Journal of Pharmaceutical Innovation最新文献

Purpose

To examine the U.S. Food and Drug Administration (FDA) historical role in regulating unapproved drugs with a focus on the Drug Efficacy Study Implementation (DESI) program and to assess how its outcomes influenced the development of approval pathways for pharmaceutical products.

Methods

This review analyzes DESI’s origin under the 1962 Kefauver–Harris Amendments and traces its impact on subsequent FDA approval mechanisms, including the Abbreviated New Drug Application (ANDA) and the 505(b)(2) pathway. A structured literature and regulatory document search was performed.

Results

DESI categorized pre-1962 drugs into efficacy-based classes, guiding market continuation or withdrawal. These determinations laid the groundwork for modern pathways (ANDA and 505(b)(2)), enabling older drugs to transition into compliance. However, DESI was often slow, leading to delayed withdrawals, shortages, litigation, and price increases.

Conclusion

DESI served as a historical model for structured drug evaluation but is unlikely to be revived. Instead, modern regulatory tools (NDA, ANDA, 505(b)(2)) are intended to confirm that a drug product meets standards for safety, efficacy and quality (CMC-Chemistry, Manufacturing and controls). A simplified re-approval pathway—transparent, time-bound, and globally adaptable—could strengthen efforts to address unapproved drugs while minimizing shortages and protecting public health.

Purpose

This study aimed to develop a thermoreversible in situ nasal gel of lithium citrate to achieve sustained release and improve nose-to-brain delivery potential for the treatment of bipolar disorder.

Method

Nine formulations of in situ gel of Tri-lithium citrate tetrahydrate were prepared by cold method using polymers carbopol 940 and poloxamer 407 based on 3² factorial design. The gel was characterized using gelation temperature and gel melting temperature, spread ability, mucoadhesion, in vitro permeability, in vitro diffusion, ex vivo permeability study. Histopathological and pharmacodynamic studies were performed only on the optimized formulation to assess nasal mucosal safety and behavioral efficacy in a ketamine-induced mania model.

Result

The optimized formulation exhibited a gelation temperature of 32–34 °C, mucoadhesive strength of 5825–7074 dyne/cm², and gel strength of 5.3–6.4 g. In vitro studies demonstrated 98–100% drug release within 7–8 h, while ex vivo permeation through sheep nasal mucosa showed 90% release in 8 h, following a Korsmeyer–Peppas model (R² = 0.9988; n = 0.67). Histopathological studies indicated that there was no indication of haemorrhage, necrosis, or ulceration in the nasal mucosa, whether it was treated with lithium citrate or left untreated. The trajectory data obtained by radial arm maze clearly showed higher movement of animals under study treated with controlled formulation (pseudo formulation without drug), entering almost every arm of the apparatus.

Conclusion

The optimized lithium citrate nasal gel exhibits favorable thermogelling, mucoadhesive, and sustained-release characteristics, along with acceptable mucosal safety. While pharmacodynamic outcomes suggest potential for enhanced nose-to-brain delivery, definitive evidence of brain targeting will require further pharmacokinetic quantification of lithium in brain tissues.

Tuberculosis infected 10.8 million people worldwide in 2023, resulting in 1.09 million deaths. Rifampicin (RIF) is one of the main drugs used in the treatment, but its low solubility and side effects, such as hepatotoxicity, limit its therapeutic efficacy. Polymeric nanoparticles (PNs) emerge as a promising strategy to optimize RIF delivery. This study aimed to develop RIF-PNs guided by molecular dynamics (MD), perform their physicochemical characterization and evaluate their in vitro cytotoxicity. MD allowed observing the molecular interactions between the components of the formulation and led to the formation of PNs. The PNs presented an average size of 177.0 ± 0.80 nm, polydispersity index of 0.094 ± 0.046, zeta potential of -15.0 ± 0.65 mV, encapsulation efficiency of 20.98% and drug loading of 2.29%, with colloidal stability maintained for up to 180 days. The physicochemical characterizations indicated the polymorphic form II of RIF, amorphous pattern of ethylcellulose (EC) and encapsulation of RIF in PN. Atomic force microscopy observed a spherical shape of the particles with a size of 38.4 ± 14.6 nm. RIF-EC-PN presented a sustained release profile with release of 20.65 ± 0.44% in 24 h and and the unencapsulated RIF demonstrated a release of 90.75% in 15 min. Cell viability was demonstrated in monkey renal epithelial cells (LLC-MK2). PNs showed favorable properties as RIF delivery systems.

