Pharmaceutics

19 pages, 7317 KiB

Open AccessArticle

Development and Characterization of Spray-Dried Combined Levofloxacin–Ambroxol Dry Powder Inhaler Formulation

by Ruwani K. Suraweera, Kirsten M. Spann, Emad L. Izake, Timothy J. Wells, Xiaodong Wang and Nazrul Islam

Pharmaceutics 2024, 16(12), 1506; https://doi.org/10.3390/pharmaceutics16121506 - 22 Nov 2024

Abstract

Background: This study explores the development and characterization of spray-dried composite microparticles consisting of levofloxacin (LVX, a broad-spectrum antibiotic), and ambroxol (AMB, a mucolytic agent that has antibacterial and antibiofilm properties), for the intended application of the drug against lower respiratory tract infections [...] Read more.

Background: This study explores the development and characterization of spray-dried composite microparticles consisting of levofloxacin (LVX, a broad-spectrum antibiotic), and ambroxol (AMB, a mucolytic agent that has antibacterial and antibiofilm properties), for the intended application of the drug against lower respiratory tract infections (LRTIs). Methods: A range of LVX to AMB mass ratios (1:1, 1:0.5, and 1:0.25) were prepared, with and without the use of the dispersibility enhancer leucine (LEU), and spray-dried following pre-optimized parameters to achieve the required particle size (1–5 µm) and flow properties. The formulations were characterized by attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy, scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), and a thermogravimetric analysis (TGA). The in vitro aerosolization performance of the new formulation was evaluated with a twin-stage impinger (TSI) at a flow rate of 60 ± 5 L/min. Using a validated RP-HPLC method, LVX and AMB were quantitatively determined. Results: The combined spray-dried LVX, AMB, and LEU particles were spherically shaped with sizes ranging from 1.9 to 2.9 µm, thus complying with the size requirements for effective deep lung deposition. The dispersibility enhancer leucine produced a high yield and enhanced the flow properties and aerosolization characteristics of the spray-dried formulations. The LVX to AMB mass ratios showed a remarkable impact on the aerosolization properties, with the LVX to AMB 1:1 mass ratio demonstrating the best flow and FPFs for both drugs. There must be a balanced ratio of these components for spray drying the composite particles to obtain composite particles of the required size and with the appropriate flow property. The addition of 5% of LEU significantly (p < 0.005) improved the FPF of all the formulations, probably by enhancing the surface hydrophobicity of the composite particles. Conclusions: The spray-dried combined antibiotics formulation has a strong potential for efficient lung delivery intended for the management of LRTIs. Full article

(This article belongs to the Special Issue Development of Spray-Dried Powders for Pulmonary Drug Delivery)

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20 pages, 10346 KiB

Open AccessArticle

Preparation and In Vitro/In Vivo Characterization of Mixed-Micelles-Loaded Dissolving Microneedles for Sustained Release of Indomethacin

by Baojie Wang, Langkun Liao, Huihui Liang, Jiaxin Chen and Yuqin Qiu

Pharmaceutics 2024, 16(12), 1505; https://doi.org/10.3390/pharmaceutics16121505 - 22 Nov 2024

Abstract

Background/Objectives: Indomethacin (IDM) is commonly used to treat chronic inflammatory diseases such as rheumatoid arthritis and osteoarthritis. However, long-term oral IDM treatment can harm the gastrointestinal tract. This study presents a design for encapsulating IDM within mixed micelles (MMs)-loaded dissolving microneedles (DMNs) to [...] Read more.

Background/Objectives: Indomethacin (IDM) is commonly used to treat chronic inflammatory diseases such as rheumatoid arthritis and osteoarthritis. However, long-term oral IDM treatment can harm the gastrointestinal tract. This study presents a design for encapsulating IDM within mixed micelles (MMs)-loaded dissolving microneedles (DMNs) to improve and sustain transdermal drug delivery. Methods: Indomethacin-loaded mixed micelles (IDM-MMs) were prepared from Soluplus^® and Poloxamer F127 by means of a thin-film hydration method. The MMs-loaded DMNs were fabricated using a two-step molding method and evaluated for storage stability, insertion ability, in vitro release, in vitro transdermal penetration, and in vivo PK/PD studies. Results: The obtained MMs were stable at 4 °C and 30 °C for 60 days. The in vitro IDM transdermal penetration was remarkably improved by the MMs-loaded DMNs compared to a commercial patch. A pharmacokinetic study demonstrated that the MMs-loaded DMNs had a relative bioavailability of 4.1 in comparison with the commercial patch. Furthermore, the MMs-loaded DMNs showed a significantly shorter lag time than the commercial patch, as well as a more stable plasma concentration than the DMNs without MMs. The therapeutic efficacy of the IDM DMNs was examined in Complete Freund’s Adjuvant-induced arthritis mice. The IDM DMN treatment effectively reduced arthritis severity, resulting in decreased paw swelling, arthritis index, spleen hyperplasia, and serum IL-1β and TNF-α levels. Conclusions: Our findings demonstrated that the novel MMs-loaded DMNs were an effective strategy for sustained IDM release, providing an alternate route of anti-inflammatory drug delivery. Full article

(This article belongs to the Special Issue Microarray Patches for Transdermal Drug Delivery)

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Graphical abstract

15 pages, 1954 KiB

Open AccessReview

Hydroxytyrosol: A Promising Therapeutic Agent for Mitigating Inflammation and Apoptosis

by Wafa Ali Batarfi, Mohd Heikal Mohd Yunus, Adila A. Hamid, Yi Ting Lee and Manira Maarof

Pharmaceutics 2024, 16(12), 1504; https://doi.org/10.3390/pharmaceutics16121504 - 22 Nov 2024

Abstract

Inflammation and apoptosis are interrelated biological processes that have a significant impact on the advancement and growth of certain chronic diseases, such as cardiovascular problems, neurological conditions, and osteoarthritis. Recent research has emphasized that focusing on these mechanisms could result in novel therapeutic [...] Read more.

