Pharmaceutical Development and Technology最新文献

Dry, nutrient-poor wounds often heal slowly because inflammation persists and tissue repair is impaired. This study developed a biotin-loaded acacia-alginate nanogel (BOT-ACC-SA) to improve biotin's poor water solubility, limited skin penetration, and therapeutic performance in wound healing. Biotin was first adsorbed onto acacia gum and then incorporated into sodium alginate nanogels using sonication-assisted self-assembly. The formulation was thoroughly characterized by thermal, spectroscopic, crystallographic, microscopic, particle-size, and rheological analyses. The optimized nanogel showed a mean size of about 120 nm, a zeta potential of -32.7 mV, and high encapsulation efficiency (90.1%). It increased biotin solubility 2.8-fold and released 97% of the drug within 24 hours, following the Higuchi release model. In vivo evaluation in Wistar rats over 14 days demonstrated superior wound closure with BOT-ACC-SA (94.6%) compared with BOT-SA, ACC-SA, and untreated controls. The nanogel also significantly increased VEGF, TGF-β1, and collagen I while reducing IL-6, indicating enhanced angiogenesis, extracellular matrix remodeling, and inflammation resolution. Stability testing confirmed that the formulation remained stable for 12 months at refrigerated conditions. Overall, BOT-ACC-SA appears to be a promising topical treatment for difficult-to-heal wounds.

Paroxetine (PX) is a first-line selective serotonin reuptake inhibitor (SSRI) for major depressive disorder. Currently, the enteric-coated sustained-release tablet represents the dominant clinical standard due to its ability to mitigate gastric irritation and ensure sustained release in the intestine to reduce adverse effects. However, these tablets must be swallowed intact, making them unsuitable for patients with dysphagia; manipulation (e.g. crushing or chewing) destroys the functional coating, leading to dose dumping and unpredictable systemic exposure. To address these critical therapeutic gaps, this study developed a novel reconstitutable enteric-coated sustained-release powder using ion-exchange resin technology for oral suspension of PX. PX was loaded onto Amberlite^® IRP88 and subsequently coated with cellulose acetate phthalate via fluidized-bed processing to inhibit gastric release while enabling prolonged release in the intestine. The optimized formulation (PX@CM) demonstrated high drug entrapment efficiency and a robust zero-order release profile in simulated intestinal fluid. In vivo pharmacokinetic studies in rats confirmed its potential clinical advantages: compared to commercial immediate-release (IR) oral tablets, the suspension significantly lowered C_max (0.24 vs. 0.44 μg/mL) and prolonged T_max (6.67 vs. 4.00 h). These pharmacokinetic improvements provide a 'peak-blunting' effect that suggests a potential to minimize concentration-dependent side effects. Consequently, this formulation emerges as a promising, patient-centric alternative for vulnerable populations requiring long-term antidepressant therapy.

Diabetic wounds need effective and prompt treatment otherwise, it will be complicated with sever bacterial infections. In this study, hydrogels containing Lepidium sativum seeds aqueous extract (LS_ae), metformin (MET) and combination (LS_ae and MET) were prepared and characterized for their pH, contents, spreadability, viscosity, rheology, morphology, physical stability and in vitro release. Percentage of wound contraction in streptozotocin induced diabetic rats was studied. In addition, certain biochemical parameters, like tumor necrosis factor-alpha, TNF-α, interleukin, IL-6, malondialdehyde, MDA and matrix metalloproteinase-9, MMP-9 as inflammatory and oxidative stress biomarkers were quantified. Histopathological changes were studied and immunohistochemical staining was used to detect vascular endothelial growth factor, VEGF and platelet endothelial cell adhesion molecule-1, PECAM-1/CD31. Pharmaceutical characterization revealed the suitability of hydrogels for topical administration. Combination hydrogel group 2 showed a significant reduction in TNF-α, IL-6, MMP-9 and MDA (296.36 ± 16.31, 8.33 ± 1.06 pg/ml, 0.61 ± 0.35 ng/ml and 13.30 ± 1.4 nmol/ml) compared to other tested groups. Histopathological examination showed complete re-epithelization with granulation tissue formation and thicker well-organized collagen fibers for groups 1 and 2 after 7 days. However, LS_ae hydrogel group 1 had a faster effect, a significant expression of VEGF (64.00 ± 17.08 positively stained cells) and (95.73 ± 2.4% wound contraction). It could be concluded that LS_ae hydrogel is a promising formulation for effective rapid management of diabetic wounds.

