AAPS PharmSciTech最新文献

Efavirenz (EFZ), a BCS (Biopharmaceutical classification system) class-II/IV drug, suffers from low oral bioavailability (40–50%) and significant inter/intra-individual variability due to its low solubility and poor dissolution properties. The present investigation aimed to prepare a stable amorphous system of EFZ to improve its dissolution using the slurry method with various polymers and examine the nature of the interaction between them and its impact on the stability (recrystallization) of the formed systems and their in-vitro dissolution performance. Differential Scanning Calorimetry (DSC) and Powder X-ray Diffraction (PXRD) studies proved the formation of a complete amorphous system of EFZ with Eudragit® E100, HPMC E5, and HPMCAS-LF up to 50% drug loading. During 90 days accelerated stability studies, amorphous systems prepared using Eudragit® E100 remained stable at 50% drug loading however those prepared with HPMC E5, and HPMCAS-LF only remained stable at 25% drug loading. The ability of Eudragit® E100 based system to stabilize the drug at higher drug loading was attributed to the formation of stronger ionic interaction as revealed by the Fourier-transform infrared spectroscopy (FTIR) study. During in-vitro dissolution study, Eudragit® E100 based amorphous system generated and maintained significantly higher supersaturation compared to those prepared with HPMC E5, and HPMCAS-LF due to the formation of ionic interaction between EFZ and Eudragit® E100 as revealed by solution ¹H NMR study.

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Eberconazole nanostructured lipid carrier (EBR-NLC) 1% w/w optimization was done using the Quality by Design (QbD) approach, employing a 2³ Full Factorial Design (FFD) for experimental planning, followed by thorough physico-chemical, in-vitro, and ex-vivo evaluations. The 2³ FFD assessed the impact of total lipid amount, surfactant amount, and sonication time on critical quality attributes such as particle size and % entrapment efficiency. In-vitrorelease testing (IVRT) validation was performed using vertical diffusion cells. IVRT, a compendial technique by pharmacopoeias, was for performing semi-solid formulations analysis. The optimized EBR-NLC 1% w/w was characterized for assay, organic impurities, amplitude sweep, viscosity, IVRT, ex-vivo permeation testing, and skin retention. The validated IVRT technique was meeting the acceptance criteria of regulatory guidelines. The results showed that in-vitro release, ex-vivo permeation, and skin retention were significantly higher (P < 0.05) for the optimized EBR-NLC 1% w/w formulation compared to the innovator formulation (EBERNET^® Cream 1% w/w). Applying QbD principles systematically facilitated the successful development and optimization of an EBR-NLC 1% w/w. The optimized EBR-NLC 1% w/w formulation proved to be a viable alternative, showing stability for at least six months under conditions of 40°C/75% RH and 30°C/75% RH.

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We earlier reported comparable efficacy in bone parameters of sublingually administered salmon calcitonin hydroxyapatite nanoparticles (SCT-HAP-NPs) compared to the subcutaneous injection, in the ovariectomy rat model, despite a bioavailability of barely ~ 15%. We ascribed this intriguing finding to targeted bone delivery, facilitated by translocation of significant quantity of intact NP into systemic circulation. In the present study we track the translocation of FITC-SCT-HAP-NPs (~ 100 nm) across porcine sublingual mucosa using the Franz diffusion cell to validate our hypothesis. Confocal Laser Scanning microscopy (CLSM) established that SCT-HAP-NPs permeated into the deeper layers of sublingual porcine mucosal tissue. We confirmed the nanoparticles were present in the receptor medium of the Franz diffusion cell by DLS and TEM. We also demonstrate for the first time quantification of the NPs (%) translocated across the porcine mucosa, using the Amnis Image StreamX Mk II imaging flow cytometer. Computation revealed transport of ~ 60% of the FITC-SCT-HAP-NPs across mucosa in 2 h, substantiated that high NP concentrations could reach systemic circulation. Such high NP concentration in systemic circulation coupled with the small size (~ 100 nm) and the high bone affinity of HAP, validate our hypothesis of targeted bone delivery following sublingual administration. Furthermore, quantification of translocated NPs, which we demonstrate for the first time, would permit rational development of optimal targeted nanoparticulate carriers for delivery by noninvasive routes.

