Pakistan journal of pharmaceutical sciencesMuhammad Sajid Nawaz, Muhammad Zaman, Huma Hameed, Waqar Siddique, Ahmad Salawi, Yosif Almoshari, Jawaher Abdullah Alamoudi
BACKGROUND: Multiparticulate Drug Delivery (MDD) system are particularly considered as well suited systems for controlling oral preparations that have low risk of dose-dumping. OBJECTIVES: The current research work was aimed to prepare Fexofenadine HCl immediate release (IR) and Paracetamol sustained release (SR) pellets in a single dosage unit for the treatment of Allergic Rhinitis. Extrusion-spheronization was used to fabricate pellets. METHODS: The formulations were analyzed for several parameters, including micromeritic studies, Friability, Weight variation test, Swelling, X-Ray Diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), in-vitro release and stability studies. RESULTS: The results showed that the formulated pellets have an excellent flowability (23.01° to 25.23°), bulk density falls in the range of 1.23 g cm -3 to 1.42 g cm -3 , tapped density ranges 1.43 g/cm 3 1.58 g/cm 3 , carr's compressibility index lie between 10.31 % to 15.17 %, Hausner's ratio ranges 1.11 to 1.18 which concluded pellets had good flow properties. Friability was less than 1%; the T6 formulation showed the maximum swelling of 99.28%. No interaction between excipient and drug was found. T6 showed a drug release of 99.08% in 24 hours. CONCLUSION: The research effectively demonstrated that preparing a single-unit dosage form of paracetamol and fexofenadine is a safe, simple and promising technique for SR of Paracetamol, thereby increasing patient compliance by reducing the dosage frequency.
Drug development researchShuyu Jia, Jieman Lin, Janjun Wu, Hao Xu, Qingwei Zeng, Meipin Liu, Jiayi Shen
BRAF is a cytoplasmic serine-threonine protein kinase that plays a critical role in the MAPK signaling pathway. BRAF is the only member of the RAF family activated by mutation in human cancers. Many classes of B-Raf small molecule inhibitors have been identified. In this review, we will highlight typical BRAF inhibitors developed during these decades and provide a reference for the exploration of more potential BRAF inhibitors in the future.
ChemMedChemJosé Arion da Silva Moura, Matheus Vinicius Guimarães de Melo, Diane Regis Santos do Nascimento, Thaynara Paula Warren Bezerra, Mathieu Métifiot, Patricia Reco…
The therapy to treat the Human Immunodeficiency virus (HIV) and decrease the viral load has been a challenge since its discovery due to its ability to mutate, escape from drug therapies, and immunologic system. Consequently, the development of new therapies, especially potential molecules that focus on specific viral mechanisms to block viral replication, became a critical challenge in recent decades. The Reverse Transcriptase (RT) is an RNA- and DNA-dependent DNA polymerase enzyme that is responsible for transcribing viral RNA into double-stranded DNA. Non-nucleoside RT Inhibitors perform important role in HIV therapy, and they are responsible for inhibiting RT by blocking its allosteric site, which shows physico-chemical properties such as high hydrophobicity and key amino acid-to-hydrogen bond interactions. For this reason, designing new molecules with innovative heterocycles compatible with these characteristics can provide new potential inhibitors. For example, pentacyclic heterocycles like thiazole and its derivatives like thiazolidinedione, which have physico-chemical properties that can interact with the allosteric site of RT, can be a new perspective in designing new Non-nucleoside RT Inhibitors. This work reviews the scientific literature concerning these compounds and can help the design of new antiviral therapeutics.
The present study explores the potential of sorafenib (SOR) and atorvastatin (ATST) to induce a ferroptosis and apoptosis-based hybrid cell death mechanism. The synergistic ATST + SOR combination was delivered through Glutamine-tagged PLGA nanoparticles (ATST + SOR/G-PLGA NPs) to promote intratumoral specificity. The formulation was optimized using DesignExpert® software by adopting Box-Behnken design (BBD). The optimized ATST + SOR/G-PLGA NPs had a spherical particle size of ~ 178.3 ± 12.6 nm, a PDI of 0.151 ± 0.08, and a Z-potential of -24.8 ± 5.8 mV. The formulation revealed a biphasic sustained release with higher release at acidic pH. In-vitro biological assessment showed a dose-dependent decrease in cell viability with reduced IC50 values. In the presence of ferrostatin-1, the IC50 value was significantly increased. The exposure to ATST + SOR/G-PLGA NPs led to elevated levels of malondialdehyde (MDA), reactive oxygen species (ROS), glutathione (GSH), increased late apoptotic/necrotic cells, and mitochondrial membrane depolarization. Pharmacokinetic study revealed a 2.63- and 2.93-fold improved AUC0-∞, and 2.58- and 2.84-fold improvement in MRT as compared to free SOR and ATST. Preclinical efficacy study showed a marked reduction in tumor volume and a higher inhibition rate. Toxicity assessment revealed no signs of systemic or organ toxicity, implying suitability of formulation for in-vivo delivery. In a nutshell, the proposed strategy offers a powerful avenue to manage advanced malignancies by inducing a hybrid cell death mechanism. Also, the nutrient transporter targeted polymeric nanosystems present an effective approach, which warrants further investigation.
Pakistan journal of pharmaceutical sciencesAmina Arshad, Muhammad Zaman, Humayun Riaz, Muhammad Sajjad Haider, Wafa Ishaq, Sherjeel Adnan, Zeeshan Masood, Hammad Ahmed, Nabeela Ameer, Hafiz Muhammad Abd…
BACKGROUND: Pitavastatin (PVN), a BCS class-II drug, exhibits poor aqueous solubility leading to limited oral bioavailability and therapeutic efficacy. OBJECTIVES: This study aimed to enhance the solubility and anti-hyperlipidemic efficacy of Pitavastatin (PVN) by encapsulating it in chitosan-based polymeric nanoparticles. METHODS: Pitavastatin-loaded chitosan nanoparticles (NPs) were prepared using the ionic gelation method. Formulations were characterized by particle size, zeta potential, drug loading, In-vitro drug release and surface morphology. Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermal analysis (TGA and DSC), ex-vivo intestinal permeability and in-vivo pharmacodynamic analysis were also performed. RESULTS: The size of PVN-loaded NP ranged from 219.9±1.11 to 292.7±2.29 nm with PDI 0.2-0.4, surface charge of +28.4 ± 0.43 to 32.5 ± 1.02 mV and entrapment efficiency 65±1.12-93±1.23%. Solubility in different media (PBS (pH 6.8), 0.1N HCl (pH 1.2) and distilled water showed a 56-102-fold increase compared to PVN. SEM analysis revealed a smooth surface and spherical geometry of the NP. FTIR analysis confirmed that there was no physicochemical interaction between PVN and chitosan in NP formulations (NP1-NP5). XRD and thermal analysis indicated the amorphous nature of PVN-loaded NP. In-vitro drug release from NP formulations (NPI-NP5) ranged from 80.97±4.80 to 81±3.90% indicating sustained release, while ex-vivo intestinal permeability was 1.5-fold higher than PVN. The optimized formulation (NP1) followed Higuchi release model, indicating Fickian diffusion. Pharmacodynamic analysis of lipid profiles in hyperlipidemic albino rats suggested that NP1 reduced low-density lipoprotein (LDL) by 33±1.24 %, total cholesterol by 29±2.13% and triglycerides by 23±1.21%, showing better results than PVN. CONCLUSION: Chitosan-based Pitavastatin nanoparticles successfully enhanced drug solubility and provided sustained release, leading to improved ex-vivo permeability and greater in-vivo anti-hyperlipidemic activity in albino rats. This approach represents a promising strategy for enhancing therapeutic potential of Pitavastatin.
