AAPS PharmSciTech最新文献

Compared to the conventional blood–brain barrier crossing over, nose-to-brain delivery provides a potentially effective substitution, particularly when large molecules of drugs need to be delivered. The majority of macromolecules degrade quickly in a physiological environment. Therefore, drug molecules can be protected against early breakdown by using nanocarrier systems. Targeting nanocarrier system with ligand potential of enhancing bioavailability due to tailored binding affinity to targeting site. In the current study, we prepared paclitaxel (PTX) loaded ascorbic acid (AA) conjugated polycaprolactone (PCL) nanoparticles (NPs) for intranasal administration. Polymeric nanoparticles (PNPs) were prepared using the solvent evaporation method, which was further analyzed for particle size, polydispersity index (PDI), surface charge, encapsulation-efficiency (EE), drug loading (DL), surface morphology, in-vitro drug release, and in-vivo pharmacokinetic evaluation. Results showed the optimized PTX-PNPs showed particle size 114.7 ± 2.96 nm, zeta potential -27.6 ± 1.63 mV, with entrapment efficiency 97.3 ± 0.41%, and drug loading 35.3 ± 0.38%. In-vitro PTX release showed a biphasic release pattern, primary burst release followed by sustained release was observed. An in-vivo pharmacokinetic study showed a 5.6-fold increase in the PTX concentration reaching to the brain. Histopathological results of the nasal mucosa showed minimal alteration after 72 h of administering surface-modified paclitaxel loaded polymeric nanoparticles (AA-PTX-PNPs). Thus, this study highlighted the suitability of a AA-PTX-PNPs as a promising strategy for intranasal administration therapy for various brain disorders.

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Metabolic syndrome (MS) has a high prevalence, with an estimated one-quarter of the world population affected by this pathological condition. Among the diseases of this syndrome are dysregulation of lipids, hypertension, and insulin resistance. Unfortunately, available drugs in the market used for treating MS, as almost 75% of all drugs, are highly insoluble, presenting a significant demand for strategies to increase their solubility. Taking advantage of the fact that drugs in the amorphous state can provide a solubility enhancement, a new drug-drug co-amorphous (CoA) formulation to potentially simultaneously treat two or more MS conditions was explored, combining the co-formers Bezafibrate (BZT) a lipid-regulating drug, and Gliclazide (GZD) a hypoglycemic agent. A phase diagram was constructed to characterize the binary system's thermal properties, including glass transition temperatures of all compositions studied. The formulations were characterized by FTIR; redshifts of IR bands from 1547 to 1538 cm^–1 and 1717 to 1609 cm^–1 were observed due to the formation of intermolecular interactions, such as hydrogen bonds. The co-amorphous binary systems lead to an increase in the solubility of both BZT and GZD; specifically, for the composition x_BZT = 0.5, the increase was 2.1× for BZT and 1.5 times for GZD while for x_BZT = 0.7 an increase of 4× of BZT was achieved. The structural stability of the samples was verified by XRD and DSC, showing long-term stability retention of the amorphous state for more than eight years. The enhanced solubility and stability of the co-amorphous systems make them potential formulations for regulating lipids and lowering glycemia.

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Amorphous solid dispersion (ASD) is one of the most studied strategies for improving the dissolution performance of poorly water-soluble drugs, but ASDs often have low drug loadings, thereby necessitating larger dosage sizes. This study intended to create Soluplus® (SOL)-based microparticle ASDs with high drug loading (up to 60 w/w%) and long-term stability (at least 16 months) using electrospraying to enhance the dissolution of poorly water-soluble celecoxib (CEL). X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analyses showed that the electrosprayed SOL-CEL microparticles were amorphous, and Fourier transform infrared spectroscopy (FTIR) data indicated the presence of hydrogen bonding between SOL and CEL in the microparticles, which helped stabilize the ASDs. In vitro dissolution studies demonstrated that these ASDs improved the CEL dissolution rate by up to 8.2-fold compared to the crystalline form. Electrospraying presents a promising alternative to conventional methods like hot-melt extrusion (HME) and spraying drying (SD) for the production of ASDs, providing simplicity, high drug loading capability and long-term stability, thus catering to a variety of poorly water-soluble drugs.

