARS-CoV-2 in detail, including; a brief history of coronavirus, various transmission routes, range of mild to severe symptoms, available diagnostic tests, treatment options, measures for infection control and prevention, and particular emphasis on self-acceptance and upholding to face mask-wearing. The impact of the COVID-19 pandemic is limitless and has affected all the nation throughout the horizon; the voyage is indeed hard but not impossible to overcome. However, it is the responsibility of each and every individual to be cautious, know, and understand their role in this difficult situation. To conclude, due to the lack of cohesive data, this review has collated the most recent literature regarding COVID-19 and provided the reader with clear and simple knowledge and instructions on the control and prevention of COVID-19 and hence to protect the most vulnerable population

Impact of liquid lipid on development and stability of trimyristin nanostructured lipid carriers for oral delivery of resveratrol

Nanostructured lipid carriers (NLCs) have emerged as versatile carriers to improve oral bioavailability of poorly water-soluble drugs as well as to protect labile drugs from degradation and metabolism. Prepared by blending solid and liquid lipids, the choice of liquid lipid can have a great influence on their physicochemical characteristics and stability. The present work investigated the impact of six different liquid lipids with diverse chemical structures and hydrophilic and lipophilic balance (HLBs) on the critical quality attributes (CQAs) and storage stability of NLCs with trimyristin as solid lipid. Resveratrol (RES) was used as model drug as its low water solubility, poor bioavailability, rapid metabolism and clearance from systemic circulation restricts its clinical use despite its wide spectrum of biological activities. Liquid lipids investigated included, two triglycerides, one medium chain (C8) glycerol tricaprylate (GTC) and second, long chain (C18) glyceryl trioleate (GTO); two propylene glycol fatty acid esters, propylene glycol monocaprylate (PGMC) and propylene glycol monolaurate (PGML); fatty acid ester decyl oleate (DO) and a PEGylated lipid polyethylene glycol-8 caprylic/capric glycerides (PCG). Box–Behnken experimental design was employed to ascertain the effect of four independent factors viz. type of liquid lipid, amount of liquid lipid, amount of drug and surfactant concentration and interactions between these factors on the CQAs of NLCs as response variables viz. particle size (PS), polydispersity index (PDI), zeta potential (ZP), drug encapsulation efficiency (EE), and drug loading (DL). The relationship between various factors and responses was established by response surface methodology (RSM). The oils with higher lipophilicity C18 triglycerides (GTO) and C18 fatty acid ester DO yielded NLCs with lower PS as compared to the oils with lower lipophilicity (PGC, PGMC and PGML). Although increasing the concentration of liquid lipids had an upward trend on the PS of NLCs, its PDI was more predominantly influenced by the nature of liquid lipid. The characteristic of the liquid lipid influenced the DL remarkably which varied from 2.94 to 7.56%. The ZP of nanoparticles varied from −21.3 to −39.9 mV with liquid lipids with free hydroxyl groups and higher HLB playing a more prominent role contributing to the increase in the negative surface charge. The characteristics of liquid lipid influenced the depression of melting point of RES with maximum distortion of the crystal lattice was caused by PGMC and least by GTO. The two, long chain oleates, DO and GTO exhibited a shift of lipid peak in NLCs to higher melting points (116 and 111 °C) than the less lipophilic liquid lipids (103–104 °C). The attributes of liquid lipid also discriminate whether the particle growth during storage followed Oswald's ripening or coalescence. NLC containing GTO exhibited the highest stability in terms of maintenance of the PS and particle size distribution at 20 °C. This study provides vital insight on impact of liquid lipids and future strategy for rational design of stable NLC systems for delivery of various bio-actives for drug delivery applications

