Pharmaceutics最新文献

Objectives: This study aimed to identify and develop a novel, safe, and effective transdermal penetration enhancer derived from the leaves of Perilla frutescens (L.) Britt, and to explore the underlying mechanisms of its penetration enhancement effects. Methods: To evaluate the safety profile of the penetration enhancer, both skin irritation tests and histopathological analyses were conducted. The transdermal enhancement capabilities of the penetration enhancer were assessed in vitro using five model drugs. Furthermore, to gain insights into the penetration enhancement mechanism of this novel penetration enhancer, a range of analytical methods were used, including a spectroscopic technique, differential scanning calorimetry, micro-optical techniques, and molecular docking simulations. Results: Perilla essential oil contained 93.70% perilla ketone (PEK), which exhibited a safety profile superior to that of azone. PEK significantly increased the cumulative skin permeation of all the model drugs (p < 0.05). PEK exhibited the most obvious impact on puerarin penetration, with quantitative enhancement ratios of 2.96 ± 0.07 and 3.39 ± 0.21 at concentrations of 3% and 5% (w/v), respectively. A strong correlation between the enhancement effect of PEK and the physicochemical properties of the drugs was observed. Mechanistic studies revealed that PEK facilitates drug distribution from the solution phase to the stratum corneum (SC). Conclusions: PEK, seldom discussed in former studies, was observed to show extensive penetration enhancement effects by inducing conformational changes in SC lipids and disrupting the tightly ordered bilayer arrangement of lipids. These findings highlight the potential of PEK as a promising and safe natural transdermal penetration enhancer.

Transmucosal drug products, such as aerosols, films, semisolids, suppositories, and tablets, have been developed for the treatment of various human diseases and conditions. Transmucosal drug absorption is highly influenced by the biological structures of the mucosa and the physiological environment specific to the administration route (e.g., nasal, rectal, and vaginal). Over the last few decades, in vitro permeation testing (IVPT) using animal tissues or in vitro cell cultures have been utilized as a cost-effective and efficient tool for evaluating drug release and permeation behavior, assisting in formulation development and quality control of transmucosal drug delivery systems. This review summarizes the key mucosal permeation barriers associated with representative transmucosal administration routes, as well as considerations for IVPT method development. It highlights various IVPT methods, including vertical diffusion cell, flow-through diffusion cell, Ussing chamber, and transwell systems. Additionally, future perspectives are discussed, such as the use of optical methods to study in vitro drug permeation and the development of in vitro-in vivo correlation (IVIVC) for transmucosal drug development. The potential of IVPT as part of in vitro bioequivalence assessment strategies for locally acting transmucosal drug products is also highlighted.

Background: Kidney proton- and sodium-dependent monocarboxylate transporters (MCT/SMCT) are involved in the renal reabsorption of substrates, and thus factors involved in their regulation may have pharmacokinetic implications. Previous studies have demonstrated sex hormone-dependent regulation of MCTs and SMCTs in tissues involved in drug disposition. The present study evaluates the impact of puberty on renal MCT/SMCT expression with ovariectomy and castration conducted before puberty, removing the initial exposure to sex hormones. Methods: Male and female rats were castrated or ovariectomized before puberty (4 weeks of age), and subsequently treated with testosterone, 17β-estradiol, progesterone, or both 17β-estradiol and progesterone for 21 days starting at 10 weeks of age. MCT1, CD147, and SMCT1 membrane-bound kidney expression were quantified by Western blot. Results: SMCT1 and CD147 expression were significantly higher in OVX and CST rats treated with testosterone, and testosterone plasma concentrations showed a significant positive correlation with MCT1, SMCT1, and CD147 expression. CD147 expression was significantly downregulated in OVX rats treated with estrogen, compared to placebo controls, and estrogen plasma concentrations were significantly negatively correlated with CD147 expression. Conclusions: Sex and cross-sex hormone treatment altered MCT1, CD147, and SMCT1 expression when gonadectomy was conducted before puberty. The magnitude and direction of the expression differences differed when compared to animals that underwent gonadectomy after puberty, suggesting that sex hormone exposure during puberty plays a key role in MCT1/SMCT1 renal expression. Further studies are needed to elucidate the underlying mechanisms for the differential regulation of MCTs/SMCTs when gonadectomy occurs before or after puberty.