The natural flavonoids quercetin (Que) and kaempferol (Kae) show great potential for anti-aging applications but suffer from poor solubility and skin permeability. This study aimed to develop a synergistic topical emulsion system to overcome the poor bioavailability of the Que and Kae for enhanced efficacy. The optimal synergistic molar ratio (Que:Kae = 1:2) was first identified via 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and cellular assays. The drugs were then loaded into milk-derived exosomes (mExo) using a Box-Behnken design (BBD), achieving high encapsulation (>69%), a size of ∼120 nm, and a polydispersity index (PDI) of 0.180. This complex was incorporated into an oil-in-water emulsion, with its formulation also BBD-optimized for stability. In a D-galactose-induced skin aging mouse model, the final Que/Kae-mExo@Eml formulation significantly outperformed control groups (free drug mixture, blank exosome emulsion, and vitamin C). It most effectively reduced oxidative stress (malondialdehyde, MDA), enhanced antioxidant enzymes (superoxide dismutase, SOD and glutathione, GSH), suppressed matrix metalloproteinase-1 (MMP-1), promoted collagen I (Col I) synthesis, and improved skin histology, elasticity, and hydration. In conclusion, an optimized, stable emulsion leveraging a synergistic 1:2 drug ratio and an mExo delivery system was successfully developed, demonstrating superior comprehensive efficacy against skin aging.

A new micellar delivery system for the dual loading of resveratrol and rutin (RES-RU-micelles) is described and characterized. Analyzes were carried out to determine the size parameters (mean particle size and polydispersity index) and surface electrical charge, 24 h after production and after 2 months of storage at two different temperatures (4 °C and 25 °C). In silico ADME predictions revealed striking differences in skin permeability between resveratrol (Log Kp = -5.47 cm/s) and rutin (Log Kp = -10.26 cm/s). Molecular analysis demonstrated that the contrasting physicochemical properties of RES (Log P = 2.57, TPSA = 60.69 Å) and RU (Log P = -2.11, TPSA = 269.43 Å) enable their spatial segregation within the micelles. RES is located predominantly in the hydrophobic core through hydrophobic interactions, while RU positions at the core-shell interface via hydrogen bonding with the hydrophilic components. The encapsulation efficiency achieved values above 98% for both bioactives in the dual loading. The viscoelastic profile showed that the G' was higher than the G″ in the applied frequency range, demonstrating that the developed micelles are more elastic than viscous. DSC analysis showed the absence of peaks, corroborating that no bioactive crystallization happened when loaded into the micelles. Transmission electron microscopy analysis confirmed the morphology and spherical shape of the produced micelles.

Patient rejection of unpalatable products can adversely affect therapeutic adherence, potentially leading to treatment failure. Taste masking is a goal in pharmaceutical development, particularly when developing formulations for paediatric patients. The use of an electronic tongue (e-tongue) enables rapid, objective, and robust taste evaluation. Its use is gaining traction in the quality assessment of pharmaceutical products. The capability of an Alpha Astree II taste-sensing system to evaluate the palatability of commercially available hyoscine butylbromide (HBB) syrup brands in South Africa, was investigated. Principal component analysis (PCA) was used to process the e-tongue data and the resultant biplots can distinguish between the taste of reference compounds and HBB syrups. The sensor values and taste screening rankings indicate the three brands exhibit a bitter-sweet taste. Brand Z has greater bitterness and sourness than brands, X and Y due to citric acid monohydrate in the formulation. Brand Y included sodium cyclamate and was the most palatable syrup. The findings indicate the e-tongue can differentiate the taste of HBB syrups when different excipients are used to alter taste. Pharmaceutical companies could use these data to improve the palatability of currently available hyoscine syrups. The E-tongue is a complementary instrument to human sensory panels used to inform product development in alignment with customer preferences.

Neutrophillic asthma, characterized by persistent airway inflammation and poor corticosteroid responsiveness, presents a significant therapeutic challenge. Repurposing rapamycin, an mTOR inhibitor, and simvastatin, a statin with anti-inflammatory effects, through targeted pulmonary delivery may provide a novel therapeutic strategy. A combinatorial dry powder inhalation formulation was developed by blending rapamycin and simvastatin with lactose carriers, and a Box-Behnken design was employed to optimize blending time, fine lactose content, and leucine content. Analytical characterization using FTIR, P-XRD, DSC, and SEM confirmed effective adsorption of actives onto lactose carriers with no significant drug-excipient incompatibilities. Aerodynamic evaluation demonstrated a fine particle fraction of 53.35% and 58.67% and a mass median aerodynamic diameter 2.037 µm and 4.307 µm, for simvastatin and rapamycin respectively indicating efficient pulmonary deposition. Stability studies showed acceptable stability for 6 months and in-vivo inhalational toxicity in healthy C57BL/6 mice confirmed safety. This preclinical proof-of-concept highlights the potential of localized pulmonary delivery to reduce systemic exposure while targeting inflammatory pathways in neutrophillic asthma. Further in vivo and translational studies are warranted to establish therapeutic efficacy. This approach provides a platform for repurposing simvastatin and rapamycin as an asthma treatment and addresses the unmet need in managing steroid-resistant asthma endotypes.