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The biopharmaceutical industry has witnessed significant growth in the development and approval of biosimilars. These biosimilars aim to provide cost-effective alternatives to expensive originator biosimilars, alleviating financial pressures within healthcare. The manufacturing of biosimilars is a highly complex process that involves several stages, each of which must meet strict regulatory standards to ensure that the final product is highly similar to the reference biologic. To gain regulatory approval, biosimilars must undergo rigorous analytical characterization including in vitro assays, bioanalytical evaluations, and clinical similarity studies like pharmacokinetic (PK), pharmacodynamic (PD) assessments-to demonstrate safety, efficacy, quality comparability with reference products. Leading regulatory agencies such as the European Medicines Agency (EMA), the World Health Organization (WHO), and the United States Food and Drug Administration (US FDA) have established stringent guidelines for biosimilar evaluation and post-marketing surveillance. Despite this regulatory clarity, challenges around interchangeability, market exclusivity, and patent protection often delay market access and limit adoption, particularly in regions where automatic substitution is restricted. Case studies of biosimilars such as rituximab, adalimumab, filgrastim, and trastuzab reveal both advancements and ongoing hurdles in achieving broader market integration. The introduction of biosimilars has shown potential to reduce healthcare costs; for example, a recent analysis indicates a 20–30% cost reduction in the U.S. due to biosimilar adoption. As the biosimilar market expands, collaborative efforts among regulatory bodies, industry stakeholders, and healthcare providers are essential to enhance access to biologic therapies. This collaboration is poised to improve patient outcomes and catalyse transformative change in global healthcare systems.

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Valsartan (VST) is an angiotensin II receptor antagonist with low oral bioavailability. The present study developed a solid self-nanoemulsifying drug delivery system (S-SNEDDS) to enhance the oral absorption and bioavailability of VST. VST-loaded liquid SNEDDS (VST@L-SNEDDS) was prepared by investigating the solubility of VST and constructing the pseudo-ternary phase diagrams. The formulation of VST@S-SNEDDS was obtained by adsorbing VST@L-SNEDDS onto a solid carrier. In vitro studies including drug dissolution, stability, cytotoxicity, and Caco-2 uptake of VST@S-SNEDDS were assessed. An in vivo pharmacokinetic study of VST@S-SNEDDS was employed to evaluate the oral bioavailability of VST. VST@L-SNEDDS, with an average particle size of 19.90 nm and zeta potential of -20.57 mV, consisted of 12.37% VST (drug loading), 21.91% ethyl oleate, 45.50% RH 40, and 20.22% Transcutol HP. VST@S-SNEDDS was prepared using Neusilin® UFL2 as a solid adsorbent, which contained VST@L-SNEDDS at 2.28 ± 0.15 g/g. The in vitro release study demonstrated that VST@S-SNEDDS exhibited rapid release characteristic without affecting by the pH of the media, and dissolution rates exceeded 90% within 60 min in different media. The long-term stability of VST@S-SNEDDS was better than that of VST@L-SNEDDS. These two formulations increased the Caco-2 uptake significantly. The area under the drug concentration–time curve (AUC_0-24h) and peak drug concentration in plasma (C_max) of VST@S-SNEDDS increased by 2.28-fold and 4.86-fold compared to raw VST, respectively. The proposed VST@S-SNEDDS represents a novel approach to enhance the oral absorption and bioavailability of VST, providing a promising avenue for hypertension treatment.

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Dosage forms containing Ivermectin (IVER) and Praziquantel (PRAZ) are important combination drug products in animal health. Understanding the relationship between products with differing in vitro release characteristics and bioequivalence could facilitate generics. The goal of this study was to create granulations for each active ingredient, with similar release mechanisms, but substantially different in vitro release rates, and then compressing these granulations into tablets with differing release rates. Four granulation formulations were created: fast and modified release for PRAZ and IVER, respectively. The manufacturing process used high shear wet granulation and fluid bed drying, milling and sieving. Solid components, including the granulating agent, were blended in a high shear granulator and then water or a hydroalcoholic solution was added to activate the binder and initiate granule formation. Drying in a fluid bed with inlet air temperature set for 70°C and inlet air volume adjusted as required to maintain fluidization. Milling was performed in a cone mill and classification of final product was done using a vibratory sieve shaker with 18, 20, 40, and 60 mesh sieves. Formulations and processing approaches were successfully developed to produce a collection of PRAZ and IVER granules with differing particle size distributions and in vitro release characteristics. Differences in drug content in the classified granulations were observed and attributed to the low surface energy of PRAZ and the different approaches used to incorporate the active ingredients. The granulations were compressed via compaction simulator and the results show the monolithic tablets had four different release profiles.

