Drug Development and Industrial Pharmacy最新文献

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.

Objective: To elucidate the application potential of ferritin nanocarriers in targeted cancer therapy, particularly for central nervous system (CNS) tumors (e.g. glioblastoma), focusing on their structural advantages, drug-loading capacity, targeting strategies, and emerging therapeutic directions.

Review significance: Ferritin, leveraging its natural biocompatibility, biodegradability, and unique cage-like structure, is a highly promising drug delivery platform. Its intrinsic ability to specifically bind the tumor-overexpressed transferrin receptor 1 (TfR1/CD71) and penetrate the blood-brain barrier (BBB) provides a unique solution for the precise delivery of chemotherapeutics, metal ions, gene therapy molecules, and novel therapeutics.

Main findings: Ferritin achieves efficient loading of diverse therapeutics (chemotherapeutic agents, metal ions, siRNA) through pH-mediated reassembly, thermally-gated mechanisms, or high hydrostatic pressure methods. Genetic and chemical engineering enhances its intrinsic TfR1/CD71 targeting affinity, significantly improving penetration specificity toward tumor cells and the blood-brain barrier. Successful delivery of regorafenib and immune checkpoint inhibitors to central nervous system tumors has been demonstrated, while combination therapy with ferroptosis inducers or natural bioactive compounds exhibits synergistic efficacy in breast cancer models. Furthermore, ferritin demonstrates potential for multimodal therapeutic integration with ferroptosis induction, photodynamic therapy, and immune checkpoint blockade strategies.

Conclusion: Ferritin nanocarriers exhibit significant advantages for targeted cancer therapy, particularly in blood-brain barrier penetration and precise delivery. Genetic/chemical engineering enhances their efficacy. However, clinical translation faces key challenges: optimizing drug-carrier compatibility, characterizing in vivo pharmacokinetics, and achieving scalable production. Future research priorities include developing smart stimuli-responsive release systems, establishing multimodal therapeutic regimens, and standardizing manufacturing protocols to advance clinical application.

Objective: The Saudi market offers dosages of metformin that have varying release rates and can lead to different pharmacological reactions. Studying formulation bioequivalences helps patients choose the optimum medicine without affecting pharmacological responses.

Significance: This study affects patient care clinically, which can improve Saudi diabetes management by improving efficacy, safety, adherence, access, and cultural relevance.

Method: The bioequivalence and pharmacokinetic parameters were studied using the convolution method. Similarity factor f₁ and different factors f₂ of different types of metformin tablets were calculated. Furthermore, the pharmacokinetic parameters were estimated using the convolution method.

Results: At pH = 6.8 (phosphate buffer) and 50 rpm, 100% of metformin was released within 2 h. While, after two hours in HCl at pH = 1.1 followed by five hours in phosphate buffer at pH = 6.8, 100% of the medication was released after 7 h. The release kinetics showed zero-order kinetics with r² = 0.961 for Formit^® and 0.971 for Glucophage^®, while the release mechanism showed that it follows the Higuchi equation with r² = 0.974 for Formit^® and 0.971 for Glucophage^®, respectively, indicating that the mechanism of drug release was controlled by diffusion. The two brands were lyo-equivalent, with a similarity factor and difference factor equal to 59.36 and 7.26, respectively.

Conclusion: The convolution approach indicated that Glucophage^® and Formit^® have bioequivalent C_max of 601 and 592 ng/ml, respectively. The two products had the same projected T_max of 2.0 h and a modest AUC_∞ differential that did not violate the FDA's 80-125% limit.

Objectives: This study presents a sustainable extraction process for obtaining plant active substances (PAS) from the leaves of Salvia rosmarinus Spenn. (rosemary) and semi-solid microemulsions (SSME) at the same time. The extraction method uses a sustainable solvent system of surfactants, co-surfactants, and water, yielding high PAS miscibility.

Methods: The method was developed using pseudo-ternary phase diagrams, particle size determination and ultrasound-assisted extraction. Optimization was performed via response surface methodology, assessing antioxidant capacity, total phenols, terpenoids, and flavonoids for efficiency evaluation.

Results: Optimal extraction conditions, identified using response surface methodology, which produced SSME with high antioxidant capacity (0.04 to 0.150 mmol/ml) and significant polyphenolic content (0.055 to 0.219 mg of gallic acid/ml). Additionally, the resulting formulations showed a total terpenoid content of 0.04 to 0.150 mmol/ml and a total flavonoid content of 5.4 to 10.5 mg/ml mg quercetin equivalent/ml. The droplet size and polydispersity index values of the optimized extracts were evaluated, yielding mean droplet sizes below 250 nm, indicating the presence of microemulsions. By means of UPLC-ESI-MS/MS the primary PAS were identified, validating the effectiveness of the extraction process in isolating of bioactive compounds with therapeutic potential.

Conclusions: This eco-friendly method not only aligns with green chemistry principles but also supports the development of PAS-rich SSME as candidates for dermal therapies.

Purpose: Oridonin (ORI) is an ent-kaurene tetracyclic diterpenoid with anti-tumor activities in various tumor cell lines. However, its hydrophobicity and non-targeting have greatly limited the clinical application of ORI. In the present study, long-circulating liposomes loading ORI and targeting lung cancer cells were established to solve these problems.

Methods: 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene-glycol (DSPE-PEG), modified with a homing peptide with the sequence YSAYPDSVPMMSK (YSA), was employed to constitute the matrix of liposomes in combination with soybean lecithin and cholesterol. Meanwhile, the characterization, stability, in vitro release, and delivery in vitro and in vivo of the prepared liposomes were studied.