Graphical Abstract

Background

Curcumin, a bioactive extracted from turmeric (Curcuma longa L.), has been used in traditional medicine for its anti-microbial and antioxidant activity. However, curcumin’s poor water solubility limits its bioavailability when taken orally. This study aimed to enhance curcumin’s dissolution by adsorbing the drug onto a pharmaceutical carrier.

Methods

Curcumin was dissolved in a cosolvent containing ethanol and acetone (1:3 v/v), then added dropwise to the adsorbent under wet grinding. The wet mass was then dried at 60 °C for 2 h and passed through a 35-mesh sieve. Various adsorbents, i.e., lactose monohydrate, mannitol, microcrystalline cellulose, and silica dioxide, at differing drug-to-carrier ratios were used to investigate their effect on the dissolution of the curcumin-loaded adsorption powders.

Results

Curcumin adsorbed onto lactose monohydrate at a 1:10 curcumin: lactose ratio exhibited higher dissolution than pure curcumin and other adsorption systems. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) spectra showed that curcumin was in amorphous form in the lactose-based system. Scanning electron microscopy (SEM) imaging demonstrated curcumin’s successful adsorption onto lactose monohydrate with smaller drug particle size. Fourier-transform infrared (FTIR) analysis confirmed the presence of hydrogen bonding interactions between curcumin and the adsorption carrier. Stability studies indicated that the curcumin-lactose monohydrate adsorption system maintained its dissolution profile and amorphous state after 6-month storage under accelerated conditions (40 °C and 75% RH).

Conclusion

The adsorption method effectively enhanced curcumin’s dissolution, which could subsequently improve its oral bioavailability.

Purpose

This research investigated the formulation and optimization of a candesartan cilexetil ethosomal gel, with an emphasis on improving patient adherence and medication delivery. This study investigated the transdermal administration of candesartan cilexetil using ethosomes as a colloidal carrier, which can assist in boosting its solubility, potentially increasing bioavailability and minimizing side effects.

Methods

Propylene glycol was dissolved in the distilled water used as the aqueous phase, while the drug and soya lecithin dissolved in ethanol used as the organic phase. With a box-Behnken statistical design, the generated formulation was optimized for vesicle size, entrapment efficiency, and zeta potential as the dependent variables and soya lecithin amount and percentages of ethanol, and propylene glycol as the independent variables. A number of characteristics were used to characterize the optimal formulation. The ethosomal gel was created by incorporating an optimized formulation into the gel base. Parameters such as pH, viscosity, drug content, stability studies, in vitro release, ex vivo permeability, skin irritation, and histological investigations were used to characterize the ethosomal gel.

Results

The optimized ethosomal dispersion via box-behnken statistical design showed vesicles size of 94.89 ± 1.21 nm, % entrapment efficiency (%EE) of 98.74 ± 1.33% and zeta potential of -15.08 ± 3.14 mV. The ex-vivo study confirmed the enhanced delivery of candesartan cilexitil from ethosomal gel than compare to free drug gel by virtue of better permeation and solubility. Histopathological studies demonstrated the safety of the candesartan cilexitil loaded ethosomal gel for transdermal administration without any allergic dermal reactions.

Conclusion

The present study provides insightful insights into the development of improved transdermal drug delivery systems and highlights the significant potential of candesartan cilexetil ethosomal gel in therapeutic contexts.

Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) remain persistent global health threats due to their high transmissibility and continuous evolution. Conventional vaccination approaches are limited by cold chain requirements, the need for trained personnel, and needle-associated risks, underscoring the demand for next-generation, self-administered, and thermostable delivery systems. This review highlights microneedle array (MNA) technology as a promising platform for coronavirus vaccine delivery. It provides an overview of MNA design, formulation, antigen-loading strategies, and packaging considerations that enhance antigen stability, patient compliance, and large-scale distribution. The discussion integrates current insights on coronavirus immune responses and vaccine limitations to contextualize the advantages of microneedle-based systems. Furthermore, the review addresses post-infection complications, such as cardiac and renal manifestations, emphasizing the need for effective preventive vaccination. By consolidating recent advancements, this article underscores MNA-based vaccines as scalable and equitable tool to strengthen global immunization strategies against emerging coronaviruses.

