A novel film spray containing curcumin inhibits SARS-CoV-2 and influenza virus infection and enhances mucosal immunity.

BACKGROUND: Infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and influenza virus is still a major worldwide health concern. Plants are a good source of bioactive compounds to be used as preventive measures for both inhibiting the virus binding and enhancing mucosal innate immunity. Curcumin has been shown to possess antiviral activity and modulate innate immunity. Therefore, the purpose of this study was to develop an oro-nasal film spray containing curcumin and determine its antiviral activity against SARS-CoV-2 and influenza virus infection, as well as its effects on mucosal innate immunity and inflammatory cytokines in vitro. METHODS: The antiviral activity of the film spray against SARS-CoV-2, influenza A/H1N1, A/H3N2, and influenza B was assessed in vitro by plaque reduction assay. Cytotoxicity of the film spray to oral keratinocytes and nasal epithelial cells was assessed by MTT assay, and cytotoxicity to Vero and MDCK cells was assessed by an MTS-based cytotoxicity assay. Oral and nasal innate immune markers in response to the film spray were determined by ELISA and by a commercial Milliplex Map Kit, respectively. RESULTS: Our data show that the film spray containing curcumin can inhibit both SARS-CoV-2 and influenza virus infections while maintaining cell viability. Results obtained among 4 viruses revealed that curcumin film spray demonstrated the highest inhibitory activity against SARS-CoV-2 with the lowest EC50 of 3.15 µg/ml and the highest SI value of 4.62, followed by influenza B (EC50 = 6.32 µg/ml, SI = 2.04), influenza A/H1N1 (EC50 = 7.24 µg/ml, SI = 1.78), and influenza A/H3N2 (EC50 > 12.5 µg/ml, SI < 1.03), respectively. Antimicrobial peptides LL-37 and HD-5, IL-6 and TNF-α produced by oral keratinocytes were significantly induced by the film spray, while hBD2 was significantly reduced. CONCLUSION: Film spray containing curcumin possesses multiple actions against SARS-CoV-2 infection by inhibiting ACE-2 binding in target cells and enhancing mucosal innate immunity. The film spray can also inhibit influenza virus infection. Therefore, the curcumin film spray may be effective in preventing the viral infection of both SARS-CoV-2 and influenza.

The potential of turmeric extract-loaded chitosan microparticles for the treatment of gastrointestinal disorders.

AIM: To develop turmeric extract-loaded chitosan microparticles for treating gastrointestinal disorders. METHODS: The microparticles were prepared using a spray-drying process, optimised the characteristics by biomarker loading, and encapsulation efficiency, and assessed for bioactivities related to gastrointestinal diseases. RESULTS: The optimised microparticles were spherical, with a mean diameter of 2.11 ± 0.34 µm, a SPAN of 4.46 ± 0.68, a zeta potential of +37.6 ± 0.2 mV, loading of 15.7% w/w curcuminoids, 5.4% w/w ar-turmerone, and encapsulation efficiency of 63.26 ± 1.62% w/w curcuminoids and 43.75 ± 1.33% w/w ar-turmerone. Encapsulation of turmeric extract improved release at 6 h by 20 times and mucoadhesion by 3.6 times. The microparticles exhibited high acid-neutralising capacity (1.64 ± 0.34 mEq/g) and inhibited nitric oxide production about twice as effectively as the turmeric extract, while maintaining antioxidant and antibacterial activities. CONCLUSION: Encapsulation of turmeric extract in chitosan microparticles effectively enhanced therapeutic potential for gastrointestinal disorders.

Formulation and Antimycotic Evaluation of Colloidal Itraconazole-Loaded Metered Dose Sprays for Treating Superficial Mycoses.

