Pharmaceutics doi: 10.3390/pharmaceutics16030422
Authors: He Zhang Anle Ge Yulin Wang Boran Xia Xichu Wang Zhonghui Zheng Changsheng Wei Bo Ma Lin Zhu Rose Amal Sung Lai Jimmy Yun Zi Gu
The therapeutic application of biofunctional proteins relies on their intracellular delivery, which is hindered by poor cellular uptake and transport from endosomes to cytoplasm. Herein, we constructed a two-dimensional (2D) ultrathin layered double hydroxide (LDH) nanosheet for the intracellular delivery of a cell-impermeable protein, gelonin, towards efficient and specific cancer treatment. The LDH nanosheet was synthesized via a facile method without using exfoliation agents and showed a high loading capacity of proteins (up to 182%). Using 2D and 3D 4T1 breast cancer cell models, LDH–gelonin demonstrated significantly higher cellular uptake efficiency, favorable endosome escape ability, and deep tumor penetration performance, leading to a higher anticancer efficiency, in comparison to free gelonin. This work provides a promising strategy and a generalized nanoplatform to efficiently deliver biofunctional proteins to unlock their therapeutic potential for cancer treatment.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030423
Authors: Anand A. Sable Amit Kunwar Atanu Barik
One of the major challenges in harnessing the therapeutic benefits of curcumin (an active ingredient from turmeric) is its poor bioavailability due to its short biological half-life. In this regard, nanoformulations have shown tremendous hope for improving the pharmacokinetic and therapeutic behavior of curcumin by altering its biological stability and bioavailability. Biopolymers, especially alginate and chitosan, have received special attention as excipients to prepare nanoformulations of curcumin due to their abundant availability, biocompatibility, and amicability to form different types of self-assembled structures and ease of undergoing chemical modifications. However, there are certain challenges, such as poor water solubility under physiological conditions and heterogeneity with regard to molecular weight and large-scale production of well-preserved nanostructures. Substantial advancement has been achieved towards overcoming these challenges by developing newer derivatives through a chemical modifications approach, and this has ascertained the suitability of alginate and chitosan as excipients for drug delivery systems (DDS). The present minireview briefly discusses curcumin and its limitation as a drug molecule, carbohydrates as DDS, and the recent developments related to the alginate and chitosan-based nanoformulations of curcumin. Special emphasis has been given to highlighting the impact of alginate and chitosan-based nanoformulations in improving the therapeutic efficacy and bioavailability of curcumin.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030421
Authors: Indah Suasani Wahyuni Irna Sufiawati Amira Shafuria Wipawee Nittayananta Jutti Levita
The rhizome of Kaempferia galanga (Zingiberaceae) is extensively used in traditional medicine by utilizing its various biological activities. It has been proven that ethyl-para-methoxycinnamate (EPMC) and other polyphenolic compounds are present in considerable amounts in the ethanolic extract of K. galanga rhizome (EKG). Our previous study confirmed that a dose of 0.5–1% of EKG demonstrated anti-inflammatory activity and a wound-healing effect in chemical-induced oral mucosal ulcers of Wistar rats. Currently, there are no reports on the formulation of oral gel containing EKG, thus revealing the potential of EKG to be developed as a herbal oral gel for mucosal ulcers. This study aims to formulate the best mucoadhesive oral care gel containing EKG in terms of physical stability. The presence of EPMC and the total phenols in the best EKG gel were also determined. The results revealed that Carbopol 934 is the best gelling agent for EKG gel preparations as proven by its stability during 14 days of storage. The statistical analysis resulted in a significant difference between the physical stability of the Carbopol 934-based EKG gel preparation compared to three commercial oral care gel products (p < 0.05). RP-HPLC chromatograms indicated that EPMC was identified in Carbopol 934-based gels containing 5% and 10% EKG at 6.056 and 6.146 min, respectively, with polyphenol levels of 1201.2557 mg/kg and 1849.1506 mg/kg, respectively. The hedonic test performed on 30 respondents to measure the degree of consumer acceptance and satisfaction confirmed that 5% EKG gel is the most sensorially accepted by the respondents. Data were analyzed using paired t-tests, one-way ANOVA, and a Kruskal–Wallis test. Taken together, the Carbopol 934-based gel containing 5% EKG could potentially be further developed as a topical anti-oral mucosal ulcer drug for clinical purposes.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030420
Authors: Alessio Corrado Mila Toppazzini Alessandro Vadi Carmine Malzone Rosy Galasso Alessandro Donati Riccardo De Ricco Francesco Berti
Several alum-adjuvanted vaccines have been licensed in the past 40 years. Despite its extensive and continuous use, the immune mechanism of action of alum adjuvants is not yet completely understood. Many different variables during the formulation process have been assessed as critical for alum-adjuvanted vaccines, although most of them are still not yet fully understood. The absence of a clear understanding of all the possible variables regulating the mechanism of action and the behavior that alum adjuvant imposes on the protein antigen may also be related to analytical challenges. For this reason, there is an urgent need for a fast and simple tool that is possible without a preliminary sample manipulation and is able to control the amount and the degree of antigen adsorption levels and their consistency across different production processes. This work attempts to develop new analytical tools with the aim of directly quantifying and assessing both the content and/or the purity of formulated alum-adsorbed antigens, without any preliminary sample manipulation (e.g., antigen desorption) being reported. In addition, the different confirmation/behavior in terms of the response to specific monoclonal antibodies in the presence of different ratios of alum-OH adsorbent antigens have been investigated. As a proxy to develop new analytical tools, three recombinant protein adsorbed models were used as follows: Neisseria adhesin A (NadA), Neisserial Heparin Binding Antigen (NHBA), and factor H binding protein (fHbp) as antigens, as well as aluminum hydroxide (AH) as an adjuvant system. The selection of the adjuvanted system model was dictated due to the substantial quantity of the literature regarding the protein structure and immunological activities, meaning that they are well characterized, including their adhesion rate to alum. In conclusion, three different analytical tools were explored to quantify, detect, and study the behavior of antigens in the presence of the alum adjuvant.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030418
Authors: Shelby Coates Keti Bardhi Philip Lazarus
Opioids are commonly prescribed for the treatment of chronic pain. Approximately 50% of adults who are prescribed opioids for pain co-use cannabis with their opioid treatment. Morphine is primarily metabolized by UDP-glucuronosyltransferase (UGT) 2B7 to an inactive metabolite, morphine-3-glucuronide (M3G), and an active metabolite, morphine-6-glucuronide (M6G). Previous studies have shown that major cannabis constituents including Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) inhibit major UGT enzymes. To examine whether cannabinoids or their major metabolites inhibit morphine glucuronidation by UGT2B7, in vitro assays and mechanistic static modeling were performed with these cannabinoids and their major metabolites including 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC), 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (11-COOH-THC), 7-hydroxy-cannabidiol (7-OH-CBD), and 7-carboxy-cannabidiol (7-COOH-CBD). In vitro assays with rUGT-overexpressing microsomes and human liver microsomes showed that THC and CBD and their metabolites inhibited UGT2B7-mediated morphine metabolism, with CBD and THC exhibiting the most potent Ki,u values (0.16 µM and 0.37 µM, respectively). Only 7-COOH-CBD exhibited no inhibitory activity against UGT2B7-mediated morphine metabolism. Static mechanistic modeling predicted an in vivo drug–drug interaction between morphine and THC after inhaled cannabis, and between THC, CBD, and 7-OH-CBD after oral consumption of cannabis. These data suggest that the co-use of these agents may lead to adverse drug events in humans.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030419
Authors: D. Thisuri N. De Silva Tobias Strunk Michael Petrovski Madhu Page-Sharp Brioni R. Moore Kevin T. Batty
Sildenafil is used to treat pulmonary hypertension in neonatal intensive care unit (NICU) settings. As multiple intravenous (IV) medications are co-administered in NICU settings, we sought to investigate the physicochemical compatibility of sildenafil with a range of IV drugs. Sildenafil 600 mcg/mL or 60 mcg/mL was mixed 1:1 with the secondary drug solution to simulate Y-site co-administration procedures. Physical compatibility was evaluated by visual observation against a black and white background and under polarized light for two hours for changes in colour, precipitation, haze and evolution of gas. Chemical compatibility was determined from sildenafil concentrations, using a validated, stability-indicating high-performance liquid chromatography assay. Sildenafil 600 mcg/mL was physicochemically compatible with 29 of the 45 drugs tested at ‘high-end’ clinical concentrations and physically incompatible with 16 drugs and six ‘2-in-1’ parenteral nutrition solutions. Sildenafil 600 mcg/mL was compatible with lower, clinically relevant concentrations of calcium gluconate, heparin and hydrocortisone. Aciclovir, amoxicillin, ampicillin, ibuprofen lysine, indometacin, phenobarbitone and rifampicin were incompatible with sildenafil 600 mcg/mL, however these IV medications were compatible with sildenafil 60 mcg/mL. Sildenafil 600 mcg/mL and 60 mcg/mL were incompatible with amphotericin, flucloxacillin, furosemide, ibuprofen, meropenem and sodium bicarbonate. Sildenafil compatibility with commonly used syringe filters was also investigated. Sildenafil solution was compatible with nylon syringe filters, however, absorption/adsorption loss occurred with polyethersulfone and cellulose ester filters.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030417
Authors: Marwa A. Malouh Julie A. Y. Cichero Yu Sun Esther T. L. Lau Lisa M. Nissen Kathryn J. Steadman
Swallowing oral solid dosage forms is challenging for those who have medication swallowing difficulties, including patients with dysphagia. One option is to mix the drug (whole or crushed) with a thick vehicle (medication lubricant). Previous in vitro studies consistently suggest that thick vehicles could impact the dissolution of solid dosage forms, potentially influencing their therapeutic effectiveness, but do not account for changes that happen during oral processing and swallowing. This study aims to investigate the potential impact of medication lubricants on drug release and examine the effect of oral processing. In vitro dissolution of whole and crushed paracetamol tablets mixed with five commercially available medication lubricants (two IDDSI level 2, two IDDSI level 3, and one IDDSI level 4) were tested with and without oral processing; a medication lubricant with/without paracetamol was placed in the mouth (five healthy volunteers), prepared for swallowing, but then expectorated and assessed for physical characteristics and drug release. Medication lubricants, both alone and mixed with crushed paracetamol tablets, showed a significant decrease in viscosity after oral processing. Without oral processing, IDDSI level 3 and 4 lubricants significantly delayed the dissolution of paracetamol tablets. After oral processing, particularly with crushed tablets, there was a substantial increase in the dissolution rate. These findings suggest that dissolution testing overestimates the impact of medication lubricants on drug dissolution. Therefore, using in vitro dissolution tests to predict the dissolution rate of medications mixed with thick vehicles is discouraged. It is essential to consider ways to incorporate the effects of the oral environment and oral processing on thick vehicles used for oral medication administration.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030416
Authors: Yi Liu Yingyi Niu Wenjie Zhang Kaikai Wang Tianqing Liu Weizhong Zhu
Purpose: It is well known that inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII) provides cardiac protection in cases of myocardial ischemia–reperfusion injury. However, there are currently no cytoplasm-impermeable drugs that target CaMKII. The aim of this study was to develop curcumin albumin nanoparticles (HSA-CCM NPs) containing AC3-I and investigate their protective effects on hypoxia–reoxygenation (H/R)-induced injuries in adult rat cardiomyocytes and ischemia–reperfusion (I/R) injuries in isolated rat hearts. Methods: HSA-CCM NPs were synthesized using β-ME methods, while the membrane-impermeable peptide AC3-I was covalently linked via a disulfide bond to synthesize AC3-I@HSA-CCM NPs (AC3-I@NPs). Nanoparticle stability and drug release were characterized. To assess the cardiomyocyte uptake of AC3-I@NPs, AC3-I@NPs were incubated with cardiomyocytes under normoxia and hypoxia, respectively. The cardioprotective effect of AC3-I@NPs was determined by using a lactate dehydrogenase kit (LDH) and PI/Hoechst staining. The phosphorylation of phospholamban (p-PLB) was detected by Western blotting in hypoxia–reoxygenation and electric field stimulation models. To further investigate the protective role of AC3-I@NPs against myocardial ischemia–reperfusion injury, we collected coronary effluents and measured creatine kinase (CK) and LDH release in Langendorff rat hearts. Results:AC3-I@NPs were successfully prepared and characterized. Both HSA-CCM NPs and AC3-I@NPs were taken up by cardiomyocytes. AC3-I@NPs protected cardiomyocytes from injury caused by hypoxia–reoxygenation, as demonstrated by decreased cardiomyocyte death and LDH release. AC3-I@NPs reduced p-PLB levels evoked by hypoxia–reoxygenation and electrical field stimulation in adult rat cardiac myocytes. AC3-I@NPs decreased the release of LDH and CK from coronary effluents. Conclusions: AC3-I@NPs showed protective effects against myocardial injuries induced by hypoxia–reoxygenation in cardiomyocytes and ischemia–reperfusion in isolated hearts.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030415
Authors: Mariana G. Selener Jimena Borgo Maria Belen Sarratea Maria Alicia Delfino Laura C. Laurella Natacha Cerny Jessica Gomez Mauro Coll Emilio L. Malchiodi Augusto E. Bivona Patricia Barrera Flavia C. Redko César A. N. Catalán Andrés Sánchez Alberti Valeria P. Sülsen
Chagas disease, caused by the protozoan Trypanosoma cruzi, affects 6–7 million people worldwide. The dichloromethane extract obtained from the aerial parts of Gymnocoronis spilanthoides var subcordata showed trypanocidal activity in vitro. The fractionation of the dewaxed organic extract via column chromatography led to the isolation of three diterpenoids: ent-9α,11α-dihydroxy-15-oxo-kaur-16-en-19-oic acid or adenostemmoic acid B, (16R)-ent-11α-hydroxy-15-oxokauran-19-oic acid and ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic acid. These compounds showed IC50 values of 10.6, 15.9 and 4.8 µM against T. cruzi epimastigotes, respectively. When tested against amastigotes, the diterpenoids afforded IC50 values of 6.1, 19.5 and 60.6 µM, respectively. The cytotoxicity of the compounds was tested on mammalian cells using an MTT assay, resulting in CC50s of 321.8, 23.3 and 14.8 µM, respectively. The effect of adenostemmoic acid B on T. cruzi was examined at the ultrastructural level using transmission microscopy. Treatment with 20 μM for 48 h stimulated the formation of abnormal cytosolic membranous structures in the parasite. This compound also showed an anti-inflammatory effect in murine macrophages stimulated with LPS and other TLR agonists. Treatment of macrophages with adenostemmoic acid B was able to reduce TNF secretion and nitric oxide production, while increasing IL-10 production. The combination of adenostemmoic acid B with benznidazole resulted in greater inhibition of NF-kB and a decrease in nitrite concentration. The administration of adenostemmoic acid B to mice infected with trypomastigotes of T. cruzi at the dose of 1 mg/kg/day for five days produced a significant decrease in parasitemia levels and weight loss. Treatment with the association with benznidazole increased the survival time of the animals. In view of these results, adenostemmoic acid B could be considered a promising candidate for further studies in the search for new treatments for Chagas disease.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030414
Authors: Lorenzo Monarca Francesco Ragonese Paola Sabbatini Concetta Caglioti Matteo Stamegna Federico Palazzetti Paolo Sportoletti Ferdinando Costantino Bernard Fioretti
Human glioblastoma is probably the most malignant and aggressive among cerebral tumors, of which it represents approximately 80% of the reported cases, with an overall survival rate that is quite low. Current therapies include surgery, chemotherapy, and radiotherapy, with associated consistent side effects and low efficacy. The hardness in reaching the site of action, and overcoming the blood–brain barrier, is a major limitation of pharmacological treatments. In this paper, we report the synthesis and characterization of ZIF-90 (ZIF, Zeolitic Imidazolate Framework) nanoparticles as putative carriers of anticancer drugs to the brain. In particular, we successfully evaluated the biocompatibility of these nanoparticles, their stability in body fluids, and their ability to uptake in U251 human glioblastoma cell lines. Furthermore, we managed to synthesize ZIF-90 particles loaded with berberine, an alkaloid reported as a possible effective adjuvant in the treatment of glioblastoma. These findings could suggest ZIF-90 as a possible new strategy for brain cancer therapy and to study the physiological processes present in the central nervous system.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030413
Authors: Kosei Ishii Eiji Akahoshi Oluyomi Stephen Adeyemi Hironori Bando Yasuhiro Fukuda Tomoyuki Ogawa Kentaro Kato
Toxoplasma gondii is an intracellular parasitic protozoan with a high infection rate in mammals, including humans, and birds. There is no effective vaccine, and treatment relies on antiparasitic drugs. However, existing antiprotozoal drugs have strong side effects and other problems; therefore, new treatment approaches are needed. Metal nanoparticles have attracted increased interest in the biomedical community in recent years because of their extremely high surface area to volume ratio and their unique reactivity that could be exploited for medicinal purposes. Previously, we confirmed the anti-Toxoplasma effects of gold, silver, and platinum nanoparticles, in a growth inhibition test. Here, we asked whether the anti-Toxoplasma effect could be confirmed with less expensive metal nanoparticles, specifically iron oxide nanoparticles (goethite and hematite). To improve the selective action of the nanoparticles, we modified the surface with l-tryptophan as our previous findings showed that the bio-modification of nanoparticles enhances their selectivity against T. gondii. Fourier-Transform Infrared Spectroscopy (FTIR) analysis confirmed the successful coating of the iron oxide nanoparticles with l-tryptophan. Subsequently, cytotoxicity and growth inhibition assays were performed. L-tryptophan-modified nanoparticles showed superior anti-Toxoplasma action compared to their naked nanoparticle counterparts. L-tryptophan enhanced the selective toxicity of the iron oxide nanoparticles toward T. gondii. The bio-modified nanoparticles did not exhibit detectable host cell toxicity in the effective anti-Toxoplasma doses. To elucidate whether reactive oxygen species contribute to the anti-Toxoplasma action of the bio-modified nanoparticles, we added Trolox antioxidant to the assay medium and found that Trolox appreciably reduced the nanoparticle-induced growth inhibition.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030412
Authors: Wipanan Jandang Chadarat Ampasavate Kanokwan Kiattisin
Capsaicin and curcumin, the active components of chili and turmeric, are prone to instability when exposed to light. Therefore, this research aimed to enhance the photostability of both extracts via the use of antioxidants, natural sunscreen, and nanostructured lipid carriers (NLCs). NLCs were chosen for this this study due to their advantages in terms of stability, drug loading capacity, occlusive effect, skin penetration, and controlled release. The photostability of each extract and extracts mixed with antioxidants, including grape seed extract, tea extract, and chlorogenic acid, were determined. Chlorogenic acid can enhance the photostability of capsaicin from 6.79 h to 16.50 h, while the photostability of curcumin increased from 9.63 h to 19.25 h. In addition, the use of natural sunscreen (sunflower oil) also increased the photostability of capsaicin and curcumin. The mixed extracts were then loaded into NLCs. The particle size of the formulation was 153.73 nm with a PDI value of 0.25. It exhibited high entrapment efficiency (more than 95%). In addition, it effectively reduced the decomposition of capsaicin and curcumin. Importantly, the natural stabilizers chosen for NLC fabrication significantly improved the photostability of curcumin and capsaicin by 600% and 567% compared to the unstabilized counterparts. This improvement contributes to the sustainability and bioavailability of these compounds in both cosmeceutical and pharmaceutical products.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030411