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Brazilian green propolis extract-loaded poly(ε-caprolactone) nanoparticles coated with hyaluronic acid (PE-NPsHA) were developed as a therapeutic strategy to treat vulvovaginal candidiasis (VVC) and combat the growing issue of fungal resistance. The chemical composition of PE was analyzed using UHPLC-MS/MS, revealing the presence of various bioactive compounds, such as phenolic acids, flavonoids, coumarins, and quinones. These compounds were encapsulated into the polymeric matrix of NPs, as indicated by FTIR and DSC. In addition, PE-NPsHA were characterized by DLS, AFM, encapsulation efficiency (EE), and in vitro release study. They displayed a spherical morphology with a hydrodynamic diameter of 170 nm, a low polydispersity index of 0.1, a zeta potential of -28.5 mV, and an EE of 78%. The in vitro release study indicated a controlled and sustained release of PE over a period of 96 h. The in vitro and in vivo PE-NPsHA biocompatibility were investigated as well as their antifungal activity in a murine model of VVC. PE-NPsHA did not impact the HaCaT cell viability and demonstrated no signs of in vivo vaginal toxicity. PE-NPsHA exhibited in vivo antifungal efficacy, effectively eliminating Candida albicans infection. PE-NPsHA could expand the available treatment options for VVC and counteract Candida resistance to antifungal drugs.

Filtration is an essential process step for the manufacturing and filling of biopharmaceuticals. In filling operations, sterile filtration is typically achieved through dead-end filtration using fine membrane filters that completely retain colony-forming units per square centimeter of filter area. According to FDA and USP guidelines, sterilizing filters must be product-compatible and composed of non-fiber releasing materials, typically with a absolute pore size rating of 0.22 µm. However, it has been observed that protein interaction with filters and particle shedding from filter materials, can contribute to protein aggregation when exposed to routine stresses such as agitation during manufacturing, handling, storage or transportation. Since aggregates can cause severe immune responses upon parenteral application, it is crucial to understand the possible effects of various filter materials during different manufacturing and filling set-ups in order to choose the most suitable filter types and filtration processes. To address this, we investigated particle formation on the visible, subvisible and submicron scales as well as structural changes in a specific liquid glycoprotein (GP) formulation after constant and impulse filtration (i.e., stop and go mechanisms to assess possible film formation and film disruption on the filter material) with commonly used hydrophilic membrane materials, i.e., polyvinylidene fluoride (PVDF), polyether sulfone (PES), and cellulose acetate (CA) with a pore size of 0.22 μm. In addition, we exposed the material to stirring and heating to induce aggregation and investigate the filter performances in the case of initially high particle content.

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The present study aims to develop and characterize cannabidiol (CBD) solid dispersions using Vacuum Compression Molding (VCM) to enhance the drug solubility and release profile. Solid dispersions of CBD and polymers were processed using VCM at 130 °C for 4 min after a prior physical mixing. Five percent w/w of CBD was used with 5% w/w of poloxamer 188 and 90% w/w of polymeric carrier (Polyethylene Oxide, PEO-N80 or Hydroxypropyl cellulose, HPCEF). Discs were collected and milled to obtain formulations (F1V, F2V). The degradation temperature of CBD was determined using Thermogravimetric Analysis (TGA). The formulations were further characterized using differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and Fourier-Transform Infrared Spectroscopy (FTIR). In vitro dissolution testing of pure CBD and formulations was evaluated using USP apparatus II. TGA showed that CBD degradation occurs after 200 °C. FTIR spectra of formulations indicate potential interactions between the drug and polymers. DSC thermograms of F1V showed a thermal peak at 65 °C that could correspond to PEO-N80. F2V did not show any of the thermal event peaks, which suggests the conversion of the drug to the amorphous state. Images from the SEM showed irregular surfaces for both formulations. The release profile showed an increase in the CBD dissolution rate by 4.75 folds for F1V and 3.63 folds for F2V in four hours. In this study, solid dispersions of CBD formulations were successfully achieved. The VCM technology has proven to be successful in formulating solid dispersions of CBD for early-stage drug development.

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Colorectal cancer is the second most common cause of death due to growing incidence. Andrographolide (AGD) induces apoptosis in colorectal cancer cells; however, oral administration of AGD is associated with hindered aqueous solubility (3.29 ± 0.73-μg.mL⁻¹) and bioavailability of 15.87 ± 3.84%. Therefore, in the current investigation, AGD was amalgamated with Eudragit S100 (EUS100) to engineer a molecular amorphous solid dispersion (EUSD). EUSD4, an optimized molecular solid dispersion showed ~ 5.90 and ~ 7.14-fold augmentations in solubility at pH ~ 6.8 and ~ 7.4, respectively as compared to AGD alone. The% assay and drug loading were respectively measured to be 96.01 ± 3.52% and 19.85 ± 0.65%. ATR and ¹H-NMR spectroscopies confirmed that the -OH group of AGD formed an intermolecular hydrogen bond with the –C = O of EUS100. Moreover, a hallo pattern of PXRD, the disappearing of an endothermic peak in DSC, the absence of a birefringence pattern under polarized light, and disorders in the initial particle shape confirmed the amorphous state of EUSD4. In addition, a ~ 4.70- and ~ 2.94-fold enhancement in dissolution profile in simulated intestinal fluid (SIF, pH ~ 6.8) and simulated colonic fluid (SCF,pH ~ 7.4) of EUSD4 suggested amendment in the hydrophilicity, wettability properties, and dissolution rate. Furthermore, the IC50 of EUSD4 was ~ 1.42-fold higher than AGD, indicating improvement in anticancer efficacy against HT-29 cells. EUSD4 exhibited superior cytotoxicity over AGD owing to the induction of apoptotic cell death, mitochondrial membrane loss (ΔΨm), remarkable S-G2/M phase cell-cycle arrest and enhanced ROS generation in HT-29 cells. In conclusion, EUSD4 warrants further in-vivo antitumor testing under a set of stringent parameters against colorectal cancer.

