Drug Development and Industrial Pharmacy最新文献

Objectives: Enoxaparin (ENX), an anticoagulant, was developed as a topical aqueous spray that provides rapid treatment for contusions by dissolving micro-clots, reducing inflammation, and thereby alleviating pain and edema.

Significance: This spray offers rapid relief of contusions, improves drug retention in the skin, and helps to restore the aesthetic appearance of injured skin.

Methods: ENX aqueous sprays were developed using an aqueous dispersion method with medium-chain triglycerides (MCTs) as permeation enhancers and propylene glycol (PG) used as a plasticizer. Two optimized formulations, F_A9 (caproic acid-based) and F_B8 (caprylic acid-based), were selected using a Box-Behnken design via surface response methodology. The various physicochemical and spray characteristics of optimized formulations were evaluated, and therapeutic efficacy was assessed in a contusion-induced animal model.

Results: The optimized formulations (F_A9 and F_B8) exhibited favorable drying time and transparency for topical applications. Drug deposition was significantly higher in F_A9 (47.68% ± 4.61) and F_B8 (38.25% ± 3.76) compared to the marketed formulation (31.52% ± 2.37). The in vivo animal study indicated that F_A9 facilitated complete bruise resolution after five days in contusion-induced animals, whereas F_B8 required one week to recover. Histological analysis confirmed rapid vascular and tissue recovery with F_A9, while F_B8 exhibited moderate healing due to deeper tissue injury, but optimized formulations healed faster than the marketed preparation.

Conclusions: The ENX aqueous spray containing MCTs demonstrated high therapeutic efficacy and faster bruise resolution than the marketed formulation, thus presenting a promising alternative for the topical treatment of contusions.

Objective: This study aimed to develop and evaluate a dermal gel formulation incorporating the methanolic leaf extract of Guiera senegalensis (GS) for potential topical antimicrobial application.

Significance: Dermal gel formulations of GS leaf extracts may offer safe and effective alternatives against bacterial and fungal skin infections, particularly beneficial for pediatric and geriatric individuals who are most susceptible to such conditions.

Methods: Leaves of GS were extracted by maceration using methanol and fractionated with solvents of increasing polarity. The extract and fractions underwent phytochemical screening, antibacterial evaluation, and spectral characterization (GC-MS and FT-IR). Xanthan gum-based gels were formulated and evaluated for pH, viscosity, spreadability, extrudability, swelling, erosion, and antibacterial activity.

Results: The methanolic extract (26.36% yield) contained abundant phytochemicals, including flavonoids, phenolics, tannins, and terpenoids. Fractionation revealed the polarity-based distribution of phytochemicals but did not enhance antibacterial potency. The methanolic extract showed the strongest activity against Staphylococcus aureus (22.24 ± 0.12 mm). GC-MS and FT-IR confirmed the presence of bioactive compounds and functional groups linked to antimicrobial effects. The gels exhibited skin-compatible pH (5.95-6.65), appropriate viscosity (11.23-63.23 Pa·s), and desirable spreadability. Among all, formulation F2 showed the best overall characteristics for topical use.

Conclusion: GS leaf extract-loaded gels demonstrated excellent physicochemical properties and antibacterial activity. Although fractionation provided no added antimicrobial advantage, it offered insights into phytochemical distribution. Formulation F2 represents a promising natural, plant-based topical antimicrobial candidate.

Objective: The objective of this study was to develop a stable clear ophthalmic nano-micellar formulation of Nepafenac.

Significance: The current marketed suspension formulation of nepafenac indicated for post-surgical uveitis is associated with higher manufacturing complexity and cost due to the need for sterile drug substance and specialized aseptic processing inherent to suspension-based ophthalmic products. It also exhibits limitations in patient compliance due to relatively high viscosity, lacrimation, and foreign body sensation following instillation.

Methods: Pre-formulation study was done to identify the excipients required. Systematic changes in the concentration of surfactant and crystal inhibitor along with other excipients led to the development of stable nano-micellar formulation. Box-behnken method was used for the optimization. The optimized micellar composition was evaluated for physicochemical tests particle size, zeta potential, cloud point, osmolality pH, assay of drug, entrapment efficiency and dynamic viscosity. Further in-vitro cell viability, in-vitro release, ocular tolerance test and stability evaluation were also performed.