Inflammation and apoptosis are interrelated biological processes that have a significant impact on the advancement and growth of certain chronic diseases, such as cardiovascular problems, neurological conditions, and osteoarthritis. Recent research has emphasized that focusing on these mechanisms could result in novel therapeutic approaches that aim to decrease the severity of diseases and enhance patient outcomes. Hydroxytyrosol (HT), which is well-known for its ability to prevent oxidation, has been identified as a possible candidate for regulating both inflammation and apoptosis. In this review, we will highlight the multifaceted benefits of HT as a therapeutic agent in mitigating inflammation, apoptosis, and associated conditions. This review provides a comprehensive overview of the latest in vitro and in vivo research on the anti-inflammatory and antiapoptotic effects of HT and the mechanisms by which it works. Based on these studies, it is strongly advised to use HT as a bioactive ingredient in pharmaceutical products intended for mitigating inflammation, as well as those with apoptosis applications. Full article

(This article belongs to the Special Issue Natural Pharmaceuticals Focused on Anti-inflammatory Activities)

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12 pages, 1615 KiB

Open AccessArticle

Strategies to Stabilize Dalbavancin in Aqueous Solutions; Section-2: The Effects of 2 Hydroxypropyl-β-Cyclodextrin and Acetate Buffer with and Without Divalent Metal Ions

by Sardar M. Jakaria, David E. Budil, James Murtagh and Graham Revilla

Pharmaceutics 2024, 16(12), 1503; https://doi.org/10.3390/pharmaceutics16121503 - 22 Nov 2024

Abstract

Objectives: The effect of 2-hydroxpropyl-β-cyclodextrin (2HPβCD) with or without divalent metal ions (Ca²⁺, Mg²⁺, and Zn²⁺) on the stability of dalbavancin in acetate buffer was investigated. Methods: Dalbavancin recovery from formulations with 2HPβCD and divalent metal ions [...] Read more.

Objectives: The effect of 2-hydroxpropyl-β-cyclodextrin (2HPβCD) with or without divalent metal ions (Ca²⁺, Mg²⁺, and Zn²⁺) on the stability of dalbavancin in acetate buffer was investigated. Methods: Dalbavancin recovery from formulations with 2HPβCD and divalent metal ions after four weeks of storage at 5 °C and 55 °C was measured by RP-HPLC and HP-SEC; a longer-term study was carried out over six months at 5 °C, 25 °C, and 40 °C. Binding of 2HPβCD was characterized by isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR). Results: The stability of the dalbavancin formulations after 4 weeks at 55 °C in 10 mM acetate buffer was significantly improved with 0.6 mM, 5.5 mM, and 55 mM 2HPβCD relative to without 2HPβCD. No further improvement was observed with the addition of any of the divalent cations. Dalbavancin in a 1:10 molar ratio with 2HPβCD was more stable at a concentration of 1 mg/mL than at 20 mg/mL under accelerated conditions at 40 °C for six months. ITC revealed two 2HPβCD binding sites to dalbavancin in 10 mM acetate: one with a 1:1 stoichiometry and thermodynamics consistent with known cyclodextrin–drug interactions, and a second with 0.1:1 stoichiometry, a positive binding enthalpy, and an unusually large entropy of binding. NMR spectroscopy indicates that dalbavancin exhibits aggregation in acetate buffer that is disrupted by 2HPβCD binding. Conclusions: 2HPβCD significantly improves the short- and long-term heat stability of dalbavancin in pH 4.5 acetate buffer at and above molar ratios of 1:1. The strong 1:1 binding of 2HPβCD to dalbavancin demonstrated by ITC confirms that this stability is conferred by the formation of a stable complex. This observation, combined with the NMR results, points to the aliphatic hydrocarbon chain of the glycone moiety as the most likely site of 2HPβCD–dalbavancin interaction. Full article

(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)

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13 pages, 1476 KiB

Open AccessArticle

Investigating Strategies to Enhance the Aqueous Solubility of Ketamine HCl for Intranasal Delivery

by Sourour Idoudi, Alaaeldin Saleh, Mohammed Akkbik, Leena Amine, Khalid Alansari, Ousama Rachid and Alaaldin M. Alkilany

Pharmaceutics 2024, 16(12), 1502; https://doi.org/10.3390/pharmaceutics16121502 - 22 Nov 2024

Viewed by 118

Abstract

Background: Ketamine HCl, an FDA-approved therapeutic, is administered through various routes, including intranasal delivery. Administering an adequate therapeutic dose of intranasal ketamine HCl is challenging due to the limited volume that can be delivered intranasally given the current commercially available concentrations. Objectives: This [...] Read more.

Background: Ketamine HCl, an FDA-approved therapeutic, is administered through various routes, including intranasal delivery. Administering an adequate therapeutic dose of intranasal ketamine HCl is challenging due to the limited volume that can be delivered intranasally given the current commercially available concentrations. Objectives: This study investigates solubilizing strategies to enhance the aqueous solubility of ketamine HCl for intranasal administration. Methods: We assessed the solubility profile of ketamine HCl by evaluating factors such as pH, co-solvents, and surfactants. Additionally, we developed and validated a UV-Vis spectroscopy method for ketamine HCl analysis. Results: Our solubility screening in various organic co-solvents revealed the following order of effectiveness in enhancing solubility: methanol > water > propylene glycol > ethanol > dimethyl sulfoxide (DMSO) > N-methyl-2-pyrrolidone (NMP). Despite methanol’s superior solubility, its potential toxicity, coupled with the relatively lower effectiveness of other solvents compared to water, suggests that a co-solvency approach is not advantageous for ketamine HCl. We found that ketamine HCl solubility increased with medium acidity, with pH 3.5 being the optimal for further formulation studies. The impact of pharmaceutical surfactants on ketamine HCl solubility at an acidic pH was also evaluated. Surfactants tested included SDS, PEG 400, PVP, Tween 20, poloxamer 188, and lecithin. Notably, PEG 400 and PVP reduced solubility due to a salting-out effect, whereas Tween 80, lecithin, and poloxamer 188 slightly improved solubility through micelle formation. Among the surfactants tested, 1% SDS emerged as the most effective in enhancing ketamine HCl solubility. Conclusions: These outcomes highlight the potential of these solubilization strategies to address the solubility limitations of ketamine HCl, enabling the preparation of highly concentrated ketamine HCl formulations for intranasal delivery. Full article