Authors: Sepideh Jahangiri François Yu
Despite spectacular clinical successes across several cancer types, immune checkpoint inhibition is effective only in subgroups of patients and suffers from significant systemic toxicities, highlighting the need to understand and locally overcome the mechanisms of therapeutic resistance. Similarly to other therapeutics, immunotherapies face delivery challenges (for example, antibodies need to reach their targets) and immunological barriers that are unique to solid tumors and their microenvironment. Interestingly, focused ultrasound (FUS), with or without microbubbles, which has been shown to enhance gene and drug delivery, notably in oncology, has been recently found to trigger immunological responses. In recent years, there has been a strong emphasis on understanding the biological and immunological effects of FUS for cancer therapy, and FUS is now emerging as an approach that can improve cancer immunotherapy. We herein review: (1) the immunological barriers implicated in ICI resistance; (2) the fundamentals of FUS +/− MB and the current knowledge on leveraging FUS +/− MB bioeffects for improving ICI therapy efficacy; (3) the immune profile of tumor models that have been successfully treated with FUS and ICI; and finally, (4) we discuss the challenges ahead for translating FUS and MB treatments to the clinic, highlighting the exciting perspectives for this new research area.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030410
Authors: Razvan Zdrehus Cristian Delcea Lucian Mocan
Nanotechnology has provided an opportunity for unparalleled development of the treatment of various severe diseases. The unique properties of nanoparticles offer a promising strategy for enhancing antitumor immunity by enhancing immunogenicity and presentation of tumor autoantigens for cancer immunotherapy. Polymeric, liposomal, carbon or silica-based nanoparticles are among those with major immunomodulatory roles in various cancer treatments. Cancer vaccines, in particular digestive cancer vaccines, have been researched and developed on nanotechnological platforms. Due to their safety, controlled release, targeting of dendritic cells (DCs) and improved antigen uptake, as well as enhanced immunogenicity, nanoparticles have been used as carriers, as adjuvants for increased effect at the tumor level, for their immunomodulating effect, or for targeting the tumor microenvironment, thereby increasing tumor immunogenicity and reducing tumor inflammatory response. This review looks at digestive cancer vaccines developed on nanoparticle platforms and the impact nanoparticles have on the effects of these vaccines.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030409
Authors: Donatas Stakišaitis Linas Kapočius Vacis Tatarūnas Dovydas Gečys Auksė Mickienė Tomas Tamošuitis Rasa Ugenskienė Arūnas Vaitkevičius Ingrida Balnytė Vaiva Lesauskaitė
The study presents data on the anti-inflammatory effects of a combination of sodium dichloroacetate and sodium valproate (DCA–VPA) on the expression of inflammation- and immune response-related genes in T lymphocytes of SARS-CoV-2 patients. The study aimed to assess the effects of DCA–VPA on the genes of cytokine activity, chemokine-mediated signaling, neutrophil chemotaxis, lymphocyte chemotaxis, T-cell chemotaxis, and regulation of T-cell proliferation pathways. The study included 21 patients with SARS-CoV-2 infection and pneumonia: 9 male patients with a mean age of 68.44 ± 15.32 years and 12 female patients with a mean age of 65.42 ± 15.74 years. They were hospitalized between December 2022 and March 2023. At the time of testing, over 90% of sequences analyzed in Lithuania were found to be of the omicron variant of SARS-CoV-2. The T lymphocytes from patients were treated with 5 mmol DCA and 2 mmol VPA for 24 h in vitro. The effect of the DCA–VPA treatment on gene expression in T lymphocytes was analyzed via gene sequencing. The study shows that DCA–VPA has significant anti-inflammatory effects and apparent sex-related differences. The effect is more potent in T cells from male patients with SARS-CoV-2 infection and pneumonia than in females.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030408
Authors: Javier Suárez-González Eduardo Díaz-Torres Cecilia N. Monzón-Rodríguez Ana Santoveña-Estévez José B. Fariña
Three-dimensional printing in the field of additive manufacturing shows potential for customized medicines and solving gaps in paediatric formulations. Despite successful clinical trials, 3D printing use in pharmaceutical point-of-care is limited by regulatory loopholes and a lack of Pharmacopoeia guidelines to ensure quality. Semi-solid extrusion is a 3D printing technology that stands out for its versatility, but understanding the fluid dynamics of the semi-solid mass is critical. The aim of this research is to look into the advantages of instrumenting a 3D printer with a semi-solid extrusion motor-driven printhead, which is able to record the printing pressure over time, for in situ characterization of the semi-solid mass and quality evaluation of dosage forms. Four formulations using hydrochlorothiazide as the active pharmaceutical ingredient and several excipients were used. Their flow properties were studied at different printing speeds and temperatures using traditional techniques (rheometer and Texture Analyzer) and the proposed semi-solid extrusion motor-driven printhead incorporated into a printing platform. In addition, the influence of printing speed in the printing process was also evaluated by the study of printing pressure and printlet quality. The results demonstrated the similarities between the use of a Texture Analyzer and the semi-solid extrusion motor-driven. However, the latter enables temperature selection and printing speed in accordance with the printing process which are critical printing parameters. In addition, due to the incorporation of a sensor, it was possible to conclude, for the first time, that there is a link between changes in essential printing parameters like printing speed or formulations and variations in printing pressure and printlet quality attributes such as the energy require to obtain a single dosage unit, weight or diameter. This breakthrough holds a lot of potential for assuring the quality of 3D printing dosage forms and paving the way for their future incorporation into point-of-care settings.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030407
Authors: Suvankar Ghorai Harshita Shand Soumendu Patra Kingshuk Panda Maria J. Santiago Md. Sohanur Rahman Srinivasan Chinnapaiyan Hoshang J. Unwalla
The continuous evolution of new viruses poses a danger to world health. Rampant outbreaks may advance to pandemic level, often straining financial and medical resources to breaking point. While vaccination remains the gold standard to prevent viral illnesses, these are mostly prophylactic and offer minimal assistance to those who have already developed viral illnesses. Moreover, the timeline to vaccine development and testing can be extensive, leading to a lapse in controlling the spread of viral infection during pandemics. Antiviral therapeutics can provide a temporary fix to tide over the time lag when vaccines are not available during the commencement of a disease outburst. At times, these medications can have negative side effects that outweigh the benefits, and they are not always effective against newly emerging virus strains. Several limitations with conventional antiviral therapies may be addressed by nanotechnology. By using nano delivery vehicles, for instance, the pharmacokinetic profile of antiviral medications can be significantly improved while decreasing systemic toxicity. The virucidal or virus-neutralizing qualities of other special nanomaterials can be exploited. This review focuses on the recent advancements in nanomedicine against RNA viruses, including nano-vaccines and nano-herbal therapeutics.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030406
Authors: Javier Rodríguez Villanueva Pedro de la Villa Rocío Herrero-Vanrell Irene Bravo-Osuna Manuel Guzmán-Navarro
Excitotoxicity has been linked to the pathogenesis of several serious degenerative ocular diseases. Long-term overactivation of the NMDA receptor by glutamate in retinal ganglion cells (RGCs) results in degeneration, apoptosis and loss of function leading to blindness. NMDA receptor antagonists have been proposed as a pharmacological blockage of glutamate excitotoxicity. However, an inhibition of the pathway activated by glutamate receptors has intolerable side effects. An interesting pharmacological alternative would be the use of antiapoptotic compounds as RGCs’ neuroprotective active substances. Several mechanisms have been proposed to explain neuroprotection, including anti-inflammatory and scavenging activities. Here, the role of dexamethasone in neuroprotection was studied. For this purpose, original controlled release systems composed of microparticles containing dexamethasone with or without vitamin E and human serum albumin (HSA) were designed. The particles were prepared by the solid-in-oil-in-water (S/O/W) emulsion–evaporation technique. After properly characterization of the particles, they were intravitreally injected into an rat model of acute ocular excitotoxicity injury. The functionality of the retina was determined by electroretinography and RGCs were counted after cell immunohistochemistry. These microparticulate systems showed the ability to maintain normal electroretinal activity and promoted significant protection of RGCs. Through this proof of concept, we demonstrated that dexamethasone could be a useful anti-inflammatory agent to avoid the progression of degenerative ocular diseases. Furthermore, when administered in controlled release systems that provide low concentrations during prolonged periods of time, not only can the patient’s comfort be increased but the cytotoxicity of the drugs can also be avoided.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030405
Authors: Gyula Farkas Sándor Nagy Attila Dévay Aleksandar Széchenyi Szilárd Pál
The flow properties of pellets or granules are crucial for further processing drug dosage forms. Optimal compression or filling of multiparticulate dosage forms into capsules is influenced by forces between discrete particles, which could be partially characterized by flow properties. Several techniques have been developed to examine flowability, including static and dynamic methods applying empirical studies and up-to-date chaos theory; however, the newest methods seem only to be powerful with the supplementation of empirical principles. Our experiments try to refine both the technique of analysis and the methods, by finding new, alternative ways. Our approach to the flowability measurements was to set up a dynamic time-dependent model that combined empirical observations and chaos theory on a geometrical basis, thus finding new characteristics regarding the flow properties of pellets and granules that could be relevant for drug developers. Our findings indicate that sphericity and particle size are the most significant factors influencing the flowability of pharmaceutical multiparticular preparations. Furthermore, this study confirms that integrating chaos theory and empirical observations in a time-dependent dynamic model provides a comprehensive understanding of particle flow behavior, pivotal for optimizing manufacturing processes.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030404
Authors: Meliha Ekinci Tais Monteiro Magne Luciana Magalhães Rebelo Alencar Pierre Basilio Almeida Fechine Ralph Santos-Oliveira Derya Ilem-Özdemir
It is evident that radiolabeled drug delivery systems hold great promise in the field of lung cancer management. The combination of therapeutic agents with radiotracers not only allows for precise localization within lung tumors but also enables real-time monitoring of drug distribution. This approach has the potential to enhance targeted therapy and improve patient outcomes. The integration of advanced imaging modalities, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), has played a crucial role in the non-invasive tracking of radiolabeled drugs. These techniques provide valuable insights into drug pharmacokinetics, biodistribution, and tumor-targeting efficiency, offering clinicians the ability to personalize treatment regimens. The comprehensive analysis of preclinical and clinical studies presented in this review underscores the progress made in the field. The evidence suggests that radiolabeled drug delivery systems have the potential to revolutionize oncology by offering precise, targeted, and image-guided therapeutic interventions for lung cancer. This innovative approach not only enhances the effectiveness of treatment but also contributes to the development of personalized medicine strategies, tailoring interventions to the specific characteristics of each patient’s cancer. The ongoing research in this area holds promise for further advancements in lung cancer management, potentially leading to improved outcomes and quality of life for patients.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030403
Authors: George Jîtcă Zsolt Gáll Carmen-Maria Jîtcă Mădălina-Georgiana Buț Erzsébet Májai
A particular attribute of the brain lies in the ability to learn, acquire information from the environment, and utilize the learned information. Previous research has noted that various factors (e.g., age, stress, anxiety, pathological issues), including antipsychotic medications, affect the brain and memory. The current study aimed to reveal the effects of chronic metformin treatment on the cognitive performance of rats and on commonly measured markers for oxidative stress. Wistar male rats (n = 40) were randomly divided into four groups: CTR (n = 10)–control group, METF (n = 10)–animals receiving metformin 500 mg/kg, HAL (n = 10)–animals receiving haloperidol 2 mg/kg, and HALMETF (n = 10)–animals receiving haloperidol 2 mg/kg and metformin 500 mg/kg. The medication was administered daily by oral gavage for 40 days. Memory and learning were assessed using the Morris Water Maze (MWM) test. At the end of the MWM, the rodents were decapitated under anesthesia, and the brain and blood samples were assayed by liquid chromatography for markers of oxidative stress (malondialdehyde, MDA, reduced/oxidized glutathione ratio, GSH/GSSG). The quantification of brain-derived neurotrophic factor (BDNF) was performed using the conventional sandwich ELISA technique. In the HALMETF group, metformin attenuated the negative effects of haloperidol. Brain and plasma MDA levels increased in the HAL group. Brain and plasma GSH/GSSG ratios and BDNF levels did not reveal any differences between groups. In conclusion, metformin treatment limits the deleterious cognitive effects of haloperidol. The effect on oxidative stress markers may also point toward an antioxidant-like effect of metformin, but this needs further tests for confirmation.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030402
Authors: Francesca Romana Liberati Sara Di Russo Lorenzo Barolo Giovanna Peruzzi Maria Vittoria Farina Sharon Spizzichino Federica Di Fonzo Deborah Quaglio Luca Pisano Bruno Botta Alessandra Giorgi Alberto Boffi Francesca Cutruzzolà Alessio Paone Paola Baiocco
Chronic lymphocytic leukemia (CLL) is a widespread type of leukemia that predominantly targets B lymphocytes, undermining the balance between cell proliferation and apoptosis. In healthy B cells, miR-15/16, a tandem of microRNAs, functions as a tumor suppressor, curbing the expression of the antiapoptotic B cell lymphoma 2 protein (Bcl-2). Conversely, in CLL patients, a recurring deletion on chromosome 13q14, home to the miR15-a and miR16-1 genes, results in Bcl-2 overexpression, thereby fostering the onset of the pathology. In the present research, a novel approach utilizing humanized ferritin-based nanoparticles was employed to successfully deliver miR15-a and miR-16-1 into MEG01 cells, a model characterized by the classic CLL deletion and overexpression of the human ferritin receptor (TfR1). The loaded miR15-a and miR16-1, housed within modified HumAfFt, were efficiently internalized via the MEG01 cells and properly directed into the cytoplasm. Impressively, the concurrent application of miR15-a and miR16-1 demonstrated a robust capacity to induce apoptosis through the reduction in Bcl-2 expression levels. This technology, employing RNA-loaded ferritin nanoparticles, hints at promising directions in the battle against CLL, bridging the substantial gap left by traditional transfection agents and indicating a pathway that may offer hope for more effective treatments.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030401
Authors: Matthias Bache Niels V. Heise Andreas Thiel Anne Funtan Franziska Seifert Marina Petrenko Antje Güttler Sarah Brandt Thomas Mueller Dirk Vordermark Iris Thondorf René Csuk Reinhard Paschke
Human carbonic anhydrase IX (hCA IX) is a zinc(II)-dependent metalloenzyme that plays a critical role in the conversion of carbon dioxide and water to protons and bicarbonate. It is a membrane-bound protein with an extracellular catalytic center that is predominantly overexpressed in solid hypoxic tumors. Sulfamates and sulfonamides, for example acetazolamide (AZA), have been used to inhibit hCA IX in order to improve the response to solid hypoxic tumors. In the present study, we propose a new drug targeting approach by attaching the natural cytotoxic substances betulin and betulinic acid (BA) via a linker to sulfonamides. The conjugate was designed with different spacer lengths to accumulate at the target site of hCA IX. Computational and cell biological studies suggest that the length of the linker may influence hCA IX inhibition. Cytotoxicity tests of the newly synthesized bifunctional conjugates 3, 5, and 9 show effective cytotoxicity in the range of 6.4 and 30.1 µM in 2D and 3D tumor models. The hCA IX inhibition constants of this conjugates, measured using an in vitro enzyme assay with p-nitrophenyl acetate, were determined in a low µM-range, and all compounds reveal a significant inhibition of hypoxia-induced CA activity in a cell-based assay using the Wilbur–Anderson method. In addition, the cells respond with G1 increase and apoptosis induction. Overall, the dual strategy to produce cytotoxic tumor therapeutics that inhibit tumor-associated hCA IX was successfully implemented.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030400
Authors: Islam Hamad Amani A. Harb Yasser Bustanji
Lipid-bilayer-based liposomes are gaining attention in scientific research for their versatile role in drug delivery. With their amphiphilic design, liposomes efficiently encapsulate and deliver drugs to targeted sites, offering controlled release. These artificial structures hold great promise in advancing cancer therapy methodologies. Bibliometric research analyzes systematic literary data statistically. This study used bibliometric indicators to examine, map, and evaluate the applications of liposomes in cancer therapy. A Scopus search was conducted to identify all English-language peer-reviewed scientific publications on the applications of liposomes in cancer therapy within the past twenty years. Bibliometric indicators were calculated using VOSviewer and Biblioshiny. We produced thematic, conceptual, and visualization charts. A total of 14,873 published documents were obtained. The procedure of keyword mapping has effectively identified the main areas of research concentration and prevailing trends within this specific field of study. The significant clusters discovered through theme and hotspot analyses encompassed many topics such as the use of multiple strategies in chemotherapy and different forms of cancer, the study of pharmacokinetics and nanomedicine, as well as the investigation of targeted drug delivery, cytotoxicity, and gene delivery. Liposomes were employed as drug delivery systems so as to selectively target cancer cells and improve the bioavailability of anticancer drugs. The work showcased the capacity to tailor these liposomes for accurate drug delivery by including potent anticancer medications. Our findings not only bring attention to the latest progress in utilizing liposomes for cancer treatment but also underscore the vital need for ongoing research, collaborative efforts, and the effective translation of these breakthroughs into tangible clinical applications, emphasizing the dynamic and evolving nature of cancer therapeutics.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030399
Authors: Jurga Andreja Kazlauskaite Mindaugas Marksa Jurga Bernatoniene
Adding certain excipients during the extraction process can enhance the concentration of target compounds, leading to potentially increased biological properties of the plant extract. This study explores the impact of PVP/VAC and SSG excipients on red clover bud extracts, aiming to enhance their concentration of target compounds and, consequently, their biological properties. The antioxidative potential was evaluated using DPPH, ABTS, and FRAP methods, and the chemical profile was determined using mass spectrometry. Antibacterial activity against various strains was determined through the minimal inhibitory concentration (MIC) method. The results revealed that the excipient-enriched samples exhibited significantly elevated antioxidant activities as well as phenolic and flavonoid contents compared to control samples. Notably, sample V1E3 demonstrated the highest antioxidant potential, with 52.48 ± 0.24 mg GAE/g dw (phenolic content), 463 ± 6.46 μg TE/g dw (ABTS), 12.81 ± 0.05 μg TE/g dw (DPPH), and 29.04 ± 1.16 mg TE/g dw (post-column ABTS). The highest flavonoid content was found in the S1E3 sample—24.25 ± 0.17 mg RU/g dw. Despite the increased antioxidant potential, no significant variance in antimicrobial activity was noted between the test samples and controls. This implies that excipients may hold the potential to enhance the biological properties of red clover extracts for pharmaceutical applications. These findings contribute valuable insights into optimizing extraction processes for improved functionality and application of plant-derived compounds in therapeutic formulations.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030398
