Quercetin (QUE)-a plant-derived flavonoid, is recently established as an effective quorum sensing (QS) inhibiting agent in
-the main bacterial pathogen in bronchiectasis lungs. Successful clinical ...application of QUE, however, is hindered by its low solubility in physiological fluids. Herein we developed a solubility enhancement strategy of QUE in the form of a stable amorphous nanoparticle complex (nanoplex) of QUE and chitosan (CHI), which was prepared by electrostatically driven complexation between ionized QUE molecules and oppositely charged CHI. At its optimal preparation condition, the QUE-CHI nanoplex exhibited a size of roughly 150 nm with a 25% QUE payload and 60% complexation efficiency. The complexation with CHI had no adverse effect on the antibacterial and anticancer activities of QUE, signifying the preservation of QUE's bioactivities in the nanoplex. Compared to the native QUE, the QUE-CHI nanoplex exhibited superior QS inhibition in suppressing the QS-regulated swimming motility and biofilm formation of
, but not in suppressing the virulence factor production. The superior inhibitions of the biofilm formation and swimming motility afforded by the nanoplex were attributed to (1) its higher kinetic solubility (5-times higher) that led to higher QUE exposures, and (2) the synergistic QS inhibition attributed to its CHI fraction.
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•PAP inclusion has minimal effect on CIP nanoplex’s characteristics and preparation.•Amorphous form of CIP–(DXT–PAP) nanoplex is stable during storage.•PAP inclusion does not affect ...CIP dissolution from nanoplex.•PAP inclusion enhances mucus permeability and antibiofilm activity of CIP nanoplex.•PAP presence above a certain concentration threshold is cytotoxic to lung cells.
Antibiotic-polyelectrolyte nanoparticle complex (or nanoplex in short) has been recently demonstrated as a superior antibiotic delivery system to the native antibiotic in bronchiectasis therapy owed to its ability to overcome the lung’s mucus barrier and generate high localized antibiotic exposure in the infected sites. The present work aimed to further improve the mucus permeability, hence the antibacterial efficacy of the nanoplex, by incorporating mucolytic enzyme papain (PAP) at the nanoplex formation step to produce PAP-decorated antibiotic-polyelectrolyte nanoplex exhibiting built-in mucolytic capability. Ciprofloxacin (CIP) and dextran sulfate (DXT) were used as the models for antibiotics and polyelectrolyte, respectively. The results showed that the PAP inclusion had minimal effects on the physical characteristics, preparation efficiency, and dissolution of the CIP–DXT nanoplex. The optimal CIP–(DXT–PAP) nanoplex exhibited size and zeta potential of approximately 200 nm and -50 mV with CIP and PAP payloads of 60% and 32% (w/w), respectively. The nanoplex was prepared at high efficiency with larger than 80% CIP and PAP utilization rates. The CIP–(DXT–PAP) nanoplex exhibited tenfold improvement in the mucus permeability compared to its CIP–DXT nanoplex counterpart, resulting in the former’s superior bactericidal activity against clinical Pseudomonas aeruginosa biofilm in the presence of mucus barrier. A trade-off, nevertheless, existed between antibacterial efficacy and cytotoxicity towards human lung epithelium cells upon the incorporation of PAP above a certain concentration threshold. Therefore, the optimal dosing of the CIP–(DXT–PAP) nanoplex must be carefully determined.
Dry powder inhaler (DPI) formulations of small nucleic acids (e.g. pDNA, siRNA) have been established as the preferred delivery mode for pulmonary gene therapy. While numerous studies have ...demonstrated the in vivo gene activity and in vitro aerosolization efficiency of the DPI formulations, few studies have examined their storage stability. Herein we investigated the effects of storage at 4 °C and 25 °C for 1 and 3 months on the in vitro stability and aerosolization efficiency of DPI of pDNA-chitosan nanoparticles prepared by spray-freeze-drying. The DPI of pDNA-chitosan nanoparticles exhibited sustained pDNA release profile and minimal cytotoxicity towards human lung epithelium cells. It lost approximately 10% and 20% of its activity after 3-month storage at 4 °C and 25 °C, respectively. As expected, the DPI formulation exhibited higher storage stability than the nanoparticle suspension form (40–50% loss). While the effect of raising the storage temperature to 25 °C on the pDNA activity was not very significant, it greatly affected the aerosolization efficiency, where the particle fraction suitable for deposition in the deep lungs decreased from 17% to 7%. The present results reaffirmed the previous studies performed on naked pDNA and pDNA polyplex that storage at 4 °C was generally adequate for DPI of pDNA.
