Drug Development and Industrial Pharmacy最新文献

Objective: This work aimed to prepare spanlastics nanovesicles (SNVs) loaded with gliclazide (GCZ) to increase the drug's oral bioavailability and anti-diabetic effects.

Methods: Two types of edge activators (tween 80 and/or brij35) and two types of spans (span 60 and span 80) were used to prepare SNVs using the ethanol injection method,2³ factorial design was used to investigate the effects of various span types, edge activator types, and the ratio of span to edge activator.

Results: The optimum formulation (F6) was selected and its in-vitro drug release, in-vivo pharmacokinetics, and pharmacodynamics were evaluated. A transition electron microscope (TEM) showed spherical particles with smooth surfaces, (F6) drug release was (Q₁₂ 97.05 ± 4.85) while GCZ powder was (97.89 ± 4.56 after 4 h) also showed better entrapment efficiency (EE% 95.1 ± 3.8). In- vivo pharmacokinetic study showed an increase in C_max and t_max (12.93 ± 1.34, 3.2 ± 0.83) compared to unprocessed GCZ powder (2.88 ± 1.59, 1.8 ± 0.74). In-vivo pharmacodynamics study of diabetic rats demonstrated that GCZ-loaded SNVs has a higher % maximum decrease in blood glucose levels (MR) 58.31 ± 5.70 compared to 38.33 ± 8.18 for free drug and % total drop in blood glucose levels (TD) 25.78 ± 5.31% for GCZ-SNVs compared to 20.26 ± 6.05% for free drug. Histopathological examination revealed no cytotoxic signs in any of the examined samples.

Conclusion: Results revealed a significant rise in relative bioavailability, sustained and prolonged drug release when compared to the unprocessed GCZ powder.

Objective: The aim of this work was to identify, optimize, and use nondestructive process to develop nano-formulation using polyelectrolyte complexation (PEC) between polymeric nanocarrier and bovine serum albumin.

Significance: Proteins are mostly degraded during preparation and loading into nano-carriers which hinders success in protein delivery.

Method: Herein, novel PEC consisting of model protein BSA and nanogels (NGs), were prepared to form self-assembled polyelectrolyte nanocomplexes (BSA/NGs-PEC). The BSA/NGs-PEC were obtained by mixing BSA and nanogels at various weight ratios (1:2, 1:4, 1:5, 1:6, 1:8, 1:10), pH values of solution (1.2, 4.0, 6.0), incubation time (2, 4, 6, 8 h), and stirring rate (without, 100, 200 rpm). The prepared PEC were evaluated for particle size (PS), polydispersity index (PDI), zeta potential (ZP), and percentage of complexation efficiency (%CE). To study insights into structural integrity and biological activity, the SDS-PAGE and esterase activity assay was performed on BSA released from final optimized formulation.

Results: The optimized parameters were BSA/nanogels mixing ratios at 1:8, pH of complex-forming medium at 4.0, incubation time of 6 h, and stirring rate at 100 rpm. The SDS-PAGE and esterase activity assay revealed that the primary structure and bioactivity, respectively, of BSA was still intact.

Conclusion: The results suggest that current scheme for optimization has considerable potential for creating protein-based delivery system by using PEC via electrostatic interaction.

Objective: To enhance solubility and bioavailability of GM, an inclusion compound of glimepiride/hydroxypropyl-β-cyclodextrin (GM/HP-β-CD) was prepared using mechanical ball milling.

Significance: Based on response surface optimization for the ball milling preparation of the inclusion compound, this study investigates its in vitro and in vivo release and pharmacokinetics.

Methods: GM/HP-β-CD inclusion compound was prepared by optimized ball milling based on response surface methodology and characterized using powder x-ray diffraction, differential scanning calorimetry, scanning electron microscopy, and Fourier transform infrared spectroscopy, and the stability of the compound was studied. In addition, GM/HP-β-CD inclusion compound's in vitro release and in vivo release assays were performed.

Results: Optimal ball milling conditions for a 1:1 molar ratio of GM/HP-β-CD were a milling speed of 296 rpm, a milling time of 88 min, and a filling rate of 17.7%. Solubility and dissolution rate experiments indicated that the solubility of the GM/HP-β-CD inclusion compound was 20 times higher than that of GM, and the dissolution rate was 12.7 times faster. Additionally, the thermal stability and photostability of the inclusion compound were improved. In vivo pharmacokinetics and pharmacodynamics studies showed that, compared to GM, the GM/HP-β-CD inclusion compound shortened the T_max by 1 h, increased the maximum plasma concentration by nearly 3.5 times, and significantly enhanced bioavailability.

Conclusion: GM/HP-β-CD inclusion compound demonstrates potential for developing sustained-release formulations, thereby prolonging the hypoglycemic effect of GM, reducing dosing frequency, and improving patient compliance with oral administration.