Authors: Riley T. Schweizer Mani Ordoubadi Cody A. Prather Reinhard Vehring Kimberly B. Shepard
Designing spray-dried particles for inhalation aims at specific physicochemical properties including a respirable aerodynamic diameter and adequate powder dispersibility. Leucine, an amphiphilic amino acid, has been shown to aid in optimizing bulk powder properties. Mannitol, a model crystalline active and common bulking agent, was co-sprayed with leucine at several excipient ratios, ethanol/water ratios, and spray dryer outlet temperatures in order to experimentally probe the underlying particle formation mechanisms in this binary crystalline system. During the droplet drying of two crystallizing components, the material that nucleates first will preferentially enrich the surface. It is desired to have a completely crystalline leucine shell to improve powder properties, however, mannitol competes with leucine for the surface depending on excipient concentration and manufacturing parameters. The resulting particles were studied initially and at a two-month timepoint via solid state characterization, visual analysis, and particle size analysis in order to detect changes in bulk powder properties. It was determined that, similar to systems where only leucine can crystallize, initial leucine saturation in the formulation dictates powder characteristics.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030397
Authors: Mengyang Liu Darren Svirskis Thomas Proft Jacelyn Loh Yuan Huang Jingyuan Wen
Background: Although its immunomodulatory properties make thymopentin (TP5) appealing, its rapid metabolism and inactivation in the digestive system pose significant challenges for global scientists. PEGylated niosomal nanocarriers are hypothesized to improve the physicochemical stability of TP5, and to enhance its intestinal permeability for oral administration. Methods: TP5-loaded PEGylated niosomes were fabricated using the thin film hydration method. Co-cultured Caco-2 and HT29 cells with different ratios were screened as in vitro intestinal models. The cytotoxicity of TP5 and its formulations were evaluated using an MTT assay. The cellular uptake and transport studies were investigated in the absence or presence of variable inhibitors or enhancers, and their mechanisms were explored. Results and Discussion: All TP5 solutions and their niosomal formulations were nontoxic to Caco-2 and HT-29 cells. The uptake of TP5-PEG-niosomes by cells relied on active endocytosis, exhibiting dependence on time, energy, and concentration, which has the potential to significantly enhance its cellular uptake compared to TP5 in solution. Nevertheless, cellular transport rates were similar between TP5 in solution and its niosomal groups. The cellular transport of TP5 in solution was carried out mainly through MRP5 endocytosis and a passive pathway and effluxed by MRP5 transporters, while that of TP5-niosomes and TP5-PEG-niosomes was carried out through adsorptive- and clathrin-mediated endocytosis requiring energy. The permeability and transport rate was further enhanced when EDTA and sodium taurocholate were used as the penetration enhancers. Conclusions: This research has illustrated that PEG-niosomes were able to enhance the cellular uptake and maintain the cellular transport of TP5. This study also shows this formulation’s potential to serve as an effective carrier for improving the oral delivery of peptides.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030396
Authors: Anam Ahsan Nicky Thomas Timothy J. Barnes Santhni Subramaniam Thou Chen Loh Paul Joyce Clive A. Prestidge
The opportunistic bacteria growing in biofilms play a decisive role in the pathogenesis of chronic infectious diseases. Biofilm-dwelling bacteria behave differently than planktonic bacteria and are likely to increase resistance and tolerance to antimicrobial therapeutics. Antimicrobial adjuvants have emerged as a promising strategy to combat antimicrobial resistance (AMR) and restore the efficacy of existing antibiotics. A combination of antibiotics and potential antimicrobial adjuvants, (e.g., extracellular polymeric substance (EPS)-degrading enzymes and quorum sensing inhibitors (QSI) can improve the effects of antibiotics and potentially reduce bacterial resistance). In addition, encapsulation of antimicrobials within nanoparticulate systems can improve their stability and their delivery into biofilms. Lipid nanocarriers (LNCs) have been established as having the potential to improve the efficacy of existing antibiotics in combination with antimicrobial adjuvants. Among them, liquid crystal nanoparticles (LCNPs), liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs) are promising due to their superior properties compared to traditional formulations, including their greater biocompatibility, higher drug loading capacity, drug protection from chemical or enzymatic degradation, controlled drug release, targeted delivery, ease of preparation, and scale-up feasibility. This article reviews the recent advances in developing various LNCs to co-deliver some well-studied antimicrobial adjuvants combined with antibiotics from different classes. The efficacy of various combination treatments is compared against bacterial biofilms, and synergistic therapeutics that deserve further investigation are also highlighted. This review identifies promising LNCs for the delivery of combination therapies that are in recent development. It discusses how LNC-enabled co-delivery of antibiotics and adjuvants can advance current clinical antimicrobial treatments, leading to innovative products, enabling the reuse of antibiotics, and providing opportunities for saving millions of lives from bacterial infections.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030395
Authors: Seung-Yeon Jeong Ye-Seul Lee Ji-Yeun Park Jung-Hwan Park Hi-Joon Park Song-Yi Kim
Recently, several clinical studies have been conducted using microneedles (MNs), and various devices have been developed. This study aimed to propose and confirm the feasibility of a placebo control for activating MN clinical research. A 0.5 mm MN stamp with 42 needles was used as a treatment intervention, and a placebo stamp with four acupressure-type needles that did not penetrate was proposed and designed as a control for comparison. First, to check whether the placebo stamp did not invade the skin and to set an appropriate level of pressure to be provided during skin stimulation, two participants were stimulated with five different forces on the forearm, and then the skin was dyed. Secondly, to evaluate the validity of the placebo control group, a blinded study between the MN and placebo stamps was performed on 15 participants. We confirmed that the placebo stamp did not penetrate the skin at any intensity or location. Both types of stamps reported relatively low pain levels, but the MN stamp induced higher pain compared to the placebo stamp. Based on the speculation regarding the type of intervention received, the MN stamp was successfully blinded (random guess), whereas the placebo stamp was unblinded. However, according to a subgroup analysis, it was confirmed that the group with low skin sensitivity was completely blind. Blinding the placebo MN stamp had limited success in participants with low skin sensitivity. Future research on suitable placebo controls, considering the variations in MN stamp length and needle count, is warranted.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030394
Authors: Donald J. Clancy Gulenay Guner Sayantan Chattoraj Helen Yao M. Connor Faith Zahra Salahshoor Kailey N. Martin Ecevit Bilgili
This study aimed to develop a practical semi-mechanistic modeling framework to predict particle size evolution during wet bead milling of pharmaceutical nanosuspensions over a wide range of process conditions and milling scales. The model incorporates process parameters, formulation parameters, and equipment-specific parameters such as rotor speed, bead type, bead size, bead loading, active pharmaceutical ingredient (API) mass, temperature, API loading, maximum bead volume, blade diameter, distance between blade and wall, and an efficiency parameter. The characteristic particle size quantiles, i.e., x10, x50, and x90, were transformed to obtain a linear relationship with time, while the general functional form of the apparent breakage rate constant of this relationship was derived based on three models with different complexity levels. Model A, the most complex and general model, was derived directly from microhydrodynamics. Model B is a simpler model based on a power-law function of process parameters. Model C is the simplest model, which is the pre-calibrated version of Model B based on data collected from different mills across scales, formulations, and drug products. Being simple and computationally convenient, Model C is expected to reduce the amount of experimentation needed to develop and optimize the wet bead milling process and streamline scale-up and/or scale-out.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030393
Authors: Madeline Günther Peter Schnierle Thorsten Rose Jonathan Schlegel Georg Boonen Jürgen Drewe Eduardo Muñoz Bernd L. Fiebich Carsten Culmsee
Cimicifuga racemosa extracts (CREs) have gained well-established use for the treatment of menopausal symptoms such as hot flushes and excessive sweating, and weight gain. While the clinical effects of CREs have been well documented, the mechanisms underlying these effects are largely unknown. More recently, the metabolic effects of the CRE Ze 450 were demonstrated in cultured cells in vitro and in mouse models of obesity in vivo. At the molecular level, metabolic regulation, enhanced insulin sensitivity, and increased glucose uptake were linked to the activation of AMP-activated protein kinase (AMPK). Therefore, we tested the effects of Ze 450 on AMPK phosphorylation and thus activation in cells from different tissues, i.e., murine C2C12 myoblast cells, human HEPG2 liver cells, mouse HT22 neuronal cells, and in murine 3T3L1 adipocytes. Using a FRET-based HTRF-assay, we found that Ze 450 induced AMPK phosphorylation and the activation of this key enzyme of metabolic regulation in cells from various different tissues including C2C12 (muscle), HEPG2 (liver), HT22 (hippocampal), and 3T3-L1 (adipocyte) cells. In C2C12 muscle cells, enhanced AMPK activation was accompanied by reduced mitochondrial respiration and enhanced glucose uptake. Further, Ze 450 enhanced the resilience of the cells against oxidative death induced by ferroptosis inducers erastin or RSL3. Our findings suggest a general effect of Cimicifuga racemosa on AMPK activation in different tissues and across species. This may have a significant impact on expanded therapeutic applications of Ze 450, since AMPK activation and the related metabolic effects have been previously associated with anti-aging effects and the prevention of the metabolic syndrome.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030392
Authors: Xabier Guarrochena Panagiotis Kanellopoulos Anna Stingeder Lisa-Maria Rečnik Irene V. J. Feiner Marie Brandt Wolfgang Kandioller Theodosia Maina Berthold A. Nock Thomas L. Mindt
The use of metabolically stabilized, radiolabeled somatostatin (SST) analogs ([68Ga]Ga/[177Lu]Lu-DOTA-TATE/TOC/NOC) is well established in nuclear medicine. Despite the pivotal role of these radioligands in the diagnosis and therapy of neuroendocrine tumors (NETs), their inability to interact with all five somatostatin receptors (SST1–5R) limits their clinical potential. [111In]In-AT2S is a radiolabeled DOTA-conjugate derived from the parent peptide SST-14 that exhibits high binding affinity to all SSTR subtypes, but its poor metabolic stability represents a serious disadvantage for clinical use. In order to address this issue, we have replaced strategic trans-amide bonds of [111In]In-AT2S with metabolically stable 1,4-disubstituted 1,2,3-triazole bioisosteres. From the five cyclic triazolo-peptidomimetics investigated, only [111In]In-XG1 combined a preserved nanomolar affinity for the SST1,2,3,5R subtypes in vitro and an improved stability in vivo (up to 17% of intact peptide 5 min postinjection (pi) versus 6% for [111In]In-AT2S). The involvement of neprilysin (NEP) in the metabolism of [111In]In-XG1 was confirmed by coadministration of Entresto®, a registered antihypertensive drug, in vivo releasing the selective and potent NEP-inhibitor sacubitrilat. A pilot SPECT/CT imaging study conducted in mice bearing hSST2R-positive xenografts failed to visualize the xenografts due to the pronounced kidney uptake (>200% injected activity (IA)/g at 4 h pi), likely the result of the formation of cationic metabolites. To corroborate the imaging data, the tumors and the kidneys were excised and analyzed with a γ-counter. Even if receptor-specific tumor uptake for [111In]In-XG1 could be confirmed (1.61% IA/g), further optimization is required to improve its pharmacokinetic properties for radiotracer development.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030391
Authors: Béla Kovács Erzsébet-Orsolya Tőkés Éva Katalin Kelemen Katalin Zöldi Francisc Boda Edit Suba Boglárka Kovács-Deák Tibor Casian
Solid pharmaceutical formulations with class II active pharmaceutical ingredients (APIs) face dissolution challenges due to limited solubility, affecting in vivo behavior. Robust computational tools, via data mining, offer valuable insights into product performance, complementing traditional methods and aiding in scale-up decisions. This study utilizes the design of experiments (DoE) to understand fluidized hot-melt granulation manufacturing technology. Exploratory data analysis (MVDA) highlights similarities and differences in tablet manufacturability and dissolution profiles at both the lab and pilot scales. The study sought to gain insights into the application of multivariate data analysis by identifying variations among batches produced at different manufacturing scales for this technology. DoE and MVDA findings show that the granulation temperature, time, and Macrogol type significantly impact product performance. These factors, by influencing particle size distribution, become key predictors of product quality attributes such as resistance to crushing, disintegration time, and early-stage API dissolution in the profile. Software-aided data mining, with its multivariate and versatile nature, complements the empirical approach, which is reliant on trial and error during product scale-up.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030390
Authors: Isabel Gonzalez-Alvarez Alejandro Ruiz-Picazo Ruben Selles-Talavera Andres Figueroa-Campos Virginia Merino Marival Bermejo Marta Gonzalez-Alvarez
The purpose of this study was to predict the in vivo bioequivalence (BE) outcome of valsartan (VALS, BCS class IV) from three oral-fixed combination products with hydrochlorothiazide (HCTZ, BCS class III) (Co-Diovan® Forte as reference and two generic formulations in development) by conducting in vivo predictive dissolution with a gastrointestinal simulator (GIS) and a physiologically based biopharmaceutic model (PBBM). In the first BE study, the HCTZ failed, but the VALS 90% CI of Cmax and the AUC were within the acceptance limits, while, in the second BE study, the HCTZ 90% CI of Cmax and the AUC were within the acceptance limits, but the VALS failed. As both drugs belong to different BCS classes, their limiting factors for absorption are different. On the other hand, the gastrointestinal variables affected by the formulation excipients have a distinct impact on their in vivo exposures. Dissolution tests of the three products were performed in a GIS, and a PBBM was constructed for VALS by incorporating in the mathematical model of the in vitro–in vivo correlation (IVIVC) the gastrointestinal variables affected by the excipients, namely, VALS permeability and GI transit time. VALS permeability in presence of the formulation excipients was characterized using the in situ perfusion method in rats, and the impact of the excipients on the GI transit times was estimated from the HCTZ’s in vivo results. The model was able to fit the in vivo BE results with a good prediction error. This study contributes to the field by showing the usefulness of PBBM in establishing in vitro–in vivo relationships incorporating not only dissolution data but also other gastrointestinal critical variables that affect drug exposure in BCS class IV compounds.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030389
Authors: Maizbha Uddin Ahmed Jian Li Qi (Tony) Zhou
Accumulation of polymyxins in the lung epithelial cells can lead to increased mitochondrial oxidative stress and pulmonary toxicity. Aminoglycosides and polymyxins are used, via intravenous and pulmonary delivery, against multidrug-resistant Gram-negative pathogens. Our recent in vitro and animal studies demonstrated that the co-administration of polymyxins with aminoglycosides decreases polymyxin-induced pulmonary toxicity. The aim of this study was to investigate the in vitro transport and uptake of polymyxin B and tobramycin in human lung epithelial Calu-3 cells and the mechanism of reduced pulmonary toxicity resulting from this combination. Transport, intracellular localization, and accumulation of polymyxin B and tobramycin were investigated using doses of 30 mg/L polymyxin B, 70 mg/L tobramycin, and the combination of both. Adding tobramycin significantly (p < 0.05) decreased the polymyxin B-induced cytotoxicity in Calu-3 cells. The combination treatment significantly reduced the transport and uptake of polymyxin B and tobramycin in Calu-3 cells, compared to each drug alone, which supported the reduced pulmonary toxicity. We hypothesized that cellular uptake of polymyxin B and tobramycin shared a common transporter, megalin. We further investigated the megalin expression of Calu-3 cells using confocal microscopy and evaluated megalin activity using a megalin substrate, FITC-BSA, and a megalin inhibitor, sodium maleate. Both polymyxin B and tobramycin significantly inhibited FITC-BSA uptake by Calu-3 cells in a concentration-dependent manner. Sodium maleate substantially inhibited polymyxin B and tobramycin transport and cellular accumulation in the Calu-3 cell monolayer. Our study demonstrated that the significantly reduced uptake of polymyxin B and tobramycin in Calu-3 cells is attributed to the mechanism of action that determines that polymyxin B and tobramycin share a common transporter, megalin.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030388
Authors: Agnija Kivrane Viktorija Ulanova Solveiga Grinberga Eduards Sevostjanovs Anda Viksna Iveta Ozere Ineta Bogdanova Maksims Zolovs Renate Ranka
Genetic polymorphisms can exert a considerable impact on drug pharmacokinetics (PK) and the development of adverse drug reactions (ADR). However, the effect of genetic polymorphisms on the anti-tuberculosis (anti-TB) drug, and particularly rifampicin (RIF), exposure or anti-TB drug-induced liver injury (DILI) remains uncertain. Here, we evaluated the relationship between single nucleotide polymorphisms (SNPs) detected in the RIF pharmacogenes (AADAC, SLCO1B1, SLCO1B3, ABCB1, and NR1I2) and RIF PK parameters, as well as anti-TB treatment-associated DILI. In total, the study enrolled 46 patients with drug-susceptible pulmonary TB. The RIF plasma concentration was measured using the LC-MS/MS method in the blood samples collected pre-dose and 2 and 6 h post-dose, whilst the DILI status was established using the results from blood biochemical analysis performed before and 10–12 days after treatment onset. The genotyping was conducted using a targeted NGS approach. After adjustment for confounders, the patients carrying the rs3732357 GA/AA genotype of the NR1I2 gene were found to have significantly lower RIF plasma AUC0–6 h in comparison to those with GG genotype, while the difference in RIF plasma Cmax was insignificant. None of the analyzed SNPs was related to DILI. Hence, we are the first to report NR1I2 intronic SNP rs3732357 as the genetic component of variability in RIF exposure. Regarding anti-TB treatment-associated DILI, the other preexisting factors promoting this ADR should be considered.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030387
Authors: Cristina Matteo Isabella Orienti Adriana Eramo Ann Zeuner Mariella Ferrari Alice Passoni Renzo Bagnati Marianna Ponzo Ezia Bello Massimo Zucchetti Roberta Frapolli
We describe the development and validation of a HPLC-MS/MS method to assess the pharmacokinetics and tumor distribution of fenretinide, a synthetic retinoid chemically related to all-trans-retinoic acid, after administration of a novel oral nanoformulation of fenretinide, called bionanofenretinide (BNF). BNF was developed to overcome the major limitation of fenretinide: its poor aqueous solubility and bioavailability due to its hydrophobic nature. The method proved to be reproducible, precise and highly accurate for the measurement of the drug and the main metabolites. The lower limit of quantification resulted in 1 ng/mL. The curve range of 1–500 ng/mL and 50–2000 ng/mL, for plasma and tumor homogenate, respectively, was appropriate for the analysis, as demonstrated by the accuracy of between 96.8% and 102.4% for plasma and 96.6 to 102.3% for the tumor. The interdays precision and accuracy determined on quality controls at three different levels were in the ranges of 6.9 to 7.5% and 99.3 to 101.0%, and 0.96 to 1.91% and 102.3 to 105.8% for plasma and tumor, respectively. With the application of the novel assay in explorative pharmacokinetic studies, following acute and chronic oral administration of the nanoformulation, fenretinide was detected in plasma and tumor tissue at a concentration higher than the IC50 value necessary for in vitro inhibitory activity (i.e., 1–5 µM) in different cancer cells lines. We were also able to detect the presence in plasma and tumor of active and inactive metabolites of fenretinide.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030386