In today's world, research has evolved a lot in the field of cancer and docetaxel (DTX) has been intensively studied for its ability to cure different types of cancers. However, the intravenous delivery of DTX puts forth various undesirable side effects, while oral delivery has its own solubility and permeability drawbacks. The advancements in research have focused on overcoming these disadvantages by developing novel and efficient DTX-based drug delivery systems. The review aims at identifying challenges faced by DTX and thereby forecasting the different DTX formulations established to surpass them. The successful DTX delivery is mediated by certain efficient nanocarriers, inclusion complexes, etc., effectively destroying the cancerous cells. The current clinical status of these formulations has also been listed in this review. The dedicated efforts of researchers have been fruitful in site-specific targeting of DTX by novel formulations, thus enhancing its antitumor effect. However, this success has been restricted only to preclinical studies and only a few formulations have entered the CTs, while none have received market approval. A deep understanding of the basics of nanoformulations, along with their toxicological insights and flexible production procedures, will help to combat the clinical hurdles faced by them.
AAPS PharmSciTechRaghda Abd El Moneum Ali Abdel Mawla, Wedad Sakran, Fares Ibrahim Farag Masry, Mohammed Salah Ahmed Teiama
This study was designed to develop and optimize a thermosensitive intranasal gel incorporating temozolomide (TMZ) and N-acetylcysteine (NAC) as a promising platform for direct nose-to-brain drug delivery. Formulations were fabricated via cold technique utilizing Carbopol 934P and poloxamer 407 to improve gelation and mucoadhesion. After evaluating the formulations for clarity, pH, gelation temperature, gelling time, mucoadhesion, and drug loading, the formula A13 was elected as the optimized formulation based on a factorial design optimization approach. The optimized formula was further evaluated for stability, ex-vivo permeability, histopathology and in-vivo pharmacokinetic in rats. Compared with the corresponding in-situ gels containing the pure drugs, formulation A13 enhanced the ex-vivo nasal mucosal permeation of TMZ and NAC by 1.42-fold and 1.64-fold, respectively, indicating the superior permeability-enhancing effect of A13. Furthermore, histopathological examination revealed no evidence of structural damage following administration of formulation A13, confirming its safety for intranasal application. The in-vivo studies performed on rats showed significantly higher Cmax and AUC 0-24 results in brain of the optimized A13 by 1.4, 1.4, 2.6 and 1.87 folds in TMZ and NAC, respectively compared to in-situ gel of pure TMZ and in-situ gel of pure NAC, with a delayed (Tmax). The brain-to-blood concentration ratios of the TMZ-NAC-loaded in-situ gel were consistently higher than those of the pure-drug in-situ gels at most sampling time points, indicating more efficient nose-to-brain transport. Overall, these findings demonstrate that the optimized A13 is a promising and safe intranasal delivery system for enhancing the nose-to-brain delivery and bioavailability of TMZ and NAC.
Burn wound infections remain a major clinical challenge due to extensive tissue damage, delayed healing, and increased susceptibility to microbial contamination, which can limit the effectiveness of conventional topical formulations. This study aimed to develop and optimize a Quality-by-Design (QbD)-based non-propellant foam (NPF) containing silver nitrate, chlorhexidine, and asiaticoside for enhanced burn wound management. A sequential design of experiments strategy was employed, involving Taguchi L8 screening followed by Box-Behnken optimization to identify the critical formulation variables influencing foam performance and drug release. The optimized formulation exhibited desirable physicochemical characteristics, including a foam density of 0.192 ± 0.002 g/mL, a skin-compatible pH of 5.56 ± 0.04, uniform drug content (98-99%), and satisfactory foam stability. In-vitro studies demonstrated cumulative drug release of 94.69% chlorhexidine, 82.13% asiaticoside, and 78.63% silver nitrate within 6 h, with the release profiles predominantly following the Higuchi diffusion model. Accelerated stability studies indicated that the formulation remained stable over six months. In a Sprague-Dawley rat burn wound model, the optimized foam achieved 93.29 ± 1.75% wound contraction by day 14, outperforming both the untreated control and the marketed formulation. Furthermore, biochemical analyses revealed increased hydroxyproline, hexosamine, and hexuronic acid levels, while histopathological examination confirmed enhanced collagen deposition, neovascularization, and re-epithelialization. These findings demonstrate that the developed QbD-based non-propellant foam represents a promising preclinical topical delivery platform capable of supporting both antimicrobial protection and tissue repair during burn wound healing.
AAPS PharmSciTechAawaz Raj Pokhrel, Jayanti Das, Boren Ke, Lisa Ma, Shawn Zhang, Maxwell Korang-Yeboah
Microstructural characterization of pharmaceutical drug products is essential for understanding process-microstructure-performance relationships and ensuring consistent product quality. However, quantitative characterization is limited by a trade-off between imaging resolution and field of view: high-resolution imaging captures fine structural detail but over small sample volumes, whereas lower-resolution imaging provides broader coverage while missing critical morphological features. To address this limitation, we developed and validated an integrated framework combining convolutional neural network (CNN)-based super-resolution with Generative Adversarial Network (GAN)-based microstructure synthesis. Lyophilized drug products imaged by X-ray microscopy at multiple resolutions served as the model system. We first demonstrated that imaging resolution is a governing factor in quantitative microstructural analysis: mean pore size showed a coefficient of variation of 40.2% across resolution levels, compared with only 0.47% attributable to spatial heterogeneity within the same sample. CNN-based upscaling using ESRGAN/BSRGAN recovered solid-wall structures and pore-size distributions lost after downsampling and restored effective diffusivity toward values measured in the original high-resolution data. In an independent validation using a separate formulation imaged at 5 and 10 µm per voxel, the upscaled images reproduced pore-size distributions and diffusivity profiles closer to the 5 µm reference and showed better recovery of CQA-relevant structural features than conventional bicubic interpolation, despite lower pixel-level image fidelity scores. GAN-based synthesis expanded the field of view four-fold from a small high-resolution seed region while preserving pore-size distributions and transport properties. Together, these findings demonstrate a scalable approach for improving microstructural characterization under practical imaging constraints.