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The aim of the present study was to investigate the potential of human plasma derived exosomes for the delivery of hydroxyurea to enhance its therapeutic efficacy in breast cancer. Plasma derived exosomes were isolated using differential centrifugation along with ultrafiltration method. Hydroxyurea was encapsulated in exosomes using a freeze–thaw method. The exosomes and Exo-HU were characterized for their size distribution, drug entrapment efficiency, in-vitro drug release profile, morphological analysis and cytotoxic effects on MCF-7 cell line. The results showed a mean size of 178.8 nm and a zeta potential of -18.3 mV, indicating good stability and 70% encapsulation effectiveness for HU. Exo-HU produced sustained drug release action with a considerable percentage released within 72 h. The morphological analysis indicated that the plasma derived exosomes were spherical, and cup shaped. In cytotoxicity studies on MCF-7 cells, Exo-HU has reduced cell viability compared to HU and blank exosomes. Findings of this study showed that human plasma-derived exosomes have been considered as effective delivery vehicle for hydroxyurea, potentially improving breast cancer treatment outcomes.

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The current project was designed to develop piperine-loaded solid lipid microparticles (SLMs) to assess the anti-arthritic potential of piperine (PIP). Variable proportions of carnauba wax, beeswax, and tween 80 were employed for preparing SLMs by using the solvent evaporation technique. The developed formulations were subjected to particle size measurements, entrapment efficiency (EE), and zeta potential (ZP) determination. Microparticles were also investigated for piperine-lipid compatibility, thermal analysis, surface morphology, piperine (PIP) release trend, and anti-rheumatic activity in rats. The network's grafting was confirmed by FTIR and XRD results. The thermal stability of the constructed network was confirmed by the DSC and TGA results. SEM findings confirm porous surface morphology. The dissolution experiments on SLMs confirmed the sustained release profile, delivering 87.82% to 94.92% of piperine at 7.4 pH for 24 h. All developed formulations followed a zero-order kinetic model and the Korsmeyer-Peppas model. Furthermore, the anti-rheumatic potentials of piperine from SLMs were also investigated and compared with diclofenac sodium (the standard treatment) in a rat model. The analysis revealed that PIP significantly reduced the severity of arthritis, as confirmed by the findings of multiple arthritic assessment parameters.

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The transdermal route is one of the effective routes for delivering drugs. It also overcomes many limitations associated with oral delivery. One of the limitations of this route is the drug’s poor skin permeability—stratum corneum, the skin’s outermost layer that also acts as a barrier for the drug to penetrate. Traditional liposomal formulation is utilized to overcome these limitations. However, these liposomes also have certain difficulty in delivering drugs across the barriers. Ultra-deformable vesicles are novel vesicular structures that are flexible and stable, they can easily bypass the skin barriers more efficiently and thus enhance bioavailability. These vesicles consist of ethosomes, transethosomes, and transferosomes. Transethosomes are more advanced than other vesicular systems because they contain ethanol, phospholipids, and edge activators, making them more deformable and easier to penetrate deeper skin membranes. These vesicular systems can be prepared by various methods, such as cold, hot, and thin film hydration. Characterization of transethosomes includes vesicular size, zeta potential, polydispersity index and encapsulation efficiency, stability, and drug release studies. These vesicular systems can be utilized to deliver a variety of medications transdermally, including analgesics, antibiotics, and arthritis medications. Despite their promising potential, ethanol-based formulations present several problems requiring additional study. This review aims to describe various vesicular structures that have been used to overcome the barrier for the transdermal delivery of drugs and also describe brief composition, method of preparation, characterization, mechanism of penetration of transethosomes, as well as highlighted various applications of transethosomes in medicine, clinical trials and patents.

Pharmaceutical salts are a cornerstone in drug development, offering a robust, economical, and industry-friendly option for improving the crucial physicochemical properties of drugs, particularly solubility and dissolution. This review article explores all critical aspects of salt formation, including its importance, the basic chemistry involved, the principles governing counterion selection, the range of counterions used, and the methods for preparing salts along with their advantages and limitations. Additionally, it explores analytical techniques for confirming salt formation and the different approaches various countries adopt in considering new salts as intellectual property. Furthermore, the review sheds light on US FDA-approved salts from 2019 to 2023, providing a unique perspective by analyzing trends in counterion selection observed in FDA-approved salts during this period. Despite the extensive literature on pharmaceutical salts, a comprehensive review addressing all these critical aspects in a single article with a focus on current trends and particularly on US FDA-approved salts from 2019 to 2023 is lacking. This review bridges this gap by thoroughly exploring all mentioned facets of pharmaceutical salts and providing an up-to-date overview.

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