Commercial topical formulations containing itraconazole (poorly water soluble), for mycotic infections, have poor penetration to infection sites beneath the nails and skin thereby necessitating oral administration. To improve penetration, colloidal solutions of itraconazole (G1-G4) containing Poloxamer 188, tween 80, ethanol, and propylene glycol were prepared and incorporated into HFA-134-containing sprays. Formulations were characterized using particle size, drug content, and Fourier-transform infrared spectroscopy (FTIR). In vitro permeation studies were performed using Franz diffusion cells for 8 h. Antimycotic activity on Candida albicans and Trichophyton rubrum was performed using broth micro-dilution and flow cytometry, while cytotoxicity was tested on HaCaT cell lines. Particle size ranged from 39.35-116.80 nm. FTIR and drug content revealed that G1 was the most stable formulation (optimized formulation). In vitro release over 2 h was 45% for G1 and 34% for the cream. There was a twofold increase in skin permeation, fivefold intradermal retention, and a sevenfold increase in nail penetration of G1 over the cream. Minimum fungicidal concentrations (MFC) against C. albicans were 0.156 and 0.313 µg/mL for G1 and cream, respectively. The formulations showed optimum killing kinetics after 48 h. MFC values against T. rubrum were 0.312 and 0.625 µg/mL for the G1 and cream, respectively. Transmission electron microscopy revealed organelle destruction and cell leakage for G1 in both organisms and penetration of keratin layers to destroy T. rubrum. Cytotoxicity evaluation of G1 showed relative safety for skin cells. The G1 formulation showed superior skin permeation, nail penetration, and fungicidal activity compared with the cream formulation.

Wound healing efficacy of a polymeric spray film solution containing Centella asiatica leaf extract on acute wounds.

OBJECTIVE: To study the clinical efficacy of a polymeric spray film containing Centella asiatica extract to heal acute wounds. METHOD: A polymeric spray film solution for wound healing was formulated using Centella asiatica extract, which contained triterpenes, including asiatic acid, madecassic acid, asiaticoside and madecassoside. The stability and physicochemical properties of the formulation were evaluated, and a multicentre, randomised, controlled trial was conducted to assess its clinical wound-healing efficacy. The Pressure Ulcer Scale for Healing (PUSH Tool) score was used to evaluate wound healing on days 0, 3, 5 and 7. RESULTS: The cohort consisted of 60 volunteers with clean-contaminated wounds (class 1), randomly assigned to the Control (n=30) and Testing (n=30) groups. The spray product contained asiatic acid, madecassic acid, asiaticoside and madecassoside at 0.20±0.02mg/ml, 0.16±0.01mg/ml, 0.32±0.03mg/ml and 0.10±0.00mg/ml, respectively. The pH value was 5.5±0.01, and the viscosity was 33±4cP. The product was stable for six months when stored at 30±2°C and at 40±2°C, in 75±5% relative humidity. The tested product significantly reduced the total PUSH and exudate scores, indicating that the polymeric spray film solution containing Centella asiatica improved wound healing. The average healing recovery times for the Testing and Control groups were 4.6±1.1 days and 4.87±1.0 days, respectively. CONCLUSION: In this study, Centella asiatica extract-containing polymeric spray film solution was beneficial as an acute wound medication, which could shorten healing time with no adverse effects.

Assessing the Anti-Aging and Wound Healing Capabilities of Etlingera elatior Inflorescence Extract: A Comparison of Three Inflorescence Color Varieties.

Torch ginger, Etlingera elatior, is a Zingiberaceae plant with various red, pink, and white inflorescence. The wound healing potential and anti-aging effects of freeze-dried torch ginger inflorescence extracts (FTIEs) from three varieties were compared. The red FTIE had the highest content of phenolic, flavonoid, caffeoylquinic acid, and chlorogenic acid, followed by the white and pink FTIE. Consistent with the chemical constituents, the red FTIE demonstrated the greatest capacities for free radical scavenging, anti-tyrosinase, and anti-collagenase activity, followed by the white and pink FTIE. In cell-based studies, FTIEs displayed cytotoxicity to B16F10 melanoma cells, with the red FTIE showing the greatest activity (LC50 of 115.5 µg/mL). In contrast, the pink and the white FTIEs had less cytotoxicity impact. Nonetheless, at 1000 µg/mL, all three FTIE variants were safe on L929 fibroblasts or RAW 264.7 monocyte cells. White FTIE (500 µg/mL) exhibited the highest activity in stimulating collagen production and the greatest impact on cell migration, whereas the pink and red FTIE had a lesser effect. All FTIEs slightly suppressed the pro-inflammatory cytokines produced by lipopolysaccharide-stimulated monocytes, with no significant variation between FTIE variants. In conclusion, all FTIEs revealed promising potential for anti-aging cosmeceuticals and wound care products at specific concentrations.