(This article belongs to the Section Physical Pharmacy and Formulation)

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22 pages, 11317 KiB

Open AccessArticle

Exploring 3D Printing in Drug Development: Assessing the Potential of Advanced Melt Drop Deposition Technology for Solubility Enhancement by Creation of Amorphous Solid Dispersions

by Nabil Lamrabet, Florian Hess, Philip Leidig, Andreas Marx and Thomas Kipping

Pharmaceutics 2024, 16(12), 1501; https://doi.org/10.3390/pharmaceutics16121501 - 22 Nov 2024

Viewed by 137

Abstract

Background: Melt-based 3D printing technologies are currently extensively evaluated for research purposes as well as for industrial applications. Classical approaches often require intermediates, which can pose a risk to stability and add additional complexity to the process. The Advanced Melt Drop Deposition (AMDD) [...] Read more.

Background: Melt-based 3D printing technologies are currently extensively evaluated for research purposes as well as for industrial applications. Classical approaches often require intermediates, which can pose a risk to stability and add additional complexity to the process. The Advanced Melt Drop Deposition (AMDD) technology, is a 3D printing process that combines the principles of melt extrusion with pressure-driven ejection, similar to injection molding. This method offers several advantages over traditional melt-based 3D printing techniques, making it particularly suitable for pharmaceutical applications. Objectives: This study evaluates the AMDD printing system for producing solid oral dosage forms, with a primary focus on the thermo-stable polymer polyvinyl alcohol (PVA). The suitability of AMDD technology for creating amorphous solid dispersions (ASDs) is also examined. Finally, the study aims to define the material requirements and limitations of the raw materials used in the process. Methods: The active pharmaceutical ingredients (APIs) indometacin and ketoconazole were used, with PVA 4-88 serving as the carrier polymer. Powders, wet granulates, and pellets were investigated as raw materials and characterized. Dissolution testing and content analyses were performed on the printed dosage forms. Solid-state characterization was conducted using differential scanning calorimetry (DSC) and X-ray diffraction (XRD). Degradation due to thermal and mechanical stress was analyzed using nuclear magnetic resonance spectroscopy (NMR). Results/Conclusions: The results demonstrate that the AMDD 3D printing process is well-suited for producing solid dosage forms. Tablets were successfully printed, meeting mass uniformity standards. Adjusting the infill volume from 30% to 100% effectively controlled the drug release rate of the tablets. Solid-state analysis revealed that the AMDD process can produce amorphous solid dispersions with enhanced solubility compared to their crystalline form. The experiments also demonstrated that powders with a particle size of approximately 200 µm can be directly processed using AMDD technology. Full article

(This article belongs to the Special Issue Impact of Raw Material Properties on Solid Dosage Form Processes)

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23 pages, 7292 KiB

Open AccessArticle

Sustainable Carbon Dots Loaded into Carboxymethylcellulose Based Hydrogels for Uterine Cancer Bioimaging

by Jordane S. Rodrigues, Pedro Brandão, Sofia O. D. Duarte, Izabela Boueri da Silveira, Maria de Fátima Leite, Max P. Gonçalves, Fernanda G. L. Medeiros Borsagli and Pedro Fonte

Pharmaceutics 2024, 16(12), 1500; https://doi.org/10.3390/pharmaceutics16121500 - 22 Nov 2024

Viewed by 119

Abstract

Background/Objectives: The development of innovative materials for disease diagnostics and therapeutics is a fast-growing area of scientific research. In this work, we report the development of innovative hydrogels incorporating carbon dots (Cdots) for bioimaging purposes. Methods: The Cdots were prepared using [...] Read more.

Background/Objectives: The development of innovative materials for disease diagnostics and therapeutics is a fast-growing area of scientific research. In this work, we report the development of innovative hydrogels incorporating carbon dots (Cdots) for bioimaging purposes. Methods: The Cdots were prepared using a sustainable and low-cost process, starting with an underused fiber from the Brazilian semiarid region. Spectroscopy analysis (Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, UV-visible spectroscopy), X-ray diffraction, photoluminescence, zeta potential, scanning electron microscopy, and transmission electron microscopy were used to characterize these hydrogels. In addition, biocompatibility using the resazurin assay and cellular uptake by confocal microscopy were evaluated. Results: Our results showed that the Cdots changed the structure and crystallinity of hydrogels, mainly due to heat treatment. In addition, hydrogels’ chemical groups suffer red and blue shifts following the Cdots incorporation. Moreover, the Cdots were homogeneously incorporated into the hydrogel matrix. Importantly, the cytotoxicity levels were maintained above 90% (p < 0.01), and cellular uptake studies using HeLa cells demonstrated intracellular fluorescence of both the Cdots and hydrogels after incubation. Additionally, the concentration of Cdots within hydrogels significantly affected fluorescence intensity, even compared with pure Cdots. Conclusions: These results showcase the potential for these hydrogels to be further developed as biomarkers and therapeutic biomaterials for women’s health. Full article

(This article belongs to the Special Issue Novel Micro/Nanomaterials Based Drug Delivery Systems for Theranostic Applications)

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14 pages, 2139 KiB

Open AccessArticle

Exploring Orodispersible Films Containing the Proteolysis Targeting Chimera ARV-110 in Hot Melt Extrusion and Solvent Casting Using Polyvinyl Alcohol

by Valentina Meloni, Laura Halstenberg, Lena Mareczek, Jankin Lu, Bonnie Liang, Nadine Gottschalk and Lena K. Mueller

Pharmaceutics 2024, 16(12), 1499; https://doi.org/10.3390/pharmaceutics16121499 - 22 Nov 2024

Viewed by 139

Abstract

Background/Objectives: This project aims to provide valuable insights into the formulation of orodispersible films (ODFs) for the delivery of PROTAC ARV-110. The primary objective of this drug delivery formulation is to enhance the solubility of PROTAC ARV-110, which faces significant challenges due to [...] Read more.

