Journal of Pharmaceutical Innovation最新文献

Purpose

The research aimed to develop nisin-silver nanoconjugates within a dissolving microneedle formulation using green synthesis chemistry and solvent casting methods. The objective was to assess potential of these nanoconjugates to enhance antimicrobial efficacy against gram-positive and gram-negative bacteria, such as Bacillus subtilis and Escherichia coli, offering an alternative to conventional antibiotics that often cause resistance and side effects.

Methods

Nisin-silver nanoconjugates were developed using green synthesis chemistry and incorporated into dissolving microneedles through solvent casting methods. Optimization was conducted using 3² factorial design. Characterization included measuring particle size (288 ± 5.49 nm), polydispersity index (0.381 ± 0.57), and zeta potential (-21.4 ± 1.54 mV). ATR-FTIR studies confirmed conjugation by identifying a characteristic C-O-C stretch peak at 1019 cm^-1, and DSC studies revealed an endothermic peak at 242 °C. The microneedle formulation was tested for in-vitro release of Nisin Z over 48 h. Antimicrobial efficacy was assessed using agar disc diffusion method, demonstrating significant zones of inhibition against Bacillus subtilis, Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa.

Results

The microneedle formulation (DMN 3) showed in-vitro release of 85.03 ± 0.53% over 48 h. The antimicrobial efficacy tests showed significant inhibition zones for Bacillus subtilis (20 ± 0.5 mm), Escherichia coli (12 ± 4 mm), Staphylococcus aureus (19 ± 4 mm), and Pseudomonas aeruginosa (11 ± 3 mm).

Conclusion

The study successfully developed nisin-silver nanoconjugates incorporated into dissolving microneedles. These nanoconjugates demonstrated synergistic antimicrobial action, showing promise for treating bacterial infections effectively. This suggests they could be viable alternative to traditional antibiotics, potentially reducing the risks of resistance and side effects associated with conventional treatments.

Purpose

Inhibitors of the calciprotein particle (CPP) maturation have been developed so far as therapeutics for vascular calcification. However, the short blood half-life limited their application. Here we designed the conjugate of a CPP maturation inhibitor, alendronate (ALN) with human serum albumin (HSA) to utilize the long blood retention nature of HSA.

Method

The HSA-ALN conjugates with different modification numbers of ALN per HSA were prepared. The inhibitory effect of the conjugates on the CPP maturation was evaluated using a reported cell-free system as a time of conversion from CPPI to CPPII. The CPP binding of fluorescent-labeled conjugates was carried out using flow cytometry. The plasma half-life of the conjugates was evaluated in mice after intravenous injection.

Results

We found that the HSA-ALN conjugates bound to CPP via the specific interaction between ALN and calcium phosphate of CPP. As a result, the conjugates showed a much higher inhibition effect of CPP maturation than those of free ALN and intact HSA. A modification ratio of two ALN molecules per HSA was found to be significant enough to inhibit the CPP maturation. Such a small modification ratio minimized the impact on the long blood retention nature of HSA.

Conclusion

This study showed that HSA-ALN conjugates not only have superior CPP growth inhibition effects but also possess significantly higher blood half-lives compared to those of free ALN. These findings suggest that HSA-ALN conjugates are promising therapeutics for vascular calcification associated with the deposition of CPP.

Purpose

This study aims to develop and evaluate a micellar in situ gel formulation of ketoconazole for ocular drug delivery, to enhance solubility, prolong retention time, and improve therapeutic efficacy against fungal eye infections.

Methods

A micellar-based, ion-sensitive in situ gel system was prepared using the solvent evaporation technique. The micelles were formed by incorporating Pluronic F127 and chitosan for ketoconazole solubilization, and sodium alginate was added to impart ion sensitivity. The micellar system was optimized using a central composite design and evaluated for particle size, surface morphology, and drug entrapment efficiency. The in-situ gel was characterized for its appearance, gelation capacity, pH, viscosity, drug content, in vitro release, sterility, and stability.