Authors: Tim Becker Jan Heitkötter Anna K. Krome Andrea Schiefer Kenneth Pfarr Alexandra Ehrens Miriam Grosse Birthe Sandargo Ingo Stammberger Marc Stadler Marc P. Hübner Stefan Kehraus Achim Hoerauf Karl G. Wagner
Toxicological studies are a part of the drug development process and the preclinical stages, for which suitable vehicles ensuring easy and safe administration are crucial. However, poor aqueous solubility of drugs complicates vehicle screening for oral administration since non-aqueous solvents are often not tolerable. In the case of the anti-infective corallopyronin A, currently undergoing preclinical investigation for filarial nematode and bacterial infections, commonly used vehicles such as polyethylene glycol 200, aqueous solutions combined with cosolvents or solubilizers, or aqueous suspension have failed due to insufficient tolerability, solubility, or the generation of a non-homogeneous suspension. To this end, the aim of the study was to establish an alternative approach which offers suitable tolerability, dissolution, and ease of handling. Thus, a corallopyronin A-mesoporous silica formulation was successfully processed and tested in a seven-day toxicology study focused on Beagle dogs, including a toxicokinetic investigation on day one. Sufficient tolerability was confirmed by the vehicle control group. The vehicle enabled high-dose levels resulting in a low-, middle-, and high-dose of 150, 450, and 750 mg/kg. Overall, it was possible to achieve high plasma concentrations and exposures, leading to a valuable outcome of the toxicology study and establishing mesoporous silica as a valuable contender for challenging drug candidates.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030385
Authors: Chrystalla Protopapa Angeliki Siamidi Siva Satyanarayana Kolipaka Laura Andrade Junqueira Dennis Douroumis Marilena Vlachou
Three-dimensional (3D) printing is quickly being adopted in pharmaceutics due to the many advantages it offers, including treatment, adaptability, the reduction in waste and the accelerated development of new formulations. In this study, micro-extrusion printing was implemented for the production of modified-release hydrocortisone (HCT) mini-tablets for paediatric patients. For the developed formulations, Gelucire® 44/14 and Precirol® ATO 5 were used as the main inks at three different ratios: 70%/30%, 60%/40% and 50%/50%, respectively. The printing parameters (temperature and pressure) were altered accordingly for each ratio to achieve printability. The printed mini-tablets exhibited excellent printing quality, featuring consistent layer thicknesses and smooth surfaces. Dissolution tests were performed, and the results indicated a successful modified release of HCT from the mini-tablets. In summary, micro-extrusion exhibited favourable processing abilities for powder blends, facilitating quick printing and the fabrication of potential personalized dosages.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030384
Authors: Ivana Massud Kenji Nishiura Susan Ruone Angela Holder Chuong Dinh Jonathan Lipscomb James Mitchell George M. Khalil Walid Heneine J. Gerardo Garcίa-Lerma Charles W. Dobard
Pre-exposure prophylaxis (PrEP) with a weekly oral regimen of antiretroviral drugs could be a suitable preventative option for individuals who struggle with daily PrEP or prefer not to use long-acting injectables. We assessed in macaques the efficacy of weekly oral tenofovir alafenamide (TAF) at doses of 13.7 or 27.4 mg/kg. Macaques received weekly oral TAF for six weeks and were exposed twice-weekly to SHIV vaginally or rectally on day 3 and 6 after each dose. Median TFV-DP levels in PBMCs following the 13.7 mg/kg dose were 3110 and 1137 fmols/106 cells on day 3 and 6, respectively. With the 27.4 mg/kg dose, TFV-DP levels were increased (~2-fold) on day 3 and 6 (6095 and 3290 fmols/106 cells, respectively). Both TAF doses (13.7 and 27.4 mg/kg) conferred high efficacy (94.1% and 93.9%, respectively) against vaginal SHIV infection. Efficacy of the 27.4 mg/kg dose against rectal SHIV infection was 80.7%. We estimate that macaque doses of 13.7 and 27.4 mg/kg are equivalent to approximately 230 and 450 mg of TAF in humans, respectively. Our findings demonstrate the effectiveness of a weekly oral PrEP regimen and suggest that a clinically achievable oral TAF dose could be a promising option for non-daily PrEP.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030382
Authors: Qi An Cheng Xing Zhipeng Wang Shuang Li Wenwen Wang Shiying Yang Linglei Kong Dezhi Yang Li Zhang Guanhua Du Yang Lu
Nonsteroidal anti-inflammatory drugs (NSAIDs) are class II biopharmaceutics classification system drugs. The poor aqueous solubility of NSAIDs can lead to limited bioavailability after oral administration. Metformin (MET), a small-molecule compound, can be used in crystal engineering to modulate the physicochemical properties of drugs and to improve the bioavailability of orally administered drugs, according to the literature research and preliminary studies. We synthesized two drug–drug molecular salts (ketoprofen–metformin and phenylbutazone–metformin) with NSAIDs and thoroughly characterized them using SCXRD, PXRD, DSC, and IR analysis to improve the poor solubility of NSAIDs. In vitro evaluation studies revealed that the thermal stability and solubility of NSAIDs-MET were substantially enhanced compared with those of NSAIDs alone. Unexpectedly, an additional increase in permeability was observed. Since the structure determines the properties, the structure was analyzed using theoretical calculations to reveal the intermolecular interactions and to explain the reason for the change in properties. The salt formation of NSAIDs with MET could substantially increase the bio-absorption rate of NSAIDs, according to the in vivo pharmacokinetic findings, which provides an experimental basis for developing new antipyretic and analgesic drugs with rapid onset of action.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030383
Authors: Sara Galimberti Elisabetta Abruzzese Giacomo Luci Claudia Baratè Luigia Luciano Alessandra Iurlo Giovanni Caocci Riccardo Morganti Fabio Stefanelli Antonello Di Paolo
Ponatinib may be effective in chronic myeloid leukemia (CML) patients after failure of first/second line therapies. Although its efficacy for minimum plasma concentrations (Cmin) is >21.3 ng/mL (equal to 40 nM), ponatinib may cause adverse events (AE) that require dose optimization. The present study was aimed at investigating any possible correlations among ponatinib dose, plasma concentration, molecular response (MR), and tolerability in a real-world setting. Clinical and laboratory records (including MR and drug plasma concentrations) of 32 CML patients treated with ponatinib were harvested and analyzed. Twenty-seven patients (71%) had ponatinib Cmin values > 21.3 ng/mL, but Cmin values > 10.7 ng/mL (considered efficacious in BCR-Abl unmutated patients) were achieved by 80% of the patients receiving ≥30 mg/day and 45% of the subjects treated with 15 mg/day. No significant correlations were identified among clinical efficacy, tolerability, daily dose, and plasma concentration. Notably, patients who underwent dose tapering for tolerability or safety reasons did not experience treatment failure. In a real-world setting, adjustment of ponatinib daily doses lower than those registered may maintain therapeutic efficacy while reducing the risk of vascular events and improving tolerability. Further studies are warranted to confirm the present results in a larger cohort of patients.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030381
Authors: Jennifer McDonald Sidhesh Mohak Zsolt Fabian
Cardiovascular disease constitutes a noteworthy public health challenge characterized by a pronounced incidence, frequency, and mortality rate, particularly impacting specific demographic groups, and imposing a substantial burden on the healthcare infrastructure. Certain risk factors, such as age, gender, and smoking, contribute to the prevalence of fatal cardiovascular disease, highlighting the need for targeted interventions. Current challenges in clinical practice involve medication complexities, the lack of a systematic decision-making approach, and prevalent drug therapy problems. Stem cell-derived extracellular vesicles stand as versatile entities with a unique molecular fingerprint, holding significant therapeutic potential across a spectrum of applications, particularly in the realm of cardio-protection. Their lipid, protein, and nucleic acid compositions, coupled with their multifaceted functions, underscore their role as promising mediators in regenerative medicine and pave the way for further exploration of their intricate contributions to cellular physiology and pathology. Here, we overview our current understanding of the possible role of stem cell-derived extracellular vesicles in the clinical management of human cardiovascular pathologies.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030380
Authors: Bashiru Ibrahim Taiwo Hassan Akere Swaroop Chakraborty Eugenia Valsami-Jones Hanene Ali-Boucetta
Heat-shock proteins (HSPs) are stress-responsive molecules belonging to the family of evolutionary molecular chaperones known to be crucial in many cancer types, including human alveolar adenocarcinoma cells (A549). These proteins are highly overexpressed in cancers to support their ability to accommodate imbalances in cell signalling, DNA alterations, proteins, and energy metabolism associated with oncogenesis. The current study evaluated the effects of gold nanoparticles (AuNPs) combined with cisplatin (CDDP) on molecular chaperone HSPs in A549 cells. It was found that AuNPs:CDDP decreased the percentage of cell viability (38.5%) measured using the modified lactated dehydrogenase (mLDH) and 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assays. AuNPs:CDDP exposure caused a significant (p < 0.05) increase in reactive oxygen species (ROS) generation by 1.81-fold, apoptosis induction, and a decrease in the mitochondrial membrane potential (MMP) compared to AuNPs or CDDP alone. Similarly, exposure to the AuNPs:CDDP combination had pronounced cytotoxic effects on the expression of HSPs and PI3K/AKT/mTOR, as well as apoptosis-related proteins. The results demonstrate that the combination of AuNPs with CDDP might enhance the anticancer efficacy of CDDP.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030379
Authors: Sangseo Kim Souha H. Youssef Kyung Min Kirsten Lee Yunmei Song Sachin Vaidya Sanjay Garg
5-fluorouracil (5-FU), commercially available as a topical product, is approved for non-melanoma skin cancer (NMSC) treatment with several clinical limitations. This work aimed to develop 5-FU-loaded topical patches as a potential alternative to overcome such drawbacks. The patches offer accurate dosing, controlled drug release and improved patient compliance. Our study highlights the development of Eudragit® E (EuE)-based drug-in-adhesive (DIA) patches containing a clinically significant high level of 5-FU (approximately 450 µg/cm2) formulated with various chemical permeation enhancers. The patches containing Transcutol® (Patch-TRAN) or oleic acid (Patch-OA) demonstrated significantly higher skin penetration ex vivo than their control counterpart, reaching 5-FU concentrations of 76.39 ± 27.7 µg/cm2 and 82.56 ± 8.2 µg/cm2, respectively. Furthermore, the findings from in vitro permeation studies also validated the superior skin permeation of 5-FU achieved by Patch-OA and Patch-TRAN over 72 h. Moreover, the EuE-based DIA patch platform demonstrated suitable adhesive and mechanical properties with an excellent safety profile evaluated through an inaugural in vivo human study involving 11 healthy volunteers. In conclusion, the DIA patches could be a novel alternative option for NMSC as the patches effectively deliver 5-FU into the dermis layer and receptor compartment ex vivo for an extended period with excellent mechanical and safety profiles.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030378
Authors: Paula A. Santana Camila Arancibia Laura Tamayo Juan Pablo Cumillaf Tanya Roman Constanza Cárdenas Cinthya Paillan Suarez Claudio A. Álvarez Fanny Guzman
Currently, one of the primary challenges in salmon farming is caligidosis, caused by the copepod ectoparasites Caligus spp. The infection process is determined by the copepod’s ability to adhere to the fish skin through the insertion of its chitin-composed filament. In this study, we examined several antimicrobial peptides previously identified in salmonid mucosal secretions, with a primary focus on their potential to bind to chitin as an initial step. The binding capacity to chitin was tested, with hepcidin and piscidin showing positive results. Further assessments involving cytotoxicity in salmonid cells RTgill-W1, SHK-1, RTS-11, and RT-gut indicated that the peptides did not adversely affect cell viability. However, hemolysis assays unveiled the hemolytic capacity of piscidin at lower concentrations, leading to the selection of hepcidin for antiparasitic assays. The results demonstrated that the nauplius II stage of C. rogercresseyi exhibited higher susceptibility to hepcidin treatments, achieving a 50% reduction in parasitic involvement at 50 µM. Utilizing fluorescence and scanning electron microscopy, we observed the localization of hepcidin on the surface of the parasite, inducing significant spherical protuberances along the exoskeleton of C. rogercresseyi. These findings suggest that cysteine-rich AMPs derived from fish mucosa possess the capability to alter the development of the chitin exoskeleton in copepod ectoparasites, making them therapeutic targets to combat recurrent parasitic diseases in salmon farming.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030377
Authors: Mrinal Gaurav Srivastava Nur Hidayatul Nazirah Kamarudin Merve Kübra Aktan Kai Zheng Naiera Zayed Derick Yongabi Patrick Wagner Wim Teughels Aldo R. Boccaccini Annabel Braem
Peri-implantitis is a growing pathological concern for dental implants which aggravates the occurrence of revision surgeries. This increases the burden on both hospitals and the patients themselves. Research is now focused on the development of materials and accompanying implants designed to resist biofilm formation. To enhance this endeavor, a smart method of biofilm inhibition coupled with limiting toxicity to the host cells is crucial. Therefore, this research aims to establish a proof-of-concept for the pH-triggered release of chlorhexidine (CHX), an antiseptic commonly used in mouth rinses, from a titanium (Ti) substrate to inhibit biofilm formation on its surface. To this end, a macroporous Ti matrix is filled with mesoporous silica (together referred to as Ti/SiO2), which acts as a diffusion barrier for CHX from the CHX feed side to the release side. To limit release to acidic conditions, the release side of Ti/SiO2 is coated with crosslinked chitosan (CS), a pH-responsive and antimicrobial natural polymer. Scanning electron microscopy coupled with energy dispersive X-ray spectroscopy (SEM/EDX) and Fourier transform infrared (FTIR) spectroscopy confirmed successful CS film formation and crosslinking on the Ti/SiO2 disks. The presence of the CS coating reduced CHX release by 33% as compared to non-coated Ti/SiO2 disks, thus reducing the antiseptic exposure to the environment in normal conditions. Simultaneous differential scanning calorimetry and thermogravimetric analyzer (SDT) results highlighted the thermal stability of the crosslinked CS films. Quartz crystal microbalance with dissipation monitoring (QCM-D) indicated a clear pH response for crosslinked CS coatings in an acidic medium. This pH response also influenced CHX release through a Ti/SiO2/CS disk where the CHX release was higher than the average trend in the neutral medium. Finally, the antimicrobial study revealed a significant reduction in biofilm formation for the CS-coated samples compared to the control sample using viability quantitative polymerase chain reaction (v-qPCR) measurements, which were also corroborated using SEM imaging. Overall, this study investigates the smart triggered release of pharmaceutical agents aimed at inhibiting biofilm formation, with potential applicability to implant-like structures.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030376
Authors: Snehashis Nandi Laura Verstrepen Mariana Hugo Silva Luis Padrela Lidia Tajber Alain Collas
A bottom-up approach was investigated to produce long-acting injectable (LAI) suspension-based formulations to overcome specific limitations of top-down manufacturing methods by tailoring drug characteristics while making the methods more sustainable and cost-efficient. A Secoya microfluidic crystallization technology-based continuous liquid antisolvent crystallization (SCT-CLASC) process was optimized and afterward compared to an earlier developed microchannel reactor-based continuous liquid antisolvent crystallization (MCR-CLASC) setup, using itraconazole (ITZ) as the model drug. After operating parameter optimization and downstream processing (i.e., concentrating the suspensions), stable microsuspensions were generated with a final solid loading of 300 mg ITZ/g suspension. The optimized post-precipitation feed suspension consisted of 40 mg ITZ/g suspension with a drug-to-excipient ratio of 53:1. Compared to the MCR-CLASC setup, where the post-precipitation feed suspensions contained 10 mg ITZ/g suspension and had a drug-to-excipient ratio of 2:1, a higher drug concentration and lower excipient use were successfully achieved to produce LAI microsuspensions using the SCT-CLASC setup. To ensure stability during drug crystallization and storage, the suspensions’ quality was monitored for particle size distribution (PSD), solid-state form, and particle morphology. The PSD of the ITZ crystals in suspension was maintained within the target range of 1–10 µm, while the crystals displayed an elongated plate-shaped morphology and the solid state was confirmed to be form I, which is the most thermodynamically stable form of ITZ. In conclusion, this work lays the foundation for the SCT-CLASC process as an energy-efficient, robust, and reproducible bottom-up approach for the manufacture of LAI microsuspensions using ITZ at an industrial scale.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030375
Authors: Matthijs W. van Hoogdalem Ryota Tanaka Khaled Abduljalil Trevor N. Johnson Scott L. Wexelblatt Henry T. Akinbi Alexander A. Vinks Tomoyuki Mizuno
Buprenorphine readily crosses the placenta, and with greater prenatal exposure, neonatal opioid withdrawal syndrome (NOWS) likely grows more severe. Current dosing strategies can be further improved by tailoring doses to expected NOWS severity. To allow the conceptualization of fetal buprenorphine exposure, a maternal–fetal physiologically based pharmacokinetic (PBPK) model for sublingual buprenorphine was developed using Simcyp (v21.0). Buprenorphine transplacental passage was predicted from its physicochemical properties. The maternal–fetal PBPK model integrated reduced transmucosal absorption driven by lower salivary pH and induced metabolism observed during pregnancy. Maternal pharmacokinetics was adequately predicted in the second trimester, third trimester, and postpartum period, with the simulated area under the curve from 0 to 12 h, apparent clearance, and peak concentration falling within the 1.25-fold prediction error range. Following post hoc adjustment of the likely degree of individual maternal sublingual absorption, umbilical cord blood concentrations at delivery (n = 21) were adequately predicted, with a geometric mean ratio between predicted and observed fetal concentrations of 1.15 and with 95.2% falling within the 2-fold prediction error range. The maternal–fetal PBPK model developed in this study can be used to forecast fetal buprenorphine exposure and would be valuable to investigate its correlation to NOWS severity.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030374
Authors: Marta M. D. C. Vila Liliane M. N. Balcão Victor M. Balcão
This review aims at presenting the main strategies that are currently available for the delivery of bacteriophages to combat bacterial infections in humans, animals, and plants. It can be seen that the main routes for phage delivery are topical, oral, systemic, and airways for humans. In animals, the topical and oral routes are the most used. To combat infections in plant species, spraying the plant’s phyllosphere or drenching the soil are the most commonly used methods. In both phage therapy and biocontrol using phages, very promising results have been obtained so far. However, more experiments are needed to establish forms of treatment and phage doses, among other parameters. Furthermore, in general, there is a lack of specific standards for the use of phages to combat bacterial infections.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030373
Authors: Carmela Dell’Aversana Federica Sarno Rosaria Benedetti Wouter Leonard Megchelenbrink Donato Cappetta
Recent advances in comprehending the essential molecular mechanisms that govern cancer signaling have revealed the pivotal involvement of kinases in the development and progression of various cancer types [...]