Background/Objectives: This project aims to provide valuable insights into the formulation of orodispersible films (ODFs) for the delivery of PROTAC ARV-110. The primary objective of this drug delivery formulation is to enhance the solubility of PROTAC ARV-110, which faces significant challenges due to the low solubility of this active pharmaceutical ingredient, as it belongs to a molecular class that is considered to exceed the “Rule of Five”. Methods: We employed the concept of developing a rapidly disintegrating ODF to enhance the solubility of PROTAC ARV-110, utilizing polyvinyl alcohol as the polymer of choice. Given the high thermal stability of ARV-110, the PROTAC was subjected to two primary ODF manufacturing techniques: Hot melt extrusion (HME) and solvent casting. To establish the HME method, pre-screening through vacuum compression molding was performed. The films were characterized based on their disintegration in artificial saliva, drug release in a physiological environment, and mechanical strength. Results: All formulations demonstrated enhanced solubility of ARV-110, achieving exceptional results in terms of disintegration times and resistance to applied stress. Conclusions: The findings from the experiments outlined herein establish a solid foundation for the successful production of orodispersible films for the delivery of PROTACs. Full article

(This article belongs to the Special Issue Emerging Technologies to Improve the Solubility of Poorly Soluble Drugs)

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17 pages, 7711 KiB

Open AccessArticle

Arginine Hydrochloride Reduce Rectal Mucosal Irritation of Sodium Aescinate: Molecular Docking, Physical Properties, Anti-Hemorrhoidal Activity, Safety and Topical Gel Formulations Investigation

by Di Hu, Qiuyang Zeng, Huanrong Wang and Wei Jiang

Pharmaceutics 2024, 16(12), 1498; https://doi.org/10.3390/pharmaceutics16121498 - 22 Nov 2024

Viewed by 113

Abstract

Background/Objectives: Sodium aescinate (SA) is commonly used topically due to its anti-inflammatory, anti-edematous, and anti-swelling properties. However, the clinical application of SA is limited by strong irritation, and cannot be used on the damaged skin and mucous membrane. This study aimed to [...] Read more.

Background/Objectives: Sodium aescinate (SA) is commonly used topically due to its anti-inflammatory, anti-edematous, and anti-swelling properties. However, the clinical application of SA is limited by strong irritation, and cannot be used on the damaged skin and mucous membrane. This study aimed to investigate whether arginine hydrochloride (Arg·HCl) could reduce the rectal mucosal irritation of SA through the formation of a gel. Methods: Molecular docking was first used to explore potential interactions between SA and Arg·HCl. Gels for rectal administration were then formulated by combining SA with various ratios of Arg·HCl (from 1:0 to 1:10). In vitro tests, including pH, centrifuge stability, viscosity, and spreadability analysis, were conducted. The optimal gel formulation was determined based on rectal mucosal irritation tests and anti-inflammatory experiments. Additionally, the anti-hemorrhoidal characteristics and safety of the optimal gel in terms of acute toxicity and dermal sensitivity were evaluated. Results: The optimal SA to Arg·HCl ratio of 1:6 (F5-SA gel) was identified, significantly reducing rectal mucosal irritation while enhancing anti-inflammatory activity. The F5-SA gel demonstrated high efficacy against hemorrhoids, notably promoting anal ulcer healing. When administered rectally to rabbits at a dose of 132 mg·kg⁻¹·d⁻¹ (198 times the recommended therapeutic dose), no other obvious side effects were observed except a significant reduction in food intake on the day of administration. In addition, the gel did not induce dermal sensitivity. Conclusions: The F5-SA gel is a promising formulation that can reduce irritation and toxic side effects, and enhance the therapeutic effect to some extent, ultimately achieving a safer and more effective rectal delivery system for SA. Full article

(This article belongs to the Section Physical Pharmacy and Formulation)

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13 pages, 278 KiB

Open AccessReview

The Use of Tissue Concentrations of Biological and Small-Molecule Therapies in Clinical Studies of Inflammatory Bowel Diseases

by Ahmed B. Bayoumy, Luc J. J. Derijks, Bas Oldenburg and Nanne K. H. de Boer

Pharmaceutics 2024, 16(12), 1497; https://doi.org/10.3390/pharmaceutics16121497 - 22 Nov 2024

Viewed by 135

Abstract

Abstract: The introduction of biological therapies has revolutionized inflammatory bowel disease (IBD) management. A critical consideration in developing these therapies is ensuring adequate drug concentrations at the site of action. While blood-based biomarkers have shown limited utility in optimizing treatment (except for TNF-alpha [...] Read more.

Abstract: The introduction of biological therapies has revolutionized inflammatory bowel disease (IBD) management. A critical consideration in developing these therapies is ensuring adequate drug concentrations at the site of action. While blood-based biomarkers have shown limited utility in optimizing treatment (except for TNF-alpha inhibitors and thiopurines), tissue drug concentrations may offer valuable insights. In antimicrobial therapies, tissue concentration monitoring is standard practice and could provide a new avenue for understanding the pharmacokinetics of biological and small-molecule therapies in IBD. Various methods exist for measuring tissue concentrations, including whole tissue sampling, MALDI-MSI, microdialysis, and fluorescent labeling. These techniques offer unique advantages, such as spatial drug-distribution mapping, continuous sampling, or cellular-level analysis. However, challenges remain, including sampling invasiveness, heterogeneity in tissue compartments, and a lack of standardized bioanalytical guidelines. Drug pharmacokinetics are influenced by multiple factors, including molecular properties, disease-induced changes in the gastrointestinal tract, and the timing of sample collection. For example, drug permeability, solubility, and interaction with transporters may vary between Crohn’s disease and ulcerative colitis. Research into the tissue concentrations of drugs like anti-TNF agents, ustekinumab, vedolizumab, and tofacitinib has shown variable correlations with clinical outcomes, suggesting potential roles for tissue concentration monitoring in therapeutic drug management. Although routine clinical application is not yet established, exploring tissue drug concentrations may enhance understanding of IBD pharmacotherapy. Full article

(This article belongs to the Special Issue Therapeutic Drugs and Delivery Strategies for Gastrointestinal Diseases)

15 pages, 3230 KiB

Open AccessArticle

Enhanced Ocular Bioavailability and Prolonged Duration via Hydrophilic Surface Nanocomposite Vesicles for Topical Drug Administration

by Sa Huang, Yuan Xu, Yingyao Luo, Zhijiong Wang, Fan Li, Zhenmiao Qin and Junfeng Ban

Pharmaceutics 2024, 16(12), 1496; https://doi.org/10.3390/pharmaceutics16121496 - 21 Nov 2024

Viewed by 190

Abstract

Background: Internal ocular diseases, such as macular edema, uveitis, and diabetic macular edema require precise delivery of therapeutic agents to specific regions within the eye. However, the eye’s complex anatomical structure and physiological barriers present significant challenges to drug penetration and distribution. Traditional [...] Read more.

