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 review on the synthesis of bio-based surfactants using green chemistry principles.

OBJECTIVES: With increasing awareness of the potential adverse impact of conventional surfactants on the environment and human health, there is mounting interest in the development of bio-based surfactants (which are deemed to be safer, more affordable, are in abundance, are biodegradable, biocompatible and possess scalability, mildness and performance in formulation) in personal care products. METHOD: A comprehensive literature review around alkyl polyglucosides (APGs) and sucrose esters (SEs) as bio-based surfactants, through the lens of the 12 green chemistry principles was conducted. An overview of the use of bio-based surfactants in personal care products was also provided. RESULTS: Bio-based surfactants are derived primarily from natural sources (i.e. both the head and tail molecular group). One of the more common types of bio-based surfactants are those with carbohydrate head groups, where alkyl polyglucosides (APGs) and sucrose esters (SEs) lead this sub-category. As global regulations and user mandate for sustainability and safety increase, evidence to further support these bio-based surfactants as alternatives to their petrochemical counterparts is advantageous. Use of the green chemistry framework is a suitable way to do this. While many of the discussed principles are enforced industrially, others have only yet been applied at a laboratory scale or are not apparent in literature. CONCLUSION: Many of the principles of green chemistry are currently used in the synthesis of APGs and SEs. These and other bio-based surfactants should, therefore, be considered suitable and sustainable alternatives to conventional surfactants. To further encourage the use of these novel surfactants, industry must make an effort to implement and improve the use of the remaining principles at a commercial level.

Overcoming Skin Damage from Pollution via Novel Skincare Strategies.

Urban pollution is one of the main problems encountered worldwide, with a major impact on public health as well as the environment. The health impact of urban pollution is not limited to respiratory conditions but also encompasses major skin problems, including irritation, skin ageing, and skin cancer. Toxic gases and particulate matter are the main pollutants that exhibit extensive local variability. The aforementioned pollutants are small particles that attach to the skin or penetrate it, enhancing free radicals' production inside the inner skin layers. This urges the need to propose cosmetic products that help prevent and/or minimise pollutants' effects on the skin, whether irritation, ageing, and cancer. Furthermore, intrinsic and extrinsic factors contribute to skin irritation and ageing. Intrinsic factors are within skin factors and include genetic and physiological characteristics of individuals. Moreover, extrinsic factors comprise environmental factors such as humidity, temperature, and smoke. Subsequently, active ingredients with anti pollutant properties addressed the intrinsic and extrinsic factors by four mechanisms: free radical neutralisation, film-forming ability, skin barrier enhancement, and fortification. Such ingredients include vitamin A derivatives, vitamin C derivatives, carbohydrates, and plantbased products. Yet, very limited studies have evaluated the effectiveness of the aforementioned active ingredients against irritation or ageing, which should be considered in future work.

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 < 0.01), at lower plasticiser concentrations, than films cast from micro-suspensions (differences in thickness up to 100 µm); however, exhibited comparative gastro-resistant properties (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.

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.

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 are astoundingly high. Thus, there is a definitive need for the identification of novel compounds with the 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 the 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) limit 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 cardioprotective 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.

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.

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

A simplistic approach was adopted to manufacture novel paclitaxel (PTX) loaded protransfersome tablet formulations for pulmonary drug delivery. The large surface area offered by the pulmonary system acts as a desirable site for anti-cancer drug deposition; offering localized effect within 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 a 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, entrapment and targetted delivery via transfersome vesicles. 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 excellent powder flowability via angle of repose (AOR) and good compressibility index due to associated smaller and uniform particle size and shape of LMH. Following hydration, these formulations also showed smaller volume median diameters (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 to 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 the 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 a shorter nebulization time and high output rate when using Ultrasonic nebulizer 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 were found to be a superior combination, eliciting enhanced output efficiency. Moreover, PTX-loaded F3, F6 and F9 tablet formulations (10%) exhibited toxicity (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 ±â€¯1.08°, and when compacted the resultant tablets had low friability (0.20 ±â€¯0.03%), appropriate hardness (crushing strength) (120.67 ±â€¯12.04 N), short disintegration time (5.85 ±â€¯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 ±â€¯6.42% and 57.43 ±â€¯9.12%) than D-mannitol formulations (39.90 ±â€¯4.30% and 35.22 ±â€¯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 ±â€¯0.70 µm to 14.79 ±â€¯0.79 µm and from -3.08 ±â€¯0.26 mV to -11.97 ±â€¯0.26 mV respectively at month 18, when samples were stored under HT conditions. Moreover, the entrapment efficiency of BDP decreased from 57.43 ±â€¯9.12% to 17.93 ±â€¯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.