In vitro dissolution testing is central to pharmaceutical development, yet it is increasingly challenged by poorly soluble drugs, which account for over 40% of marketed products and up to 90% of new chemical entities, for which dissolution often limits absorption. Surfactants are widely incorporated into dissolution media to achieve sink conditions and improve the discriminatory powder of dissolution methods, but inappropriate surfactant selection or concentration can alter drug release mechanisms, mask formulation differences, and reduce biopredictive performance. This review examines the mechanisms of surfactant action, including wetting enhancement, micellar solubilization, and drug-surfactant interactions, together with the physicochemical properties of anionic, cationic, non-ionic, and zwitterionic surfactant relevant to dissolution testing. Building on these principles, we discuss practical considerations for surfactant selection, concentration optimization, analytical compatibility, surfactant quality and source variability, formulation-specific considerations for enabled drug delivery systems, integration with physiologically based biopharmaceutics modeling, and evolving regulatory expectations. Together, these provide a practical framework for developing robust, reproducible, and discriminating dissolution methods that better reflect in vivo performance and support decision-making across drug development.
AAPS PharmSciTechMagdi E A Abobaker, Mershen Govender, Yahya E Choonara
The therapeutic efficacy of interferon alpha (IFNα) is well-established in various conditions, including Hepatitis B and C, lymphoma and skin cancer, attributed to its potent angiostatic, immunomodulatory, and antiproliferative properties. Clinical applications using this bioactive are, however, hindered by systemic toxicity due to the high doses used, increasing costs and reducing patient adherence. The use of a controlled-release polymeric nanoparticulate system that can potentially decrease the administered dose, and therefore the associated costs, may additionally improve overall patient acceptability without affecting therapeutic efficacy. This study provides for the development, statistical optimization and characterization of poly(lactic-co-glycolic acid) nanoparticles (PLGANPs) for the controlled release of IFNα. A double-emulsion solvent evaporation method was employed for nanoparticle (NP) synthesis, with formulation optimization achieved through a Central Composite Design (CCD) approach to ensure adequate size, stability, and sustained release over five days. Characterization of the optimized IFNα-PLGANPs using dynamic light scattering, zeta potential analysis, scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and drug release studies at pH 7.2 displayed an average particle size of 97.03 nm (PDI = 0.182), zeta potential of - 34.10 mV and a maximum drug release of 5 days, with morphological analysis revealing the formation of spherical NPs with a smooth surface topology, confirming the homogeneity and structural stability of the formulation. These findings underscore the potential of the developed PLGANPs as a suitable platform for the controlled release of IFNα, noting the use of advanced nanotechnology-driven solutions to overcome the limitations of conventional therapies.
Statins are widely regarded as the gold standard first-line treatment for hyperlipidemia, as they inhibit HMG-CoA reductase in the liver. This effectively reduces LDL cholesterol levels and reduces cardiovascular risks, such as heart attack and stroke. Simvastatin is a well-established, effective, and cost-efficient statin for lowering LDL cholesterol and reducing cardiovascular risk. However, it causes myopathy, rhabdomyolysis, myalgia, constipation, kidney failure, headache, abdominal pain, diarrhoea, nausea, and increased blood sugar levels with its use and higher doses of 80 mg/day. To address this, a liposomal simvastatin formulation with particle sizes of 150-250 nm was developed for intravenous administration. This formulation can potentially accumulate in the liver via passive targeting via the RES, thereby enhancing hepatic uptake and improving safety. The liposome was formulated using the thin-film hydration method and optimised using a central composite design. The optimized formulation's vesicle size was 204.66 ± 2.84 nm, with a PDI of 0.27 and a zeta potential of -58.11 mV, indicating uniform distribution and high stability. In-vitro drug release demonstrated controlled release of up to 92.46% over 60 h. The cellular toxicity assay showed that the optimized liposome was 10 times safer than pure simvastatin. In-vivo, the liposomal formulation significantly reduced lipid levels after administration of a 5 mg/kg dose in Triton X-100-induced hyperlipidemic rats, outperforming marketed formulations and standard drugs. Simvastatin-liposomes are safe, stable, and a more potent alternative to traditional oral simvastatin, offering improved liver targeting and a reduced toxicity profile.
AAPS PharmSciTechMariame A Hassan, Bhanu Prakash Dongala, Annette DeSantiago, Ziyaur Rahman, Mansoor A Khan
Divalproex Sodium (DVS) is an antiepileptic agent with a narrow therapeutic window and a wide range of side effects. Its delayed-release forms demonstrated better tolerability in terms of gastrointestinal side effects. DVS has high sensitivity to temperature and humidity. Owing to a high frequency of daily administration, outpatients may keep their medication supply accessible in places that might not qualify for proper drug storage. In this study, five FDA-approved DVS delayed-release tablet products (A-E) were assessed for physical integrity, physicochemical changes and drug release pattern before and after repackaging in amber-colored closed pharmacy vials and storage at 30°C/75%RH. Initially, one product showed dissimilarity to the others (f1 = 19.6, f2 = 41.6). Upon storage, tablets showed signs of physical damage after 1 month. At 3 months, A, B and E tablets lost their integrity completely. Product C displayed high variability in acid (44.9 ± 31.5% drug release). Tablets that remained intact after storage failed the f1 and f2 tests. The images showed evidence of chemical changes in all products. The results indicated that repackaging and improper in-use keep could result in unpredictable drug release. It is debated that the total daily systemic bioavailability of DVS, rather than the peak-to-trough differences, is the primary determinant of seizure control. However, variability in drug release can result in gastric irritation, systemic side effects, drug intolerance and patients' noncompliance. This unnecessary burdening of the health care system can be avoided when revising dispensing and storage recommendations of DVS products.
ChemMedChemPascal Heitel, Philipp Barbie, Alessia Gambardella, Marta Pinto, Felix Pape, Anika Tarasewicz, Gerhard Hessler, Bernhard Wünsch, Matthias Schiedel, Christina L…
The Frontiers in Medicinal Chemistry (FiMC) was held in Münster from March 24th to 27th as the largest international Medicinal Chemistry conference in Germany. Welcoming more than 240 participants from around 20 countries, it was a vibrant conference, celebrating the community and the Medicinal Chemistry division of the German Chemical Society (GDCh). The program filled 4 days with over 40 lectures from industry and academia, and 125 posters. Herein, the NextGenMedChem group reports their highlights from this conference.
Real-time quality control of pharmaceutical dosage forms requires rapid, non-destructive analytical technologies that provide chemical specificity while maintaining high throughput. Here, an extended short-wave infrared (eSWIR, 1000-2500 nm) line-scan hyperspectral imaging system (L-EOS 2.5e, Photon Etc.) was evaluated for spatially resolved classification of pharmaceutical tablets. The system was evaluated at integration times of 2, 0.2, and 0.02 ms using Standard Normal Variate normalization, Savitzky-Golay second-derivative preprocessing, and an error-correcting output codes support vector machine classifier. Product-level classification of 11 pharmaceutical products achieved accuracies of 99.99%, 100%, and 97.6% at 2, 0.2, and 0.02 ms, respectively. A more challenging manufacturer-level discrimination task involving three 500 mg acetaminophen products containing the same active pharmaceutical ingredient and labeled dose achieved accuracies of 99.7%, 98.6%, and 89.3% at the corresponding integration times. These results demonstrate the potential of eSWIR hyperspectral imaging for rapid, spatially resolved pharmaceutical product discrimination and high-throughput inspection.