α-Mangostin and lawsone methyl ether in tooth gel synergistically increase its antimicrobial and antibiofilm formation effects in vitro.

OBJECTIVES: α-Mangostin (α-MG) and lawsone methyl ether (LME) show antimicrobial and anti-biofilm activities. The objectives of this study were to develop a herbal tooth gel containing α-MG and LME plus fluoride and determine its antimicrobial, anti-biofilm formation, anti-cancer, anti-inflammatory, wound healing, and enamel microhardness effects. METHODS: Antimicrobial assays against Streptococcus mutans, Porphyromonas gingivalis, and Candida albicans were performed. The microbes' ultrastructural morphology was assessed using Transmission Electron Microscopy. The effect on microbial biofilm formation was tested by a broth microdilution. Cell viability was assessed with MTT assay. The anti-inflammatory effect was investigated by measuring inhibition of nitric oxide production. Enamel microhardness was measured via Vickers microhardness testing. The enamel chemical composition was investigated with Fourier Transform Spectrometer. The enamel surface morphology and fluoride content were examined by Scanning Electron Microscopy and Energy Dispersive X-ray Spectroscopy. RESULTS: The results show synergistic effects of α-MG and LME on antimicrobial activity and antibiofilm formation without cytotoxicity at a therapeutic dose. At a higher dose, the tooth gel inhibited proliferation of cancer cell line. Enamel microhardness was increased after brushing with the tooth gel plus fluoride. A large amount of fluoride was detected on the enamel surface. CONCLUSION: The tooth gel containing α-MG and LME synergized its antimicrobial activity and antibiofilm formation and inhibited oral cancer cell proliferation. Incorporating fluoride into the tooth gel increased enamel microhardness. Thus, the herbal tooth gel containing α-MG and LME plus fluoride may be useful for preventing dental caries and promoting oral health.

Using polyvinyl alcohol-ionic hydrogels containing a wound healing agent to manage wounds in different environments.

OBJECTIVE: To explore the effects of pH on properties of polyvinyl alcohol (PVA)-ionic hydrogels containing wound healing promoters. METHOD: PVA was combined with a natural wound healing promoter (silk sericin (SS)), and an anionic agent (eosin (ES)) or cationic agent (methylene blue (MB)), and made into hydrogels. Properties of the hydrogels and behaviour at different pHs were investigated. RESULTS: The density and gel fraction of PVA/SS-ES hydrogel and PVA/SS-MB hydrogel were considerably lower compared with hydrogel without SS. The swelling ratio and degradation of the hydrogels increased with increasing SS concentration in all pH solutions. The influence of SS in interrupting long-chain PVA molecules was confirmed based on changes in Fourier-transform infrared spectroscopy (FTIR). The SS released from the gels was found to interact with the ionic agent and influenced the release profile of the ionic agent. Surprisingly, the anionic agent in PVA/SS-ES hydrogel showed 70% release in high pH solution whereas the cationic agent in PVA/SS-MB hydrogel showed 86% release in low pH solution. Moreover, the active agent could accumulate on the skin layer and had a positive effect on a specific wound area. CONCLUSION: Based on the results obtained in this study, it is suggested to use anionic hydrogels containing wound healing promoter for wounds at high pH and cationic hydrogels containing wound healing promoter for wounds with low pH. Ability to improve wound healing using a natural healing agent combined with ionic agents and controlling the pH of hydrogels will help in developing quick and low-cost treatment for wounds.

A facile one-step jet-milling approach for the preparation of proliposomal dry powder for inhalation as effective delivery system for anti-TB therapeutics.

