AAPS PharmSciTech最新文献

Thought should be given to the desirability for similar approaches for the present transition to low global warming potential (LGWP) propellants for pressurized metered dose inhalers (pMDIs)  to be adopted by both European Medicines Agency (EMA) and the United States Food and Drug Administration  (FDA) for the performance testing of pMDIs that include the evaluation with an add-on spacer or valved holding chamber as part of the in vitro component for product registration. If such an add-on device was to be included as part of the registration package in either US or European regulatory environments, the content of United States Pharmacopeia (USP) chapter <1602> could support the process.

The purpose of study was to exploit distinctive features of nasal administration route to boost agomelatine permeation and upgrade its anti-depressant action after being embedded in Brij^®-enriched novasomes (NVs) as non-phospholipid vesicular systems. Different amounts and types of excipients were used to evaluate NVs using definitive screening design (DSD). Optimal NV was incorporated in thermosensitive in-situ gels containing poloxamer 407 (P-407) and hydroxypropyl methyl cellulose (HPMC). After evaluation of novasomal in-situ gels (NVGs), optimal NVG was subjected to ex-vivo, in-vivo, and biochemical investigations. Results showed significant increase in entrapment capability (EC%), particle size (P.S), and zeta potential (Z.P) of NVs after increasing free fatty acid, surfactant, and cholesterol amounts. The capability of Brij^® to improve fluidization of lipid bilayers, decrease P.S, and increase Z.P was observed. Lipohilicity, EC%, and Z.P of Brij^® 56-enriched NVs were higher than those containing Brij^® 35. Gradual increase in HPMC concentration and gel/NV ratio led to marked decrease in gelation time and spreadability and increase in gel strength and viscosity values of NVGs. Optimal NVG9 displayed higher permeation profile (538.34 μg/cm²) and drug flux (39.38 μg/cm².h⁻¹) through fresh sheep nasal mucosa in comparison to control gel (150.76 μg/cm² and 14.44 μg/cm².h⁻¹, respectively). Rats treated with nasal optimal NVG9 manifested increased sucrose preference (SP) percent (80.73%) and levels of dopamine (50.42 ng/g) and serotonin (44.92 ng/g) with decreased low latency time values (5.86 min). This study confirmed the in-vivo safety and amplification of precognitive and anti-depressant action of agomelatine after intranasal administration.

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Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown cause, with few effective therapies available and high mortality rates. Our preceding research indicated that formononetin (FMN) could improve the symptoms of the bleomycin-induced pulmonary fibrosis and be a promising drug against IPF. In this study, an inhalable formononetin-loaded poly(lactic-co-glycolic) acid (PLGA) large porous microspheres (FMN-PLGA-MSs) was prepared by the method of emulsion solvent evaporation. SEM showed that FMN-PLGA-MSs were loose particles existing many pores on the surfaces, and the measured mean geometric diameter was more than 10 µm. The encapsulation efficiency (EE) and drug loading efficiency (DL) were 87.72 ± 6.34% and 4.18 ± 0.30%. FMN in FMN-PLGA-MSs could be rapidly released within 2 h and sustainably released for 21 d. Cell tests and q-RT-PCR tests showed that FMN could inhibit the activation of fibroblasts and the deposition of extracellular matrix (ECM) by acting on the TGF-β1/Smad3 signaling pathway. FMN-PLGA-MSs showed higher antifibrotic effects than free FMN oral administration in the pulmonary fibrosis models of mice, remarkably improving pulmonary function, decreasing hydroxyproline levels, and attenuating lung injuries. By formulating formononetin into microsphere preparations, its solubility can be significantly enhanced, enabling effective pulmonary drug delivery. This approach not only improves lung targeting but also reduces systemic toxicity. Additionally, it facilitates superior lung deposition and extends the retention time of the formononetin within the lungs. Taken together, FMN-PLGA-MSs may be a promising inhaled medication for the treatment of IPF.