Background

Anthemis cotula L. is an alien invasive weed consider allergic but traditionally reported with a single use in the form paste for psoriasis treatment.

Objective

In this context, it was the first time to explore A. cotula flowers extracts for its combined potential phytochemicals and biological activities.

Methodology

Therefore, the solvent-based extracts of flower samples were analyzed by Gas Chromatography-Mass Spectroscopy (GC-MS) and Energy Dispersive X-ray (EDX) analysis for phytochemical profile, followed by biological attributes including antimicrobial, phytotoxic and antioxidant activities.

Results

The GC-MS analysis revealed the most important and frequent AFE-7, AFE-10, AFE-14, AFE-15, AFM-1, AFM-4, AFM-5, AFM-6, AFC-10, AFC-13, AFC-15 and AFC-16 encoded phyto-constituents with biological properties observed in ethanolic, methanolic and chloroform fractions. Similarly, the EDX analysis revealed the concentration order of elements i.e. Carbon (C) > Oxygen (O) > Nitrogen (N) > Silicon (Si) > Potassium (K) > Aluminium (Al) > Calcium (Ca) > Iron (Fe) > Chlorine (Cl) > Magnesium (Mg) > Sodium (Na) > Phosphorus (P) > Sulphur (S) for the samples. Furthermore, the antibacterial activity of ACFEE exhibited a dose-dependent maximum inhibition of 21.67 ± 1.25 mm against E. coli, followed by significant Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) of 0.99 ± 0.60 µg/ml & 1.12 ± 0.38 µg/ml, respectively, against the same bacteria. Similarly, the antifungal assay of Anthemis cotula Flower Ethanolic Extract (ACFEE) displayed momentous 21.0 ± 0.82 mm inhibition, followed by MIC and Minimum Fungicidal Concentration (MFC) of 0.57 ± 0.199 µg/ml and 1.12 ± 0.398 µg/ml, respectively, against Candida albicans (C. albicans). Moreover, the phytotoxic activity of ACFEE inhibits the highest seed percentage (90 ± 8.16) of B. rapa at 1000 µl concentration, revealing dose-dependent effects among all the test seeds (Brassica rapa, Cicer arietinum, Lactuca sativa & Pisum sativum). Finally, the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay for antioxidant potential disclosed a significant 82.97 ± 1.06% RSA at 200 µl concentration after a 60-minute duration in the dark. The dose-dependent results showed significant IC50 values (207.49 µg/ml) at 200 µl concentration after 60 min.

Conclusion

The current comprehensive study of A. cotula flowers extracts concluded that the plant contains several biologically active compounds that contribute to antimicrobial, phytotoxic and antioxidant activities. Therefore, this study provides solvent-based extracts GCMS profiling together with biological activities supporting the traditional use against psoriasis.

Purpose

Hippobroma longiflora has been traditionally used in herbal medicine and is believed to possess anticancer properties. Nevertheless, its comprehensive metabolite profile has not been thoroughly examined. This study aimed to identify its metabolites profile, discover bioactive compounds and evaluate their potential for lung cancer therapy.

Methods

An integrative approach was employed, combining metabolomics and bioinformatics using LC-MS/MS analysis, molecular docking, molecular dynamics simulations, and and in vitro cytotoxicity validation through MTT assays.

Results

A total of 52 metabolites were identified, primarily consisting of alkaloids, terpenes, tannins, and saponins. Network pharmacology analysis revealed 259 lung cancer-related gene targets, including P53, EGFR, BCL-2, and AKT1. The key compounds were lapidin, parfumine, and ugaferin. ADMET predictions indicated favorable pharmacokinetic properties, including good gastrointestinal absorption and blood-brain barrier permeability for parfumine, with no significant predicted toxicity. Molecular dynamics simulations further confirmed the stability of ligand-protein complexes. The MTT assays with the highest activity of 96% ethanolic leaf extract showed the IC₅₀ values of 94.39 µg/mL for A549 lung cancer cells and 110.15 µg/mL for Vero cells.