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030372
Authors: Marija M. Babić Radić Marija Vukomanović Jasmina Nikodinović-Runić Simonida Tomić
This study proposes synthesis and evaluation of gelatin-/alginate-based hydrogel scaffolds reinforced with titanium dioxide (TiO2) nanoparticles which, through their combination with allantoin, quercetin, and caffeic acid, provide multi-target therapy directed on all phases of the wound healing process. These scaffolds provide the simultaneous release of bioactive agents and concurrently support cell/tissue repair through the replicated structure of a native extracellular matrix. The hydrogel scaffolds were synthesized via a crosslinking reaction using EDC as a crosslinker for gelatin. Synthesized hydrogel scaffolds and the effect of TiO2 on their properties were characterized by structural, mechanical, morphological, and swelling properties, and the porosity, wettability, adhesion to skin tissue, and simultaneous release features. The biocompatibility of the scaffolds was tested in vitro on fibroblasts (MRC5 cells) and in vivo (Caenorhabditis elegans) in a survival probe. The scaffolds revealed porous interconnected morphology, porosity of 88.33 to 96.76%, elastic modulus of 1.53 to 4.29 MPa, full hydrophilicity, favorable skin adhesivity, and biocompatibility. The simultaneous release was investigated in vitro indicating dependence on the scaffold’s composition and type of bioactive agents. The novel scaffolds designed as multi-target therapy have significant promise for improved wound healing in a beneficial and non-invasive manner.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030371
Authors: Bashnona Attiah Garrett Alewine Mary-Kate Easter Robert A. Coover Cale D. Fahrenholtz
Neurofibromatosis Type 1 (NF1) is a common neurogenic condition characterized by heterozygous loss of function mutations in the neurofibromin gene. NF1 patients are susceptible to the development of neurofibromas, including plexiform neurofibromas (pNFs), which occurs in about half of all cases. Plexiform neurofibroma are benign peripheral nerve sheath tumors originating from Schwann cells after complete loss of neurofibromin; they can be debilitating and also transform into deadly malignant peripheral nerve sheath tumors (MPNSTs). Here, our data indicates that silver nanoparticles (AgNPs) may be useful in the treatment of pNFs. We assessed the cytotoxicity of AgNPs using pNF cells and Schwann cells derived from the same NF1 patient. We found that AgNPs are selectively cytotoxic to pNF cells relative to isogenic Schwann cells. We then examined the role of neurofibromin expression on AgNP-mediated cytotoxicity; restoration of neurofibromin expression in pNF cells decreased sensitivity to AgNP, and knockdown of neurofibromin in isogenic Schwann cells increased sensitivity to AgNP, outlining a correlation between neurofibromin expression and AgNP-mediated cytotoxicity. AgNP was able to selectively remove pNF cells from a co-culture with patient-matched Schwann cells. Therefore, AgNPs represent a new approach for clinical management of NF1-associated pNF to address significant clinical need.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030370
Authors: Joanne Lai Abul Kalam Azad Wan Mohd Azizi Wan Sulaiman Vinoth Kumarasamy Vetriselvan Subramaniyan Salah Abdalrazak Alshehade
Alginate is a natural biopolymer widely studied for pharmaceutical applications due to its biocompatibility, low toxicity, and mild gelation abilities. This review summarizes recent advances in alginate-based encapsulation systems for targeted drug delivery. Alginate formulations like microparticles, nanoparticles, microgels, and composites fabricated by methods including ionic gelation, emulsification, spray drying, and freeze drying enable tailored drug loading, enhanced stability, and sustained release kinetics. Alginate microspheres prepared by spray drying or ionic gelation provide gastric protection and colon-targeted release of orally delivered drugs. Alginate nanoparticles exhibit enhanced cellular uptake and tumor-targeting capabilities through the enhanced permeation and retention effect. Crosslinked alginate microgels allow high drug loading and controlled release profiles. Composite alginate gels with cellulose, chitosan, or inorganic nanomaterials display improved mechanical properties, mucoadhesion, and tunable release kinetics. Alginate-based wound dressings containing antimicrobial nanoparticles promote healing of burns and chronic wounds through sustained topical delivery. Although alginate is well-established as a pharmaceutical excipient, more extensive in vivo testing is needed to assess clinical safety and efficacy of emerging formulations prior to human trials. Future opportunities include engineered systems combining stimuli-responsiveness, active targeting, and diagnostic capabilities. In summary, this review discusses recent advances in alginate encapsulation techniques for oral, transdermal, and intravenous delivery, with an emphasis on approaches enabling targeted and sustained drug release for enhanced therapeutic outcomes.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030369
Authors: Adina Căta Ioana Maria Carmen Ienaşcu Adina Frum Daniel Ursu Paula Svera Corina Orha Gerlinde Rusu Adriana Aurelia Chiș Carmen Maximiliana Dobrea Claudiu Morgovan Oana-Raluca Pop
Bioactive compounds extracted from plants can provide wide health benefits. However, some molecules have limited applications as pharmaceuticals due to their limited solubility, poor bioavailability, and low stability when exposed to environmental factors. Their integration in formulations that can deliver them to physiological targets while preserving their biological activity can enhance their usage in improving human health. This research provides a delivery system design to enhance the solubility, stability and to mask the bitter taste of salicin. Thus, a novel salicin-β-cyclodextrin complex was prepared and analyzed by X-ray diffraction, scanning electron microscopy, thermogravimetric analysis, FTIR, Raman and UV-Vis spectroscopy. The analytical and computational methods provided clear and distinct evidence for inclusion of salicin within the β-cyclodextrin cavity and brought important findings for the characterization of the inclusion complex. The present study showed that salicin and β-cyclodextrin can form inclusion complexes, both in solution and in solid state, and that the inclusion of salicin in the cavity of β-cyclodextrin leads to the improvement of its solubility and stability. Thus, the study communicates both qualitative and quantitative knowledge about the preparation of a new salicin-β-cyclodextrin inclusion complex suggesting its potential applications in pharmaceutical industry and medical sciences, as formulations with better compliance for the patient, with increased bioavailability, and easier control of dosage.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030368
Authors: Nicolle Schwarz Marcel Enke Franka V. Gruschwitz Daniela Winkler Susanne Franzmann Lisa Jescheck Felix Hanf Achim Schneeberger
A threat to human health in developed and, in particular, in developing countries, counterfeit medicines represent the largest identified fraud market worldwide. 3D screen printing (3DSP), an additive manufacturing technology that enables large-scale production, offers unique opportunities to combat counterfeit drugs. One such possibility is the generation of oral dosage forms with a distinct colored inner structure that becomes visible upon breakage and cannot be copied with conventional manufacturing methods. To illustrate this, we designed tablets containing a blue cross. Owing to paste properties and the limited dimensions of the cross, the production process was chosen to be continuous, involving two screen and paste changes. The two pastes (tablet body, cross) were identical except for the blue color of the latter. This ensured the build-up and mechanical stability of the resulting tablets in a mass production environment. The ensuing tablets were found to be uniform in weight and size and to comply with regulatory requirements for hardness, friability, and disintegration time (immediate release). Moreover, all tablets exhibited the covert anticounterfeit feature. The study delivers a proof-of-concept for incorporating complex structures into tablets using 3DSP and showcases the power of the technology offering new avenues for combating counterfeit drugs.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030366
Authors: Giedre Kasparaviciene Yuliia Maslii Nataliia Herbina Daiva Kazlauskiene Mindaugas Marksa Jurga Bernatoniene
The formulation of biphasic gels as potential semi-solid carriers for hydrophilic and lipophilic active substances is promising for the development of pharmaceutical preparations. The aim of this study was to design a stable bigel composition and to determine the influence of the organogel/hydrogel ratio on the gel’s physical-chemical and structural-mechanical properties. The investigated compositions of organogel/hydrogel remained stable at ratios ranging from 5/95 to 40/60. After texture and microstructure analysis, bigels with 20/80 and 25/75 ratios were selected as carriers for the active ingredients, sodium diclofenac and camphor, for use as topical preparations for the treatment of muscle-joint inflammation and pain. Although other researchers have published data on the preparation and evaluation of bigels, there are no scientific results on the development of a two-phase gel with our proposed combination of APIs. Sodium diclofenac release was found to be higher when combined with camphor, which revealed the advantages of the biphasic formulation. The pseudoplastic behavior, thixotropy, and thermal stability of flow of the studied bigel samples was investigated by rheological analysis. Ongoing stability studies confirmed the minimal 6-month period.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030367
Authors: Doreen Schmidl Nikolaus Hommer Martin Kallab Andreas Schlatter Clemens Nadvornik Franz Obermayr Stefan Sperl Eric J. Daniels Gerhard Garhöfer
Purpose: Inhibitors of dihydroorotate dehydrogenase (DHODH) have been found to be potent anti-inflammatory agents. Recently, a topical formulation (KIO-101 eye drops) of a DHODH inhibitor has been developed. The aim of the present study was to evaluate the safety and tolerability of KIO-101 eye drops in Healthy Volunteers (HVs) and patients with conjunctival hyperemia. Methods: The study was carried out in a double-masked, placebo-controlled, randomized, parallel-group design with two parts. In part I, HVs received single and multiple instillations (four times daily for 12 consecutive days) of KIO-101 eye drops in ascending doses of 0.05%, 0.15%, and 0.30%, respectively. Part II was conducted in patients with conjunctival hyperemia who received 0.15% KIO-101 eye drops twice daily for 12 consecutive days. Ophthalmic and systemic safety examinations were performed on all participants. In part II, ocular hyperemia grading and an ocular surface disease index (OSDI) questionnaire were performed. Results: 24 HVs participated in part I and 21 patients in part II. KIO-101 eye drops were well tolerated in all subjects. No serious adverse events (SAEs) occurred, and all AEs that were reported were transient and considered mild to moderate. In the highest dose cohort (0.30%), epistaxis occurred in two subjects after multiple instillations. In part II, after 12 days treatment with 0.15% KIO-101, conjunctival hyperemia decreased by −1.1 ± 0.27 points in the treatment and −0.6 ± 0.79 points in the placebo group (p = 0.0385). OSDI decreased from 47.9 ± 18.7 to 27.6 ± 19.13 points in the treatment group, while in the placebo group, a change from 41.3 ± 12.08 to 27.3 ± 18.63 points occurred. Conclusions: A 12-day treatment regimen with topical KIO-101 eye drops at low and mid doses was safe and well tolerated in both HVs and patients with conjunctival hyperemia. The obtained results point towards an early sign of reduction in conjunctival hyperemia.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030365
Authors: Chae-Hyun Kim Yong-Jin Kwon Young-Ah Jang
Corticosteroids are commonly used anti-inflammatory agents. However, their prolonged use can lead to side effects. Therefore, the development of natural compounds with minimal side effects is necessary. This study was performed to investigate the anti-inflammatory effects and mechanisms of action of Chamaecyparis obtusa (Siebold & Zucc.) Endl. leaf (COL), bioconverted using Ganoderma applanatum (G. applanatum) in lipopolysaccharide (LPS)-induced RAW264.7 cells. The COL 70% EtOH extract fermented by G. applanatum (70COLGA) improved the high cytotoxicity of 70% EtOH extracts (70COL). When RAW264.7 cells were pre-treated with 100 and 200 μg/mL of 70COLGA for 2 h and then treated with LPS for 16 h, LPS induced the production of nitric oxide (NO), and the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) were significantly inhibited. When RAW264.7 cells were pre-treated with 100 and 200 μg/mL of 70COLGA for 2 h and then treated with LPS for 4 h, the phosphorylation of signal transducers and activators of transcription (STAT) was markedly decreased. In addition, 70COLGA markedly suppressed the production of the inflammatory cytokines interleukin (IL)-1β and IL-6 in LPS-induced RAW264.7 cells. Analysis of pro-inflammatory molecules using cytokine arrays showed that macrophage inflammatory protein (MIP)-2, granulocyte–macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) and IL-27 expressions were also suppressed by 200 μg/mL of 70COLGA in LPS-induced RAW264.7 cells. These results demonstrate that 70COLGA significantly prevented inflammatory responses by inhibiting the secretion of pro-inflammatory molecules in LPS-induced RAW264.7 cells. When RAW264.7 cells were pre-treated with 100 and 200 μg/mL of 70COLGA for 2 h and then treated with LPS-conditioned medium (LPS-CM) for 30 min, 70COLGA directly inhibited STAT activation. In summary, our findings suggest that 70COLGA has therapeutic potential for the treatment of inflammatory diseases.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030364
Authors: Bum Soo Lee Hoon Kim Jiwon Baek Rhim Ryoo Seoung Rak Lee Ki Hyun Kim
The determination of natural product stereochemistry plays a significant role in drug discovery and development. Understanding the stereochemistry of natural products is essential for predicting and optimizing their interactions with biological targets, which, in turn, influences their therapeutic efficacy, safety, and overall impact on living organisms. Here, we present the first application of competitive enantioselective acylation (CEA) reactions in conjunction with LC/MS analysis for determining the absolute configuration of secondary alcohols in natural products which were purified as a mixture. This approach utilizes the enantiomeric pair of HBTM (homobenzotetramisole) catalysts, demonstrating sufficient kinetic resolution for the acylation of secondary alcohols. The rapid reaction kinetics were quantitatively estimated with LC/MS analysis as the characterization technique for the enantioselective transformations. Our study has expanded the application of the CEA reaction coupled with LC/MS analysis to mixtures. Utilizing LC/MS analysis, the CEA reaction offers a sensitive and simple method for stereochemistry determination. Additionally, the application of the CEA reaction is cost/time-effective since only small quantities of substrates and a short reaction time are required for characterizing the absolute configuration of secondary alcohols in natural products compared to other conventional methods.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030363
Authors: Amanda Sales Conniff Julie Singh Richard Heller Loree C. Heller
Gene therapy approaches may target skeletal muscle due to its high protein-expressing nature and vascularization. Intramuscular plasmid DNA (pDNA) delivery via pulsed electric fields (PEFs) can be termed electroporation or electrotransfer. Nonviral delivery of plasmids to cells and tissues activates DNA-sensing pathways. The central signaling complex in cytosolic DNA sensing is the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING). The effects of pDNA electrotransfer on the signaling of STING, a key adapter protein, remain incompletely characterized. STING undergoes several post-translational modifications which modulate its function, including palmitoylation. This study demonstrated that in mouse skeletal muscle, STING was constitutively palmitoylated at two sites, while an additional site was modified following electroporation independent of the presence of pDNA. This third palmitoylation site correlated with STING polymerization but not with STING activation. Expression of several palmitoyl acyltransferases, including zinc finger and DHHC motif containing 1 (zDHHC1), coincided with STING activation. Expression of several depalmitoylases, including palmitoyl protein thioesterase 2 (PPT2), was diminished in all PEF application groups. Therefore, STING may not be regulated by active modification by palmitate after electroporation but inversely by the downregulation of palmitate removal. These findings unveil intricate molecular changes induced by PEF application.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030362
Authors: Valentyn Mohylyuk Artūrs Paulausks Oskars Radzins Liga Lauberte
Using microcrystalline cellulose (MCC) with plastic behaviour and calcium phosphate anhydrous (CaHPO4) with brittle behaviour under compaction is very popular in the pharmaceutical industry for achieving desirable structural–mechanical properties of tablet formulations. Thus, mixtures of specific grades of MCC and CaHPO4 were tested in volume proportions of 100-0, 75-25, 50-50, 25-75, and 0-100 at a constant weight-by-weight concentration of sodium stearyl fumarate lubricant, utilizing a state-of-the-art benchtop compaction simulator (STYL’One Nano). Tablet formulations were prepared at 100, 150, 250, 350, 450, and 500 MPa, and characterized by tabletability profile, ejection force profile, proportion–tensile strength relationship, proportion–porosity relationship, pressure–displacement, and elastic recovery profiles, as well as by in-/out-of-die Heckel plots and yield pressures. Interestingly, the 25-75 formulation demonstrated a two-stage out-of-die Heckel plot and was additionally investigated with X-ray micro-computed tomography (µCT). By post-processing the µCT data, the degree of brittle CaHPO4 particles falling apart, along with the increasing compression pressure, was quantified by means of the surface area to volume (S/V) ratio. For the 25-75 formulation, the first stage (up to 150 MPa) and second stage (above the 150 MPa) of the out-of-die Heckel plot could be attributed to predominant MCC and CaHPO4 deformation, respectively.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030361
Authors: Toshihiko Tashima Nicolas Tournier
We will be serving as the Guest Editor for this very interesting Special Issue on “Non-Invasive Device-Mediated Drug Delivery to the Brain Across the Blood–Brain Barrier” [...]