Results: The results revealed that the prepared ORI-loaded liposomes exhibited a regular sphere with particle size of 140.64 ± 12.94 nm. The prepared liposomes showed good stability at 5 °C and sustained release profile in PBS solution. YSA modification to the liposomes enabled increased uptake by human lung cancer A549 cells, thereby increasing cytotoxicity on A549 cells. The pharmacokinetics study showed a higher area under the concentration time curve (AUC), a longer mean residence time (MRT), a slower plasma clearance (CL) and a prolonged half life time (t1/2) for ORI-loaded liposomes. Of important, the prepared liposomes exhibited a concentrated distribution in tumor tissues after intravenous injection. Therefore, ORI-loaded liposomes significantly inhibited tumor growth in tumor xenograft nude mice inoculated with A549 cells.

Conclusion: In conclusion, the constructed ORI-loaded liposomes might be a novel and promising delivery system for ORI in the treatment of lung cancer.

Objective: To enhance the aqueous solubility and dissolution rate of cilnidipine (CLN), a BCS Class II antihypertensive drug with poor oral bioavailability (13%), by developing oral nanocrystals (NCs) using a scalable antisolvent precipitation and high-speed homogenization technique.

Significance: CLN's therapeutic potential is limited by its low solubility. This study addresses this challenge through nanocrystal formulation, offering a cost-effective and industrially viable strategy to improve bioavailability and dissolution performance.

Methods: CLN-NCs were prepared by antisolvent precipitation coupled with high-speed homogenization. Stabilizers (PVPk30, mannitol), drug concentrations, and flow rates were systematically optimized. The lead formulation (F19) was characterized for particle size, saturation solubility, and dissolution rate. Solid-state properties were evaluated using SEM, XRPD, DSC, and FTIR to confirm crystalline stability.

Results: The optimized NCs (F19) exhibited a nanosized particle diameter (19.1 ± 3.8 nm), a 3.3-fold increase in saturation solubility, and a 4.1-fold faster dissolution rate compared to raw CLN. XRPD and DSC confirmed retained crystallinity, while FTIR revealed no drug-stabilizer interactions. SEM showed uniform morphology with no aggregation.

Conclusions: CLN-NCs significantly improved in vitro solubility and dissolution, demonstrating a scalable preparation method suitable for industrial translation. This approach offers a promising pathway to enhance CLN's therapeutic efficacy in hypertension management.

Objective: This study aimed to compare the dissolution kinetics of sustained-release bolus tablets formulated with different pharmaceutical binders using two systems-the continuous-flow artificial saliva rig and the Ankom Daisy II incubator-to evaluate how the experimental setup influences the interpretation of release behavior and kinetic modeling.

Significance: A precise understanding of method-dependent variations is critical for designing reliable sustained-release veterinary formulations. By isolating the effect of the testing environment itself, this study provides a methodological perspective that enhances the predictive accuracy of in vitro systems and supports the development of cost-effective, sustainable approaches in ruminant drug delivery research.

Methods: Bolus tablets containing 1% or 2% binder (starch, polyvinylpyrrolidone-PVP, or gum acacia-GA) were tested using a continuous-flow artificial saliva system and the Daisy II incubator with real rumen liquor. Granule morphology, particle size, bulk density, and mechanical strength were characterized. Dissolution kinetics were analyzed through standard models, and the model fits were evaluated using R² and AIC parameters.

Results: The binder composition and test environment had a significant impact on the release profiles. Starch-based bolus tablets dissolved rapidly, PVP showed moderate release, and GA provided prolonged, steady release. The Daisy II incubator produced stronger model correlations, with the 2% GA formulation showing the best fit (R²=0.9909, AIC=-71.08). The higher binder concentrations improved granule compactness and hardness.

Conclusions: The binder type and concentration strongly influence dissolution kinetics, while the testing environment determines release predictability. Gum acacia at 2% concentration achieved the most controlled and stable release, and the Daisy II incubator most accurately simulated rumen conditions for predictive in vitro evaluation.

Objective: The research is aimed at fulfilling long-term and high-performance synergistic anticancer effects of 5-fluorouracil (Flu), opening up new horizons for drug-nutrient cocrystal formulation.

Methods: An integration strategy of cocrystallization and micellar preparation techniques is established. The former targets to play synergistic effects by introducing nutriment ferulic acid (FR), and meanwhile, enhances the interplay with polymers to promote efficient encapsulation, whereas the latter focuses on the modulation of release behavior. Based on this clue, cocrystal Flu-FR-H₂O with synergistic ability is loaded in carriers to prepare cocrystal nanomicelles. The cocrystal nanomicelles were characterized by dynamic light scattering (DLS) and transmission electron microscope (TEM), with the in vivo/vitro biopharmaceutical properties evaluated.

Results: The obtained nanomicelles exhibit preferable encapsulation efficiency, as supported by theoretical simulation calculations. This higher efficient entrapment has positive impacts on antitumor efficacy and pharmacokinetic behavior. Particularly, the cocrystal micelles can provide sustained-release ability, thus facilitating the lasting-efficacy.

Conclusion: This investigation exemplifies the availability of the integrated strategy in realizing transformation of Flu-nutraceutical cocrystal dosage form, therefore contributing to the technical support for synergistic antitumor pharmaceutical cocrystal formulations.