Background: Hepatitis D virus (HDV) is a defective virus requiring co-infection with hepatitis B virus (HBV) to replicate, occurring in 5% of HBV+ patients. Bulevirtide (BLV) is now the first-in-class specific anti-HDV agent, inhibiting HDV binding to NTCP, with good tolerability and good virological and biochemical response rates. Currently, little is known about its pharmacokinetic/pharmacodynamic (PK/PD), as well as potential drug-drug interaction (DDI) profile. In this work we provide a systematic review of the current knowledge on these aspects. Methods: A literature review of PK, PD and DDI profiles of BLV was conducted from Pubmed and EMA websites. Experimentally tested interactions and hypothetical mechanisms of interaction were evaluated, mostly focusing on usually co-administered anti-infective agents and other drugs interacting on NTCP. Results: BLV shows non-linear PK, due to target-mediated drug disposition, so its PK as well as PD is expected to be influenced by interactions of other drugs with NTCP, while it is not substrate of CYPs and ABC transporters. In-vivo investigated DDIs showed no clinically relevant interactions, but a weak inhibitory effect was suggested on CYP3A4 in a work when used at high doses (10 mg instead of 2 mg). In vitro, a weak inhibitory effect on OATP transporters was observed, but at much higher concentrations than the ones expected in vivo. Conclusions: The drug-drug interaction potential of BLV can be considered generally very low, particularly at the currently approved dose of 2 mg/day. Some attention should be paid to the coadministration of drugs with known binding and/or inhibition of NTCP.

Background/Objectives: The identification of inflammatory mediators and the involvement of CD206 macrophages in anti-inflammatory responses, along with the synthesis of fibrotic mediators, are crucial for the diagnosis and treatment of Idiopathic Pulmonary Fibrosis (IPF). Methods: In this study, the assessment of ⁶⁸Ga-labeled linear and cyclic forms of the RP832c peptide, which demonstrate a specific affinity for CD206 macrophages, was performed to evaluate efficacy for CD206 imaging through PET/CT, biodistribution studies, and CD206 staining in a bleomycin-induced lung injury mouse model (BLM). This model serves as a representative framework for inflammation and fibrosis. Results: The findings reveal significant peak PET/CT signals (SUV means), ID/gram values, and CD206 staining scores in lung tissues at one week post bleomycin instillation, likely due to the heightened expression of CD206 in the bleomycin-induced lung injury model. In contrast, the healthy mice exhibited no detectable CD206 staining, lower PET signals, and reduced radiopharmaceutical accumulation in lung tissues at the same timepoint. Conclusions: These findings suggest that both linear and cyclic [⁶⁸Ga]Ga-RP832c may function as promising PET imaging agents for CD206 macrophages, and thereby a strategy to non-invasively explore the role of macrophages during fibrogenesis.

Immunotherapy is one of the most promising approaches for cancer management, as it utilizes the intrinsic immune response to target cancer cells. Normally, the human body uses its immune system as a defense mechanism to detect and eliminate foreign objects, including cancer cells. However, cancers develop a 'switch off' mechanism, known as immune checkpoint proteins, to evade immune surveillance and suppress immune activation. Therefore, significant efforts have been made to develop the strategies for stimulating immune responses against cancers. Among these, the use of extracellular vesicles (EVs) to enhance the anti-tumor immune response has emerged as a particularly promising approach in cancer management. EVs possess several unique properties that elevate the potency in modulating immune responses. This review article provides a comprehensive overview of recent advances in this field, focusing on the strategic usage of EVs to overcome tumor-induced immune tolerance. We discuss the biogenesis and characteristics of EVs, as well as their potential applications in medical contexts. The immune mechanisms within the tumor microenvironment and the strategies employed by cancers to evade immune detection are explored. The roles of EVs in regulating the tumor microenvironment and enhancing immune responses for immunotherapy are also highlighted. Additionally, this article addresses the challenges and future directions for the development of EV-based nanomedicine approaches, aiming to improve cancer immunotherapy outcomes with greater precision and efficacy while minimizing off-target effects.

