Proliposome powder or tablets for generating inhalable liposomes using a medical nebulizer

Purpose: The aim of this study was to develop and compare proliposome powder and proliposome tablet formulations for drug delivery from a Pari-LC Sprint nebulizer. Methods: Proliposome powders were prepared by the slurry method and sorbitol or mannitol carbohydrate carrier were used in a 1:10 and 1:15 w/w lipid phase to carrier ratio. Beclometasone dipropionate (BDP; 2 mol%) was incorporated in the lipid phase. Proliposome powders were compressed into tablets, and liposomes were generated from proliposome powders or tablets within the nebulizer reservoir for subsequent aerosolization. Results: Comparatively, shorter sputtering times were reported for the tablet formulations (≈ < 2.7±0.45 min), indicating uniform aerosolization. Post-nebulization, liposomes size was larger in the nebulizer reservoir in the range of 7.79±0.48 µm–9.73±1.53 µm for both powder and tablet formulations as compared to freshly prepared liposomes (5.38±0.73 µm–5.85±0.86 µm), suggesting liposome aggregation/fusion in the nebulizer’s reservoir. All formulations exhibited more than 80% mass output regardless of formulation type, but greater BDP proportions (circa 50%) were delivered to the Two-stage Impinger when tablet formulations were used. Moreover, the nebulized droplet median size and size distribution were lower for all tablet formulations in comparison to the powder formulations. Proliposome tablet and powdered formulations demonstrated the ability to generate vesicles that sustained the release of BDP. Conclusion: Overall, this study showed that proliposome tablets could be disintegrated within a Pari-LC Sprint nebulizer to generate inhalable aerosol, with high drug output and hence can be manufactured on large scale to overcome the storage problems associated with powder formulations

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

Proliposome Tablets Manufactured Using A Slurry-Driven Lipid-Enriched Powders: Development, Characterization and Stability Evaluation

Proliposome powders were prepared via a slurry method using sorbitol or D-mannitol as carbohydrate carriers in 1:10 or 1:15 w/w lipid phase to carrier ratios. Soya phosphatidylcholine (SPC) and cholesterol were employed as a lipid phase and Beclometasone dipropionate (BDP) was incorporated as a model drug. Direct compaction using a Minipress was applied on the lipid-enriched powder in order to manufacture proliposome tablets. Sorbitol-based proliposome tablets in a 1:15 w/w ratio were found to be the best formulation as it exhibited excellent powder flowability with an angle of repose of 25.62 ± 1.08°, and when compacted the resultant tablets had low friability (0.20 ± 0.03%), appropriate hardness (crushing strength) (120.67 ± 12.04 N), short disintegration time (5.85 ± 0.66 min), and appropriate weight uniformity. Moreover, upon hydration into liposomes, the entrapment efficiency for sorbitol formulations in both 1:10 and 1:15 lipid to carrier ratios were significantly higher (53.82 ± 6.42% and 57.43 ± 9.12%) than D-mannitol formulations (39.90 ± 4.30% and 35.22 ± 6.50%), respectively. Extended stability testing was conducted for 18 months, at three different temperature conditions (Fridge Temperature (FT; 6°C), Room Temperature (RT; 22°C) and High Temperature (HT; 40°C)) for sorbitol-based proliposome tablets (1:15 w/w ratio). Volume median diameter (VMD) and zeta potential significantly changed from 5.90 ± 0.70 µm to 14.79 ± 0.79 µm and from -3.08 ± 0.26 mV to -11.97 ± 0.26 mV respectively at month 18, when samples were stored under HT conditions. Moreover, the entrapment efficiency of BDP decreased from 57.43 ± 9.12% to 17.93 ± 5.37% following 18 months storage under HT conditions. Overall, in this study for the first time, proliposome tablets were manufactured and thoroughly characterized, and sorbitol showed to be a promising carrier. [Abstract copyright: Copyright © 2017. Published by Elsevier B.V.

Impact of dispersion media and carrier type on spray-dried proliposome powder formulations loaded with beclomethasone dipropionate for their pulmonary drug delivery via a next generation impactor