Results

The optimized formulation exhibited an average particle size of 161.1 ± 2.4 nm with uniform dispersion, and a zeta potential of + 11.7 ± 0.4 mV, indicating favorable stability and bioadhesion. The entrapment efficiency was 81.44 ± 3.6%, indicating effective solubilization of ketoconazole within the micellar core. The in vitro release study demonstrated a sustained release profile, with 91 ± 2.4% of the drug released over 12 h. The in-situ gel exhibited prolonged stability for 30 days, good ocular tolerance, and extended drug retention time.

Conclusion

The ketoconazole-loaded micellar in situ gel formulation represents a promising approach for ocular drug delivery, offering sustained drug release and enhanced therapeutic efficacy. This formulation has the potential to improve patient compliance by reducing dosing frequency and enhancing ocular bioavailability, ultimately providing an effective treatment for fungal eye infections.

Purpose

The solid dispersion (SD) method has long been used to solubilize poorly soluble drugs in aqueous solutions. The aim of this study was to develop a celecoxib (CXB) dual polymer multisystem with CXB solubility characteristics, using the SD method. The hypothesis was: changing the pH environment of CXB in SD formulations using a Neusilin®UFL2 and maximizing solubilization through dual polymer.

Methods

The CXB SD formulations were prepared with carrier and dual polymer by solvent evaporation method. The optimal SD formulation were evaluated the physicochemical properties such as thermal change, crystallinity, and drug-excipient interaction.

Results

The optimal SD formulation (SD4, CXB:UFL2®:PVP/VA S630:K12®:chitosan = 1:1:0.5:0.5:0.5, weight ratio) significantly improved the dissolution (%) of CXB compared with the dissolution achieved using the commercial product (Celebrex®) in various dissolution media. The structure of CXB in the SD4 formulation changed from crystalline to amorphous, and intermolecular interactions between CXB and the excipients were confirmed. The SD4 formulation was shown to be stable for 12 months.

Conclusions

A novel CXB solubilization method using a dual polymer multisystem was tested and found to be effective; the results showed improved stabilization compared with the conventional method. These results are likely due to changes in the pH environment, drug crystallinity, and intermolecular interactions between CXB and the excipients. Further investigation of the SD4 formulation as well as animal studies are warranted, in order to test whether oral bioavailability is higher than that of Celebrex®.

Objective

Ginsenoside compound K (GCK) is a drug with various pharmacological activities and can be used to treat a wide range of diseases. However, water solubility and low membrane permeability, which reduces its permeability in the body and limits its clinical application. To overcome these drawbacks, nanostructured lipid carriers (NLCs) with optimal process prescription were prepared and evaluated in this study.

Methods

Molecular dynamics (MD) simulations were applied to screen the excipients and investigate the blend system. GCK-loaded NLCs (GCK-NLCs) were prepared by high pressure homogenization method, and the morphology was observed by transmission electron microscopy. Differential scanning calorimetry, X-raydiffraction, fourier transform infrared spectroscopy were used to investigate the presence of GCK in GCK-NLCs. The in vitro release study was performed by dialysis, and in vivo studies using in situ intestinal perfusion were investigated in rats.

Results

The prepared GCK-NLCs particles were spherical with smooth surface, particle size of about 128.3 ± 0.9 nm, PDI of 0.202 ± 0.017 and encapsulation efficiency of 92.8%. Spectral analysis showed that the drug was amorphous and was successfully encapsulated in the lipid cavity. In vitro release studies showed that GCK-NLCs exhibited high release characteristics. Single-pass intestinal perfusion experiments showed that GCK-NLCs were absorbed predominantly in the small intestine and the prepared GCK-NLCs enhanced the permeability of the drug.

Conclusion

NLCs formulation can be used as a good delivery system to enhance the solubility and permeability of GCK and provides a promising nanocarrier for the prolonged release of hydrophobic drugs.

Purpose

Efonidipine hydrochloride ethanolate (EHE) is a third-generation dihydropyridine calcium channel blocker, used to treat hypertension. Despite its therapeutic efficacy, EHE suffers from low aqueous solubility (less than 10 µg/mL) and oral bioavailability, which restrict its clinical impact. To address these limitations, this study employed a co-crystallization approach to enhance EHE’s solubility while maintaining its molecular structure intact.