Results: Average particle size of the micelle ranged from 10 to 20 nm, 43.5 mPas dynamic viscosity, osmolality of 319 mOsm/Kg, pH 7.4 and cloud point of 59.7 °C. The optimized formulation demonstrated in-vitro safety as confirmed by MTT cell viability and HET-CAM ocular irritation assays, and exhibited physicochemical stability for up to 6 months under real-time storage conditions.

Conclusion: The optimized micelle formulation can serve as a better alternative for ophthalmic delivery of nepafenac.

Objectives: This study aimed to develop and evaluate rifampicin (RIF) and isoniazid (INH) co-loaded liposome for sustained drug delivery to enhance therapeutic efficacy against tuberculosis (TB) and overcome challenges associated with prolonged treatment and drug resistance.

Significance: The novel biocompatible liposomal system enables sustained co-delivery of RIF and INH, providing a scalable and stable platform with enhanced antimicrobial efficacy and strong potential to advance tuberculosis therapy.

Methods: Liposome were prepared using soybean lecithin and cholesterol (L-CH) via rotary evaporator-assisted thin film hydration, optimized by Box-Behnken design, and characterized for size, PDI, entrapment efficiency, and physicochemical properties (FT-IR, DSC, HR-TEM). In vitro release, accelerated stability, antimicrobial efficacy against M. smegmatis and M. tuberculosis H₃₇Rv, and LC-MS/MS-based metabolomic profiling were systematically evaluated.

Results: The optimized liposome exhibited a mean size of 129.5 ± 2.20 nm, PDI of 0.369 ± 0.06, and entrapment efficiencies of 63.84 ± 1.62% (RIF) and 56.92 ± 1.69% (INH). The release study indicated sustained diffusion-controlled kinetics consistent with the Higuchi model, achieving cumulative releases of approximately 92% for INH and 85% for RIF over a 45-hour period. The accelerated stability studies confirmed negligible drug degradation, while antimicrobial assays demonstrated a twofold reduction in MIC relative to free drugs, and metabolomic profiling indicated modulation of glutathione, citric acid, and tyrosine pathways associated with enhanced redox balance and antimicrobial activity.

Conclusions: The co-loaded RIF-INH liposomal system offers a promising, clinically translatable approach for sustained drug release and improved tuberculosis therapy.

Objective: To develop a green and efficient ultrasound-assisted extraction (UAE) process to obtain bioactive resins from Cannabis sativa with potential pharmaceutical applications, optimizing extraction parameters to maximize antioxidant capacity and total polyphenol content.

Significance: UAE using ethanol under mild temperature and time conditions as a green technique was applied to reduce solvent consumption, energy demand, and extraction time while preserving thermolabile bioactive compounds. Optimizing UAE enables the recovery of cannabinoid- and terpene-rich extracts that may serve as natural active pharmaceutical ingredients or functional excipients for drug development. This study integrates a Doehlert-based optimization of UAE with a functional evaluation of antioxidant efficiency and antimicrobial activity, providing a comprehensive framework for the development of cannabis-derived pharmaceutical ingredients.

Methods: A Doehlert experimental design combined with response surface methodology was employed to optimize temperature and extraction time. The optimized extract was characterized for its phytochemical composition. Antimicrobial activity was evaluated against Gram-positive and Gram-negative bacterial strains to assess potential therapeutic relevance.

Results: Under optimal conditions (54.5 °C, 28 min 25 s), the extract showed a total phenolic content of approximately 0.11 mg gallic acid/mg resin and an IC₅₀ value of about 0.24 mg resin/mL extract, indicating enhanced antioxidant performance compared to non-optimized conditions. Also, it showed selective bactericidal activity against Staphylococcus aureus ATCC 25923 and Staphylococcus epidermidis ATCC 12228, while Gram-negative strains remained resistant.

Conclusion: UAE extraction efficiently recovered antioxidant and selectively antimicrobial compounds from Cannabis sativa resins under mild, eco-friendly conditions, supporting their potential use as bioactive ingredients in pharmaceuticals.