AAPS PharmSciTechShang-Yin Wu, Yun-Jie He, Ci Qian, Si-Ru Zhong, Hong-Xing Xiao, Changyun Xiong, Bin Di, Wei-Jie Fang
High-concentration protein formulations for subcutaneous administration have developed rapidly, while viscosity-related pipetting errors remain a key bottleneck for accurate protein concentration quantification, with commercial detection instruments showing significant limitations in direct measurement of these samples. Here, we developed two pipetting-optimized quantification strategies using two high-concentration monoclonal antibody formulations with distinct viscosities as models: a motorized continuous pipette-based direct measurement method and a weight-corrected method. We validated the high accuracy and repeatability of the motorized continuous pipette for high-viscosity liquid handling, and systematically compared the performance of our optimized methods with the traditional manual pipetting method and three mainstream commercial protein analyzers. Direct measurements using the three evaluated analyzers showed formulation-dependent deviations under the tested conditions. Both optimized workflows improved pipetting precision and provided concentration estimates with improved repeatability for the two high-concentration mAb formulations examined. These findings support motorized pipetting and weight correction as practical options when viscosity compromises volumetric transfer, while their applicability to other protein modalities and formulations with intermediate viscosity requires further validation.
Polymeric nanospheres are promising drug delivery systems capable of controlling the release of active molecules. However, their inherent colloidal instability necessitates the use of drying techniques to enhance physicochemical stability and microbial resistance. However, conventional multi-step production processes hinder industrial-scale-up due to increased complexity and longer processing times. This work aimed to develop a single-step spray-drying process to obtain Eudragit® L100 nanospheres in powder form, thereby eliminating the need for traditional solvent evaporation, and to investigate the effects of incorporating these nanospheres into hydroxyethyl cellulose gels for dermatological applications. Eudragit® L100 was selected for its controlled release at approximately pH 6.00, facilitating delivery to specific areas, particularly on barrier-disrupted skin. Nanospheres were produced via nanoprecipitation followed by direct spray-drying to reduce production time. The nanosuspension and redispersed dried formulations were characterized by particle size, polydispersity index, morphology, and zeta potential. Before drying, the nanospheres had an average size (Z-average) of 114 nm and a polydispersity index (PdI) of 0.19 and successfully preserved their properties after a single drying step (Z-average = 140 nm and PdI = 0.2). Zeta potential was altered (p < 0.05) but remained high (-23 to -17 mV), indicating electrostatic stabilization. Gel formulations exhibited dose-dependent pseudoplastic behavior, with consistency decreasing proportionally to nanosphere concentration. Finally, moderate to strong correlations were found between rheology and textural analysis. This single-step solvent removal methodology represents a significant manufacturing advancement, offering reduced processing time and costs. The pH-responsive nanospheres showed excellent redispersibility and gel compatibility, establishing their potential as carriers for dermatological systems.
AAPS PharmSciTechGabriel S Oliveira, Ana Luiza Lima, Pedro Granados Muñoz, Idejan P Gross, Livia Sa-Barreto, Patrícia Medeiros-Souza, Tais Gratieri, Guilherme M Gelfuso, Marcil…
Pediatric maintenance therapy for acute lymphoblastic leukemia requires prolonged daily administration of 6-mercaptopurine (6-MP), a drug characterized by a narrow therapeutic index and substantial interindividual variability, creating a need for flexible and patient-friendly dosage forms. This study aimed to develop pediatric chewable tablets 6-MP using hot-melt extrusion and fused deposition modeling (FDM) 3D printing. Preformulation studies and rheological characterization were performed to support formulation development. The influence of internal architecture on porosity, disintegration, mechanical properties, and chewability was investigated by varying infill density. Among the evaluated architectures, 30% infill provided the best balance between structural integrity, porosity, rapid disintegration, and softening after saliva exposure, ensuring adequate chewability. Tablets exhibited accurate drug content (99.5 ± 2.2%). Beyond their immediate-release behavior, complete drug release was achieved within 15 min, while colloidal nanostructures were spontaneously formed, associating approximately 11% of dissolved 6-MP, suggesting a hybrid release mechanism combining rapid drug availability with nano-mediated modulation. Dynamic light scattering and transmission electron microscopy confirmed these findings. Overall, the developed platform demonstrates the potential of FDM-based structural engineering to produce personalized pediatric medicines and reveals that thermally processed polymeric matrices may function as dynamic drug delivery systems rather than conventional immediate-release dosage forms.
AAPS PharmSciTechParoma Chakravarty, Minhthi Bui, Kellie K Sluga, Bifan Chen, Simon Chan, Hao Helen Hou
GENE-A, a small molecule classified as a BCS Class IV compound, was formulated as a spray dried amorphous solid dispersion (SDD) using HPMC-AS polymer for oral delivery and compressed with additional excipients to yield tablets. Owing to a high clinical daily dose projection, the possibility of administering multiple tablets in applesauce was explored for patient compliance. Since GENE-A crystallized to a hydrate in aqueous media in previously conducted solubility studies, dispersion of SDD tablets in applesauce (aqueous medium) necessitated the development of an analytical method to detect low levels of crystallinity in these mixtures. Using transmission PXRD and multistep sample preparation procedure, a calibration curve was obtained by employing powder blends with matching composition as SDD tablets, spiked with different amounts of crystalline hydrate, dispersed in applesauce. From this curve, the limits of detection and quantitation of crystalline active in these samples were determined to be 1.8 and 4.9% respectively. A 8.5-12% error of prediction for % crystallinity was obtained for validation samples which may be attributed primarily to sample preparation challenges such as retention of water in the centrifuged samples. Using this method, % crystallinity was determined to be < LOD in the test samples, i.e. film coated SDD tablets (for clinical use) dispersed in applesauce at T = 0 and 2 h. Our study is the first to demonstrate the development of a PXRD based method for detecting low levels of crystallinity in a semi-solid matrix to monitor physical stability of an active in drug-vehicle mixtures.
This study aimed to enhance the physicochemical properties of curcuminoids by preparing an inclusion complex and formulate an orodispersible tablet (ODT) suitable for elderly patients. A purified curcuminoid was complexed with hydroxypropyl-β-cyclodextrin (HP-β-CD). A design of experiments was employed to optimize the formulation by investigating the effects of a binder and a superdisintegrant on critical tablet attributes. The final optimized ODT was evaluated for compliance with pharmacopeial standards. The 1:1 molar ratio curcuminoid:HP-β-CD complex was identified as optimal, providing a substantial (214-fold) increase in solubility. The complex demonstrated superior photostability, thermal resistance, and ambient storage stability compared to the uncomplexed curcuminoid. The optimized ODT formulation, exhibited excellent mechanical robustness and achieved a rapid disintegration time of 22.21 ± 1.94 s. In vitro dissolution studies showed enhanced drug release, achieving 97.79 ± 0.66% release at 60 min and demonstrating a distinct dissolution profile compared to a commercial non-complexed formulation. This work presented a rational, dual-strategy formulation approach that combines molecular-level solubility enhancement with dosage form optimization to improve the in vitro performance of curcuminoids. The findings highlight the potential of cyclodextrin-based ODT systems as a scalable platform for delivering poorly soluble phytochemicals, particularly for geriatric and dysphagic populations.