Methods

Co-crystals of EHE with malonic acid (MA) and tartaric acid (TA) were prepared using solvent evaporation method with equimolar concentrations of EHE and the respective co-formers. The resulting malonic acid co-crystals (MAC) and tartaric acid co-crystals (TAC) were extensively characterized in terms of fourier-transform infrared spectra (FTIR), NMR, powder X-ray diffraction patterns (PXRD), differential scanning calorimetry thermogram (DSC), solubility/dissolution, and docking analysis. Further, in vivo pharmacokinetics and pharmacodynamics studies were performed in Wistar rats.

Results

The DSC, PXRD, and FTIR of MAC and TAC co-crystals unequivocally confirmed the formation of co-crystals. These co-crystals exhibited a 25- and 12-fold increase in solubility, coupled with significantly enhanced dissolution rates. Molecular docking studies indicated favorable binding energies between EHE and TA (− 0.65 kcal/mol) and MA (− 0.24 kcal/mol). Additionally, 1 H NMR spectroscopy validated the formation of a distinct phase. In bioavailability and anti-hypertensive studies conducted in Wistar rats, MAC and TAC demonstrated a 2- and 2.5-fold increase in AUC_0−∞, respectively, alongside notable reductions in mean atrial blood pressure, systolic blood pressure, and diastolic blood pressure compared to pure EHE.

Conclusion

The findings suggest that co-crystallization represents an effective strategy to enhance the dissolution rate, oral absorption, and clinical applicability of drugs with low solubility such as EHE.

Graphical Abstract

Purpose

Pharmaceutical three-dimensional (3D) printing is an innovative production technique which enables the manufacturing of personalized medicine at the point-of-care. A reliable 3D printer is paramount for the successful implementation in clinical practice. In this paper, the design strategy of a pharmaceutical semi-solid extrusion 3D printer is described, where the concept of quality-by-design is applied.

Methods

The technical design stages are divided in the conceptual design and detailed design stage. The minimal viable product, critical process parameters and implemented control strategies were defined.

Results

The critical process parameter with the highest impact is the temperature of the cartridge during preheating, i.e. prior to the production process. The temperature is controlled with an accurate thermistor, closed feedback loop and thermal isolation. The temperature can be monitored at all times using the graphical user interface and there is an audit trail using the logging system. Software was developed conforming to GAMP5.

Conclusions

Build-in control strategies in the design of the pharmaceutical 3D printer can mitigate risks during the production process of personalized medicine. The regulatory landscape surrounding 3D-printed drug products remains challenging. By using this design approach, relevant guidelines were taken into account during the design of a pharmaceutical 3D printer. Future development of the 3D printer should include the incorporation of process analytical technology tools and upscaling of feedstock production to further support the implementation of personalized medicine 3D-printed at the point-of-care.

Purpose

Heart failure, a progressive cardiovascular disorder, significantly affects patient morbidity and mortality. Valsartan, an angiotensin II receptor antagonist, is widely used to mitigate the effects of heart failure, but its oral administration faces challenges such as poor solubility and variable bioavailability. The purpose of this study was to develop and enhance a sublingual fast-dissolving Valsartan tablet via excluding the gastrointestinal tract (GIT) and using a quality by design (QbD) approach to achieve fast drug dissolution.

Methods

A three-factor, two-level Box-Behnken Design (BBD) was employed to investigate the influence of Sodium Starch Glycolate (SSG), Crospovidone (CP), and Croscarmellose Sodium (CCS) on disintegration time (DT) and cumulative drug release. Response Surface Methodology (RSM) was used to model the interactions between these factors and optimize the formulation.

Results

The optimized formulation (OVSF-18) comprised 9 mg of SSG, 9 mg of CP, and 6.44 mg of CCS, achieving a rapid disintegration time of 33.33 seconds and a cumulative drug release of 92.33%. Statistical analysis confirmed the robustness of the model, with an Adjusted R² of 0.9961 for DT and 0.9806 for drug release, and a desirability score of 0.998. The formulation was validated experimentally, with minimal deviation from predicted values. This optimized sublingual tablet formulation addresses the limitations of oral administration by enhancing Valsartan’s bioavailability and therapeutic efficiency.