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•DPI of pDNA-CHI nanoparticles lost 10% of its activity after 3-month storage at 4 °C.•3-month storage at 25 °C led to 20% loss in activity and poor aerosolization efficiency.•pDNA conformation change during storage had minimal impact on its activity.•The DPI form as expected had higher storage stability than the nanoparticle suspension form.•DPI of pDNA-CHI nanoparticles had comparable storage stability as lyophilized naked pDNA.
Despite lubricants' indispensable roles in the production of pharmaceutical tablets. The selection of lubricant for pharmaceutical tableting has been largely empirical, where most tablets are ...produced using magnesium stearate (MgSt) as the lubricant. Even though many other lubricants (e.g., inorganic materials, polymers, surfactants) can deliver comparable lubrication efficiency as MgSt and often produce tablets with superior characteristics, these alternative lubricants remain not widely used. As the pharmaceutical industry strives to improve the environmental sustainability of its manufacturing, the present work aimed to employ environmental sustainability metrics as one of the decision tools (the other being the tablet's characteristics) in the lubricant selection process. Ibuprofen tablets prepared with four types of lubricants, i.e., MgSt, talc, polyethylene glycol (PEG 6000), and sodium dodecyl sulfate (SDS), were studied. For each lubricant, environmental impacts of its production from raw materials were quantitatively characterized by life cycle assessment (LCA). Subsequently, LCA of ibuprofen tablets prepared using different lubricants was performed. Kilo-scale tableting experiments were carried out to generate material and energy flow data for the LCA. The results of the tableting experiments showed that ibuprofen tablets' characteristics were minimally affected by the type of lubricant used and all tablets could meet the criteria for friability, weight variation, drug content uniformity, and dissolution. The LCA results revealed that PEG 6000 had the best environmental sustainability profile, followed by talc, MgSt, and SDS. Owing to PEG 6000's superior sustainability profile, tablets prepared using PEG 6000 as the lubricant generated smaller environmental impacts than tablets prepared using MgSt. Therefore, the incorporation of environmental sustainability metrics into the lubricant selection methodology can improve the environmental sustainability of pharmaceutical tablet production.
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•Non-MgSt lubricant is as good as MgSt in producing tablets that meet USP's criteria.•Lubricant production affects mostly human health and ecosystem quality.•PEG 6000 has the best environmental sustainability, followed by talc, MgSt, SDS.•Tablet with PEG 6000 as lubricant has superior sustainability than tablet with MgSt.•Environmentally friendly lubricant lowers environmental impact of tablet production.
The solubility enhancement afforded by amorphous drug nanoparticles was demonstrated in several studies to be superior to the traditional amorphization approach by microscale amorphous solid ...dispersion (or micro ASD in short). A closer look at these studies, however, revealed that they were performed using a very limited number of poorly-soluble drug models (i.e. itraconazole and cefuroxime). Herein we aimed to re-examine the solubility enhancement and physical stability of amorphous nanoparticles relative to that of the micro ASD using a different poorly-soluble drug model, i.e. ciprofloxacin (CIP). Two types of amorphous CIP nanoparticles, i.e. CIP nanorod prepared by pH-shift precipitation and CIP nanoplex prepared by drug-polyelectrolyte complexation, were compared with CIP micro ASD prepared by spray drying with hydroxypropylmethylcellulose (HPMC). The results showed that (1) the solubility enhancement of amorphous drug nanoparticles was not necessarily superior to that of the micro ASD, particularly in their dry-powder form, and (2) the amorphization strategy of drug nanoparticles significantly influenced their solubility enhancement and physical stability. In short, the solubility enhancement was in the order of CIP micro ASD>CIP nanorod>CIP nanoplex, whereas the amorphous state stability during storage was in the order of CIP nanoplex>CIP micro ASD>CIP nanorod. A trade-off thus existed between the solubility enhancement and physical stability of amorphous CIP particles. The present work concluded that the superior solubility enhancement of amorphous drug nanoparticles was not drug independent.