Background: Internal ocular diseases, such as macular edema, uveitis, and diabetic macular edema require precise delivery of therapeutic agents to specific regions within the eye. However, the eye’s complex anatomical structure and physiological barriers present significant challenges to drug penetration and distribution. Traditional eye drops suffer from low bioavailability primarily due to rapid clearance mechanisms. Methods: The novel ocular drug delivery system developed in this study utilizes poly(lactic-co-glycolic acid) (PLGA) nanoparticles modified with cell-penetrating peptides (CPPs). In vitro drug release studies were conducted to evaluate the sustained-release properties of the nanoparticles. Ex vivo experiments using MDCK cells assessed corneal permeability and uptake efficiency. Additionally, in vivo studies were performed in rabbit eyes to determine the nanoparticles’ resistance to elimination by tears and their retention time in the aqueous humor. Results: In vitro drug release studies demonstrated superior sustained-release properties of the nanoparticles. Ex vivo experiments revealed enhanced corneal permeability and increased uptake efficiency by MDCK cells. In vivo studies in rabbit eyes confirmed the nanoparticles’ resistance to elimination by lacrimal fluid and their ability to extend retention time in the aqueous humor. CPP modification significantly improved ocular retention, corneal penetration, and cellular endocytosis efficiency. Conclusions: The CPP-modified PLGA nanoparticles provide an effective and innovative solution for ocular drug delivery, offering improved bioavailability, prolonged retention, and enhanced drug penetration, thereby overcoming the challenges of traditional intraocular drug administration methods. Full article

(This article belongs to the Special Issue Polymer-Based Delivery System)

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15 pages, 1518 KiB

Open AccessArticle

Two in One: Size Characterization and Accelerated Short-Term Physical Stability of Dual-Drug Suspensions with Two Acidic Compounds (Indomethacin and Naproxen)

by Nadina Zulbeari, Signe Malig Hansen and René Holm

Pharmaceutics 2024, 16(12), 1495; https://doi.org/10.3390/pharmaceutics16121495 - 21 Nov 2024

Viewed by 191

Abstract

Background/Objectives: Co-delivering dual-drug systems have proven to be effective in, for example, anticancer therapy or HIV prophylaxis due to a higher target selectivity and therapeutic efficacy from compound synergism. However, various challenges regarding physical stability can arise during the formulation definition when multiple [...] Read more.

Background/Objectives: Co-delivering dual-drug systems have proven to be effective in, for example, anticancer therapy or HIV prophylaxis due to a higher target selectivity and therapeutic efficacy from compound synergism. However, various challenges regarding physical stability can arise during the formulation definition when multiple drug compounds are included in the same formulation. In this work, the focus was on aqueous suspensions, which could be applied as long-acting injectable formulations to release the drug compounds over weeks to months after administration. Methods: It was possible to gain insights into dual-drug nano- and microsuspensions containing two acidic compounds (indomethacin and naproxen) prepared by milling with dual centrifugation. Information regarding the physical stability of individual suspensions was subtracted and compared to dual-drug suspensions when prepared with the same milling conditions and stored at elevated temperatures of 40 °C. Results: Distinct particle size profiles after milling were obtained dependent on the stabilizer used in both individual and dual-drug suspensions. Most notably, the combination of indomethacin and naproxen in one formulation resulted in smaller sizes of drug particles compared to individual suspensions under the presence of some stabilizers. The obtained particle size profiles further indicated that at least one of the model compounds needed to be sufficiently stabilized from a stabilizer to obtain physically stable dual-drug suspensions over 28 days when stored at 40 °C. Similarly, the particle size distribution was dependent on the individual distribution of the suspensions, which showed a monomodal distribution could be achieved for dual-drug suspensions when at least one of the individual suspensions demonstrated a monomodal distribution in the presence of the stabilizer alone. Over a 28-day period, the smallest particle size was obtained in dual-drug suspensions stabilized with a combination of polysorbate 85 and poloxamer 338 compared to dual-drug suspensions stabilized with only a single stabilizer during preparation, indicating tendencies towards stabilization synergism from a combination of stabilizers as well as the model compounds. Conclusion: Overall, the study showed insights into the preparation and physical stability of dual-drug suspensions containing indomethacin and naproxen. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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19 pages, 2737 KiB

Open AccessArticle

Formulation and Characterization of β-Cyclodextrins–Nitazoxanide Inclusion Complexes: Enhanced Solubility, In Vitro Drug Release, and Antiviral Activity in Vero Cells

by Kuppu Sakthi Velu, Sonamuthu Jegatheeswaran, Muhammad Saeed Akhtar, Mohammad Rizwan Khan, Sonaimuthu Mohandoss and Naushad Ahmad

Pharmaceutics 2024, 16(12), 1494; https://doi.org/10.3390/pharmaceutics16121494 - 21 Nov 2024

Viewed by 228

Abstract

Background/Objectives: Nitazoxanide (NTX) exhibits promising therapeutic potential; its effectiveness is constrained by its low oral bioavailability due to its poor water solubility and limited permeability. Methods: This study focused on developing a complex of NTX with β-cyclodextrins (β-CDs), specifically β-CD and hydroxypropyl-β-cyclodextrin (Hβ-CD), [...] Read more.