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030360
Authors: Miguel T. Campos Filipa A. L. S. Silva José Ramiro Fernandes Susana G. Santos Fernão D. Magalhães Maria J. Oliveira Artur M. Pinto
Non-melanoma skin cancer (NMSC) is one of the most common types of cancer worldwide. Despite the low mortality rate, rising incidence and recurrence rates are a burden on healthcare systems. Standard treatments such as chemotherapy, radiotherapy, and surgery are either invasive or toxic to healthy tissues; therefore, new, alternative, selective treatments are needed. In this work, a combined photothermal and chemotherapeutic approach is proposed. MoS2 was used as photothermal agent. It was prepared by a liquid-phase exfoliation and intercalation method using polyvinylpyrrolidone (PVP), followed by recirculation through a custom-built high-power ultrasonication probe. After 6 h of ultrasonication treatment, the average particle size was 165 ± 170 nm. Near-infrared (NIR) irradiation assays (810 nm, 0.1 W/cm2, 30 min, 180 J/cm2) confirmed that MoS2 nanosheets can efficiently convert NIR light into heat and reach 52 °C. The therapeutic doses of MoS2 (125 µg/mL) and Tegafur (50 µg/mL) were optimized and both were simultaneously incorporated into a Carbopol hydrogel. The cells were brought into contact with the hydrogel and irradiated with a custom-built NIR LED system. In HFF-1 cells (normal human fibroblasts), the metabolic activity was 78% (above the 70% toxicity limit—ISO 10993-5:2009(E)), while in A-431 skin cancer cells, it was 28%. In addition, the MoS2 + Tegafur hydrogels led to a 1.9-fold decrease in A-431 cancer cell metabolic activity, 72 h after irradiation, in comparison to MoS2 hydrogels, indicating a combined effect of photothermal and chemotherapy.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030359
Authors: Magdalena Paczkowska-Walendowska Ioanna Koumentakou Maria Lazaridou Dimitrios Bikiaris Andrzej Miklaszewski Tomasz Plech Judyta Cielecka-Piontek
The plant material Scutellariae baicalensis radix, which is rich in flavones (baicalin), possesses antibacterial, antifungal, antioxidant, and anti-inflammatory properties. This work aimed to develop a 3D-printed chitosan-based hydrogel rich in Scutellariae baicalensis extract as an innovative approach for the personalized treatment of periodontal diseases. Chitosan-based hydrogels were prepared, and the printability of the prepared hydrogels was determined. The hydrogel with 2.5% w/v of high molecular-weight chitosan (CS), 2% w/v gelatin (Gel), and 10% w/w of extract (Ex) presented the best printability, producing smooth and uniform scaffolds. It was proved that the CS/Gel/Ex hydrogel was stabilized by hydrogen bonds and remained in amorphous dispersion in the 3D-printed structures (confirmed by ATR-FTIR and XRPD). Due to the amorphization of the active substance, a significant increase in the release of baicalin in vitro was observed. It was demonstrated that there was an initial burst release and a continuous release profile (n = 3). Higuchi kinetic was the most likely baicalin release kinetic. The second fit, the Korsmeyer–Peppas kinetics model, showed coupled diffusion of the active ingredient in the hydrated matrix and polymer relaxation regulated release, with n values ranging from 0.45 to 0.89. The anti-inflammatory properties of 3D-printed scaffolds were assessed as the ability to inhibit the activity of the hyaluronidase enzyme. Activity was assessed as IC50 = 63.57 ± 4.98 mg hydrogel/mL (n = 6). Cytotoxicity tests demonstrated the biocompatibility of the material. After 24 h of exposure to the 2.5CS/2Gel/10Ex scaffold, fibroblasts migrated toward the scratch, closed the “wound” by 97.1%, and significantly accelerated the wound healing process. The results render the 3D-printed CS/Gel/extract scaffolds as potential candidates for treating periodontal diseases.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030358
Authors: Gellért Balázs Karvaly István Vincze Michael Noel Neely István Zátroch Zsuzsanna Nagy Ibolya Kocsis Csaba Kopitkó
Population pharmacokinetic (pop-PK) models constructed for model-informed precision dosing often have limited utility due to the low number of patients recruited. To augment such models, an approach is presented for generating fully artificial quasi-models which can be employed to make individual estimates of pharmacokinetic parameters. Based on 72 concentrations obtained in 12 patients, one- and two-compartment pop-PK models with or without creatinine clearance as a covariate were generated for piperacillin using the nonparametric adaptive grid algorithm. Thirty quasi-models were subsequently generated for each model type, and nonparametric maximum a posteriori probability Bayesian estimates were established for each patient. A significant difference in performance was found between one- and two-compartment models. Acceptable agreement was found between predicted and observed piperacillin concentrations, and between the estimates of the random-effect pharmacokinetic variables obtained using the so-called support points of the pop-PK models or the quasi-models as priors. The mean squared errors of the predictions made using the quasi-models were similar to, or even considerably lower than those obtained when employing the pop-PK models. Conclusion: fully artificial nonparametric quasi-models can efficiently augment pop-PK models containing few support points, to make individual pharmacokinetic estimates in the clinical setting.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030357
Authors: Rafaela de Andrade Rita de Cássia dos Reis Schmidt Leonardo Santos Gomes Legna Colina-Vegas Ruth Hinrichs Marcos Antônio Zen Vasconcellos Tania Maria Haas Costa Monique Deon Wilmer Villarreal Edilson Valmir Benvenutti
Malaria is a dangerous tropical disease, with high morbidity in developing countries. The responsible parasite has developed resistance to the existing drugs; therefore, new drug delivery systems are being studied to increase efficacy by targeting hemozoin, a parasite paramagnetic metabolite. Herein, magnetic mesoporous silica (magMCM) was synthesized using iron oxide particles dispersed in the silica structure for magnetically driven behavior. The X-ray diffractogram (XRD) and Mössbauer spectra show patterns corresponding to magnetite and maghemite. Furthermore, Mössbauer spectroscopy revealed superparamagnetic behavior, attributed to single magnetic domains in particles smaller than 10 nm. Even in the presence of iron oxide particles, the hexagonal structure of MCM is clearly identified in XRD (low-angle region) and the channels are visible in TEM images. The drug chloroquine (CQ) was encapsulated by incipient wetness impregnation (magMCM-CQ). The N2 adsorption–desorption isotherms show that CQ molecules were encapsulated in the pores, without completely filling the mesopores. BET surface area values were 630 m2 g−1 (magMCM) and 467 m2 g−1 (magMCM-CQ). Encapsulated CQ exhibited rapid delivery (99% in 3 h) in buffer medium and improved solubility compared to the non-encapsulated drug, attributed to CQ encapsulation in amorphous form. The biocompatibility assessment of magMCM, magMCM-CQ, and CQ against MRC5 non-tumoral lung fibroblasts using the MTT assay after 24 h revealed no toxicity associated with magMCM. On the other hand, the non-encapsulated CQ and magMCM-CQ exhibited comparable dose–response activity, indicating a similar cytotoxic effect.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030356
Authors: Beena G. Singh Nalin Bagora Minati Nayak Juby K. Ajish Nitish Gupta Amit Kunwar
In the field of preparing cosmetic formulations, recent advances recommend the usage of excipients derived from biocompatible materials. In this context, the present study aimed to prepare and characterize the curcumin-loaded Pickering emulsion for possible applications in cosmetic formulation. The coconut oil which is often the component of skin care formulations is used as the oily phase. Curcumin, which is well known for absorbing solar radiation, is expected to work synergistically with coconut oil towards improving the sun protection factor (SPF) of the formulation. Additionally, curcumin can also protect the intracellular components through its well-known antioxidant mechanisms. The Pickering emulsion of coconut oil into water was prepared using the composite colloidal particles derived from β-carboxymethyl chitosan (CMC) and Gelatin-A (GA) as the emulsifying agent. The reaction conditions in terms of the weight ratios of CMC and GA, the pH of the reaction medium, the oil volume fraction, and the homogenization speed were optimized to obtain the most stable Pickering emulsion. The obtained systems were physico-chemically characterized by dynamic light scattering, zeta potential, optical microscopy, and rheometric measurements. The final CMC-GA-stabilized emulsion demonstrated an oil droplet size of 100 µm and a SPFspectrophotometric (290–320 nm) value of 8.5 at a curcumin loading of 4 mg/mL. Additionally, the final formulation facilitated the uptake of curcumin into fibroblast (WI26) cells under in vitro conditions. Together, the investigation demonstrates a bio-inspired approach to prepare a curcumin-loaded green Pickering emulsion using biocompatible pharmaceutical grade excipients, which may find utility in cosmetic applications.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030355
Authors: Lilia Jadith Bernal-Cepeda Ronald Andrés Jiménez Myriam L. Velandia-Romero Paola Acosta-Guzmán Jaime E. Castellanos
The modulation of TRPV1 emerges as a promising strategy for dental pain management. This study aimed to assess TRPV1 modulation in a human odontoblast-like cell model using Capsazepine (CZP) loaded in a nanogel delivery system. Gelatin nanogels, synthesized via the emulsification-gelation technique, were characterized and loaded with the TRPV1 antagonist, CZP. HPLC determined a remarkable 67.5 ± 0.04% CZP loading efficiency, with 71.7% of nanogels falling within the 300–950 nm size range, as evidenced by light microscopy. Moreover, CZP-loaded nanogels had a low cytotoxicity. An FTIR analysis showed no adverse chemical interactions, ensuring stability and active release. When examining biological responses, TRPV1 expression and channel activity were assessed in odontoblast-like cells. On the fifth day post-treatment, cells treated with CZP-loaded nanogels exhibited an increased TRPV1 expression and a reduction in calcium fluxes after agonist stimulus (F/F0 ratio 1.18 ± 0.18), resembling the response in free CZP-treated cells (1.28 ± 0.15). A two-way analysis of variance and the Tukey’s test were used to determine statistical significance (p < 0.05). This delivery system, proven to be economical and straightforward, holds promise for dental pain management and potential local use. Local administration minimizes systemic adverse effects, making it a practical solution for releasing molecules in the oral cavity.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030354
Authors: Blaž Grilc Odon Planinšek
The objective of this study was to develop buccal film formulations containing metoclopramide hydrochloride monohydrate (MCP) with and without a backing layer and to evaluate their release properties and physiochemical stability. The crystallization of MCP in the polymer matrix was monitored with image analysis techniques for rapid and scalable observation. The results showed that the addition of a protective layer and its thickness significantly affected the release rate and crystallization behavior of MCP in the formulations. The crystallization of MCP increased over time, and certain formulations showed higher susceptibility to crystallization. To understand the factors affecting the crystallization of MCP, the relationship between the viscosity and pH of the casting solution was examined, but no significant correlation was found. A significant correlation was observed between the plasticizer concentration and the physical state of MCP. Through a systematic Design of Experiment (DOE) approach, an optimal formulation was devised, successfully preventing crystallization of the active ingredient. However, enhancing the overall chemical stability of the formulated product remains a challenge.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030353
Authors: Hamidreza Heidari Nontawat Muanpaopong Gulenay Guner Helen F. Yao Donald J. Clancy Ecevit Bilgili
We examined the evolution of fenofibrate (FNB, drug) particle size distribution (PSD) during the production of nanosuspensions via wet stirred media milling (WSMM) with a cell-based population balance model (PBM). Our objective was to elucidate the potential impacts of batch size, suspension volumetric flow rate, and imperfect mixing in a recirculating WSMM. Various specific breakage rate functions were fitted to experimental PSD data at baseline conditions assuming perfect mixing. Then, the best function was used to simulate the PSD evolution at various batch sizes and flow rates to validate the model. A novel function, which is a product of power–law and logistic functions, fitted the evolution the best, signifying the existence of a transition particle size commensurate with a grinding limit. Although larger batches yielded coarser and wider PSDs, the suspensions had identical PSDs when milled for the same effective milling time. The flow rate had an insignificant influence on the PSD. Furthermore, the imperfect mixing in the mill chamber was simulated by considering more than one cell and different back-mixing flow ratios. The effects were weak and restricted to the first few turnovers. These insights contribute to our understanding of recirculating WSMM, providing valuable guidance for process development.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030352
Authors: Stefania Mottola Iolanda De Marco
In this work, polyvinylpyrrolidone (PVP)- and β-cyclodextrin (β-CD)-based composite powders containing curcumin (CURC) were obtained through the supercritical antisolvent (SAS) technique. Pressure, total concentration of CURC/carrier in dimethylsulfoxide, and CURC/carrier ratio effects on the morphology and size of the precipitated powders were investigated. Using PVP as the carrier, spherical particles with a mean diameter of 1.72 μm were obtained at 12.0 MPa, 20 mg/mL, and a CURC/PVP molar ratio equal to 1/2 mol/mol; using β-CD as the carrier, the optimal operating conditions were 9.0 MPa and 200 mg/mL; well-defined micrometric particles with mean diameters equal to 2.98 and 3.69 μm were obtained at molar ratios of 1/2 and 1/1 mol/mol, respectively. FT-IR spectra of CURC/ β-CD inclusion complexes and coprecipitated CURC/PVP powders revealed the presence of some peaks of the active compounds. The stoichiometry of the complexes evaluated through the Job method revealed that β-CD formed inclusion complexes with CURC at a molar ratio equal to 1/1. Dissolution profiles revealed that in comparison with the curve of the pure ingredient, the SAS-processed powders obtained using both PVP and β-CD have an improved release rate.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030351
Authors: Gustavo Serafim Rodrigues João Miguel Barboza Laís Pereira Buranello Vitor Melo Brandão Priscileila Colerato Ferrari Guilherme Augusto Soares José Ricardo de Arruda Miranda
Floating controlled systems seek to extend the gastric retention time (GRT) of solid pharmaceutical forms by sustaining buoyancy in the stomach without affecting gastric emptying rates. This investigation aimed to evaluate a magnetic floating drug delivery system (MFDDS) under diverse physiological conditions (pressure and viscosity) using an Alternating Current Biosusceptometry (ACB) system by conducting assessments in vitro and in vivo. For in vitro experiments, MFDDSs were placed under different pressures (760, 910, and 1060 mmHg) and viscosities (1, 50, 120, and 320 mPa·s) for evaluation of floating lag time (FLT). For in vivo experiments, eight healthy volunteers participated in two phases (fasting and fed) for gastric parameters (GRT, FLT, and OCTT—orocaecal transit time) assessment, employing the ACB system. The results indicated that pressure, viscosity, and FLT were directly proportional in the in vitro assay; in addition, increases in the OCTT (fasting = 241.9 ± 18.7; fed = 300 ± 46.4), GRT (fasting = 139.4 ± 25.3; fed = 190.2 ± 47.7), and FLT (fasting = 73.1 ± 16.9; fed = 107.5 ± 29.8) were detected in vivo. Our study emphasizes that the ACB system is a valuable technique, and it is capable of tracking and imaging MFDDS in in vitro and in vivo experiments.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030350
Authors: Maria Tsakiri Ioannis Tsichlis Cristina Zivko Costas Demetzos Vasiliki Mahairaki
Neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, affect a wide variety of the population and pose significant challenges with progressive and irreversible neural cell loss. The limitations of brain-targeting therapies and the unclear molecular mechanisms driving neurodegeneration hamper the possibility of developing successful treatment options. Thus, nanoscale drug delivery platforms offer a promising solution. This paper explores and compares lipidic nanoparticles, extracellular vesicles (EVs), and hybrid liposomal–EV nanoplatforms as advanced approaches for targeted delivery to combat neurodegeneration. Lipidic nanoparticles are well-characterized platforms that allow multi-drug loading and scalable production. Conversely, EVs offer the ability of selectively targeting specific tissues and high biocompatibility. The combination of these two platforms in one could lead to promising results in the treatment of neurodegeneration. However, many issues, such as the regulatory framework, remain to be solved before these novel products are translated into clinical practice.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030349
Authors: Natalia Łapińska Adam Pacławski Jakub Szlęk Aleksander Mendyk
Understanding the features of compounds that determine their high serotonergic activity and selectivity for specific receptor subtypes represents a pivotal challenge in drug discovery, directly impacting the ability to minimize adverse events while maximizing therapeutic efficacy. Up to now, this process has been a puzzle and limited to a few serotonergic targets. One approach represented in the literature focuses on receptor structure whereas in this study, we followed another strategy by creating AI-based models capable of predicting serotonergic activity and selectivity based on ligands’ representation by molecular descriptors. Predictive models were developed using Automated Machine Learning provided by Mljar and later analyzed through the SHAP importance analysis, which allowed us to clarify the relationship between descriptors and the effect on activity and what features determine selective affinity for serotonin receptors. Through the experiments, it was possible to highlight the most important features of ligands based on highly efficient models. These features are discussed in this manuscript. The models are available in the additional modules of the SerotoninAI application called “Serotonergic activity” and “Selectivity”.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030348
Authors: M. Melissa Peet Vivek Agrahari Meredith R. Clark Gustavo F. Doncel
HIV/AIDS remains a global public health issue, and products available for the prevention of HIV infections are limited, especially those for short-acting, on-demand, user-controlled applications. Topical inserts are products that can be applied vaginally or rectally and have been explored as drug delivery systems. To fill the gap in the HIV prevention product pipeline, CONRAD has developed a topical insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG), two potent and synergistic antiretrovirals, as a simple, low-cost, and discreet option that can be self-administered vaginally and/or rectally, before and after coitus. In this review, we have described the development path of the TAF/EVG insert up to its current point in clinical testing, highlighting findings from acceptability, preclinical safety, pharmacokinetics, and efficacy evaluations and early clinical studies. In summary, the TAF/EVG inserts are stable, easy to manufacture, low-cost, acceptable, and show highly promising preclinical and clinical results for on-demand topical pre- or post-exposure HIV prevention.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030347
Authors: Gabriella Costabile Gemma Conte Susy Brusco Pouria Savadi Agnese Miro Fabiana Quaglia Ivana d’Angelo Francesca Ungaro