OBJECTIVE: Physicochemical characterization and assessment of aerosol dispersion performance of anti-TB proliposome dry powders for inhalation (DPIs) prepared using a single-step jet-milling (JM) approach. SIGNIFICANCE: Conventional tuberculosis (TB) treatment involves isoniazid and rifampicin as first-line agents in extended oral multi-drug regimes. Liposomal DPIs are emerging as promising alternatives for targeted delivery of anti-TB agents to alveolar macrophages harboring Mycobacterium tuberculosis. However, traditional approaches for liposomal DPI preparation are tedious, time consuming and require sophisticated/expensive equipment. The proposed JM technique for preparation of proliposome DPIs could obviate these limitations and facilitate use of these drugs for more effective and safer treatment. METHODS: Proliposome DPIs containing isoniazid and/or rifampicin, cholesterol and cholesterol sulfate were successfully prepared via JM (injection pressure, 7.4 bar; milling pressure, 3.68 bar). Their physicochemical, content uniformity, and in vitro aerosol dispersion performance were assessed using scanning electron microscopy/energy-dispersive X-ray spectroscopy, transmission electron microscopy, dynamic light scattering/Zeta potential, X-ray diffraction spectroscopy, thermogravimetric analysis, high-performance liquid chromatography, and the Next-Generation Impactor. RESULTS: The DPIs exhibited consistent, spherically shaped, smooth particles. Drug particles were evenly distributed with acceptable content uniformity. Drug crystallinity was not significantly affected by milling and the formulations had minimal (<2.0%) water content. After reconstitution of the DPIs, the hydrodynamic size was about 370.9-556.2 nm and charge was -12.3 to -47.3 mV. Furthermore, the proliposome DPIs presented emitted dose (69.04-89.03%), fine particle fraction, <4.4 µm (13.7 - 57.8%), and mass median aerodynamic diameter (<3.0 µm), which satisfied the requirements for deep lung delivery. CONCLUSION: The proposed approach was suitable for preparation of proliposome DPIs that could be deployed for local targeting of the lower respiratory tract for the treatment of TB.

Silver Nanoparticles Conjugated with Colistin Enhanced the Antimicrobial Activity against Gram-Negative Bacteria.

Colistin is a potent peptide antibiotic that is effective against Gram-negative bacteria. However, nephrotoxicity limited its clinical use. Silver nanoparticles (AgNPs) have gained attention as a potential antimicrobial agent and nanodrug carrier. The conjugation of antibiotics and AgNPs has been found to increase the activity and decrease drug toxicity. In this study, colistin was conjugated with AgNPs (Col-AgNPs), which was confirmed by Fourier-transform infrared (FT-IR) and energy-dispersive X-ray (EDX) spectra. The optimized Col-AgNPs had the proper characteristics, including spherical shape, monodispersity, nanosized particle, high surface charge, and good stability. The powder X-ray diffraction (PXRD) pattern supported the crystallinity of Col-AgNPs and AgNPs. The drug loading of Col-AgNPs was 11.55 ± 0.93%. Col-AgNPs had higher activity against Gram-negative bacteria (Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa) than AgNPs and colistin. The mechanism of actions of Col-AgNPs involved membrane disruption and genomic DNA damage. The Col-AgNPs and AgNPs were biocompatible with human red blood cells and renal cells at concentrations up to 16 µg/mL. Interestingly, Col-AgNPs exhibited higher cell survival than AgNPs and colistin at 32 µg/mL. Our results revealed that the Col-AgNPs could enhance the antimicrobial activity and cell biocompatibility more than colistin and AgNPs.

Oral inhalation of cannabidiol delivered from a metered dose inhaler to alleviate cytokine production induced by SARS-CoV-2 and pollutants.