Objective: The purpose of the present study was to apply the design of experiments (DoE) to develop an omeprazole enteric pellets suspension for use in the pediatric population.

Methodology: This experimental study employed a Full Factorial Design for drug development, encompassing three factors (Aerosil^® R972, cetostearyl alcohol, and Span 80) at two levels (2% and 6% for factor A (Aerosil^® R972) and 2% and 4% for factors B and C (cetostearyl alcohol and Span 80, respectively)).

Results: Following the statistical optimization, the suspension F10 was formulated and subjected to a stability study for one month. The dissolution test results were suboptimal, achieving only an 22% release. Subsequently, eight additional suspensions were devised using hydrophilic oily vehicles (Labraphac Hydrophile WL 1219, Labrafil M2125 CS, and Labrafil M 1944 CS) and excipients (Gelucire 44/14 and Aerosil^® 200) to enhance the dissolution profile. Suspension F17 showed over 75% within 30 min, displaying superior sedimentation time when compared to all other formulations, along with effortless resuspension.

Conclusion: The findings suggest that the optimal vehicle for the administration of omeprazole enteric pellets in suspension is the formulation comprising Labrafil M 1944 CS, Span 80, and Aerosil^® 200. This study has paved the way for an oily suspension vehicle, opening new avenues of research for developing pediatric omeprazole formulations that fulfill gastro-resistance requirements.

Objective: To enhance the solubility of Montelukast sodium using three generation polymers by solid dispersion method.

Material and method: Montelukast sodium with selected generation of carriers were used for phase solubility and to optimize the stoichiometric ratio for the preparation of SD with MS. Various characterization techniques (FTIR, DSC and XRD) have been used to evaluate the MS-SD formulations with selected hydrophilic carriers. Dissolution and stability study were also investigated.

Result and discussion: The two best-selected formulations (MS-PVP & MS-HPMC SD) have shown the highest dissolution profile as compared to pure drug, physical mixture and commercially available marketed product (Montel-10, Cipla). The FTIR, DSC and XRD results of these SD formulations have shown interaction between drug and polymers, decrease in enthalpy compared to the drug and amorphous behavior respectively. Finally, MS-PVP & MS-HPMC SD formulations have shown good stability for one-month period under accelerated storage condition.

Conclusion: The study showed increase in solubility of Montelukast sodium with second generation polymers (PVP & HPMC) in comparison to pure drug as well as marketed formulation.

Objective: In the current research work, we synthesized triamcinolone acetonide palmitate (TAP), a lipophilic prodrug of triamcinolone acetonide (TA) and formulated it into lipid nanospheres (TAP-LN) to improve pharmacokinetics and tissue distribution on intravenous administration.

Significance: Triamcinolone acetonide is a parenteral glucocorticoid used to treat several inflammatory disorders. It has a short plasma half-life (2-3 h) and its parenteral administration causes severe side effects.

Methods: -TAP-LNs were composed of soy lecithin, soybean oil, Miglyol 812N as a lipid phase and poloxamer 188 and glycerol in distilled water as an aqueous phase. The coarse emulsion was subjected to probe sonication followed by a microfluidizer by applying 20,000 psi pressure with 10 cycles. Similarly, TAP-lipid microspheres (TAP-LMs) were prepared for comparative study without microfluidization.

Results: The optimized TAP-LN exhibited a size of 106.8 nm, zeta potential of -45.7 mV, and entrapment efficiency of 82.35%. A pharmacokinetic study showed that in rats, TAP-LN exhibited a 4.5-fold plasma concentration and 10-fold AUC_0-t than TAP-LMs. The slow clearance of TAP-LN could be associated with lower uptake by eliminating organs that eventually increased the residence time. In the spleen, TAP-LM concentrations were higher than TAP-LN; TAP-LN could not be detected in the liver, unlike TAP-LM, attributing to the carboxylesterase lipase, the metabolizing enzyme responsible for the conversion of TAP to TA.

Conclusion: Thus, TAP nanospheres showed improved pharmacokinetic parameters and reduced tissue distribution, which would benefit the intravenous treatment of this glucocorticoid.

Background: Buspirone is a critical in treatment for generalized anxiety disorder (GAD), but the synthesis of its key intermediate, 2-(piperazin-1-yl) pyrimidine faces challenges in terms of cost, yield and purity. Traditional synthesis methods are hindered by high material costs and significant by-product formation, necessitating a more efficient and economical approach.

Objective: To develop a novel, cost-effective synthesis strategy for the 2-(piperazin-1-yl) pyrimidine intermediate that improves yield and purity while reducing production costs and environmental impact.

Methods: A four-step synthesis process was optimized as follows: First, piperazine reacts with sulfuric acid and cyanamide, followed by precipitation with cold methanol. Next, 1,1,3,3-tetramethoxypropane reacts with hydrochloric acid and amidine, and the mixture was extracted with dichloromethane (DCM). In the third step, the product was dissolved in isopropanol (IPA), treated with charcoal and converted to the oxalate salt using oxalic acid. Finally, the oxalate salt was converted to the freebase with ammonia, followed by a final extraction with DCM. Key variables such as reagent equivalents, reaction conditions and purification techniques were systematically optimized throughout the process.