Drug delivery via aerosolization for localized and systemic effect is a non-invasive approach to achieving pulmonary targeting. The aim of this study was to prepare spray-dried proliposome (SDP) powder formulations to produce carrier particles for superior aerosolization performance, assessed via a next generation impactor (NGI) in combination with a dry powder inhaler. SDP powder formulations (F1-F10) were prepared using a spray dryer, employing five different types of lactose carriers (Lactose monohydrate (LMH), lactose microfine (LMF), lactose 003, lactose 220 and lactose 300) and two different dispersion media. The first dispersion medium was comprised of water and ethanol (50:50% v/v ratio), and the second dispersion medium comprised wholly of ethanol (100%). In the first dispersion medium, the lipid phase (consisting of Soya phosphatidylcholine (SPC as phospholipid) and Beclomethasone dipropionate (BDP; model drug) were dissolved in ethanol and the lactose carrier in water, followed by spray drying. Whereas in second dispersion medium, the lipid phase and lactose carrier were dispersed in ethanol only, post spray drying. SDP powder formulations (F1-F5) possessed significantly smaller particles (2.89 ± 1.24-4.48 ± 1.20 μm), when compared to SDP F6-F10 formulations (10.63 ± 3.71-19.27 ± 4.98 μm), irrespective of lactose carrier type via SEM (scanning electron microscopy). Crystallinity of the F6-F10 and amorphicity of F1-F15 formulations were confirmed by XRD (X-ray diffraction). Differences in size and crystallinity were further reflected in production yield, where significantly higher production yield was obtained for F1-F5 (74.87 ± 4.28-87.32 ± 2.42%) then F6-F10 formulations (40.08 ± 5.714-54.98 ± 5.82%), irrespective of carrier type. Negligible differences were noted in terms of entrapment efficiency, when comparing F1-F5 SDP formulations (94.67 ± 8.41-96.35 ± 7.93) to F6-F10 formulations (78.16 ± 9.35-82.95 ± 9.62). Moreover, formulations F1-F5 demonstrated significantly higher fine particle fraction (FPF), fine particle dose (FPD) and respirable fraction (RF) (on average of 30.35%, 890.12 μg and 85.90%) when compared to counterpart SDP powder formulations (F6-F10). This study has demonstrated that when a combination of water and ethanol was employed as dispersion medium (formulations F1-F5), superior formulation properties for pulmonary drug delivery were observed, irrespective of carrier type employed

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

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

Proliposome Powders for the Generation of Liposomes: the Influence of Carbohydrate Carrier and Separation Conditions on Crystallinity and Entrapment of a Model Antiasthma Steroid

Formulation effects on the entrapment of beclometasone dipropionate (BDP) in liposomes generated by hydration of proliposomes were studied, using the high-density dispersion medium deuterium oxide in comparison to deionized water (DW). Proliposomes incorporating BDP (2 mol% of the lipid phase consisting of soya phosphatidylcholine (SPC) and cholesterol; 1:1) were manufactured, using lactose monohydrate (LMH), sorbitol or D-mannitol as carbohydrate carriers (1:5 w/w lipid to carrier). Following hydration of proliposomes, separation of BDP-entrapped liposomes from the unentrapped (free) BDP at an optimized centrifugation duration of 90 min and a centrifugation force of 15,500g were identified. The dispersion medium was found to have a major influence on separation of BDP-entrapped liposomes from the unentrapped drug. Entrapment efficiency values were higher than 95% as estimated when DW was used. By contrast, the entrapment efficiency was 19.69 ± 5.88, 28.78 ± 4.69 and 34.84 ± 3.62% upon using D2O as a dispersion medium (for LMH-, sorbitol- and D-mannitol-based proliposomes, respectively). The similarity in size of liposomes and BDP crystals was found to be responsible for co-sedimentation of liposomes and free BDP crystals upon centrifugation in DW, giving rise to the falsely high entrapment values estimated. This was remedied by the use of D2O as confirmed by light microscopy, nuclear magnetic resonance (1HNMR), X-ray diffraction (XRD) and entrapment studies. This study showed that carrier type has a significant influence on the entrapment of BDP in liposomes generated from proliposomes, and using D2O is essential for accurate determination of steroid entrapment in the vesicles.Scopu

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

Impact of nanosizing on the formation and characteristics of polymethacrylate films: micro- versus nano-suspensions

Aqueous-based film coating suspensions are associated with reliance on alkalinising reagents and poor film formation. The impact of particle size in this process and resultant film properties remains unclear. This study offers the first direct comparison of film formation properties between aqueous micro- and nano-suspensions of the enteric polymer Eudragit S100. High-pressure homogenisation was employed to produce nano-suspensions of the enteric polymer. Formed enteric suspensions (micro- and nano-) were evaluated in terms of size, morphology, and ability to form film; with resultant films analysed in terms of; film thickness, mechanical and thermoplastic properties, water uptake, weight loss, and drug permeability in acidic medium. High-pressure homogenisation yielded particles within a submicron range (150–200 nm). Produced nano-suspensions formed significantly thinner films (p  0.05) in terms of water uptake (∼25% w/w), weight loss (<16% w/w) and drug permeability (<0.1%). Interestingly, nano-suspension-based films exhibited lower glass transition temperatures (Tg) (p < 0.01), when compared to films cast from micro-suspensions (∼7–20 °C difference), indicating enhanced plasticisation. This was reflected in film mechanical properties; where nano-suspension-based films demonstrated significantly lower tensile strength (p < 0.01) and higher percentage elongation (p < 0.05), suggesting high elasticity. Thinner, highly elastic films were formed from nano-suspensions, compared to films cast from micro-suspensions, exhibiting comparative properties; obviating the need for alkalinising agents and high concentrations of plasticiser.Open Access funding provided by the Qatar National Library.Scopu

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