Cannabidiol (CBD) was formulated as a metered dose inhaler (CBD-MDI) and evaluated in vitro for its efficacy as an inhaled dosage form against inflammation caused by the SARS-CoV-2 virus, lipopolysaccharide (LPS) from Escherichia coli, silica particles, nicotine, and coal tar. A CBD-MDI formulation was prepared with 50 mg of CBD in 10 mL for a CBD dose of 250 µg/puff. The formulation ingredients included CBD, absolute ethanol as a cosolvent, and HFA-134a as the propellant. High aerosol performance of CBD-MDI was obtained with mass median aerodynamic diameter of 1.25 ± 0.01 µm, geometric standard deviation of 1.75 ± 0.00, emitted dose of 244.7 ± 2.1 µg, and fine particle dose of 122.0 ± 1.6 µg. The cytotoxicity and anti-inflammatory effectiveness of CBD-MDI were performed in alveolar macrophage (NR8383) and co-culture of alveolar macrophage (NR8383) and human lung adenocarcinoma (A549) cell line. CBD delivered from an MDI was safe on respiratory cells and did not trigger an immune response in alveolar macrophages. CBD-MDI effectively reduced the generation of cytokines in immune cells treated with viral antigen S-RBD, bacterial antigen LPS, silica particles, and coal tar. The efficacy of CBD-MDI was comparable to budesonide. Furthermore, the findings demonstrated that the use of CBD-MDI was more effective in treatment rather than prevention when inflammation was induced by either a viral or bacterial stimulant.

Efficacy and safety of combined isoniazid-rifampicin-pyrazinamide-levofloxacin dry powder inhaler in treatment of pulmonary tuberculosis: A randomized controlled trial.

OBJECTIVE: To determine the efficacy and safety of add-on dry powder for inhalation (DPI) of combined anti-TB agents prepared as a particulate system (study group) compared with placebo DPI (control group) in patients diagnosed with pulmonary TB. METHODS: This study was a randomized, placebo-controlled, double-blinded parallel design. Subjects were pulmonary TB patients, new or re-treatment, aged 18 years or older. The eligible patients were randomly allocated (1:1) to either the study group or the control group using stratified blocked randomization. The add-on DPI of combined anti-TB therapy (each capsule contained isoniazid 5 mg, rifampicin 2 mg, pyrazinamide 16 mg, and levofloxacin 2 mg) was used throughout the course of the standard oral anti-TB treatment. The primary outcome was Mycobacterium tuberculosis (MTB) sputum culture conversion measured after receiving treatment for eight weeks. Secondary outcomes were clinical signs and symptoms of pulmonary TB and adverse drug reactions (ADRs) related to anti-TB agents. The percentages of patients who achieved the primary outcome were compared (95% confidence interval). All analyses were performed using the modified intention-to-treat principle. RESULTS: 91 patients were randomly allocated: 44 to the study group and 47 to the control group. Important baseline data (%peak expiratory flow rate, chest X-ray findings, resistance to anti-TB agents, renal and liver function tests) were similar between the two groups. Although the percentages of patients who achieved the primary outcome were similar in both groups (34/44 [77.3%] in the study group and (34/47 [72.3%] in the control group; relative risk [RR] 1.07, 95% CI 0.84-1.36; p = 0.589), the study group patients seemed to achieve the primary outcome earlier than the control group (22/44 [50.0%] vs 15/47 [31.9%]; RR 1.57, 95% CI 0.94-2.61; p = 0.079) at the end of week 4. Cough was significantly lower in the study group than in the control group (23/44 [52.3%] vs 43/47 [91.5%]; RR 0.57, 95% CI 0.43-0.77; p < 0.001) at week 4 of treatment. Hemoptysis was found in approximately half of each group at baseline. The percentage of patients having hemoptysis was substantially reduced at week 2 of treatment (5 [11.4%] in the study group and 11 [23.0%] in the control group, p = 0.132). Regarding safety outcomes, no dyspnea or severe ADRs were reported. Adverse events (AEs) related to oral anti-TB agents, (e.g. liver function tests) were in normal ranges in most patients in both groups during the treatment. The incidences of common AEs reported (e.g. anorexia, dizziness, numbness, arthralgia, rash, and itching) were similar between the two groups, while the incidences of nausea and vomiting were significantly lower in the study group than the control group (38.6% vs 74.5%, p = 0.001, and 43.2% vs 66.0%, p = 0.029, respectively). CONCLUSIONS: Add-on combined anti-TB DPI therapy to the standard oral anti-TB treatment did not increase MTB sputum culture conversion at two months of treatment. However, the percentage of patients having cough in the study group was significantly lower than in the control group at two months after treatment. A reduction in cough might represent adequate response to treatment, and result in a decreased risk of spread of infection. Combined anti-TB DPI therapy was safe. Further study investigated in a larger sample using higher strengths of DPI therapy is required.