Background/Objectives: Nitazoxanide (NTX) exhibits promising therapeutic potential; its effectiveness is constrained by its low oral bioavailability due to its poor water solubility and limited permeability. Methods: This study focused on developing a complex of NTX with β-cyclodextrins (β-CDs), specifically β-CD and hydroxypropyl-β-cyclodextrin (Hβ-CD), to enhance the solubility and antiviral activity of NTX. Results: The formation of the β-CD:NTX in an aqueous solution was verified using UV–visible spectroscopy, confirming a 1:1 inclusion complex. Characterization of the solid β-CD:NTX complexes was confirmed via FTIR, X-ray diffraction (XRD), scanning electron microscopy (SEM), and DSC-TGA analyses. Molecular docking studies revealed that the NTX thiazole ring with the nitro group was positioned within the β-CDs cavity, while the benzene ring remained outside. Phase solubility tests showed that β-CD:NTX complexes were formed with high stability constants, demonstrating a linear increase in NTX solubility as the β-CD concentration increased. Dissolution tests revealed rapid and nearly complete NTX release within 90 min for β-CD:NTX and Hβ-CD:NTX complexes. The β-CD:NTX complexes were tested for their antiviral activity against Herpes simplex virus (HSV-1) cultures. Results showed that the Hβ-CD:NTX complex had significantly higher antiviral efficacy than β-CD:NTX and free NTX alone. Moreover, cytotoxicity and cellular uptake studies on Vero cells indicated that the Hβ-CD:NTX complex demonstrated lower cytotoxicity and had the highest IC₅₀ value, followed by β-CD:NTX and free NTX. Conclusions: These findings suggest that Hβ-CD:NTX inclusion complexes may serve as effective carriers for delivering NTX in HSV-1 treatments using Vero cell models. Full article

(This article belongs to the Special Issue Cyclodextrin-Based Gene and Drug Delivery Applications)

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17 pages, 2647 KiB

Open AccessArticle

Biopharmaceutical Characterization and Stability of Nabumetone–Cyclodextrins Complexes Prepared by Grinding

by David Klarić, Željka Soldin, Anna Vincze, Rita Szolláth, György Tibor Balogh, Mario Jug and Nives Galić

Pharmaceutics 2024, 16(12), 1493; https://doi.org/10.3390/pharmaceutics16121493 - 21 Nov 2024

Viewed by 311

Abstract

Background: Nabumetone (NAB) is a poorly soluble nonsteroidal anti-inflammatory prodrug (BCS class II drug) whose solubility is significantly improved by complexation with cyclodextrins (CDs). Methods: The solid complexes, in a 1:1 molar ratio, were prepared by mechanochemical activation by grinding, using β-cyclodextrin [...] Read more.

Background: Nabumetone (NAB) is a poorly soluble nonsteroidal anti-inflammatory prodrug (BCS class II drug) whose solubility is significantly improved by complexation with cyclodextrins (CDs). Methods: The solid complexes, in a 1:1 molar ratio, were prepared by mechanochemical activation by grinding, using β-cyclodextrin (β-CD) and its derivatives, hydroxypropyl- and sulfobutylether-β-cyclodextrin (HP-β-CD and SBE-β-CD). The complexation was confirmed by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and attenuated total reflectance Fourier-transformed infrared spectroscopy (ATR–FTIR). Obtained products were further characterized regarding their solubility, in vitro dissolution, permeability and chemical stability. Results: Co-grinding with HP-β-CD and SBE-β-CD yielded products that showed in vitro dissolution profiles in hydrochloric acid medium (pH 1.2) that were substantially different from that of pure NAB, yielding dissolution efficiency enhancements of 34.86 ± 1.64 and 58.30 ± 0.28 times, respectively, for the optimized products. Their in vitro dissolution and gastrointestinal permeability were also studied in a low-volume environment at pH 6.8, corresponding to the intestinal environment. Both β-CD derivatives increased NAB dissolution rate and NAB mass transport across the biomimetic membrane. The effect of β-CD derivatives on NAB chemical stability was studied under the stress conditions by the developed and validated UHPLC–DAD–HRMS method. In acidic conditions, pure and complexed NAB was prone to hydrolytic degradation, yielding one degradation product—pharmacologically inactive NAB metabolite. However, under the oxidative conditions at elevated temperatures, 10 NAB degradation products were identified from co-ground samples. All systems were stable during photo- and long-term stability studies. Conclusions: NAB complexes with HP-β-CD and SBE-β-CD are promising candidates for pharmaceutical product development. Full article

(This article belongs to the Special Issue Supramolecular Systems for Gene and Drug Delivery, 2nd Edition)

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29 pages, 2805 KiB

Open AccessReview

Molecular Targeting of Ischemic Stroke: The Promise of Naïve and Engineered Extracellular Vesicles

by Jihun Lee, Dongho Geum, Dong-Hyuk Park and Jong-Hoon Kim

Pharmaceutics 2024, 16(12), 1492; https://doi.org/10.3390/pharmaceutics16121492 - 21 Nov 2024

Viewed by 266

Abstract

Ischemic stroke (IS) remains a leading cause of mortality and long-term disability worldwide, with limited therapeutic options available. Despite the success of early interventions, such as tissue-type plasminogen activator administration and mechanical thrombectomy, many patients continue to experience persistent neurological deficits. The pathophysiology [...] Read more.