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.

Potential of Natural Biomaterials in Nano-scale Drug Delivery.

BACKGROUND: The usage of natural biomaterials or naturally derived materials intended for interface with biological systems has steadily increased in response to the high demand of amenable materials, which are suitable for purpose, biocompatible and biodegradable. There are many naturally derived polymers which overlap in terms of purpose as biomaterials but are equally diverse in their applications. METHODS: This review examines the applications of the following naturally derived polymers; hyaluronic acid, silk fibroin, chitosan, collagen and tamarind polysaccharide (TSP); further focusing on the biomedical applications of each as well as emphasising on individual novel applications. RESULTS: Each of the polymers was found to demonstrate a wide variety of successful biomedical applications fabricated as wound dressings, scaffolds, matrices, films, sponges, implants or hydrogels to suit the therapeutic need. Interestingly, blending and amelioration of polymer structures were the two selection strategies to modify the functionality of the polymers to suit the purpose. Further, these polymers have shown promise to deliver small molecule drugs, proteins and genes as nano-scale delivery systems. CONCLUSION: The review highlights the range of applications of the aforementioned polymers as biomaterials. Hyaluronic acid, silk fibroin, chitosan, collagen and TSP have been successfully utilised as biomaterials in the subfields of implant enhancement, wound management, drug delivery, tissue engineering and nanotechnology. Whilst there are a number of associated advantages (i.e. biodegradability, biocompatibility, non-toxic, nonantigenic as well as amenability) the selected disadvantages of each individual polymer provide significant scope for their further exploration and overcoming challenges like feasibility of mass production at a relatively low cost.

Proliposome powders prepared using a slurry method for the generation of beclometasone dipropionate liposomes.

A novel "slurry method" was described for the preparation of proliposome powders using soya phosphatidylcholine (SPC) with cholesterol (1:1) and for incorporation of beclometasone dipropionate (BDP) at 2mole% of the total lipid phase. Proliposomes made with a range of lipid to sucrose carrier ratios were studied in terms of surface morphology using scanning electron microscopy (SEM) and thermal properties using differential scanning calorimetry (DSC). Following hydration of proliposomes, the resultant vesicles were compared to liposomes made using the traditional proliposome method, in terms of vesicle size and drug entrapment efficiency. SEM showed that sucrose was uniformly coated with lipid regardless of lipid to carrier ratio. Liposomes generated using the slurry proliposome method tended to have smaller median size than those generated with the conventional proliposome method, being in the range of 4.72-5.20µm and 5.89-7.72µm respectively. Following centrifugation of liposomes using deuterium oxide (D2O) as dispersion medium, vesicles entrapping BDP were separated as a floating creamy layer, whilst the free drug was sedimented as crystals. Drug entrapment was dependent on formulation composition and preparation method. When 1:15 w/w lipid to carrier was used, liposomes generated using the slurry method had an entrapment efficiency of 47.05% compared to 18.67% for those generated using the conventional proliposome method. By contrast, liposomes made by the thin-film hydration method had an entrapment efficiency of 25.66%. DSC studies using 50mole% BDP demonstrated that the drug was amorphous in the proliposome formulation and tended to crystallize on hydration, resulting in low drug entrapment. In conclusion, a novel approach to the preparation of proliposomes using a slurry method has been introduced, offering higher entrapment for BDP than liposomes made using the conventional proliposome method and those prepared by thin-film hydration technique.