AAPS PharmSciTechAnroop B Nair, Mohamed A Morsy, Ahmed M Agiba, Rofida Albash
Terpenes have a low potential for irritation and are classified as Generally Recognized as Safe (GRAS) chemicals. Terpenes possess favorable biological properties that support their use in drug delivery. Some terpenes and essential oils have been encapsulated in nanostructured systems called terpesomes to overcome their chemical instability. Compared to conventional vesicles, terpesomes are new vesicular structures that showed greater membrane penetration. The capacity of terpesomes to increase permeability across membranes while decreasing systemic absorption is one of their main benefits. Terpesomes enhance drug permeation by improving membrane interaction and increasing drug transport across biological barriers. The structure, characterization, penetration processes, and applications of terpesomes are all addressed in this review. Overall, this review highlights that the enhanced penetration capability of terpesomes makes them promising lipid vesicular carriers for a wide range of pharmaceutical applications.
Pharmaceutical development and technologyGeorge Patrick Devon, Dzava Prawinsyah Fairus Ismail, Jenio Lagut, Iyan Sopyan
Poor aqueous solubility remains a major barrier in drug development, affecting approximately 40% of marketed drugs, up to 75% of drugs under development, and nearly 90% of new chemical entities. To overcome this limitation, solid modification of active pharmaceutical ingredients (APIs) emerged as a strategy to enhance drug physicochemical properties, particularly for Biopharmaceutics Classification System (BCS) II and IV drugs. This review systematically analyzes recent advancements in solid modification techniques, including salt formation, cocrystallization, polymorphs, solvate and hydrate forms, amorphous and co-amorphous systems, inclusion complexes, and nanocrystallization. A systematic literature search spanning 2020-2025 was conducted using PubMed and ScienceDirect databases, focusing on studies that improve the physicochemical properties of the APIs. By categorizing APIs, matrices, and methods of each study, this review shows the most frequently used techniques and their matrices, advantages, and limitations of each modification, providing insights for optimizing drug performance and future research in pharmaceutical development. Among the various approaches reviewed, cocrystals, amorphous systems, nanocrystals, and inclusion complexes emerged as the most frequently used techniques. Amorphous systems and inclusion complexes offer the highest median solubility enhancements by maximizing kinetic supersaturation or equilibrium solubility, respectively, while nanocrystals efficiently improve equilibrium solubility via particle size reduction, and cocrystals provide reliable, moderate gains with superior long-term thermodynamic stability.
Squalene-based nanoemulsions are widely used as adjuvants in vaccine formulations, but their stability can be affected by environmental factors such as pH, oxidative stress, temperature, and light. We have produced a squalene nanoemulsion (CTVad1) to support the clinical development of new vaccines. This study aimed to develop and validate an HPLC method for squalene quantification in SpiN-Tec, a recombinant protein vaccine against COVID-19. We also aimed to evaluate the stability of the CTVad1 adjuvant and SpiN-Tec under controlled storage conditions. A reversed-phase HPLC method was developed and validated, and comprehensive forced degradation studies were performed on the raw material and SpiN-Tec under acidic, basic, oxidative, thermal, and photolytic conditions to demonstrate the stability-indicating capability of the method. Physicochemical, morphological, and biological characteristics were assessed, and stability studies of both the vaccine and the CTVad1 adjuvant were performed under accelerated and long-term conditions. The HPLC method was selective, precise, accurate, linear, and robust. Squalene raw material degraded under all tested conditions, whereas formulation in nano-sized globules improved its stability, with degradation observed only under hydrogen peroxide and light exposure. CTVad1 remained stable over time, exhibiting only minor, non-critical changes within the specification limits in both accelerated and long-term stability studies, regardless of the glass packaging used (clear or amber). In addition, the SpiN-Tec vaccine maintained its physicochemical and biological integrity under all tested conditions, with all evaluated parameters remaining within the established specification ranges. Our findings demonstrate that proper formulation, packaging, and storage conditions can preserve squalene stability in nanoemulsion-based vaccines, ensuring the quality, safety, and efficacy of the SpiN-Tec vaccine and its adjuvant throughout shelf life.
The AAPS journalVenkata Krishna Rao Balaga, Argyro Chatziadi, Luděk Ridvan, Miroslav Šoóš
Coamorphous systems are gaining interest as an effective formulation strategy to improve the solubility and dissolution of poorly water-soluble drugs. This study investigates the role of phenolic acids as coformers in enhancing the physicochemical properties of enzalutamide (ENZ), a poorly soluble anticancer drug. Five phenolic acids-p-coumaric acid (CMA), ferulic acid (FRA), cinnamic acid (CNA), vanillic acid (VNA), and p-hydroxybenzoic acid (HBA)-were selected based on their glass-forming ability and potential for molecular interactions. Coamorphous systems were prepared and characterized using powder X-ray diffraction (PXRD), modulated differential scanning calorimetry (mDSC), attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR), and Raman spectroscopy. All coformers successfully induced amorphization, evidenced by halo patterns in PXRD and single glass transition temperatures in mDSC. Spectroscopic analysis confirmed the absence of strong intermolecular bonding, indicating homogeneous mixing. The coamorphous systems exhibited improved solubility across physiological pH conditions and maintained supersaturation for at least four hours under non-sink dissolution testing. These results highlight the potential of phenolic acids as coformers in developing stable, high-performing coamorphous drug systems to enhance the bioavailability of poorly soluble APIs like enzalutamide.
Pulmonary protein delivery has proven to be an effective approach for the treatment of local and systemic diseases, and particles that can be efficiently inhaled into peripheral regions should possess aerodynamic sizes of <2 µm, for which nano-spray-drying (NSD) is a powerful tool for fabrication. However, NSD powders have a high specific surface area and surface energy, which causes severe agglomeration and poor aerosolization performance. To solve these problems, cyclodextrin/leucine delivery systems were constructed, which can evidently protect alkaline phosphatases (AKP) with >94% of their biological activities retained in NSD powders and endow nanoparticle-based AKP-cyclodextrin-leucine (ACL) powders with improved aerosolization behavior. This can be evidenced by the fine particle (<4.46 µm) fraction (FPF<4.46) and FPF<1.66 (in unit percentage), of only 49.9% and 18.7% for the leucine-free ACL0, while significantly increased to 82.1% and 33.1% for ACL15, and further increased to >88% and >41% for ACL30/ACL45. The USP Chapters of traditional <601> and newly published <1604> were employed to determine derived metrics for aerodynamic particle size distribution (APSD). It was demonstrated that the authenticity of fitted values calculated in Chapter <601> was severely influenced by APSD profiles, and the fitted values can have immense differences from the actual values determined in Chapter <1604> . The differences can be minimized when the APSD is unimodal and normal across sized impactor stages. Hence, the authenticity of the fitted values can be improved. These new data deepen the understanding of APSD analyses and generate insights into the improvement of value authenticity for derived metrics, henceforward facilitating continuous improvements in quality control of inhaled products.