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Formononetin (FMN) can improve the symptoms of idiopathic pulmonary fibrosis (IPF). Large porous microparticle can improve lung retention and lung targeting. FMN is loaded in poly(lactic-co-glycolic)acid (PLGA) to get microspheres (FMN-PLGA-MSs) for intratracheal instillation treatment of IPF. FMN-PLGA-MSs remarkably improved pulmonary function, decreased hydroxyproline, and attenuated lung injuries. FMN-PLGA-MSs are promising intratracheal instillation medication for the treatment of IPF.

The integration of nanotechnology into drug delivery systems holds great promise for enhancing pharmaceutical effectiveness. This approach enables precise targeting, controlled release, improved patient compliance, reduced side effects, and increased bioavailability. Nanoparticles are vital for transporting biomolecules—such as proteins, enzymes, genes, and vaccines—through various administration routes, including oral, intranasal, vaginal, buccal, and pulmonary. Among biodegradable polymers, chitosan, a linear polysaccharide derived from chitin, stands out due to its biocompatibility, safety, biodegradability, mucoadhesive properties, and ability to enhance permeation. Its cationic nature supports strong molecular interactions and provides antimicrobial, anti-inflammatory, and hemostatic benefits. However, its solubility, influenced by pH and ionic sensitivity, poses challenges requiring effective solutions. This review explores chitosan, its modified derivatives and chitosan nanoparticles mainly, focusing on nanoparticles physicochemical properties, drug release mechanisms, preparation methods, and factors affecting their mean hydrodynamic diameter (particle size). It highlights their application in drug delivery systems and disease treatments across various routes. Key considerations include drug loading capacity, zeta potential, and stability, alongside the impact of molecular weight, degree of deacetylation, and drug solubility on nanoparticle properties. Recent advancements and studies underscore chitosan's potential, emphasizing its modified derivatives'versatility in improving therapeutic outcomes.

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The aim of this study was to prepare and characterize amorphous clobazam (CLOB) and investigate its devitrification under various stressors (temperature/humidity, compaction and mechanical/thermal stresses). Amorphous CLOB was prepared by melt-quenching in liquid nitrogen. The quench-cooled sample (CLOB-q) was characterized via polarized light and hot-stage microscopies (PLM and HSM), X-ray powder diffraction (XRPD), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), conventional and modulated DSC (DSC-c and MDSC®), thermogravimetry (TG), dynamic mechanical analysis (DMA), X-ray photoelectron spectroscopy (XPS) and contact angle measurements. Stability of CLOB-q toward temperature/humidity, compaction, and combined mechanical and thermal stress were also evaluated. CLOB-q was a truly amorphous form, as revealed by DSC-c, MDSC® and DMA. Its calorimetric glass transition temperature (Tg) was 67.0 °C (20 °C/min) and the ratio Tm/Tg was 1.34, indicating a fragile glass. The water contact angle of CLOB-q (121.8° ± 1.7°) was lower than that of crystalline CLOB (CLOB-c, 131.3° ± 3.6°), likely due to its higher concentration of surface CL, as determined by XPS. Storage of CLOB-q at - 20 °C/0% RH, 25 °C/0% RH and 40 °C/75% RH resulted in its complete devitrification to CLOB-c within 60 days, 4 days, and 42 h respectively. Subjection of CLOB-q to compaction (19.6 kN) and combined mechanical-thermal stresses also resulted in complete crystallization to CLOB-c. In conclusion, amorphous CLOB was successfully prepared in the laboratory for the first time and thoroughly characterized. It easily devitrified to CLOB-c by effect of different stressors, and thus it could not have advantages over CLOB-c in terms of physical stability.

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BCS class II candidates pose challenges in drug development due to their low solubility and permeability. Researchers have explored various techniques; co-amorphous and solid dispersion are major approaches to enhance in-vitro drug solubility and dissolution. However, in-vivo oral bioavailability remains challenging. Physiologically based pharmacokinetic (PBPK) modeling with a detailed understanding of drug absorption, distribution, metabolism, and excretion (ADME) using a mechanistic approach is emerging. This review summarizes the fundamentals of the PBPK, dissolution—absorption models, parameterization of oral absorption for BCS class II drugs, and provides information about newly emerging artificial intelligence/machine learning (AI/ML) linked PBPK approaches with their advantages, disadvantages, challenges and areas of further exploration. Additionally, the fully integrated workflow for formulation design for investigational new drugs (INDs) and virtual bioequivalence for generic molecules falling under BCS-II are discussed.