Nilotinib (NH), a second-generation tyrosine kinase inhibitor for chronic myelogenous leukemia (CML), exhibits poor aqueous solubility and low intestinal permeability, classifying it as a Biopharmaceutics Classification System (BCS) Class IV drug. This study aimed to enhance NH solubility and dissolution through co-crystallization, guided by computational and experimental approaches. BASF's ZoomLab™ platform was utilized for rational coformer selection using the solubility parameter difference (Δδv) method. Validation with paracetamol and posaconazole datasets established 5 MPa^0.5 as the optimal Δδv threshold. Pyroglutamic acid (PG) emerged as the most suitable coformer and was co-crystallized with NH via liquid-assisted grinding (LAG). Solid-state characterization (PXRD, DSC, FTIR, SEM) confirmed formation of Nilotinib-Pyroglutamic acid co-crystal (NH-PGCC). The co-crystal displayed significantly improved wettability and a 3.23-fold increase in solubility in 0.1 N HCl compared to pure NH. Although rapid phase transformation occurred within 3 min, PEG 6K stabilized the supersaturated state, improving dissolution. The optimized NH-PGCC capsule achieved 75% drug release in 15 min, significantly outperforming marketed formulations (Tasigna^® and Nilotirel^®) and reduction of crystallinity was less than 2% in 6 months, suggesting stability of co-crystal. This study successfully demonstrates the applicability of ZoomLab™ in coformer prediction and formulation development for solubility enhancement of poorly soluble drugs.

Rosuvastatin is a BCS class II drug effective in the management of atherosclerosis. To enhance solubility and efficacy, Rosuvastatin-β-Cyclodextrin complex-loaded chitosan nanoparticles (R-CD-CNs) were developed. β-cyclodextrin was crosslinked with Citric acid to impart stability to the inclusion complex. Rosuvastatin was incorporated into lyophilized crosslinked β-cyclodextrin by kneading method. R-CD complex was loaded into chitosan-tripolyphosphate nanoparticles. The R-CD-CNs were optimized by 3² full factorial design with independent variables Chitosan, Sodium Tripolyphosphate as crosslinking agent and their effects were checked on dependent variables. Optimized R-CD-CNs showed Particle size 265 ± 17 nm, PDI 0.251 ± 0.02, EE 80 ± 7.5%, and Zeta potential +19.8 ± 3.8 mV. The results of DSC confirmed that drug gets incorporated into chitosan nanoparticles. XRD confirmed amorphous form of drug into chitosan nanoparticles. SEM study confirmed the sphericity of R-CD-CNs. The in vitro release profile was found to be 91 ± 2.5% at the end of 10 h, indicating sustained release characteristics. R-CD-CNs showed a more prominent effect compared to plain Rosuvastatin calcium and the disease control group. The synergistic effect of chitosan was confirmed by the in vivo antihyperlipidemic study. The results of stability study reveal good stability of R-CD-CNs. R-CD-CNs were developed successfully and will be helpful for the effective management of hyperlipidemia.

Ledipasvir is one of the direct-acting antiviral agents used for treating hepatitis C virus (HCV) infection. To achieve dose reduction and cost-effective therapy, this study aimed to enhance the interaction of ledipasvir with HCV-infected hepatocytes through the development of cationic bilosomes (CBs) and galactosylated bilosomes (GBs). These delivery systems were designed to promote hepatocellular targeting via the asialoglycoprotein receptors (ASGPRs). Eight bilosomal formulations were developed by the ethanol injection method following a 2³ full factorial design, and numerical optimization using Design Expert^® software identified the optimized formulation. In parallel, galactosylated stearylamine (GSA) was synthesized through conjugation of stearylamine (SA) with lactobionic acid (LB). The successful synthesis of GSA was verified through FTIR and ¹H NMR spectroscopic analyses. SA and GSA were subsequently incorporated into the optimized bilosomes to obtain CBs and GBs, respectively. The prepared systems were evaluated for particle size, polydispersity index, entrapment efficiency, and zeta potential, and their morphology was identified using transmission electron microscopy. Following 8-h incubation with HepG2 cells, CBs and GBs achieved significantly higher cumulative cellular uptake of ledipasvir (31.79% ± 3.11% and 20.62% ± 2.12%, respectively) compared to the ledipasvir free dispersion (11.02% ± 3.02%). These findings highlight CBs and GBs as promising nanocarriers for targeted delivery of ledipasvir to hepatocytes.