The present study investigates the effect of the degree of carboxymethyl substitution in tara gum (TG) on the physicochemical and mucoadhesive properties of gastroretentive tablets. The synthesis of carboxymethyl TG (CMTG) was optimized under various reaction conditions with respect to degree of substitution (DS). The DS varied from 0.47 ± 0.002 to 1.14 ± 0.014 depending on the reaction conditions. The DS significantly influenced the flow properties, swelling behavior, and erosion of the tablets. Ex vivo mucoadhesion studies on goat stomach mucosa revealed that both mucoadhesive strength (MS) and mucoadhesive time (MT) varied with changes in DS. MS and MT progressively increased from 45.51 × 103 ± 2.979 to 111.18 × 103 ± 3.901 dynes/cm2 and from 272.66 ± 2.561 to 517.33 ± 2.516 min, respectively, with increasing DS from 0.47 ± 0.002 to 1.05 ± 0.046, owing to enhanced hydrogen bonding between the -COOH groups of CMTG and functional groups of mucin. However, a further increase in DS to 1.14 ± 0.014 decreased MS and MT to 101.75 × 103 ± 0.297 dynes/cm2 and 504.33 ± 1.041 min, respectively, primarily due to excessive protonation in acidic media, which increased the rigidity of the polymeric networks and reduced interactions between polymeric chains and mucin. The most notable finding of this study was that the MS and MT values of the optimized carboxymethylated derivative (CMTG-4) were superior to those of the commercial mucoadhesives CMC, Carbopol 934, and pectin.
Prednisolone (PRED), a widely used corticosteroid for the treatment of ocular inflammation, has limited bioavailability due to its poor water solubility. In this study, Eudragit E100-based films incorporating polyethylene glycol 400 (PEG) and α-lipoic acid (ALA) as plasticizers were developed and characterized to improve the ocular delivery and corneal permeability of PRED. ALA, which is also known for its antioxidant and therapeutic properties in ocular surface disorders, plays a dual role by enhancing both the mechanical properties and drug delivery performance of the films. The E100:PEG:ALA:PRED (1:0.3:0.2:0.2) formulation exhibited flexibility, mucoadhesion, and controlled-release behavior. Furthermore, cell viability and wound-healing assays were performed to evaluate the biocompatibility of the films. In addition, ex vivo permeability studies using porcine corneas revealed significantly enhanced PRED penetration compared with a commercial eye drop formulation (Sophipren Ofteno® 1%) and demonstrated that the films induced minimal corneal irritation. Based on these findings, Eudragit E100 films containing ALA, PEG, and PRED may represent a promising alternative to conventional ophthalmic suspensions, as they provide sustained drug release while potentially simplifying dosing regimens.
Curcumin (CUR) exhibits broad therapeutic potential across multiple disease conditions. However, it's extremely low aqueous solubility, poor dissolution, and limited oral bioavailability constrain its clinical utility. Therefore, the present study aimed to address the aforesaid limitations through design, optimization, and evaluation of a pharmaceutical cocrystal of CUR with ascorbic acid (CUR-AA-C). Initially, in silico modelling was employed to predict drug-coformer interactions, followed by optimization of the CUR-AA stoichiometry using a solvent-evaporation technique. The resulting solid form was systematically characterized by spectral techniques to confirm cocrystal formation. Subsequent evaluations included solubility assessment, antioxidant activity testing, and tablettability studies. A Design of Experiments (DoE) approach was further utilized to optimize the tablet formulation, and the pharmacokinetic performance of the optimized cocrystal tablet was assessed through in vivo bioavailability studies. Spectroscopic techniques confirmed successful CUR-AA-C formation. It exhibited a significant enhancement in solubility (12-fold in SGF and 13-fold in SIF) compared to neat CUR, attributed to modifications in the crystal lattice structure induced by the coformer. Antioxidant assays demonstrated a two-fold improvement in activity. Tablettability evaluations revealed an increase in compressibility and mechanical strength, supporting the development of robust tablets. Furthermore, the DoE-optimized cocrystal tablet showed a 6.3-fold increase in oral bioavailability relative to unmodified CUR. Overall, the prepared cocrystal demonstrated potential to enhance solubility, dissolution, manufacturability, and bioavailability, thereby improving the clinical applicability of poorly soluble natural compounds.
Atopic dermatitis is a chronic inflammatory skin disease clinically characterized by pruritus, dryness, and eczematous lesions, resulting from a combination of environmental, immunological, and genetic factors. In this study, the quercetin-loaded thermosensitive hydrogel (QU-THG) was developed using the cold method and optimized through a Box-Behnken design. The concentrations of Pluronic F-127 and DMSO, and stirring speed were selected as independent variables, and sol-gel transition temperature, gelation time, and viscosity were evaluated as responses. The optimized formulation contained 18% w/v Pluronic F-127, showed a gelation temperature of 3 ± 0.3 °C, a gelation time of 5.3 ± 0.8 min, and a viscosity of 78 ± 5.3 cPs. The hydrogel underwent a reversible sol-gel transition, forming in situ stable gel at physiological temperature and enhances skin residence time. In vitro release studies demonstrated 49.9 ± 5.23% quercetin release within 7 h and 92.5 ± 3.1% over 24 h, following a non-Fickian diffusion mechanism based on the Korsmeyer-Peppas model, indicating the combined influence of diffusion and polymer relaxation. Skin permeation studies revealed maximum permeation at 18% w/v Pluronic F-127, likely due to reduced micellar packing and improved thermodynamic activity of quercetin. In vivo studies confirmed a significant reduction in inflammation and accelerated skin recovery compared to the negative control. Clinical scoring further confirmed a highly significant difference (p < 0.0001) using one-way ANOVA followed by Tukey's post hoc test. The optimized QU-THG demonstrated controlled gelation, desirable rheological properties, and sustained drug release, resulting in improved therapeutic outcomes, thereby supporting its applicability as an effective topical system for atopic dermatitis management.
Journal of medicinal chemistryDean P Phillips, Phil B Alper, Dmitry Borkin, Dong Han, Sarah E Kochanek, Jitendra Gurjar, Casey J N Mathison, John M Nelson, Wei Pei, Bao Ngoc Nguyen, Timothy…
Starting from our internally discovered, potent panKRAS inhibitor BRSD-143 (1), we executed a targeted bioisosteric optimization of the naphthol and fluoropyrrolizidine motifs to preserve (or increase) KRAS pan-inhibitory potency while improving DMPK/ADME liabilities. These studies delivered 12 (BRSD-212), a highly potent and efficacious lead in which (2-azabicyclo[4.2.0]octan-6-yl)methanol (ABO) serves as a bioisostere for the widely deployed 2-fluoropyrrolizidine substituent. In parallel, replacement of the naphthol moiety with an indazole afforded 21, which demonstrated improved pharmacokinetic performance and ADME characteristics by mitigating glucuronidation-mediated clearance as the dominant metabolic pathway.
Numerous advantages are afforded by crystallizing a compound directly from a reaction mixture; however, general information, strategies, and institutional knowledge surrounding solubility theory and crystallization are often not readily available to medicinal chemists. Herein, a series of general workflows are presented that leverage the use of antisolvents to manipulate solubility and facilitate direct-drop isolations. Distinctions are made for aqueous miscible versus aqueous immiscible reaction solvents. For high-impact reactions, a workflow is described that simplifies reaction mixtures to improve chances of success. Reslurry and recrystallization workflows are discussed with an emphasis on solvent selection to purge impurities based on LCMS retention factors. Finally, two case studies are described that successfully implemented these direct-drop workflows and significantly impacted project acceleration.