Nowadays, the interest in research towards the local administration of drugs via the inhalation route is growing as it enables the direct targeting of the lung tissue, at the same time reducing systemic side effects. This is of great significance in the era of nucleic acid therapeutics and personalized medicine for the local treatment of severe lung diseases. However, the success of any inhalation therapy is driven by a delicate interplay of factors, such as the physiochemical profile of the payload, formulation, inhalation device, aerodynamic properties, and interaction with the lung fluids. The development of drug delivery systems tailored to the needs of this administration route is central to its success and to revolutionize the treatment of respiratory diseases. With this review, we aim to provide an up-to-date overview of advances in the development of nanoparticulate carriers for drug delivery to the lung tissue, with special regard concerning lipid and polymer-based nanocarriers (NCs). Starting from the biological barriers that the anatomical structure of the lung imposes, and that need to be overcome, the current strategies to achieve efficient lung delivery and the best support for the success of NCs for inhalation are highlighted.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030346
Authors: Hyeseon Park Yoo Kyung Kang Gayong Shim
Clustered regularly interspaced short palindromic repeat-associated protein Cas9 (CRISPR/Cas9) technology is at the forefront of cancer immunotherapy innovation, offering precise and personalized treatment strategies. In this review, we discuss CRISPR/Cas9’s ability to precisely edit the genome, its impact on immune checkpoint control, and its application in immune cell engineering, where it surpasses traditional gene editing techniques. Originally inspired by bacterial defense mechanisms, this technology has made great strides in cancer immunotherapy as a mechanism to specifically target the PD-1/PD-L1 pathway in immune checkpoint blockades. In addition, CRISPR/Cas9 plays an important role in cancer treatment by facilitating genetic modifications to enhance the properties of adoptive cell therapy, optimizing the therapeutic potential of this approach. This review provides an overview of the development of CRISPR/Cas9, its important role in immune checkpoint control, applications in immune cell engineering, and the current status of clinical trials. However, safety concerns related to off-target effects and unintended mutations require continued research and caution. Continued advances in CRISPR technology hold the promise of revolutionizing the cancer treatment paradigm, providing personalized and effective therapies for patients with various types of cancer.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030345
Authors: Xiaona Sun Yuxuan Wu Xingkai Wang Xin Gao Siqi Zhang Zhicheng Sun Ruping Liu Kuan Hu
Fibroblast activation protein (FAP) is a serine protease characterized by its high expression in cancer-associated fibroblasts (CAFs) and near absence in adult normal tissues and benign lesions. This unique expression pattern positions FAP as a prospective biomarker for targeted tumor radiodiagnosis and therapy. The advent of FAP-based radiotheranostics is anticipated to revolutionize cancer management. Among various types of FAP ligands, peptides and antibodies have shown advantages over small molecules, exemplifying prolonged tumor retention in human volunteers. Within its scope, this review summarizes the recent research progress of the FAP radiopharmaceuticals based on antibodies and peptides in tumor imaging and therapy. Additionally, it incorporates insights from recent studies, providing valuable perspectives on the clinical utility of FAP-targeted radiopharmaceuticals.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030344
Authors: Juliana Palungan Widya Luthfiyah Apon Zaenal Mustopa Maritsa Nurfatwa Latifah Rahman Risfah Yulianty Nasrul Wathoni Jin-Wook Yoo Nurhasni Hasan
Self-healing hydrogels often lack mechanical properties, limiting their wound-dressing applications. This study introduced S-Nitrosoglutathione (GSNO) to self-healing hydrogel-based wound dressings. Self-healing hydrogel mechanical properties were improved via polymer blends. Applying this hydrogel to the wound site allows it to self-heal and reattach after mechanical damage. This work evaluated polyvinyl alcohol (PVA)-based self-healing hydrogels with borax as a crosslinking agent and carboxymethyl chitosan as a mechanical property enhancer. Three formulations (F1, F4, and F7) developed self-healing hydrogels. These formulations had borax concentrations of 0.8%, 1.2%, and 1.6%. An FTIR study shows that borate ester crosslinking and hydrogen bonding between polymers generate a self-healing hydrogel. F4 has a highly uniform and regular pore structure, as shown by the scanning electron microscope image. F1 exhibited faster self-healing, taking 13.95 ± 1.45 min compared to other formulations. All preparations had pH values close to neutrality, making them suitable wound dressings. Formula F7 has a high drug content (97.34 ± 1.21%). Good mechanical qualities included high tensile stress–strain intensity and Young’s modulus. After 28 h of storage at −20 °C, 5 °C, and 25 °C, the self-healing hydrogel’s drug content dropped significantly. The Korsmeyer–Peppas release model showed that the release profile of GSNO followed Fickian diffusion. Thus, varying the concentration of crosslinking agent and adding a polymer affects self-healing hydrogels’ physicochemical properties.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030343
Authors: Xing Yin Romain Harmancey Brion Frierson Jean G. Wu Melanie R. Moody David D. McPherson Shao-Ling Huang
Liposomes as carriers for CRISPR/Cas9 complexes represent an attractive approach for cardiovascular gene therapy. A critical barrier to this approach remains the efficient delivery of CRISPR-based genetic materials into cardiomyocytes. Echogenic liposomes (ELIP) containing a fluorescein isothiocyanate-labeled decoy oligodeoxynucleotide against nuclear factor kappa B (ELIP-NF-κB-FITC) were used both in vitro on mouse neonatal ventricular myocytes and in vivo on rat hearts to assess gene delivery efficacy with or without ultrasound. In vitro analysis was then repeated with ELIP containing Cas9-sg-IL1RL1 (interleukin 1 receptor-like 1) RNA to determine the efficiency of gene knockdown. ELIP-NF-κB-FITC without ultrasound showed limited gene delivery in vitro and in vivo, but ultrasound combined with ELIP notably improved penetration into heart cells and tissues. When ELIP was used to deliver Cas9-sg-IL1RL1 RNA, gene editing was successful and enhanced by ultrasound. This innovative approach shows promise for heart disease gene therapy using CRISPR technology.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030342
Authors: Iqra Mubeen Ghulam Abbas Shahid Shah Abdullah A Assiri
Oral delivery, the most common method of therapeutic administration, has two significant obstacles: drug solubility and permeability. The challenges of current oral medicine delivery are being tackled through an emerging method that uses structures called polymeric micelles. In the present study, polymeric micelles were developed using conjugates of linoleic acid–carboxymethyl chitosan (LA-CMCS) for the oral delivery of paclitaxel (PCL). The developed micelles were evaluated by particle size, zeta potential, Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). When PCL was contained within micelles, its solubility increased by almost 13.65 times (around 60 µg/mL). The micelles’ zeta potentials were −29 mV, their polydispersity indices were 0.023, and their particle diameters were 93 nm. Micelles showed PCL loading and entrapment efficiencies of 67% and 61%, respectively. The sustained release qualities of the PCL release data from micelles were good. In comparison to the pure PCL suspension, the permeability of the PCL from micelles was 2.2 times higher. The pharmacokinetic data revealed that PCL with LA-CMCS micelles had a relative bioavailability of 239.17%, which was much greater than the PCL in the suspension. The oral bioavailability of PCL was effectively increased by LA-CMCS micelles according to an in vivo study on animals. The polymer choice, maybe through improved permeability, plays an essential role when assessing oral bioavailability enhancement and solubility improvement (13.65 times). The outcomes demonstrated that PCL’s solubility and pharmacokinetics were improved in the micelles of the LA-CMCS conjugate.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030341
Authors: Phaedra Denduyver Chris Vervaet Valérie Vanhoorne
Hydroxypropyl methylcellulose (HPMC) is a preferred hydrophilic matrix former for controlled release formulations produced through continuous twin-screw wet granulation. However, a non-homogeneous API distribution over sieve fractions with underdosing in the fines fraction (<150 µm) was previously reported. This could result in content uniformity issues during downstream processing. Therefore, the current study investigated the root cause of the non-homogeneous theophylline distribution. The effect of process parameters (L/S-ratio and screw configuration) and formulation parameters (matrix former and filler type) on content uniformity was studied. Next, the influence of the formulation parameters on tableting and dissolution behavior was investigated. Altering the L/S-ratio or using a more aggressive screw configuration did not result in a homogeneous API distribution over the granule sieve fractions. Using microcrystalline cellulose (MCC) as filler improved the API distribution due to its similar behavior as HPMC. As excluding HPMC or including a hydrophobic matrix former (Kollidon SR) yielded granules with a homogeneous API distribution, HPMC was identified as the root cause of the non-homogeneous API distribution. This was linked to its fast hydration and swelling (irrespective of the HPMC grade) upon addition of the granulation liquid.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030340
Authors: Victoria Vitkova Krassimira Antonova Ognyan Petkov Angelina Stoyanova-Ivanova Sirine Jaber Vladislava Ivanova Emilia Naydenova Dancho Danalev
Background: Specifically designed peptide mimetics offer higher selectivity regarding their toxicity to mammalian cells. In addition to the α-helix conformation, the specific activity is related to the peptide’s ability to penetrate the cell membrane. The alterations in lipid membrane properties were addressed in the presence of the peptide KLAKLAK-NH2 and analogs containing β-alanine, strengthening the antibacterial activity and/or naphtalimide with proven anticancer properties. Methods: The molecular interactions of the peptide mimetics with POPC bilayers were studied using FTIR-ATR spectroscopy. The thermal shape fluctuation analysis of quasispherical unilamellar vesicles was applied to probe the membrane bending elasticity. The impedance characteristics of bilayer lipid membranes were measured using fast Fourier-transform electrochemical impedance spectroscopy. Results: A lateral peptide association with the membrane is reported for β-alanine-containing peptides. The most pronounced membrane softening is found for the NphtG-KLβAKLβAK-NH2 analog containing both active groups that corroborate with the indications for 1,8-naphthalimide penetration in the lipid hydrophobic area obtained from the FTIR-ATR spectra analysis. The β-alanine substitution induces strong membrane-rigidifying properties even at very low concentrations of both β-alanine-containing peptides. Conclusions: The reported results are expected to advance the progress in tailoring the pharmacokinetic properties of antimicrobial peptides with strengthened stability towards enzymatic degradation. The investigation of the nonspecific interactions of peptides with model lipid membranes is featured as a useful tool to assess the antitumor and antimicrobial potential of new peptide mimetics.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030338
Authors: Valeria Friuli Claudia Urru Chiara Ferrara Debora Maria Conti Giovanna Bruni Lauretta Maggi Doretta Capsoni
The study focuses on the synthesis and characterization of Meloxicam–halloysite nanotube (HNT) composites as a viable approach to enhance the solubility and dissolution rate of meloxicam, a poorly water-soluble drug (BCS class II). Meloxicam is loaded on commercial and modified halloysite (acidic and alkaline etching, or APTES and chitosan functionalization) via a solution method. Several techniques (XRPD, FT-IR, 13C solid-state NMR, SEM, EDS, TEM, DSC, TGA) are applied to characterize both HNTs and meloxicam–HNT systems. In all the investigated drug–clay hybrids, a high meloxicam loading of about 40 wt% is detected. The halloysite modification processes and the drug loading do not alter the structure and morphology of both meloxicam and halloysite nanotubes, which are in intimate contact in the composites. Weak drug–clay and drug-functionalizing agent interactions occur, involving the meloxicam amidic functional group. All the meloxicam–halloysite composites exhibit enhanced dissolution rates, as compared to meloxicam. The meloxicam–halloysite composite, functionalized with chitosan, showed the best performance both in water and in buffer at pH 7.5. The drug is completely released in 4–5 h in water and in less than 1 h in phosphate buffer. Notably, an equilibrium solubility of 13.7 ± 4.2 mg/L in distilled water at 21 °C is detected, and wettability dramatically increases, compared to the raw meloxicam. These promising results can be explained by the chitosan grafting on the outer surface of halloysite nanotubes, which provides increased specific surface area (100 m2/g) disposable for drug adsorption/desorption.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030339
Authors: Liana Suciu Sebastian Mihai Ardelean Mihai Udrescu Florina-Diana Goldiş Daiana Hânda Maria-Medana Tuică Sabina-Oana Vasii Lucreţia Udrescu
Drug–drug interactions (DDIs) can either enhance or diminish the positive or negative effects of the associated drugs. Multiple drug combinations create difficulties in identifying clinically relevant drug interactions; this is why electronic drug interaction checkers frequently report DDI results inconsistently. Our paper aims to analyze drug interactions in cardiovascular diseases by selecting drugs from pharmacotherapeutic subcategories of interest according to Level 2 of the Anatomical Therapeutic Chemical (ATC) classification system. We checked DDIs between 9316 pairs of cardiovascular drugs and 25,893 pairs of cardiovascular and other drugs. We then evaluated the overall agreement on DDI severity results between two electronic drug interaction checkers. Thus, we obtained a fair agreement for the DDIs between drugs in the cardiovascular category, as well as for the DDIs between drugs in the cardiovascular and other (i.e., non-cardiovascular) categories, as reflected by the Fleiss’ kappa coefficients of κ=0.3363 and κ=0.3572, respectively. The categorical analysis of agreement between ATC-defined subcategories reveals Fleiss’ kappa coefficients that indicate levels of agreement varying from poor agreement (κ<0) to perfect agreement (κ=1). The main drawback of the overall agreement assessment is that it includes DDIs between drugs in the same subcategory, a situation of therapeutic duplication seldom encountered in clinical practice. Our main conclusion is that the categorical analysis of the agreement on DDI is more insightful than the overall approach, as it allows a more thorough investigation of the disparities between DDI databases and better exposes the factors that influence the different responses of electronic drug interaction checkers. Using categorical analysis avoids potential inaccuracies caused by particularizing the results of an overall statistical analysis in a heterogeneous dataset.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030337
Authors: Zixu Wang Fangying Yu Fuqiang Hu
In the struggle against diseases, the development of nano-therapy has certainly been a tremendous progression owing to the various superiority, and chitosan is no doubt a kind of prominent biopolymer material with versatility for applications in disease treatments. For the rational construction of chitosan-related nano-biodevices, it is necessary to pay full attention to the material itself, where it is the material properties that guide the design criteria. Additionally, the well-matched preparation methods between material carriers and therapeutic agents draw much attention to the final construction since they seem to be more realistic. In detail, we present a comprehensive overview of recent advances in rational construction of chitosan-related nano-therapies with respect to material-property-oriented design criteria and preparation methods in the current review article, based on the foundation of continuous investigations. Based on this review, a portion of the various uses of chitosan-related nano-biodevices for biomedical applications are specifically discussed. Here, the strategies demonstrate the versatility of chitosan well, and the concept of being simple yet effective is well illustrated and vividly communicated. Altogether, a fresh concept concerning multi-functional chitosan and its derivative-related drug delivery systems for nano-therapy is proposed in this review, and this could be applied to other materials, which seems to be a novel angle.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030336
Authors: Line Pourtau Fabien Wauquier Line Boutin-Wittrant David Gaudout Benjamin Moras Adeline Vignault Carole Vaysse Tristan Richard Arnaud Courtois Stéphanie Krisa Véronique Roux Nicolas Macian Gisèle Pickering Yohann Wittrant
Safe and anti-inflammatory plant-based natural products present an increasing focus in the treatment of chronic inflammatory diseases such as osteoarthritis or inflammatory bowel diseases. Among them, saffron, a spice derived from the stigma of Crocus sativus, could have anti-inflammatory properties and would be therefore a promising therapeutic agent for the treatment of such conditions. However, the anti-inflammatory molecular mechanisms of saffron in humans are still understudied and unclear. In this study, combining human serum metabolites and cell cultures, we evaluated the effect of circulating metabolites from the consumption of a patented saffron extract (Safr’InsideTM) on the chondrocytes and colon epithelial cell responses to inflammatory stress. Parametric or non-parametric Analysis of Variance with post hoc tests was performed. We demonstrated that human serum containing metabolites from saffron intake attenuated IL-1β-stimulated production of PGE2 and MMP-13 in chondrocyte cells and limited the increase in ICAM-1, MCP-1, iNOS, and MMP-3 in human epithelial cells following combined IL-1β and TNF-α inflammatory stimulation. Altogether, these data provide new findings into the mechanisms underlying the beneficial effects of saffron on chondrocytes and enterocyte cells at the cellular level and in the context of chronic inflammatory disorders.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030335
Authors: Yijiang Jia Renbo Jia Ayijiang Taledaohan Yanming Wang Yuji Wang
Protein arginine deiminase 4 (PAD4) plays an important role in cancer progression by participating in gene regulation, protein modification, and neutrophil extracellular trap (NET) formation. Many reversible and irreversible PAD4 inhibitors have been reported recently. In this review, we summarize the structure–activity relationships of newly investigated PAD4 inhibitors to bring researchers up to speed by guiding and describing new scaffolds as optimization and development leads for new effective, safe, and selective cancer treatments. In addition, some recent reports have shown evidence that PAD4 inhibitors are expected to trigger antitumor immune responses, regulate immune cells and related immune factors, enhance the effects of immune checkpoint inhibitors, and enhance their antitumor efficacy. Therefore, PAD4 inhibitors may potentially change tumor immunotherapy and provide an excellent direction for the development and clinical application of immunotherapy strategies for related diseases.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030334
Authors: Sukyong Yoon Byung Hak Jin Choon Ok Kim Kyungsoo Park Min Soo Park Dongwoo Chae