Safety and Biocompatibility of Mupirocin Nanoparticle-Loaded Hydrogel on Burn Wound in Rat Model.

Mupirocin nanoparticle-loaded hydrogel (MLH) was successfully developed. This study focused on the safety of cell lines and the biocompatibility of MLH for wound healing in rat models. MLH was assessed by an analysis of cytotoxicity and the secretion of inflammatory cytokines in cell lines. The cytocompatibility of MLH was compared with mupirocin ointment on full-thickness burn wounds in rats. The results indicated that MLH and blank hydrogel had no toxicity to human epidermal keratinocytes and human fibroblast cells. MLH inhibited lipopolysaccharide (LPS) activity in macrophage-like cells resulting in low nitric oxide production and reduced inflammatory cytokine production (interleukin (IL)-1ß) compared with a positive control (LPS only). In burn wounds, MLH and hydrogel healed the wound better than the other groups determined by wound contraction, reduced secretion, and the generation of new blood vessels, as well as promotion of hair follicle cells. Better granulation tissue proliferation, less necrosis, and a lower degree of inflammation were found in the MLH and blank hydrogel than in the mupirocin ointment. The hydrogel group reduced the macrophages (CD68) on day 14 at the edge of the wound. On day 28, T cells (CD3), B cells (CD20), and CD68+ cells were concentrated in the deeper subcutaneous tissue. Additionally, the transforming growth factor ß1 (TGF-ß1) concentration and matrix prometalloproteinase-2/tissue inhibitor of metalloproteinases-2 ratio in the MLH and hydrogel groups were less than those in the other groups. The MLH formulation was safe and effective in burn wound healing. Therefore, MLH formulations are promising candidates for further evaluation in clinical trials.

Mucoadhesive film containing α-mangostin shows potential role in oral cancer treatment.

BACKGROUND: Oral cancer is often preceded by a mucosal lesion called an oral potentially malignant disorder (OPMD). Many plant-derived compounds are of value in medicine. The objectives of this study were to develop a soluble mucoadhesive film containing α-mangostin (α-MG), a compound extracted from the peel of mangosteen fruit, and determine its activities against oral cancer cells, against human papillomavirus type 16 (HPV-16) pseudovirus, and its anti-inflammatory properties. METHODS: A soluble mucoadhesive film containing α-MG was prepared. Oral squamous carcinoma cell line (SCC25), murine macrophage cells (RAW264.7), and human gingival fibroblast cell line were cultured. Anticancer activity and viability of SCC25 cells in response to α-MG film solution were determined by MTT assay. HPV-16 pseudovirus was constructed and effects of the film solution on attachment and post-attachment steps of the infection were investigated. Anti-inflammatory activity was assessed by nitric oxide (NO) inhibition. Fibroblast cell migration was determined by in vitro scratch assay. RESULTS: The soluble α-MG film showed cytotoxic effects on SCC25 cells in concentration > 125 µg/ml with IC50 of 152.5 µg/ml. Antiviral activity against HPV-16 pseudovirus was observed at attachment step, but not at post-attachment step. The film also possessed a strong anti-inflammatory effect and promoted wound healing without cytotoxicity. CONCLUSIONS: Mucoadhesive film containing α-MG has a cytotoxic effect on oral squamous carcinoma cell line and an inhibitory effect on HPV-16 pseudovirus at attachment step. The α-MG film also shows a potent anti-inflammatory activity and enhances wound healing. Thus, the soluble α-MG film may have a potential role in treating oral cancer.

Montelukast nasal spray: formulation development and in vitro evaluation.