Results: The optimized process achieved a purity level of over 99% and reduced production costs by 25-30%. Significant improvements included controlled bis-product formation with cyanamide, effective addition of 1,1,3,3-tetramethoxypropane and efficient removal of by-products through oxalate salt formation and charcoal treatment.

Conclusion: The developed synthesis method for 2-(piperazin-1-yl) pyrimidine was both cost-effective and efficient, significantly enhancing the yield and purity. This method is highly suitable for large-scale pharmaceutical production, aligning with industry goals of improved process efficiency, cost reduction and environmental sustainability.

As the global demographic shifts toward an aging society, the geriatric patient population is steadily increasing. These patients often suffer from comorbidities and require numerous oral medications, which can be especially challenging for dysphagic geriatric patients. Mucoadhesive buccal films (MBFs) seem promising and could reduce pill burden, simplify administration, and enable individualized drug therapy. This review aims to explore the age-related changes in the oral cavity and their impact on MBF delivery, including potential strategies to overcome these age-related barriers to drug delivery. It was observed that aging impacts the oral mucosa as well the properties of the saliva. There are several studies in the application of buccal films including the use of a wide range of permeation enhancers. The 3D printing of buccal films seems to introduce dosing flexibility to buccal film manufacturing.

Background: Skin delivery of a therapeutically effective drug is imperative for local cutaneous leishmaniasis (CL) treatment.

Objective: This study aimed to formulate, optimize, and characterize curcumin-loaded nanoemulgel for enhanced skin drug retention to treat CL locally.

Methods: Nanoemulsions were prepared by high-speed homogenization, characterized, and optimized for size, PDI, zeta potential, stability, morphology, drug contents, encapsulation efficiency, in vitro drug release, antileishmanial activity, and cell viability. The optimized nanoemulsion (C3) was then incorporated into a carbopol-based gel and evaluated for pH, viscosity, spreadability, and in vitro drug release. Both formulations were then assessed for ex-vivo and in vivo skin permeation/retention, and pharmacokinetic analysis.

Results: All nanoemulsion formulations had size in nano range with negative surface charge, homogeneously distributed, with spherical droplet geometries, where C3 being highly stable, had good encapsulation efficiency and drug contents (85 ± 5.4 and 68 ± 3.2%), released 90% of drug within 4 h, while C3 gel released the drug significantly sustained up to 46% in 24 h. The C3 formulation demonstrated significant in vitro antileishmanial activity across all tested concentrations, while the IC₅₀ value against NIH3T3 fibroblasts was 0.6202 mM (Log IC₅₀: 2.7, R²: 0.98). The C3 gel showed significantly low skin permeation (341.7 ± 43.6 and 52.6 ± 8.9 µg) with significantly higher skin drug retention (129.5 ± 16.7 and 190.2 ± 33.4 µg) ex-vivo and in vivo, with significantly lower C_max, AUC_0-t, and AUC_0-∞.

Conclusion: These results suggested that curcumin nanoemulgel could be an effective alternative strategy for treating CL locally.

Objective: The fabrication of furosemide (FSM) with enhanced oral bioavailability and encapsulation was achieved using a nanostructured lipid carriers (NLCs) drug delivery system.

Significance: The uniform drug distribution is a barrier due to its low dose. The lipid-based delivery system was selected based on its poor solubility and permeability, limiting its poor partitioning and solubility in water-based polymeric delivery systems. The lipophilicity of the FSM makes it favorable to partition with triglyceride-based Compritol 888 ATO and oleic acid with minimized drug expulsion, high drug payload, and sustained release over extended time frames.

Methods: The Organic and aqueous phases of the microemulsion were stabilized using Tween 80, a hydrophilic surfactant. Box-Behnken design-based optimization was done using alteration in various formulation variables to obtain nano-formulation with the lowest particle size and polydispersity, maximal zeta potential and entrapment efficiency.

Results: Design-Expert yielded several optimized formulations with the desirability function. Maximum desirability was obtained at a particle size of around 178 nm, a surface charge of -19.6 mV, and an EE of above 85%.The in vitro release profile depicted 86.5% of cumulative release after 24 h whereas, in vivo pharmacokinetic study revealed an increase in C_max from 0.48 µg/mL (FSM-Suspension) to 0.77 µg/mL (FSM NLCs) to increase the bioavailability to approx. 241% in FSM NLCs. The half-life escalation demonstrated that the residence time of the nanoparticles prolonged at the physiologic pH.

Conclusions: FSM-NLCs exhibited sustained release over a prolonged period, improved residence time in the body, and their action was prolonged.