Journal of cardiovascular translational researchRohit Sharma, Abhay Thakur, Rahul Sharma
Cardiovascular drugs face many barriers to oral delivery, and self-nanoemulsifying drug delivery systems (SNEDDS) are becoming a promising nano-enabled drug delivery vehicle to address these challenges and aid precision cardiovascular delivery. The poor aqueous solubility and/or intestinal permeability, combined with high intestinal and hepatic clearance and, in some cases, intestinal P-glycoprotein (P-gp) efflux, leads to variable systemic exposure and inconsistent therapeutic activity of many antihypertensive drugs, antianginal drugs, and cardioprotective agents. Under gastrointestinal dilution conditions, SNEDDS spontaneously generate nanosized oil-in-water emulsions that keep drugs in a solubilized state, promote drug dissolution, enhance membrane interactions, increase intestinal permeability levels due to surfactant activity, reduce membrane fluidization by P-glycoprotein mediated efflux, increase lymphatic transport, decrease hepatic first pass metabolism, and decrease pharmacokinetic variability. This allows for more predictable pharmacokinetic performance, reduced interpatient variability, therapeutic optimization, and therefore an enabling concept of nano-enabled precision cardiology. This graphical abstract depicts the importance of self-nanoemulsifying drug delivery systems (SNEDDS) for enhancing drug absorption, providing enhanced bioavailability, increasing drug absorption and pharmacokinetic predictability, and facilitating precision cardiovascular therapy by overcoming the oral bioavailability barriers.
AAPS PharmSciTechYeakub Zaker, Snober Ahmed, Li Tian, Huzeyfe Yilmaz, Changning Guo, Jason D Rodriguez, Daniel R Willett
Correlative spectroscopic and structural imaging provides a powerful approach for characterizing the microstructure of complex pharmaceutical formulations. Laser direct infrared (LDIR) spectroscopy is an emerging, rapid spectroscopic imaging technique that complements traditional approaches by enabling non-destructive chemical and morphological analysis over large sample surfaces within minutes. In this study, the capabilities of LDIR imaging were evaluated alongside Raman mapping, SEM-EDS, laser microscopy, and micro-CT as part of a correlative workflow to characterize the microstructure and chemical composition of pharmaceutical pellets. Resin embedding enabled consistent handling and structural preservation of extended-release pharmaceutical pellets across all imaging modalities. Two commercially available morphine sulfate ER pellets (ER-1 and ER-2) with different excipient compositions were used as model systems. Laser microscopy revealed distinct differences in surface topography, while micro-CT performed before milling confirmed inherent structural features. ER-1 displayed a smooth, intact core, whereas ER-2 exhibited internal cracks and cavities. Hyperspectral LDIR imaging successfully identified major components in both formulations (hit-quality index, HQI ≥ 0.83) with strong concordance to Raman mapping (HQI ≥ 0.85). The spatial distribution of the active pharmaceutical ingredient (API) revealed a layered structure in ER-1 and a homogeneous core in ER-2. This correlative workflow, combining resin embedding with multiple imaging modalities, underscores the value of LDIR and complementary techniques for comprehensive physicochemical characterization of complex drug products. These findings highlight the utility of correlative imaging for regulatory assessment and quality control of complex extended-release formulations.
AAPS PharmSciTechThirupathi Reddy Anekalla, Sujith Raj Bashetty, Navya Nalajala, Nagarjuna Narala, Tejaswi Appidi, L R Jaidev Chakka, Mohammed Maniruzzaman
Thermal extrusion is a well-established approach for producing amorphous solid dispersions (ASDs) to enhance the solubility, dissolution, and bioavailability of poorly water-soluble drugs. Atorvastatin calcium trihydrate (ACT), a BCS class II lipid-lowering agent, exhibits low aqueous solubility, limited oral bioavailability, and variable absorption. The present study investigated the feasibility of fabricating immediate-release ACT tablets using a direct powder extrusion (DPE) three-dimensional (3D) printing technique, thereby enabling in situ drug amorphization and tablet fabrication in a single step. Critical process parameters (CPPs), including nozzle speed, printhead temperature, infill density, and extrusion pressure, were systematically optimized to achieve reproducible oval-shaped tablets with acceptable mechanical integrity and structural fidelity. Among the evaluated polymeric systems for improved dissolution, a combination of 25% (w/w) polyethylene glycol (PEG), 25% (w/w) polyethylene oxide (PEO), 15% (w/w) Pluronic F127, and 15% (w/w) sorbitol yielded consistent DPE printing at a 25% infill density, which has been shown to improve dissolution. The 3D-printed tablets, characterized by physicochemical, structural, and thermal analyses, confirmed successful drug amorphization. In vitro dissolution testing in phosphate buffer (PBS, pH 6.8) demonstrated rapid tablet disintegration and immediate drug release, with ~86% of ACT released within 30 min, meeting United States Pharmacopeia (USP) specifications for immediate-release ACT tablets. Accelerated stability studies (40°C/75% RH) for 3 months showed retention of the amorphous state, as confirmed from DSC and pXRD, with dissolution profiles comparable to initial results. Overall, the findings demonstrated that DPE-based thermal extrusion 3D printing enables single-step fabrication of amorphous ACT tablets with improved dissolution performance and stability, highlighting its potential as a single-step, flexible, patient-centric manufacturing platform at the point of service.
The AAPS journalMaja Chronowska, Jennifer Dressman
The poor water solubility of many drugs and drug candidates is a limiting factor to their bioavailability after oral administration. Although dissolution enhancing approaches, e.g. amorphous solid dispersions, are often used to make enabling formulations, these are usually associated with high development and manufacturing costs. This study focuses on the potential of using pharmaceutical excipients (binders) in simple tablet formulations to improve drug release and thus bioavailability. Loperamide hydrochloride, fenofibrate, compound c0 (a drug candidate) and carvedilol were chosen for this study as poorly water-soluble model compounds. Their solubility in the absence and presence of three polymeric binders, polyvinylpyrrolidone (PVP) K90, hydroxypropyl methylcellulose (HPMC) E4M and E15, and methylcellulose (MC) was tested in FaSSIF-V1 buffer and biorelevant media. Additionally, after wet granulation using PVP K90 or HPMC E15 as binders and tablet compression, the dissolution of the model compounds was tested in FaSSIF-V1 buffer and biorelevant media. Although solubilities and dissolution profiles of the model compounds were mostly improved by the binders, correlation between solubility in buffers and dissolution from the tablets in biorelevant FaSSIF-V1 was poor, indicating that dissolution experiments may be a better screening tool than solubility experiments. An important conclusion of these studies is that it is possible to increase the rate, and in some cases, the extent of dissolution of four poorly soluble drugs using wet granulation with polymeric binders, followed by tablet compression - a simple and cost-effective approach to improving drug performance.