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•CIP nanoplex and CIP liposome were equally effective in overcoming mucus barrier.•CIP nanoplex and CIP liposome exhibited fast and sustained dissolution respectively.•Both nanoplex ...and liposome had equally effective antipseudomonal activity.•CIP liposome had lower payload after lyophilization leading to large dosage.•CIP nanoplex exhibited far superior aerosolization efficiency and cytotoxicity.
Inhaled antibiotic nanoparticles have emerged as an effective strategy to control infection in bronchiectasis lung owed to their mucus-penetrating ability. Using ciprofloxacin (CIP) as the model antibiotic, we evaluated dry powder inhaler (DPI) formulations of two classes of antibiotic nanoparticles (i.e. liposome and nanoplex) in their (1) physical characteristics (i.e. size, zeta potential, CIP payload, preparation efficiency), (2) dissolution in artificial sputum medium, (3) ex vivo mucus permeability, (4) antimicrobial activity against Pseudomonas aeruginosa in mucus, (5) cytotoxicity towards human lung epithelium cells, and (6) in vitro aerosolization efficiency. The results showed that the CIP nanoplex exhibited fast dissolution with CIP supersaturation generation, in contrast to the slower release of the liposome (80 versus 30% dissolution after 1 h). Both nanoparticles readily overcame the mucus barrier attributed to their nanosize and mucus-inert surface (50% permeation after 1 h), leading to their similarly high antipseudomonal activity. The CIP liposome, however, possessed much lower CIP payload than the nanoplex (84% versus 3.5%), resulting in high lipid contents in its DPI formulation that led to higher cytotoxicity and lower aerosolization efficiency. The CIP nanoplex thus represented a superior formulation owed to its simpler preparation, higher CIP payload hence lower dosage, better aerosolization, and lower cytotoxicity.
An amorphous curcumin (CUR) and bovine serum albumin (BSA) nanoparticle complex (nanoplex) was previously developed as a promising anticancer nanotherapy. The CUR-BSA nanoplex had been characterized ...in its aqueous suspension form. The present work developed a dry-powder form of the CUR-BSA nanoplex by lyophilization using sucrose as a cryoprotectant. The cryoprotective activity of sucrose was examined at sucrose mass fractions of 33.33, 50.00, and 66.66% by evaluating the lyophilized nanoplex’s (1) aqueous reconstitution and (2) CUR dissolution and kinetic solubility. The physicochemical stabilizing effects of sucrose upon the nanoplex’s 30-day exposures to 40 °C and 75% relative humidity were examined from (i) aqueous reconstitution, (ii) CUR dissolution, (iii) CUR and BSA payloads, (iv) amorphous form stability, and (v) BSA’s structural integrity. The good cryoprotective activity of sucrose was evidenced by the preserved BSA’s integrity and good aqueous reconstitution, resulting in a fast CUR dissolution rate and a high kinetic solubility (≈5–9× thermodynamic solubility), similar to the nanoplex suspension. While the aqueous reconstitution, CUR dissolution, and amorphous form were minimally affected by the elevated heat and humidity exposures, the treated nanoplex exhibited a lower BSA payload (≈7–26% loss) and increased protein aggregation postexposure. The adverse effects on the BSA payload and aggregation were minimized at higher sucrose mass fractions.
Pharmaceutical tablet productions by direct compaction (DC) are more environmentally sustainable than wet granulation (WG) owed to DC’s lower energy consumption. For drug particles with poor ...flowability, however, the environmental benefits of DC become questionable because DC of such drugs requires either pre-compaction treatment, increased excipients’ proportion in the tablets, or using excipients with unfavorable sustainability profiles. Using ibuprofen (IBU) as the model drug with poor flowability, we performed cradle-to-gate life cycle assessment (LCA) using ReCiPe 2016 method to characterize the environmental impacts of DC and WG tablet productions. Material and energy flow data from laboratory-scale (1 and 2.2 kg IBU) and simulated pilot-scale (25 kg IBU) productions were utilized in the LCA. Despite the increased proportion of excipients with less-than-ideal sustainability profile in DC tablets, the environmental impacts of DC tablet production remained smaller than WG tablet production across different production scales, as the impacts were governed by process-level energy consumption. The impacts of DC and WG tablet productions, nevertheless, became closer in magnitude with increasing production scale attributed to superior improvements in the energy requirement and yield of WG tablets. Thus, the environmental beneftis of DC tablets over WG tablets was diminished for drugs with poor flowability.