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This study introduces advanced nanoparticle-based drug delivery systems (NDDS) designed for targeted colorectal cancer treatment. We developed and characterized three distinct formulations: Bevacizumab-loaded chitosan nanoparticles (BEV-CHI-NP), polymeric micelles (BEV-PM), and BEV-conjugated exosomes enriched with AS1411 and N1-methyladenosine (AP-BEV + M1A-EXO). Each formulation exhibited optimized physicochemical properties, with particle sizes between 150 and 250 nm and surface charges ranging from + 14.4 to + 43 mV, ensuring stability and targeted delivery. The AP-BEV + M1A-EXO formulation demonstrated targeted delivery to VEGF, a protein commonly overexpressed in colorectal cancer cells, as indicated by localized staining. This suggests a more precise delivery of the therapeutic agent to VEGF-enriched regions. In contrast, the BEV-CHI-NP formulation exhibited a broader pattern of tumor suppression, evidenced by reduced overall staining intensity. The BEV-PM group showed moderate effects, with a relatively uniform protein expression across tumor tissues. In vivo studies indicated that the AP-BEV + M1A-EXO formulation achieved a notable reduction in tumor volume (~ 65.4%) and decreased levels of tumor biomarkers, including CEA and CA 19–9, compared to conventional BEV-API treatment. In vitro experiments using human colon tumor organoids (HCTOs) further supported these findings, showing a significant reduction in cell viability following exposure to AP-BEV + M1A-EXO. These results suggest that combining aptamer specificity with exosome-based delivery systems could enhance the precision and effectiveness of colorectal cancer therapies, representing a potential advancement in treatment strategies. In vivo experiments further revealed that the AP-BEV + M1A-EXO formulation outperformed conventional BEV-API treatment, achieving a four-fold increase in tumor suppression. This formulation resulted in a 65.4% reduction in tumor volume and a significant decrease in tumor biomarkers, including CEA and CA 19–9. In vitro studies also demonstrated a significant reduction in cell viability in human colon tumor organoids exposed to AP-BEV + M1A-EXO. These findings highlight the potential of combining aptamer specificity with exosome-based delivery systems to enhance the precision and efficacy of colorectal cancer therapies, marking a promising step forward in cancer treatment innovation.

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Piroxicam is a non-steroidal anti-inflammatory drug which is used topically as an adjunctive treatment of knee osteoarthritis and as an option to control joint pain in patients suffering rheumatoid arthritis. In this study, an emulgel containing optimized nano-niosomal piroxicam was formulated and characterized in terms of mean size, polydispersity index, zeta potential, drug entrapment efficiency and capacity, release and transdermal permeation. Also, animal studies including pain level assessment, synovial prostaglandin E2 levels, knee joint swelling degree and histopathologic investigations were conducted. A randomized double-blind clinical trial was also performed to compare the analgesic effect of nano-niosomal piroxicam emulgel with piroxicam gel. The results showed optimized niosome formulation with 142 ± 7nm mean size and 0.23 ± 0.08 PDI, entrapped 99.48 ± 0.79% of added piroxicam with a sustained release pattern. Permeation studies indicated a 3.31-fold transdermal permeation of niosomal piroxicam emulgel compared with the piroxicam gel. The niosomal formulation significantly reduced knee joint swelling and prostaglandin E2 levels. The clinical trial indicated that the painkilling efficiency of the niosomal piroxicam emulgel was 37.30-fold and 3.16-fold greater compared to the placebo and the positive control groups, respectively. In conclusion, the niosomal piroxicam emulgel which may enable the drug to permeate through the skin and accumulate in synovial tissue more efficiently, showed a promising performance in lowering pain and inflammation based on the animal studies and the human clinical trial.

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