This study aimed to develop an albendazole hydrochloride (ALB)-loaded ethosomal gel for topical psoriasis treatment. ALB-loaded ethosomes were prepared and characterized to select the optimal formulation, which was subsequently incorporated into an HPMC-based hydrogel. The ethosomal gel was evaluated through physicochemical, in vitro and in vivo studies. The optimized ethosomal formulation prepared by the film hydration method exhibited a mean vesicle size of 490.00 ± 0.14 nm, polydispersity index of 0.31 ± 0.14, zeta potential of -22.85 ± 2.28 mV and encapsulation efficiency of 23.90 ± 1.43%. After incorporation into the hydrogel matrix, the Gel4-E3/ALB formulation demonstrated appropriate mechanical properties (hardness 8.42 ± 0.70 mN, adhesiveness - 16.85 ± 1.50 mN·s, elasticity 0.89 ± 0.07, cohesiveness 1.14 ± 0.09) and shear-thinning behavior, ensuring ease of application and skin retention. A controlled release pattern was observed, consistent with the controlled-release behavior expected from ethosomal hydrogel systems. Radiolabeling studies demonstrated high labeling efficiency (> 95%). In vitro cytotoxicity evaluation indicated that the optimized ethosomal gel formulation was non-toxic. In vivo studies performed in an imiquimod (IMQ)-induced psoriatic mouse model revealed significant therapeutic improvement in the Gel4-E3/ALB-treated group compared with the IMQ control, with visible reduction in erythema, scaling, and skin thickening after the fifth day of treatment. Hematological analysis showed no adverse effects associated with the formulation. Histopathological evaluation confirmed the reduction in epidermal hyperplasia and inflammatory cell infiltration in the treated group. The developed ALB-loaded ethosomal gel represents a safe and promising topical therapeutic system for psoriasis management.
Oral drug delivery is the delivery method of choice, as it is non-invasive and patients will comply with the delivery method, but many contemporary therapeutics, such as poorly soluble, permeable, and unstable drugs, fail because of rapid gastrointestinal absorption, enzyme degradation, and non-targetability. The in-situ gelling systems are now considered paradigms that no longer exist as liquids; instead, they form a depot in the gastrointestinal tract and transform into a gel in response to physiological signals such as pH, ions, or enzymes. This review will discuss how these so-called smart polymers have developed over the years, starting as simple gel-forming systems and evolving into the multifunctional platforms that are also designed to have a pointed and sustained action. Next generation in situ gels combine bioadhesion, permeation enhancement, and active targeting ligands to overcome sequential barriers to delivery transit, permeability, stability, and cellular uptake. We critically assess the chemistry, mechanisms, formulation strategies, and therapeutic use of these systems, including gastro-retention and localized therapy, as well as oral delivery of biologics. Despite encouraging preclinical results, we touch on translational issues of scalability, manufacturing, and regulatory pathways. Multifunctional stimuli-responsive polymers, which actively traverse the gastrointestinal environment, are the future of oral drug delivery because they provide precision, bioavailability, and improved patient outcomes.
The AAPS journalTalia Flanagan, Diane Burgess, Marieta Duvnjak, Nikoletta Fotaki, Kate Harris, Krutika Meena Harish Jain, Dawen Kou, Adam McCartan, Heather Mead, Johanna Milsm…
A three-session webinar series was held by the IQ Consortium in early May 2023 on the topic of in vitro release testing of long acting injectable and parenteral (non-oral) drug products. Attendance was excellent, indicating the high level of interest in this topic. This paper provides a high-level overview of the talks that were given during the webinar and the open discussion session.
International journal of molecular sciencesSiva S Panda, Mohamed S Bekheit, Dalia R Aboshouk, Sudhan Sivakumar, Mohamed A Morsy, Mariam Abdur-Rahman, Abdelgawad Fahmi, Adel S Girgis
The hepatocyte growth factor (HGF)/c-Met signaling pathway plays a central role in cellular proliferation, survival, migration, invasion, angiogenesis, and therapeutic resistance. Aberrant c-Met activation, driven by gene amplification, overexpression, activating mutations, exon 14-skipping alterations, or ligand-dependent stimulation, drives the development and progression of many solid tumors, positioning c-Met as a key target for anticancer drug development. The clinical effectiveness of c-Met-targeted treatments such as crizotinib, capmatinib, tepotinib, savolitinib, and cabozantinib has confirmed c-Met as a viable oncogenic driver for therapy, leading to the development of various next-generation inhibitors with different structures. This review provides a comprehensive perspective on small-molecule c-Met inhibitors from the perspectives of medicinal chemistry and structure-based drug design, encompassing approved drugs, investigational agents, natural-product-inspired leads, and emerging multitarget anticancer therapeutics. Particular emphasis is given to the principles of molecular recognition that govern c-Met inhibition. This includes the structure of the kinase domain, interactions at the ATP-binding site, recognition of the hinge region, and the different binding modes of Type I, Type II, and allosteric inhibitors. The design, synthesis, biological evaluation, and structure-activity relationships of diverse heterocyclic scaffolds that have shaped c-Met inhibitor discovery are critically analyzed. Key medicinal chemistry strategies, including scaffold hopping, bioisosteric replacement, conformational optimization, molecular hybridization, and multitarget pharmacophore integration, are discussed in the context of potency, selectivity, resistance management, and drug-like properties. Particular attention is given to the integration of structural biology, molecular docking, binding-mode analysis, and structure-guided optimization approaches that have enabled the development of potent c-Met-directed inhibitors. In addition, recent advances in dual- and multitarget agents that simultaneously modulate c-Met and complementary therapeutic targets, including VEGFR-2, EGFR, AXL, MER, PARP1, CDK2, and tubulin, are highlighted as promising strategies for overcoming pathway redundancy and acquired resistance. This review summarizes contemporary structure-based and medicinal chemistry principles underlying c-Met inhibitor discovery, critically evaluates the relationship between biochemical potency and therapeutic efficacy, and provides a framework for the rational design of next-generation c-Met-targeted and multitarget anticancer agents.
This paper introduces a real-time, separationless method for monitoring Active Pharmaceutical Ingredient (API) concentration and dissolution kinetics in oral tablets using terahertz radiation (T-ray) transmission kinetics within simulated stomach fluid. Unlike conventional techniques such as High-Performance Liquid Chromatography (HPLC), which produce only discrete data points and require labor-intensive sample preparation, the T-ray approach offers continuous, quantitative measurement and monitoring. By leveraging the unique transmission and absorption characteristics of APIs in the T-ray region, this technique enables precise, real-time quantification of API concentration without physically separating excipients from the sample. The technique captures comprehensive kinetic profiles, providing deeper insights into dissolution processes and underlying molecular interactions. Its application can enhance Process Analytical Technology (PAT) by facilitating immediate, real-time quality control and supporting continuous manufacturing in the pharmaceutical industry. Additionally, the data generated can strengthen the modeling of in vitro-in vivo correlations (IVIVC), which is crucial for drug development and bioavailability assessment. Overall, the T-ray transmission technique represents a robust, efficient, and sustainable analytical tool for pharmaceutical research and production, offering significant advantages over traditional methods in both accuracy and operational speed.