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•Environmental impact of tablet production is centered on human/ecosystem toxicity.•Environmental impact of tablet production is ruled by process-level energy usage.•DC tablet has less environmental impact than WG tablet for poorly flowable drugs.•Environmental impacts of DC and WG tablets become more comparable at larger scales.
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•CAP submicroplex is easily prepared by ambient mixing of CAP and CHI solutions.•Structural integrity of CAP submicroplex is governed by concentration, pH, RCHI/CAP.•CAP submicroplex ...is efficiently prepared at ≈85% CAP usage rate with ≈75% payload.•Partially amorphous CAP submicroplex produces prolonged high apparent solubility.•CAP submicroplex has similar antimicrobial activity as the native CAP.
Clinical application of capsaicin – a major component of chili peppers known for its numerous therapeutic activities – faces the hurdle of poor oral bioavailability due to its low aqueous solubility. While capsaicin nanocapsules have been extensively investigated as a bioavailability enhancement strategy, their low payload limits their effectiveness. Herein we developed a new bioavailability enhancement strategy of capsaicin in the form of high-payload submicron capsaicin-chitosan colloidal particle complex (or submicroplex in short) prepared by electrostatically driven self-assembly complexation between capsaicin and chitosan. The effects of preparation conditions (i.e. capsaicin concentration, chitosan/capsaicin ratio, and pH) on the (a) structural integrity of the capsaicin submicroplex upon centrifugation and freeze drying, (b) physical characteristics (i.e. size, zeta potential, payload, colloidal stability), and (c) preparation efficiency were investigated, from which the optimal preparation conditions were determined. The optimal formulation exhibited (1) high payload (≈75%), (2) high colloidal stability, and (3) good solubility enhancement capability attributed to its partially amorphous form, resulting in high apparent solubility that was maintained for 6h at 5×of the thermodynamic solubility. Lastly, the complexation with chitosan did not have any adverse effect on the antimicrobial activity of capsaicin, hence signifying the preservation of capsaicin’s bioactivities in the submicroplex.
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•Spray freeze drying produced highly aerosolizable curcumin nanoplex aerosols.•Aerosol transformation diminished supersaturation generation of curcumin nanoplex.•Curcumin was released ...more slowly from aerosols than from aqueous suspension.•Curcumin nanoplex aerosols maintained activity against respiratory pathogens.•Curcumin nanoplex aerosols exhibited minimal cytotoxicity towards lung cells.
While the therapeutic benefits of curcumin delivery to the lung to treat various pulmonary disorders have been established, development of inhaled curcumin formulation that can address its inherently low aqueous solubility remains lacking. Although curcumin nanocapsules prepared by conventional encapsulation methods can improve the dissolution rate, their intricate preparation makes them less attractive for widespread implementation. Recently, our group developed a new class of curcumin nanoparticles in the form of curcumin-chitosan nanoparticle complex (or curcumin nanoplex in short) by a simple, cost-effective, and highly efficient method based on self-assembly drug-polysaccharide complexation. Owing to its nanosize and amorphous state, the curcumin nanoplex possessed high supersaturation generation capability upon dissolution that in turn produced high apparent solubility of curcumin.
In the present work, we developed dry powder aerosol formulation of the curcumin nanoplex by spray freeze drying (SFD) using l-leucine and d-mannitol as adjuvants. The curcumin nanoplex aerosols were found to exhibit excellent aerosolization efficiency attributed to their large and low-density morphology, and the presence of l-leucine – a well-established aerosol dispersion enhancer – in their matrix. The aerosols, however, exhibited weaker supersaturation generation capability compared to the aqueous nanoplex suspension due to their slower dissolution rates caused by irreversible aggregations of the nanoplex during SFD. Nevertheless, the curcumin nanoplex aerosols still produced apparent solubility that was approximately 50% higher than the native curcumin’s solubility, thus signifying their dissolution enhancement capability. Despite their slower dissolution rate, the curcumin nanoplex aerosols maintained the same antimicrobial activity as the nanoplex suspension against four clinically-derived respiratory bacterial pathogens (i.e. Pseudomonas aeruginosa, Burkholderia cepacia, Klebsiella pneumoniae, and Stenotrophomonas maltophilia). Lastly, the aerosols exhibited minimal cytotoxicity towards the lung epithelium cells just like the native curcumin.
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