Ischemic stroke (IS) remains a leading cause of mortality and long-term disability worldwide, with limited therapeutic options available. Despite the success of early interventions, such as tissue-type plasminogen activator administration and mechanical thrombectomy, many patients continue to experience persistent neurological deficits. The pathophysiology of IS is multifaceted, encompassing excitotoxicity, oxidative and nitrosative stress, inflammation, and blood–brain barrier disruption, all of which contribute to neural cell death, further complicating the treatment of IS. Recently, extracellular vesicles (EVs) secreted naturally by various cell types have emerged as promising therapeutic agents because of their ability to facilitate selective cell-to-cell communication, neuroprotection, and tissue regeneration. Furthermore, engineered EVs, designed to enhance targeted delivery and therapeutic cargo, hold the potential to improve their therapeutic benefits by mitigating neuronal damage and promoting neurogenesis and angiogenesis. This review summarizes the characteristics of EVs, the molecular mechanisms underlying IS pathophysiology, and the emerging role of EVs in IS treatment at the molecular level. This review also explores the recent advancements in EV engineering, including the incorporation of specific proteins, RNAs, or pharmacological agents into EVs to enhance their therapeutic efficacy. Full article

(This article belongs to the Special Issue Extracellular Vesicle-Based Delivery System for Cancer and Neurodegenerative Disease Treatment)

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20 pages, 1211 KiB

Open AccessReview

Nanotheranostics in Breast Cancer Bone Metastasis: Advanced Research Progress and Future Perspectives

by Lin Miao, Yidan Zhu, Hong Chang and Xinfeng Zhang

Pharmaceutics 2024, 16(12), 1491; https://doi.org/10.3390/pharmaceutics16121491 - 21 Nov 2024

Viewed by 258

Abstract

Breast cancer is the leading cause of cancer-related morbidity and mortality among women worldwide, with bone being the most common site of all metastatic breast cancer. Bone metastases are often associated with pain and skeletal-related events (SREs), indicating poor prognosis and poor quality [...] Read more.

Breast cancer is the leading cause of cancer-related morbidity and mortality among women worldwide, with bone being the most common site of all metastatic breast cancer. Bone metastases are often associated with pain and skeletal-related events (SREs), indicating poor prognosis and poor quality of life. Most current therapies for breast cancer bone metastasis primarily serve palliative purposes, focusing on pain management, mitigating the risk of bone-related complications, and inhibiting tumor progression. The emergence of nanodelivery systems offers novel insights and potential solutions for the diagnosis and treatment of breast cancer-related bone metastasis. This article reviews the recent advancements and innovative applications of nanodrug delivery systems in the context of breast cancer bone metastasis and explores future directions in nanotheranostics. Full article

(This article belongs to the Special Issue Micro/Nano Drug Delivery Systems)

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18 pages, 7067 KiB

Open AccessArticle

Lipid Nanoparticle Formulations for the Skin Delivery of Cannabidiol

by Maria Natalia Calienni, Mirian Ana Scavone, Ana Paula Sanguinetti, Merlina Corleto, Magalí Rocío Di Meglio, Pablo Raies, Diego Sebastián Cristos, Paulo César Maffia and Jorge Montanari

Pharmaceutics 2024, 16(12), 1490; https://doi.org/10.3390/pharmaceutics16121490 - 21 Nov 2024

Viewed by 288

Abstract

Background/Objectives: The aims of this work were to formulate cannabidiol in different lipid carriers for skin delivery after topical application and to study their stability, interaction with the skin, and antibacterial activity. Methods: Solid lipid nanoparticles and nanostructured lipid carriers loaded with cannabidiol [...] Read more.

Background/Objectives: The aims of this work were to formulate cannabidiol in different lipid carriers for skin delivery after topical application and to study their stability, interaction with the skin, and antibacterial activity. Methods: Solid lipid nanoparticles and nanostructured lipid carriers loaded with cannabidiol were prepared and characterized in terms of their physicochemical properties, colloidal stability, protection of the antioxidant capacity of cannabidiol, as well as their retention over time. Skin penetration was assessed using an in vitro model with human skin. The antibacterial activity was tested against Staphylococcus aureus and compared to free cannabidiol. Results: Three nanoformulations exhibited the best size and reproducibility values and were selected for further studies. The formulations were stable, protected the active ingredient, succeeded in delivering it to deep skin layers, and demonstrated antibacterial activity. Conclusions: These cannabidiol nanoformulations show potential for use in skin diseases and conditions, as they protect the active ingredient, enhance its delivery to the skin, and exhibit antibacterial effects. Full article

(This article belongs to the Special Issue Topical Drug Delivery: Current Status and Perspectives)

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16 pages, 5113 KiB

Open AccessArticle

Tailoring Mesalazine Nanosuspension Using Chitosan Polyelectrolyte Complexes with Alginate and Alginate/Hydroxypropyl-Methylcellulose Phthalate

by Amélia Aparecida Rocca Pereira, José Vitor Melchiades Aparecida, Maria Eduarda Ramalho, Leonardo Miziara Barboza Ferreira and Maria Palmira Daflon Gremião

Pharmaceutics 2024, 16(12), 1489; https://doi.org/10.3390/pharmaceutics16121489 - 21 Nov 2024

Viewed by 188

Abstract

Background/Objectives: This study evaluated how the relative proportion of chitosan (CS) to the polyanions alginate (ALG) and hydroxypropyl-methylcellulose phthalate (HP) affects the colloidal properties of mesalazine (MSZ) nanosuspensions as a strategy to produce particles with specific characteristics. Methods: Nanosuspensions were prepared [...] Read more.

Background/Objectives: This study evaluated how the relative proportion of chitosan (CS) to the polyanions alginate (ALG) and hydroxypropyl-methylcellulose phthalate (HP) affects the colloidal properties of mesalazine (MSZ) nanosuspensions as a strategy to produce particles with specific characteristics. Methods: Nanosuspensions were prepared using a bottom–up approach based on acid–base reactions and were modified with CS in a binary mixture with ALG or a ternary mixture with ALG and HP. The particle size, polydispersity index (PDI), zeta potential, morphology, and drug association efficiency were analyzed. Results: Higher proportions of CS relative to the polyanions resulted in smaller, less polydisperse particles. The zeta potential inversion was influenced by the relative proportion of CS in the system. These results were consistent over 30 days and pH exerted an influence on the magnitude of the observed effect. The optimized NS modified with binary CS/ALG blends had the following properties at pH 6.0: an average particle size of 324.9 nm, PDI of 0.5, and zeta potential of +40.8 mV; at pH 4.0, it had an average particle size of 310.4 nm, PDI of 0.4, and zeta potential of +43.6 mV. The optimized NS modified with ternary CS/ALG/HP had the following properties at pH 6.0: an average particle size of 316.7 nm, PDI of 0.5, and zeta potential of +33.9 mV; at pH 4.0, it had an average particle size of 363.5 nm, PDI of 0.6, and zeta potential of +33.9 mV. Conclusions: CS-based polyelectrolyte complexes with ALG and ALG/HP offer an approach to modulating the properties of MSZ nanosuspensions, enabling the production of particles with tailored characteristics. Full article