Background: Antibody-drug conjugates (ADCs) represent a novel therapeutic class that combines an antibody against a tumor-associated antigen (TAA), a payload, and a linker that binds these two components. Serious adverse events (SAEs), particularly those of grade 3 (G3) or higher, frequently contribute to the abandonment of ADCs during clinical development. Methods: In this study, we analyzed the toxicity profiles of all approved ADCs, aiming to uncover correlations between their safety profiles and the specific characteristics of their components. Results: In our analysis, dose reductions, dose delays, treatment discontinuations, and ≥G3 toxicities were not significantly different across payload types. Similarly, no association was found between the payload mechanism of action and ≥G3 toxicities, including anemia, neutropenia, febrile neutropenia, thrombocytopenia, and diarrhea. By exploring the specific toxicities of ADCs observed by organ, we identified that most were related to the payload mechanism of action, like the ≥G3 diarrhea observed in 10% of patients treated with sacituzumab govitecan (the payload SN-38 is the active metabolite of irinotecan), and very few were related to the presence of the TAA in normal tissue (presence of Nectin-4 in skin and ≥G3 rash toxicity in 14% of patients treated with enfortumab vedotin). In line with this, no major differences in ≥G3 toxicities were identified in studies with different levels of the TAA (trastuzumab deruxtecan in Destiny Breast Studies with different HER2 expression levels). Conclusions: Our analysis reveals that most ADC toxicities are driven by the payload's effects on non-transformed tissues; however, a detailed analysis of each ADC component should be taken into consideration.

Background/Objectives: Thickened waters are commonly used for dysphagic patients to ensure hydration, facilitate safer swallowing, and administer oral therapies, yet their impact on drug dissolution remains unclear. This study aims to investigate how thickening agents, viscosity, and solid oral dosage form (SODF) formulations influence drug release in gelled vehicles. Methods: Twelve commercially available thickened waters, including both ready-to-use products and powders for extemporaneous preparation, were used to disperse crushed sodium pravastatin tablets. The resulting preparations were evaluated for their rheological properties and dissolution performance. Results: Thickened water products vary in consistency, with starch-based thickeners providing more consistent results than gum-based ones. Pravastatin release profiles closely matched the original tablets with starch thickeners, while gum-based thickeners showed greater variability, primarily influenced by viscosity. Conclusions: These findings emphasize the importance of selecting the appropriate thickening agent for controlling drug release in thickened water products, highlighting the need to balance patient compliance with the potential impact on drug release during product development.

Obesity has become a major public health threat, as it can cause various complications such as diabetes, cardiovascular disease, sleep apnea, cancer, and osteoarthritis. The primary anti-obesity therapies include dietary control, physical exercise, surgical interventions, and drug therapy; however, these treatments often have poor therapeutic efficacy, significant side effects, and unavoidable weight rebound. As a revolutionized transdermal drug delivery system, microneedles (MNs) have been increasingly used to deliver anti-obesity therapeutics to subcutaneous adipose tissue or targeted absorption sites, significantly enhancing anti-obese effects. Nevertheless, there is still a lack of a review to comprehensively summarize the latest progress of MN-mediated treatment of obesity. This review provides an overview of the application of MN technology in obesity, focusing on the delivery of various therapeutics to promote the browning of white adipose tissue (WAT), suppress adipogenesis, and improve metabolic function. In addition, this review presents detailed examples of the integration of MN technology with iontophoresis (INT) or photothermal therapy (PTT) to promote drug penetration into deeper dermis and exert synergistic anti-obese effects. Furthermore, the challenges and prospects of MN technology used for obesity treatment are also discussed, which helps to guide the design and optimization of MNs. Overall, this review provides insight into the development and clinical translation of MN technology for the treatment of obesity.

Background: Colorectal cancer (CRC) is one of the common malignant tumors. Chemotherapeutic agents represented by doxorubicin (DOX) are common adjuvant therapies for patients with advanced CRC. However, DOX suffers from dose-dependent cardiotoxicity and myelosuppression due to a lack of targeting and specificity, which severely limits its clinical application. Methods: Herein, we constructed a zeolitic imidazolate framework-8 (ZIF-8) modified by a novel peptide (LT peptide) to deliver the chemotherapeutic drug doxorubicin (DOX) for the targeted treatment of CRC. Results: In this study, LT-PEG@DOX@ZIF-8 nanoparticles were prepared by a simple method with suitable particle size and zeta potential, which were also capable of pH-responsive drug release. In vitro assays exhibited that LT-PEG@DOX@ZIF-8 nanoparticles were effectively taken up by C26 cells, significantly inhibited cell proliferation, and induced apoptosis. Furthermore, in mice models with colorectal tumors, LT-PEG@DOX@ZIF-8 nanoparticles also displayed specific tumor aggregation and exerted anti-tumor effects to prolong the survival of the mice. Conclusions: In conclusion, LT-PEG@DOX@ZIF-8 provides a promising strategy for the delivery of DOX to effectively treat CRC.