Objective: The aim of this study was to develop a chemotherapy drug paclitaxel (PTX) and a tumor-specific ROS generation agent β-lapachone(LAP) co-loaded human serum albumin (HSA)-based nanoparticles (ANPs) for synergistic anticancer therapy.

Significance: Albumin-based nanoparticles (ANPs) offer unique advantages for antitumor drug delivery system, including non-immunogenicity and inherent tumor-targeting capacity. In this study, we mimicked the natural fatty acid binding process in vivo to construct ANPs to synergistically elevate ROS with β-lapachone for cooperative cancer therapy.

Methods: First, a polyethylene glycol monostearate(PGM) modified redox-sensitive paclitaxel prodrug(PTX-SS-PGM) was synthesized and stearic acid capable of binding with HSA was introduced. Further, a LAP/PTX-SS-PGM complex was engineered through the π - π stacking interaction and H-bonding between LAP and PTX. The PTX and LAP co-loaded ANPs (PTX-SS-PGM&LAP@HSA) were obtained through the binding between LAP/PTX-SS-PGM complex and HSA.

Results: The percentage of apoptosis for PTX, Abraxane^®, PTX-SS-PGM@HSA ANPs, and PTX-SS-PGM&LAP@HSA ANPs was 8.17%, 9.53%, 15.17%, and 28.6%, respectively, demonstrating synergistic cytotoxicity effect. The in vivo imaging test confirmed that PTX-SS-PGM&LAP@HSA had targeting ability to tumor tissues. The obtained ANPs exhibited better tumor growth inhibition in vitro and in vivo.

Introduction: In the early stages of drug development, evaluating physicochemical properties is crucial for anticipating a compound's absorption, distribution, and therapeutic efficacy. The distribution coefficient (logD), which accounts for both ionized and unionized species at physiological pH, provides a more biorelevant parameter than the traditional partition coefficient (logP).

Objective: The aim of the paper was to determine the distribution coefficient of gliclazide (weak acid, BCS class II) and metformin (weak base, BCS class III) under different experimental conditions.

Methods: The n-octanol-water system was used as a model for in vivo gastrointestinal absorption, and cyclohexane-water for in vivo blood-brain barrier permeation. The influence of deoxycholic acid as a potential permeability enhancer was also examined. The data were compared with in vivo results in healthy and diabetic rats.

Results: Metformin showed logD values from -1.70 to -1.20 (without DCA) and from -1.64 to -1.16 (with DCA) in the n-octanol/water system, while in cyclohexane/water, values ranged from -2.06 to -1.18 (without DCA) and from -1.61 to -1.20 (with DCA). Gliclazide exhibited logD values of 0.25-2.02 (without DCA) and 0.24-2.17 (with DCA) in n-octanol/water, and -0.64-0.93 (without DCA) vs. 0.09-1.60 (with DCA) in cyclohexane/water.

Conclusion: These results confirm the usefulness and cost-effectiveness of simple water-organic solvent models in early drug and formulation development.

Objective: Alkaloids from Evodia rutaecarpa exhibit strong antihypertensive and antioxidant effects, but oral administration suffers from low bioavailability. This study aimed to develop and optimize a transdermal gel patch containing a vinegar-water extract of E. rutaecarpa to enhance therapeutic efficacy.

Methods: Gel formulations were optimized using single-factor tests and a Box-Behnken design (BBD), with adhesion and organoleptic properties as evaluation indices. In vitro permeation and kinetic modeling were used to characterize drug release, while antihypertensive effects were assessed in L-NAME-induced hypertensive rats. Serum lactate dehydrogenase (LDH), atrial natriuretic peptide (ANP), estradiol (E2), testosterone (T), and interleukin-6 (IL-6) were quantified by ELISA. Histopathological evaluation of the heart, kidney, and aorta was also performed.