(This article belongs to the Special Issue Chitosan-Based Nanoparticles as Carriers for Drug Delivery and Biomedical Applications)

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23 pages, 6549 KiB

Open AccessFeature PaperArticle

Co-Amorphization, Dissolution, and Stability of Quench-Cooled Drug–Drug Coamorphous Supersaturating Delivery Systems with RT-Unstable Amorphous Components

by Yan-Fei Zhang, Qian Yao, Xiao-Ying Lin, Ying-Hui Ma, Hui-Feng Zhang, Huan Yu, Shang-Qiang Mu, Chuang Zhang, Hao Geng, Cheng-Yi Hao, Li-Li Zuo, Di Wu, Yue Li, Li-Li Jin and Nian-Qiu Shi

Pharmaceutics 2024, 16(12), 1488; https://doi.org/10.3390/pharmaceutics16121488 - 21 Nov 2024

Viewed by 196

Abstract

Background: Supersaturating drug delivery systems (SDDSs) have gained significant attention as a promising strategy to enhance the solubility and bioabsorption of Biopharmaceutics Classification System (BCS) II drugs. To overcome challenges associated with polymer-based amorphous SDDS (aSDDS), coamorphous (CAM) systems have emerged as [...] Read more.

Background: Supersaturating drug delivery systems (SDDSs) have gained significant attention as a promising strategy to enhance the solubility and bioabsorption of Biopharmaceutics Classification System (BCS) II drugs. To overcome challenges associated with polymer-based amorphous SDDS (aSDDS), coamorphous (CAM) systems have emerged as a viable alternative. Among them, “drug-drug” CAM (ddCAM) systems show considerable potential for combination drug therapy. However, many drugs in their pure amorphous forms are unstable at room temperature (RT), complicating their formation and long-term stability profiles. Consequently, limited knowledge exists regarding the behavior of ddCAMs containing RT-unstable components formed via quench cooling. Methods: In this study, we used naproxen (NAP), a RT-unstable amorphous drug, in combination with felodipine (FEL) or nitrendipine (NTP), two RT-stable amorphous drugs, to create “FEL-NAP” and “NTP-NAP” ddCAM pairs via quench cooling. Our work used a series of methods to perform a detailed analysis on the co-amorphization, dissolution, solubility, and stability profiles of ddCAMs containing RT-unstable drugs, contributing to advancements in co-amorphization techniques for generating SDDS. Results: This study revealed that the co-amorphization and stability profiles of ddCAMs containing RT-unstable components produced via a quench-cooling method were closely related to drug-drug pairing types and ratios. Both quench-cooling and incorporation into coamorphous systems improved the dissolution, solubility, and physical stability of individual APIs. Conclusions: Our findings provide deeper insight into the co-amorphization, dissolution, and stability characteristics of specific drug-drug coamorphous systems FEL-NAP and NTP-NAP, offering valuable guidance for developing new ddCAM coamorphous formulations containing some RT-unstable drugs. Full article

(This article belongs to the Special Issue Innovative Drug Delivery Systems for Enhanced Therapeutic Efficacy in Cancers, Liver Disease and Psoriasis)

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26 pages, 5586 KiB

Open AccessArticle

Quality by Design (QbD)-Driven Development and Optimization of Tacrolimus-Loaded Microemulsion for the Treatment of Skin Inflammation

by Sanjida Ahmed Srishti, Paromita Paul Pinky, Ryan Taylor, Jacob Guess, Natasha Karlik and Jelena M. Janjic

Pharmaceutics 2024, 16(12), 1487; https://doi.org/10.3390/pharmaceutics16121487 - 21 Nov 2024

Viewed by 222

Abstract

Background: Skin inflammation represents a hallmark of many skin conditions, from psoriasis to eczema. Here, we present a novel microemulsion formulation for delivering a low dose of potent immunosuppressant, tacrolimus, to the skin for local inflammation control. The efficacy of topically delivered tacrolimus [...] Read more.

Background: Skin inflammation represents a hallmark of many skin conditions, from psoriasis to eczema. Here, we present a novel microemulsion formulation for delivering a low dose of potent immunosuppressant, tacrolimus, to the skin for local inflammation control. The efficacy of topically delivered tacrolimus in controlling skin inflammation can be enhanced by packaging it into microemulsions. Microemulsions are small-size, thermodynamically stable, and surfactant-rich emulsions that can enhance tissue penetration and local tissue retention of poorly soluble drugs, which can reduce dosing frequency and potentially improve patient compliance. Methods: We present a novel approach for microemulsion manufacturing that uses a combination of both low and high-energy methods. The microemulsion composition and manufacturing parameters were optimized by adopting Quality by Design methodologies. The FMECA (Failure, Mode, Effects, Criticality Analysis)-based risk assessment, D-optimal Design of Experiment (DoE), and statistical analysis of parameters impacting responses through the multiple linear regression (MLR) was implemented for identifying critical formulation and process parameters. Results: Through QbD strategy, a stable microemulsion with optimized drug loading that met all critical quality attributes (CQAs) was identified. The optimal microemulsion candidate was successfully scaled up three-fold with retained CQAs. The presented microemulsion showed a slow and extended drug release profile in vitro. Conclusions: Presented findings suggest that microemulsions are a promising novel approach for tacrolimus delivery to the skin. Further, we also demonstrated that a combination of low-energy emulsification and microfluidization processes can produce stable and robust microemulsions with small droplet size that can be implemented in drug delivery of poorly soluble anti-inflammatory drugs. To the best of our knowledge, this is the first report of QbD-driven optimization of microemulsion manufacturing by microfluidization. Full article

(This article belongs to the Special Issue Nanoparticles for Local Drug Delivery)

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Pharmaceutics, Volume 16, Issue 12 (December 2024) – 20 articles

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