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Cyclosporine A (CsA) is widely used to treat dry eye disease (DED), and ocular morbidity is on the rise and is a growing concern globally. However, several drug and formulation challenges, such as poor drug solubility, short pre-corneal residence time, and poor patient compliance, have limited the ocular bioavailability of CsA to < 5%. A CsA cyclodextrin-based ternary complex loaded dissolvable nano drug reservoir films were developed to overcome these limitations and efficiently manage DED. Drug-loaded nano-reservoir films were fabricated via lithography using silicone and poly (dimethyl siloxane) (PDMS) molds. Different physicochemical characterizations were performed to confirm the formation of stable CsA-cyclodextrin-based ternary complexes. Formation of nanoreservoirs on the films was confirmed using SEM and AFM. Optimized CsA-complex-loaded nano-reservoir films were evaluated for in vitro drug release, ex vivo corneal permeation, and in vivo precorneal retention. Preclinical efficacy studies were performed to assess the efficacy of CsA-complex-loaded nano-reservoirs in an experimental dry-eye mouse model. Physicochemical characterization confirmed the formation of a stable complex and the improved solubility of CsA. In vitro release and ex vivo permeation studies indicated a controlled drug release and improved permeation, respectively. Furthermore, tear volume measurement and corneal damage assessment using slit-lamp imaging suggested decreased dry eye symptoms, significantly increasing tear volume in the drug-loaded nano-reservoir-treated group. Moreover, histopathological studies corroborated the tear volume and slit-lamp imaging results, with reduced inflammation and neovascularization. The poorly water-soluble drug with cyclodextrin complex incorporated nanoreservoir films presents a potential alternative for managing various ocular diseases.

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Sericin, a silk-derived protein, has emerged as a potential material for Digital Light Processing (DLP) printing, particularly in uses requiring biocompatibility and sustainability. Sericin is a candidate for developing durable and precise 3D-printed structures due to its natural origin and intrinsic properties like film-forming ability and cross-linking potential. Its biocompatibility makes it suitable for medical applications, such as targeted delivery of anticancer drugs or creation of therapeutic supports directly on affected skin, orthodontic and cosmetic biomaterials, disease modulation, wound healing, antioxidant and antimicrobial applications, and regenerative medicine. Additionally, sericin can strengthen and stabilize printed structures while maintaining environmental integrity, aligning with the growing demand for eco-friendly materials in advanced manufacturing. However, formulating sericin-based resins for DLP printing presents challenges, including optimizing cross-linking and curing processes for obtaining desired properties of material. Overcoming these challenges could unlock the full potential of sericin in diverse fields, such as tissue engineering, where biocompatibility and precise structural integrity are critical. This review investigates the potential of sericin-based resins for 3D printing, emphasizing the protein’s compatibility with photopolymerizable systems and its capacity to improve the overall performance of DLP-printed materials. Further research is essential to refine sericin-based formulations, enabling their broader application in 3D printing technologies. By examining the unique characteristics of sericin, including its origins and material properties, this review underscores the protein's potential to drive innovation in sustainable manufacturing. Ultimately, sericin offers a viable alternative to synthetic resins and holds promise for advancing both biomedical and environmental applications through innovative 3D printing technologies.

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The evaporation of the solvent induces significant changes in formulation, directly impacting its performance. The performance of topical products is determined by the interplay between their inherent quality attributes and the transformations that occur due to solvent evaporation when applied to the skin in clinically relevant doses. To accurately assess, in vivo performance, it is advisable to apply smaller doses to the skin and keep the donor compartment open to enable evaporation of solvents while carrying out in vitro permeation tests. This manuscript highlights the critical role of solvent evaporation in differentiating the performance of two compositionally distinct products. One gel formulation contained alcohol, while the other did not. Although both exhibited similar quality attributes, their drying profiles varied significantly. Permeation studies conducted with closed donor compartments (Evaporation-disabled (ED)) failed to reveal these differences. However, when the donor compartments were exposed to the atmosphere to allow evaporation (Evaporation-enabled (EN)), the performance differences between the two products became evident.

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