Conclusion

These findings suggest that compounds derived from H. longiflora hold significant promise as candidates for the development of anti-lung cancer therapies, although further validation is required.

Background

Invasive fungal infections (IFIs) caused by Candida, Aspergillus, and Cryptococcus species are a major cause of morbidity and mortality in immunocompromised hosts, further complicated by the relative ineffectiveness of the existing antifungal treatments. Posaconazole (PSZ), a broad-spectrum triazole antifungal agent, is hindered by its designation under the Biopharmaceutics Classification System (BCS) Class II, having low water solubility (< 1 µg/mL) and fluctuating oral bioavailability (8-47%) resulting in erratic therapeutic activity. Conventional PSZ formulations like oral suspensions and delayed-release tablets suffer from food-dependent absorption, decreased systemic exposure, and process complexity. Further, current nanocarrier systems lack Quality by Design (QbD)-guided optimization for oral delivery.

Objective

The aim of this investigation was to develop polymeric micelles based on the concepts of QbD employing polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus®) and D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) as aids to enhance the solubility, systemic bioavailability, and antifungal efficacy of PSZ against IFIs.

Methods and Results

PSZ-loaded micelles were prepared using thin-film hydration method and optimized using Design of Experiments (DoE) strategy to establish critical quality attributes: critical micelle concentration (~ 7.6 µg/mL), particle size 176.5 ± 3.49 nm, polydispersity index 0.323 ± 0.01, zeta potential -9.37 ± 0.28 mV, and encapsulation efficiency 91.11 ± 0.85%. In vitro experiments exhibited 10-fold increase in solubility of PSZ and prolonged drug release for 24 h (80.21 ± 5.89%). Antifungal susceptibility testing revealed a two-fold decrease in MIC against Candida albicans compared to free PSZ. Pharmacokinetic studies in Male Albino Wistar rats showed a ⁓2-fold increase in Cmax, area under the curve (AUC) and area under the first moment curve (AUMC) which proved enhanced systemic exposure.

Conclusion

The results validate the QbD-optimized Soluplus® and TPGS micelles as an effective, scalable, and drug-compatible nanocarrier system that enhances PSZ oral delivery for the treatment of IFIs.

Graphical Abstract

Purpose

Enterovirus D68 (EV-D68) is a viral pathogen recognized for its role in inducing severe respiratory illnesses and its link to the development of acute flaccid myelitis (AFM) in children. The 3 C protease (3Cpro) of Enterovirus D68 disrupts TRIF, impairing NF-κB and IFN-β signaling, evading host immunity. EV-D68 also inhibits IRF7 and interferes with MDA5-MAVS interaction, hindering RLR pathway-mediated IFN signaling.

Methods

Recognizing the key role of 3Cpro in modulating host immune responses, we employed structure-based drug design combined with molecular dynamics simulations to comprehensively screen phytochemical databases and pinpoint promising compounds with the potential to inhibit EV-D68 3Cpro, thereby supporting immune system restoration.

Results

Our analysis identified lead compounds with high docking score such as EA-5317333 (-9.268 kcal/mol) and EA-76313109 (-8.618 kcal/mol) from East African Natural Products Database, NA-5320945 (-7.902 kcal/mol) and NA-101630512 (-7.570 kcal/mol) from North African Natural Products Database, SA-25245604 (-8.899 kcal/mol) and SA-9064 (-7.538 kcal/mol) from South African Natural Compounds Database, NE-5280343 (-7.845) and NE-162817590 (-7.264 kcal/mol) from North-East African Natural Products Database, TCM-71665623 (-8.324 kcal/mol) and TCM-163019889 (-8.414 kcal/mol) from Traditional Chinese Medicines Database as lead compounds. Furthermore, the stronger binding affinity of these lead compounds with the 3Cpro was validated by the results of molecular dynamics (MD) simulation, binding free energy calculation and dissociation constant analysis. The selected compounds exhibited favorable ADMET properties, including high solubility in water, strong gastrointestinal absorption, and no signs of liver toxicity, aligning well with Lipinski’s rule of five.

Conclusion

Taken together, these findings provide compelling evidence to support the design of novel therapeutics directed at disrupting the immune evasion strategies employed by the EVD68 virus.