Results: Optimized formulation: NP-700 (6.8 g), DAA (0.15 g), PVP K-90 (0.1 g), tartaric acid (0.15 g), glycerol (25 g), and distilled water (60 g). In vitro, the 72 h cumulative permeation of dehydroevodiamine, evodiamine, and rutaecarpine was 302.64 ± 0.74, 129.11 ± 0.41, and 41.50 ± 0.14 μg·cm^-2, respectively. The release kinetics fitted the Weibull model. In the L-NAME-induced hypertensive rats, patch treatment reduced systolic blood pressure (SBP) from 158.5 ± 4.9 to 122.5 ± 2.5 mmHg (p < 0.001) and significantly restored serum LDH, ANP, IL-6, E2, and T (p < 0.05). Histological analysis showed attenuation of myocardial hypertrophy and fibrosis, endothelial injury and smooth muscle proliferation, and reduced renal edema, tubular atrophy, and inflammatory infiltration.

Conclusions: The E. rutaecarpa vinegar-water extract gel patch exhibited marked antihypertensive activity and protection against target organ damage, highlighting its promise as a novel transdermal therapy for hypertension.

Objective: Tacrolimus is a potent macrolide immunosuppressant widely utilized in solid organ transplantation and the management of autoimmune disorders. The current study aimed to investigate the compatibility of tacrolimus with four commonly used excipients, including sodium croscarmellose, hydroxypropyl methylcellulose (HPMC), magnesium stearate, and lactose monohydrate.

Significance: The design of Experiments transforms drug-excipient compatibility studies by allowing for a precise, data-driven evaluation of multiple key factors with minimal experimental runs, ensuring reliable formulation development while saving time and resources.

Methods: A total of 14 experimental runs were generated using Design-Expert^® software, incorporating three critical variables: temperature, relative humidity (RH), and drug-to-excipient ratio for each excipient. Tacrolimus was blended with the respective excipients at predetermined ratio and subjected to controlled storage conditions under varying temperature and RH levels. Post-incubation, the residual tacrolimus content was quantified via HPLC. Additionally, to further assess physicochemical interactions, DSC and FT-IR were employed for selected samples.

Results: The model-fitting analysis revealed that all excipients, except HPMC, followed a linear pattern, whereas HPMC exhibited quadratic behavior. In all experimental groups, increasing RH significantly accelerated tacrolimus degradation. Notably, elevated temperature and higher excipient ratio further reduced the remaining drug concentration in all formulations except those containing magnesium stearate. The DSC thermograms revealed no significant alterations. FTIR spectroscopic analysis confirmed that only magnesium stearate-containing formulations exhibited distinct spectral patterns compared to pure tacrolimus.

Conclusion: These findings underscore the need for careful consideration when using magnesium stearate in tacrolimus formulations.

Background: Simvastatin, a lipid-lowering drug, has low oral bioavailability due to poor solubility and extensive first-pass metabolism. Transdermal delivery may overcome these limitations.

Objectives: The present study aimed to develop, optimize, and evaluate a simvastatin-loaded transethosomal gel for enhanced dermal permeation and improved antihyperlipidemic efficacy.

Methods: Critical quality attributes, including particle size (PS), entrapment efficiency (%EE), and polydispersity index (PDI), were established through a Quality Target Product Profile. Transethosomes were optimized using a Face-Centered Central Composite Design (FCCCD) by varying Soya phosphatidylcholine and ethanol concentrations. The optimized formulation was characterized using dynamic light scattering, scanning electron microscope, and transmission electron microscope. It was incorporated into a 2% w/v carbopol gel and evaluated for pH, viscosity, and spreadability. In vitro diffusion, ex vivo skin permeation, and skin irritation studies were performed. Antihyperlipidemic efficacy was assessed in high-fat diet-induced hyperlipidemic rats, comparing oral simvastatin (10 mg/kg/day) and transethosomal gel (1 g containing 10 mg simvastatin).

Results: Optimized vesicles showed nanoscale PS (104.9 ± 0.42 nm), high EE (79.92 ± 0.19%), low PDI (0.113 ± 0.45), and negative zeta potential (-32.1 ± 0.48 mV). Microscopy confirmed spherical morphology. The gel exhibited sustained release, good skin compatibility, and significantly improved lipid profile in high-fat diet-fed rats, reducing total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C), while elevating high-density lipoprotein cholesterol (HDL-C) compared to oral simvastatin (p < 0.05).

Conclusion: The simvastatin-loaded transethosomal gel demonstrated superior dermal delivery, efficacy, and safety, supporting its potential as a nanoenabled transdermal alternative for hyperlipidemia management.