Conclusion

Unlike prior studies, this work presents a novel application of the QbD approach in developing sublingual tablets of Valsartan, achieving rapid disintegration and enhanced drug release. This optimized formulation is designed to address the urgent need for patient-centric dosage forms in heart failure management, providing a faster onset of action compared to conventional formulations.

This study introduces a novel application of the Quality by Design (QbD) approach to systematically develop and optimize sublingual tablets of Valsartan, addressing the limitations of conventional trial-and-error formulation methods. By employing Box-Behnken Design (BBD), the study achieved significant advancements in formulation performance, including rapid disintegration (within 33 seconds) and 92.33% drug release in 15 minutes. These results highlight the clinical relevance of the optimized formulation for providing rapid therapeutic action in heart failure management. This work bridges a critical gap in patient-centric sublingual dosage forms, offering a robust and reproducible approach for future pharmaceutical innovation.

Graphical abstract

Purpose

The purpose of the present work was to optimize the formulation of extended-release, metformin-loaded ionically-gelled propyl Moringa gum beads.

Method

The metformin-loaded beads of propyl Moringa gum were prepared by ionotropic gelation method employing calcium chloride as a cross-linking agent. A three-factor three-level central composite experimental design was applied to obtain the optimized batch of beads with maximum %yield, drug entrapment and extended-release over 24 h. The optimized batch of beads was characterized by Fourier-transform infra-red spectroscopy, X-ray diffraction, scanning electron microscopy, swelling, and mucoadhesive behavior.

Results

The optimized batch of beads contains propyl Moringa gum – 5.916 (%w/v), calcium chloride – 11.779 (%w/v), and metformin – 25 mg. The % yield and drug entrapment efficiency of polymeric beads were found to be 124.31% and 62.83% respectively. X-ray diffraction patterns revealed the crystalline behavior of an optimized batch of metformin-loaded propyl Moringa gum beads. The scanning electron micrographs demonstrated the oblong-shaped and granular surface of polymeric beads. The optimized batch of polymeric beads exhibited pH dependent release with faster release in distilled water, pH 1.2, and 4.5 medium while sustained release at pH 6.8. The beads also showed good ex vivo mucoadhesive properties.

Conclusion

The optimized batch of ionically gelled propyl Moringa gum beads showed excellent potential for extended-release formulation of metformin. However, further in vivo studies are needed to explore its commercial potential.

Background

The acceptability of oral medication by children is crucial for ensuring compliance and therapeutic effectiveness while decreasing relapse and treatment expenses.

Methods

A cross-sectional study using a web-based questionnaire was conducted in Jordan to explore acceptability factors affecting oral pediatric medications based on caregivers’ observations. The questionnaire consisted of four main parts to capture participants’ demographic data, participants’ preferences related to formulation excipients (color, flavor, odor, etc.), packaging components (packing shape, leaflet, dosing device, etc.), and acceptability factors associated with less common dosage forms (chewable, effervescent, and modified release formulations).

Results

According to caregivers’ responses, children prefer oral liquid medication with low viscosity, having strawberry and chocolate flavor, red or pink color, and strawberry and chocolate odor. Caregivers prefer lightweight toy-shaped containers with drawings in the outer pack. The leaflet should contain simplified dosing calculations and illustrations, while the dosing device and water for reconstitution must be part of the pack. Caregivers also prefer toy-shaped chewing tablets with strawberry or chocolate flavor and red or pink color.

Conclusion

The survey results summarize the preferences regarding the formulation and packing requirements in order to achieve acceptable oral liquid medication drugs for children, leading to shorter treatment times while decreasing the cost of treatment. The survey results also shed light on the concerns of caregivers regarding the safety of coloring agents and preservatives. The collaboration between caregivers, academia, and manufacturing companies can accelerate the development of an acceptable oral medication for children, leading to effective, safe, and short pediatric treatment.