Resveratrol Nanostructured Lipid Carrier for targeted delivery to breast cancer

Background: Breast cancer remains a prominent cause of mortality and morbidity in the female population. Despite advances in terms of novel compounds, exhibiting chemotherapeutic activity successful delivery remains challenging. Particulate-based system such as Nanostructured Lipid Carriers (NLCs) a new generation carrier allow encapsulation of drug and targeting of desired tissue. Resveratrol (RES) is a chemotherapeutic drug limited by its physiochemical properties (i.e. poor solubility and bioavailability), encapsulation into NLCs is potentially viable solution to the aforementioned issues. Aim: The main aim of the present work is to develop a nanostructured lipid carriers based drug delivery system of RES in order to overcome its physicochemical and pharmacokinetic limitations and impart suitable functionalities for targeting breast cancer cells. Methods: Box-Behnken experimental design (BBD) was used to understand the effect of three independent factors (amount of liquid lipid, amount of drug and surfactant concentration) and interactions between these factors for each of the six liquid lipids on the selected response variables particle size (PS), polydispersity index (PDI), zeta potential (ZP), drug encapsulation efficiency (%EE), and drug loading (%DL). The formulated resveratrol nanostructured lipid carriers (RES-NLCs) were subjected to a series of physicochemical characterization including particles size, zeta potential measurements, in-vitro drug release while the morphology of RES-NLCs was confirmed through various microscopic methods, differential scanning calorimetry, x ray diffraction and Fourier transfer infrared studies was carried out in order to understand the interactions between RES and the components of the formulation. Undertake stability studies for the formulated RES-NLCs, at various storage conditions in order to select the most stable formulation and take it for further functionalization with targeting ligands hyaluronic acid; HA-NLCs, folic acid; FA-NLCs and dual targeting system using both hyaluronic acid and folic acid; HAFANLCs, and optimization of ligand density and quantify the amount of amine groups present on the surface on RES-NLCs. The efficacy of RES-NLCs was demonstrated through various in-vitro cell lines studies carried on three breast cancer cell lines entailed: MCF-7, MCF-10A and MDAMB-231 cells. Finally, the permeability of the formulations was evaluated through Caco-2 monolayer and Caco2/HT29 co-culture cell lines in order to understand the intestinal barrier transport mechanism. Results: The employed Box Behnken design resulted in the formulation of particles which were <100nm in size, PDI <0.3, a negative surface charge (-24), high entrapment efficiency (91-99%) and drug loading of 3-4%, with tuneable characteristics within the design space. Differential scanning calorimetry and x-ray diffraction indicated amorphous nature of the drug in nanoparticles indicating its entrapment. Upon exposure to acidic medium (pH 1.2), <20% drug release was observed in 4 hours, with 100% drug release observed upon the increase of pH to 5 over a period of 24 hours. Upon stability testing of NLCs, nanoparticles formulated with GTO as a liquid lipid showed good stability and therefore was taken forward for further PEGylating and surface modification with three ligands; hyaluronic acid, folic acid and combination of both ligand in order to impart targetability for breast cancer cells. Surface modification drastically reduced drug release to < 2 % at pH 1.2, however at pH 5, drug release time plots indicated slower overall release from the surface modified NLCs. In-vitro cytotoxicity studies showed that RES-NLCs were effective against both non-TNBC; MCF-7 and TNBC; MDAMB-231 breast cancer cell lines. Dual ligand appended nanoparticles showed 2.7 folds higher toxicity in MCF-7 and 3.6 fold higher toxicity in MDAMB-231 cells as compared to RES-NLC-GTO-PEGS40 demonstrating its potential for treatment in the aggressive triple negative cancer. None of the RES-NLCs formulations containing different liquid lipids or their blanks were cytotoxic to healthy MCF-10A cells demonstrating safety of the formulations. All bare, PEGylated and surface modified RES-NLCs showed time dependent cellular uptake on both MCF-7 and MDAMB-231 cell lines. Surface modification lead to 3 fold increase in the cellular uptake confirming the targetability potential of the ligand appended formulations toward overexpressed receptors on the surface of both cancer MCF-7 and MDAMB-231 cells. Upon examination of endocytosis mechanisms when cells were treated with the formulations, it was noted that two mechanisms were prominent. Clathrin-mediated endocytosis was identified as the primary method of endocytosis for all formulations. However, specifically for surface modified NLCs receptor mediated endocytosis was also found to be responsible for uptake of nanoparticles. Bidirectional transport study demonstrated that the permeability was sensitive to the type of liquid lipid incorporated with the highest permeability exhibited for PGML based formulation, when studied using a Caco-2 monolayer. On comparison to Caco-2/HT29 co-culture free resveratrol showed higher permeability when compared to the formulated NLCs. Conclusion: The aforementioned research has demonstrated that resveratrol NLCs are a viable potential product for use in the treatment of breast cancer, exhibiting high versatility and specificity

Potential cardio-protective agents: A Resveratrol review (2000-2019)

: With a 2030 projection of 23.6 million deaths per year the prevalence and severity of cardiovascular disease is at an astounding high. Thus, a definitive need for the identification of novel compounds with potential to prevent or treat the disease and associated states. Moreover, there is also an ever-increasing need for drug delivery systems (DDS) that cope with poor and ranging physiochemical properties of therapeutic compounds to achieve clinical effect. The usage of resveratrol (RES) is a growing area of interest with innumerate pieces of research evidencing the drug’s efficacy. This drug is however marred, its notably poor physiochemical properties (namely poor water solubility) limits its use for oral drug delivery. RES analogues however, potentially possess superior physiochemical characteristics offering a remedy for the aforementioned drawback. However, particulate based DDS are equally able to offer property amelioration and targeting. This review offers an extensive examination into the role of RES as a potential cardio protective agent. The prevalence and suitability of associated analogues and the role of nanotechnology in overcoming physicochemical boundaries, particularly through the development of nanoparticulate formulations, will be discussed in detail

A Facile and Novel Approach to Manufacture Paclitaxel-Loaded Proliposome Tablet Formulations of Micro or Nano Vesicles for Nebulization