OBJECTIVES: The aim of this study was to evaluate potential development of montelukast sodium (MTS) as a nasal spray. MATERIALS AND METHODS: The formulations were prepared using hydroxypropyl cellulose (HPC) and carbomer 940 (C940). The prepared formulations were evaluated for clarity, pH, hydrodynamic size, zeta potential, viscosity, contact angle, surface tension, droplet size distribution, muco-adhesiveness, drug release, and stability. The suitable formulations were also assessed for their effects on nasal epithelial cells. RESULTS AND DISCUSSION: At room temperature (25 °C), the formulation containing 0.01% w/v C940 exhibited suitable viscosity and rheological properties. Spray droplets were in ranges of 10-40 µm, which are suitable for nasal administration. The works of adhesion of the formulations containing HPC or C940 were in the range of 0.8-4.0 and 0.2-27 µJ, respectively. In addition, the formulation containing 0.01% w/v C940 and the 0.5-15 µg/50 µL concentrations of MTS showed no signs of cytotoxicity and did not open the tight junction of nasal epithelial cells. CONCLUSION: The formulated MTS nasal spray is ideal for nasal administration for the treatment of allergic rhinitis. The formulation containing 0.01% w/v C940 had no toxicity nor alteration on the tight junction of nasal epithelial cells.

Enhanced dissolution of sildenafil citrate as dry foam tablets.

Dry foam formulation technology is alternative approach to enhance dissolution of the drug. Sildenafil citrate was suspended in sodium dodecyl sulfate solution and adding a mixture of maltodextrin and mannitol as diluent to form a paste. Sildenafil citrate paste was passed through a nozzle spray bottle to obtain smooth foam. The homogeneous foam was dried in a vacuum oven and sieved to obtain dry foam granules. The granules were mixed with croscarmellose sodium, magnesium stearate and compressed into tablet. All formulations were evaluated for their physicochemical properties and dissolution profiles. All the tested excipients were compatible with sildenafil citrate by both differential scanning calorimetry (DSC) and infrared (IR) analysis. There are no X-ray diffraction (XRD) peaks representing crystals of sildenafil citrate observed form dry foam formulations. The hardness of tablets was about 5 kg, friability test <1% with a disintegration time <5 min. The sildenafil citrate dry foam tablet had higher dissolution rate in 0.1 N HCl in comparison with commercial sildenafil citrate tablet, sildenafil citrate prepared by direct compression and wet granulation method. Sildenafil citrate dry foam tablet with the high-level composition of surfactant, water and diluent showed enhanced dissolution rate than that of the lower-level composition of these excipients. This formulation was stable under accelerated conditions for at least 6 months.

Development of nanodispersion-based sildenafil metered-dose inhalers stabilized by poloxamer 188: a potential candidate for the treatment of pulmonary arterial hypertension.

Objectives: This study aims to formulate nanodispersion-based sildenafil metered-dose inhalers (MDIs) by using poloxamer 188 (P188) as a stabilizer; to evaluate their stability, aerosol characteristics, cytotoxicity, and inflammatory effects; and to investigate the effects of P188 on stability and aerosol characteristics of the MDIs. Methods: The stability and uniformity of the formulations were evaluated by high-performance liquid chromatography method. The aerosol characteristics were evaluated by the Next Generation Impactor. The cytotoxicity and inflammatory effects on respiratory epithelial cells and alveolar macrophages were evaluated by MTT assay and TNF-α, IL-1ß, and NO assay, respectively. Results: The optimal formulation was stable and well-uniform after 6 months. The fine particle fraction and mass median aerodynamic diameter (MMAD) of the formulation were 61.9% ± 2.5% and 1.69 ± 0.06 µm, respectively. The formulation was found to be nontoxic to respiratory epithelial cells and did not induce the inflammatory responses of alveolar macrophages. A positive correlation between P188 concentration and MMAD of the MDIs was observed. P188 possesses an ability to prevent the growth of sildenafil citrate monohydrate crystals in the formulations. Conclusions: The findings provided a basis for the development of sildenafil MDI as a potential candidate for the treatment of pulmonary arterial hypertension.