Bepotastine, a second-generation antihistamine for allergic rhinitis and urticaria, is widely used in all age groups but lacks appropriate dosing guidelines for pediatric patients, leading to off-label prescriptions. We conducted this study to propose an optimal dosing regimen for pediatric patients based on population pharmacokinetic (popPK) and physiologically based pharmacokinetic (PBPK) models using data from two previous trials. A popPK model was built using NONMEM software. A one-compartment model with first-order absorption and absorption lag time described our data well, with body weight incorporated as the only covariate. A PBPK model was developed using PK-Sim software version 10, and the model well predicted the drug concentrations obtained from pediatric patients. Furthermore, the final PBPK model showed good concordance with the known properties of bepotastine. Appropriate pediatric doses for different weight and age groups were proposed based on the simulations. Discrepancies in recommended doses from the two models were likely due to the incorporation of age-dependent physiological factors in the PBPK model. In conclusion, our study is the first to suggest an optimal oral dosing regimen of bepotastine in pediatric patients using both approaches. This is expected to foster safer and more productive use of the drug.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030333
Authors: Dan Xu Chunmei Lan Juan Kou Shuxia Yao Weihua Zhao Keith M. Kendrick
The role of the hypothalamic neuropeptide oxytocin in influencing the brain and behavior has been the subject of widespread research over the last few decades due, most notably, to its reported involvement in promoting social cognition and motivation, reducing anxiety, and relieving pain. It is also increasingly being considered as an important therapeutic intervention in a variety of disorders with social dysfunction as a symptom. While, in recent years, studies in humans have administered oxytocin primarily via an intranasal route, since it may partly enter the brain directly this way via the olfactory and trigeminal nerves, there is increasing evidence that many of its functional effects can be peripherally mediated via increasing its concentration in the blood. This has opened up an oromucosal administration route as an alternative, which is beneficial since the oral consumption of peptides is problematic due to their rapid breakdown in the acidic environment of the gastrointestinal system. In this review we will discuss both the methodologies we have developed for administering oxytocin via lingual application and medicated lollipops, ‘oxipops’, in terms of increasing blood concentrations and the bioavailability of the peptide, and also their validation in terms of functional effects on the brain and behavior. While areas under the curve are significantly greater in terms of plasma oxytocin concentrations following intranasally relative to oromucosally administered oxytocin, with the estimated absolute bioavailability of the latter being around 4.4% compared with 11.1% for intranasal administration, the time to peak concentrations (around 30 min) and functional effects on the brain and behavior are broadly similar. We will also discuss potential therapeutic advantages of the oromucosal administration of oxytocin in different clinical contexts and its wider application for other peptides which are increasingly being developed for therapeutic use.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030332
Authors: Lara Marques Bárbara Costa Mariana Pereira Abigail Silva Joana Santos Leonor Saldanha Isabel Silva Paulo Magalhães Stephan Schmidt Nuno Vale
The landscape of medical treatments is undergoing a transformative shift. Precision medicine has ushered in a revolutionary era in healthcare by individualizing diagnostics and treatments according to each patient’s uniquely evolving health status. This groundbreaking method of tailoring disease prevention and treatment considers individual variations in genes, environments, and lifestyles. The goal of precision medicine is to target the “five rights”: the right patient, the right drug, the right time, the right dose, and the right route. In this pursuit, in silico techniques have emerged as an anchor, driving precision medicine forward and making this a realistic and promising avenue for personalized therapies. With the advancements in high-throughput DNA sequencing technologies, genomic data, including genetic variants and their interactions with each other and the environment, can be incorporated into clinical decision-making. Pharmacometrics, gathering pharmacokinetic (PK) and pharmacodynamic (PD) data, and mathematical models further contribute to drug optimization, drug behavior prediction, and drug–drug interaction identification. Digital health, wearables, and computational tools offer continuous monitoring and real-time data collection, enabling treatment adjustments. Furthermore, the incorporation of extensive datasets in computational tools, such as electronic health records (EHRs) and omics data, is also another pathway to acquire meaningful information in this field. Although they are fairly new, machine learning (ML) algorithms and artificial intelligence (AI) techniques are also resources researchers use to analyze big data and develop predictive models. This review explores the interplay of these multiple in silico approaches in advancing precision medicine and fostering individual healthcare. Despite intrinsic challenges, such as ethical considerations, data protection, and the need for more comprehensive research, this marks a new era of patient-centered healthcare. Innovative in silico techniques hold the potential to reshape the future of medicine for generations to come.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030331
Authors: Claudio Frezza Dalia Rosa Fraioli Francesca Conti Roberta Maria Nicolosi Luigi Scipione Ilaria Serafini Rita Petrucci Paola Di Matteo Daniele Rocco Silvia Di Giacomo Antonella Di Sotto Graziana Bonincontro Giovanna Simonetti Stefania Garzoli Daniela De Vita Sebastiano Foddai
In this work, phytochemical analysis on different extracts of Roccella tinctoria DC. was reported using different techniques with respect to the past. Twenty volatile and three non-volatile compounds were identified, some of which were found in this species for the first time. The methanolic extracts and their non-volatile components were then evaluated for their antitumor effects in cancerous A549 and Mz-ChA-1 cells and for their tolerability in non-cancerous BEAS-2B and H69 cells, showing IC50 values from 94.6 µg/mL to 416.4 µg/mL, in general. The same extracts and compounds were also tested for their antifungal effects in Candida albicans, with only compound 2 being active, with an MIC50 value of 87 µg/mL. In addition, they were tested for their anti-Candida adhesion activity, anti-Candida biofilm formation, and anti-Candida mature biofilm inhibition, with efficacy percentages generally above 50% but not for all of them. Lastly, the DF3 extract and compounds 1–2 were tested in vivo according to the Galleria mellonella survival assay, showing positive mortality rates above 50% at different concentrations. All these biological assays were conducted on this species for the first time. Comparisons with other lichens and compounds were also presented and discussed.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030330
Authors: Jianwei Jiang Lijun Luo Ziqian Zhang Xiao Liu Naihong Chen Yan Li Li Sheng
Background: Glucuronidation is an essential metabolic pathway for a variety of drugs. IMM-H004 is a novel neuroprotective agent against ischemic stroke, and its glucuronide metabolite IMM-H004G exhibits similar pharmacological activity. Despite possessing a higher molecular weight and polarity, brain exposure of IMM-H004G is much higher than that of IMM-H004. This study aimed to investigate the brain metabolism and transport mechanisms of IMM-H004 and IMM-H004G. Methods: First, the possibility of IMM-H004 glucuronidation in the brain was evaluated in several human brain cell lines and rat homogenate. Subsequently, the blood–brain barrier carrier-mediated transport mechanism of IMM-H004 and IMM-H004G was studied using overexpression cell models. In addition, intracerebroventricular injection, in situ brain perfusion model, and microdialysis/microinjection techniques were performed to study the distribution profiles of IMM-H004 and IMM-H004G. Results: IMM-H004 could be metabolized to IMM-H004G in both rat brain and HEB cells mediated by UGT1A7. However, IMM-H004G could not be hydrolyzed back into IMM-H004. Furthermore, the entry and efflux of IMM-H004 in the brain were mediated by the pyrilamine-sensitive H+/OC antiporter and P-gp, respectively, while the transport of IMM-H004G from the blood to the brain was facilitated by OATP1A2 and OATP2B1. Ultimately, stronger concentration gradients and OATP-mediated uptake played a critical role in promoting greater brain exposure of IMM-H004G. Conclusions: The active glucuronide metabolite of the brain protectant IMM-H004 with poor blood–brain barrier permeability demonstrates a high partition in the rat brain via multiple mechanisms, and our findings deepen the understanding of the mechanisms underlying the blood–brain barrier metabolism and transport of active glucuronide conjugates.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030329
Authors: Edoardo Agosti Marco Zeppieri Sara Antonietti Luigi Battaglia Tamara Ius Caterina Gagliano Marco Maria Fontanella Pier Paolo Panciani
Background: The blood–brain barrier (BBB) regulates brain substance entry, posing challenges for treating brain diseases. Traditional methods face limitations, leading to the exploration of non-invasive intranasal drug delivery. This approach exploits the direct nose-to-brain connection, overcoming BBB restrictions. Intranasal delivery enhances drug bioavailability, reduces dosage, and minimizes systemic side effects. Notably, lipid nanoparticles, such as solid lipid nanoparticles and nanostructured lipid carriers, offer advantages like improved stability and controlled release. Their nanoscale size facilitates efficient drug loading, enhancing solubility and bioavailability. Tailored lipid compositions enable optimal drug release, which is crucial for chronic brain diseases. This review assesses lipid nanoparticles in treating neuro-oncological and neurodegenerative conditions, providing insights for effective nose-to-brain drug delivery. Methods: A systematic search was conducted across major medical databases (PubMed, Ovid MEDLINE, and Scopus) up to 6 January 2024. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to “lipid nanoparticles”, “intranasal administration”, “neuro-oncological diseases”, and “neurodegenerative disorders”. This review consists of studies in vitro, in vivo, or ex vivo on the intranasal administration of lipid-based nanocarriers for the treatment of brain diseases. Results: Out of the initial 891 papers identified, 26 articles met the eligibility criteria after a rigorous analysis. The exclusion of 360 articles was due to reasons such as irrelevance, non-reporting selected outcomes, the article being a systematic literature review or meta-analysis, and lack of method/results details. This systematic literature review, focusing on nose-to-brain drug delivery via lipid-based nanocarriers for neuro-oncological, neurodegenerative, and other brain diseases, encompassed 60 studies. A temporal distribution analysis indicated a peak in research interest between 2018 and 2020 (28.3%), with a steady increase over time. Regarding drug categories, Alzheimer’s disease was prominent (26.7%), followed by antiblastic drugs (25.0%). Among the 65 drugs investigated, Rivastigmine, Doxorubicin, and Carmustine were the most studied (5.0%), showcasing a diverse approach to neurological disorders. Notably, solid lipid nanoparticles (SLNs) were predominant (65.0%), followed by nanostructured lipid carriers (NLCs) (28.3%), highlighting their efficacy in intranasal drug delivery. Various lipids were employed, with glyceryl monostearate being prominent (20.0%), indicating preferences in formulation. Performance assessment assays were balanced, with in vivo studies taking precedence (43.3%), emphasizing the translation of findings to complex biological systems for potential clinical applications. Conclusions: This systematic review reveals the transformative potential of intranasal lipid nanoparticles in treating brain diseases, overcoming the BBB. Positive outcomes highlight the effectiveness of SLNs and NLCs, which are promising new approaches for ailments from AD to stroke and gliomas. While celebrating progress, addressing challenges like nanoparticle toxicity is also crucial.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030328
Authors: André Bitterlich Andrej Mihorko Michael Juhnke
Wet media milling is a fully industrialized technology for the manufacturing of drug nanocrystal suspensions. This work describes the development of an advanced control strategy and an associated design space for a manufacturing process at a commercial scale. Full-scale experiments and mechanistic process modeling have been used to establish a physically reasonable control strategy of factors relevant to the quality attributes of the nanocrystal suspension. The design space has been developed based on a mature mechanistic process model of the wet media milling procedure. It presents the process–product attribute relationship between a multidimensional range of measured process parameters and a range of the product-quality attribute mean particle sizes. The control strategy allows for simple, robust, and sound scientific process control as well as the operational flexibility of the suspension batch size. This is an industrial case study of control strategy and design-space definition with the crucial contribution of mechanistic process modeling for an intended commercial manufacturing process.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030327
Authors: Sibusiso Alven Blessing Atim Aderibigbe
Bacterial infections are major problems in wound care due to their impact on the retarded process of wound healing, leading to chronic wounds. Most of the presently utilized wound dressing products exhibit poor antimicrobial properties. Wound dressings formulated from chitosan have been reported to be effective for treating infected wounds, resulting from the antibacterial properties of chitosan. The antibacterial properties of chitosan-based wound dressings can be further enhanced by incorporating metallic nanoparticles into them, such as silver, zinc, titanium, etc. The incorporation of silver nanoparticles into chitosan-based wound dressings has been widely explored in the design of antimicrobial wound dressings. The incorporation of silver nanoparticles into chitosan-based wound dressings promotes accelerated wound-healing processes due to enhanced antimicrobial activity. The accelerated wound healing by these metal-based nanoparticles is via the regulation of re-epithelialization and inflammation without affecting the viability of normal cells. However, there have been few reports that evaluate these wound dressings in infectious animal models to prove their efficacy. The in vivo toxicity of silver nanoparticles still needs to be addressed, revealing the need for further preclinical and clinical trials. The fabrication of wound dressings incorporated with silver nanoparticles has not been fully explored, especially for wounds requiring immediate treatment. The possible interactions between silver nanoparticles and chitosan scaffolds that result in synergistic effects still need to be understood and studied. This review provides a comprehensive report on the preclinical outcomes of chitosan wound dressing materials loaded with silver nanoparticles for managing infected wounds.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030326
Authors: Xue Wang Wei Cheng Jiandong Su
Microneedles (MNs), renowned for their painless and minimally invasive qualities, exhibit significant potential for facilitating effective drug delivery, vaccination, and targeted sample extraction. Extracellular vesicles (EVs), serving as cargo for MNs, are naturally occurring nanovesicles secreted by cells and characterized by novel biomarkers, low immunogenicity, and cell-source-specific traits. MNs prove instrumental in extracting EVs from the sample fluid, thereby facilitating a promising diagnostic and prognostic tool. To harness the therapeutic potential of EVs in tissue repair, MNs with sustained delivery of EVs leverage micron-sized channels to enhance targeted site concentration, demonstrating efficacy in treating various diseases, such as Achillea tendinopathy, hair loss, spinal cord injury, and diabetic ulcers. EV-loaded MNs emerge as a promising platform for repair applications of skin, cardiac, tendon, hair, and spinal cord tissues. This review commences with an overview of MNs, subsequently delving into the role of EVs as cargo for MNs. The paper then synthesizes the latest advancements in the use of EV-loaded MNs for tissue regenerative repair, extending to research progress in extracting EVs from MNs for disease diagnosis and prognostic evaluations. It aims to offer valuable insights and forecast future research trajectories with the hope of inspiring innovative ideas among researchers in this field.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030324
Authors: Prateek Uttreja Ahmed Adel Ali Youssef Indrajeet Karnik Kavish Sanil Nagarjuna Narala Honghe Wang Rasha M. Elkanayati Sateesh Kumar Vemula Michael A. Repka
Quetiapine fumarate (QTF) was approved for the treatment of schizophrenia and acute manic episodes. QTF can also be used as an adjunctive treatment for major depressive disorders. QTF oral bioavailability is limited due to its poor aqueous solubility and pre-systemic metabolism. The objective of the current investigation was the formulation development and manufacturing of solid self-nanoemulsifying drug delivery system (S-SNEDDS) formulation through a single-step continuous hot-melt extrusion (HME) process to address these drawbacks. In this study, Capmul® MCM, Gelucire® 48/16, and propylene glycol were selected as oil, surfactant, and co-surfactant, respectively, for the preparation of S-SNEDDS. Soluplus® and Klucel™ EF (1:1) were selected as the solid carrier. Response surface methodology in the form of central composite design (CCD) was utilized in the current experimental design to develop the S-SNEDDS formulations via a continuous HME technology. The developed formulations were evaluated for self-emulsifying properties, particle size distribution, thermal behavior, crystallinity, morphology, physicochemical incompatibility, accelerated stability, and in vitro drug release studies. The globule size and emulsification time of the optimized SNEDDS formulation was 92.27 ± 3.4 nm and 3.4 ± 3.38 min. The differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies revealed the amorphous nature of the drug within the formulation. There were no drug-excipient incompatibilities observed following the Fourier transform infrared (FTIR) spectroscopy. The optimized formulation showed an extended-release profile for 24 h. The optimized formulation was stable for three months (last time-point tested) at 40 °C/75% RH. Therefore, the developed S-SNEDDS formulation could be an effective oral delivery platform for QTF and could lead to better therapeutic outcomes.
]]>Pharmaceutics doi: 10.3390/pharmaceutics16030325
Authors: Maiara Callegaro Velho Nadine Lysyk Funk Monique Deon Edilson Valmir Benvenutti Silvio Buchner Ruth Hinrichs Diogo André Pilger Ruy Carlos Ruver Beck
Ivermectin (IVM), a widely used drug for parasitic infections, faces formulation and application challenges due to its poor water solubility and limited bioavailability. Pondering the impact of IVM’s high partition coefficient value (log P) on its drug release performance, it is relevant to explore whether IVM nanoencapsulation in organic or inorganic nanoparticles would afford comparable enhanced aqueous solubility. To date, the use of inorganic nanoparticles remains an unexplored approach for delivering IVM. Therefore, here we loaded IVM in mesoporous silica particles (IVM-MCM), as inorganic nanomaterial, and in well-known poly(ε-caprolactone) nanocapsules (IVM-NC). IVM-MCM had a well-organized hexagonal mesoporous structure, reduced surface area, and high drug loading of 10% w/w. IVM-NC had a nanometric mean size (196 nm), high encapsulation efficiency (100%), physicochemical stability as an aqueous dispersion, and drug loading of 0.1% w/w. Despite differing characteristics, both nanoencapsulated forms enhance IVM’s aqueous intrinsic solubility compared to a crystalline IVM: after 72 h, IVM-MCM and IVM-NC achieve 72% and 78% releases through a dialysis bag, whereas crystalline IVM dispersion achieves only 40% drug diffusion. These results show distinct controlled release profiles, where IVM-NC provides a deeper sustained controlled release over the whole experiment compared to the inorganic nanomaterial (IVM-MCM). Discussing differences, including drug loading and release kinetics, is crucial for optimizing IVM’s therapeutic performance. The study design, combined with administration route plans and safety considerations for humans and animals, may expedite the rational optimization of IVM nanoformulations for swift clinical translation.
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