© 2020, The Author(s). Purpose: The aim of this study was to develop novel paclitaxel-loaded proliposome tablet formulations for pulmonary drug delivery. Method: Proliposome powder formulations (i.e. F1 – F27) were prepared employing Lactose monohydrate (LMH), Microcrystalline cellulose (MCC) or Starch as a carbohydrate carriers and Soya phosphatidylcholine (SPC), Hydrogenated soya phosphatidylcholine (HSPC) or Dimyristoly phosphatidylcholine (DMPC) as a phospholipid. Proliposome powder formulations were prepared in 1:5, 1:15 or 1:25 w/w lipid phase to carrier ratio (lipid phase; comprising of phospholipid and cholesterol in 1:1 M ratio) and Paclitaxel (PTX) was used as model anticancer drug. Results: Based on flowability studies, out of 27 formulations; F3, F6, and F9 formulations were selected as they exhibited an excellent angle of repose (AOR) (17.24 ± 0.43, 16.41 ± 0.52 and 15.16 ± 0.72°), comparatively lower size of vesicles (i.e. 5.35 ± 0.76, 6.27 ± 0.59 and 5.43 ± 0.68 μm) and good compressibility index (14.81 ± 0.36, 15.01 ± 0.35 and 14.56 ± 0.14) via Carr’s index. The selected formulations were reduced into Nano (N) vesicles via probe sonication, followed by spray drying (SD) to get a dry powder of these formulations as F3SDN, F6SDN and F9SDN, and gave high yield (>53%) and exhibited poor to very poor compressibility index values via Carr’s Index. Post tablet manufacturing, F3 tablets formulation showed uniform weight uniformity (129.40 ± 3.85 mg), good crushing strength (14.08 ± 1.95 N), precise tablet thickness (2.33 ± 0.51 mm) and a short disintegration time of 14.35 ± 0.56 min, passing all quality control tests in accordance with British Pharmacopeia (BP). Upon nebulization of F3 tablets formulation, Ultrasonic nebulizer showed better nebulization time (8.75 ± 0.86 min) and high output rate (421.06 ± 7.19 mg/min) when compared to Vibrating mesh nebulizer. PTX-loaded F3 tablet formulations were identified as toxic (60% cell viability) to cancer MRC-5 SV2 cell lines while safe to normal MRC-5 cell lines. Conclusion: Overall, in this study LMH was identified as a superior carbohydrate carrier for proliposome tablet manufacturing in a 1:25 w/w lipid to carrier ratio for in-vitro nebulization via Ultrasonic nebulizer

Fabrication, Characterization and Optimization of Nanostructured Lipid Carrier Formulations using Beclomethasone Dipropionate for Pulmonary Drug Delivery via Medical Nebulizers

Aerosolization is a non-invasive approach in drug delivery for localized and systemic effect. Nanostructured lipid carriers (NLCs) are new generation versatile carriers, which offer protection from degradation and enhance bioavailability of poorly water soluble drugs. The aim of this study was to develop and optimize NLC formulations in combination with optimized airflow rates (i.e. 60 and 15 L/min) and choice of medical nebulizers including Air jet, Vibrating mesh and Ultrasonic nebulizer for superior aerosolization performance, assessed via a next generation impactor (NGI). Novel composition and combination of NLC formulations (F1 – F15) were prepared via ultrasonication method, employing five solid lipids (glycerol trimyristate (GTM), glycerol trilaurate (GTL), cetyl palmitate (CP), glycerol monostearate (GMS) and stearic acid (SA)); and three liquid lipids (glyceryl tributyrate (GTB), propylene glycol dicaprylate/dicaprate (PGD) and isopropyl palmitate (IPP)) in 1:3 w/w ratios (i.e. combination of one solid and one liquid lipid), with Beclomethasone dipropionate (BDP) incorporated as the model drug. Out of fifteen BDP-NLC formulations, the physicochemical properties of formulations F7, F8 and F10 exhibited desirable stability (one week at 25 °C), with associated particle size of ∼241 nm, and >91% of drug entrapment. Post aerosolization, F10 was observed to deposit notably smaller sized particles (from 198 to 136 nm, 283 to 135 nm and 239 to 157 nm for Air jet, Vibrating mesh and Ultrasonic nebulizers, respectively) in all stages (i.e. from stage 1 to 8) of the NGI, when compared to F7 and F8 formulations. Six week stability studies conducted at 4, 25 and 45 °C, demonstrated F10 formulation stability in terms of particle size, irrespective of temperature conditions. Nebulizer performance study using the NGI for F10 identified the Air jet to be the most efficient nebulizer, depositing lower concentrations of BDP in the earlier stages (1 – 3) and higher (circa 82 and 85%) in the lateral stages (4 – 8) using 60 and 15 L/min airflow rates, when compared to the Vibrating mesh and Ultrasonic nebulizers. Moreover, at both airflow rates, the Air jet nebulizer elicited a longer nebulization time of ∼42 min, facilitating aerosol inhalation for prophylaxis of asthma with normal tidal breathing. Based on characterization and nebulizer performance employing both 60 and 15 L/min airflow rates, the Air jet nebulizer offered enhanced performance, exhibiting a higher fine particle dose (FPD) (90 and 69 µg), fine particle fraction (FPF) (70 and 54%), respirable fraction (RF) (92 and 69%), and lower mass median aerodynamic diameter (MMAD) (1.15 and 1.62 µm); in addition to demonstrating higher drug deposition in the lateral parts of the NGI, when compared to its counterpart nebulizers. The F10 formulation used with the Air jet nebulizer was identified as being the most suitable combination for delivery of BDP-NLC formulations