Bioactivity, Safety, and Efficacy of Amphotericin B Nanomicellar Aerosols Using Sodium Deoxycholate Sulfate as the Lipid Carrier.

We report nanomicelles of amphotericin B (AmB) using various molar ratios of AmB and sodium deoxycholate sulfate (SDCS) for inhalation with improved stability, solubility, bioactivity, and safety. The particle sizes of all aerosolized formulations are expressed as mass median aerodynamic diameter (0.9-1.6 µm), fine particle fraction (70.3-86.5%), and geometric standard deviation (1.4-2.1) which indicated their sizes are appropriate for use as an inhaler. In vitro cytotoxicity studies conducted using respiratory and kidney cell lines demonstrated that the marketed Fungizone® was toxic to macrophage and embryonic kidney cells and cell viability decreased from 96 to 48% and from 97 to 67%, respectively when the AmB equivalent concentration was increased from 1 to 16 µg/mL. However, AmB-SDCS formulations showed no evidence of toxicity even up to 8 µg/mL compared to Fungizone®. Minimum inhibitory and fungicidal concentrations were significantly reduced against Cryptococcus neoformans, and Candida albicans. Also, antileishmanial activity significantly improved for AmB-SDCS formulations. There was an evidence of phagocytosis of the AmB-SDCS formulation by alveolar macrophages NR 8383. Molecular modeling studies suggested the role of hydrogen bonding in stabilization of the AmB-SDCS complex. This study indicated that AmB-SDCS nanomicelles can be used to design a safe and cost-effective AmB for inhalation. Graphical abstract ᅟ.

Anti-biofilm properties of a mupirocin spray formulation against Escherichia coli wound infections.

Mupirocin ointment is a widely used topical drug for the treatment of bacterial skin infections. However, ointments have some limitations which motivated the development of a film forming spray of mupirocin. Mupirocin spray (2%) was formulated with Eudragit E100 as a film forming agent and tested for its antibacterial and anti-biofilm activities against Escherichia coli, a skin pathogen causing wound and surgical site infections. Treatment with mupirocin spray resulted in significant antibacterial and anti-biofilm activities (inhibition and disruption) with single spray and sub-actual dose concentrations at par with the commercial ointment concentration. The spray formulation was found to be non-toxic to fibroblast cells and greatly resisted removal from the site of application upon washing, in contrast to the ointment which was significantly removed after a single wash. This is the first study to develop and evaluate a spray formulation for mupirocin that forms a stable thin film for sustained release of the drug.

Development of a topical mupirocin spray for antibacterial and wound-healing applications.

OBJECTIVE: The aim of this study was to develop mupirocin topical spray using Eudragit E100 as a film-forming agent for the treatment of bacterial skin infections as well as to promote wound healing. MATERIALS AND METHODS: Twenty-seven of mupirocin formulations were formulated containing Eudragit E100 and other excipients. Mupirocin spray was prepared by aerosol crimping and filling machine using HFA-134a as a propellant. The formulations were evaluated for their stability and physicochemical properties. The factorial study was applied to evaluate the effects of glycerol and PEG400 on mupirocin-loaded Eudragit E100 films. The optimized formulation was assessed of drug release, antibacterial activities and in vitro cell line studies in comparison to the ointment formulation. RESULTS AND DISCUSSION: Mupirocin sprays were formulated and optimized to obtain the formulation with excellent physicochemical and mechanical properties of the dressing film. The formulation had an excellent stability up to a year with more than 80% of mupirocin content. Mupirocin was released from the film up to 90% within 2 h. The formulation had a potent antibacterial effect against S. aureus and S. epidermidis. The formulation was safe to use as a topical formulation that had no toxicity to keratinocytes, fibroblasts and monocytes. The formulation also had an antiendotoxin effect without stimulating the production of NO and inflammatory cytokines (IL-1ß and TNF-α). CONCLUSIONS: Mupirocin topical spray was successful developed as a topical formulation and can be used instead of the ointment formulation. Animal experiments are warranted to further emphasize the safe use in the human skin.