Search Results (568)

Background/Objectives: In the past two decades, the primary therapeutic use of sildenafil has shifted significantly, from the treatment of angina to managing erectile dysfunction, and since the early 2000s it has been used in the treatment of pulmonary hypertension, particularly pulmonary arterial hypertension. Sildenafil is used as a citrate salt; after oral administration, it presents an absorption of ~90% and an absolute bioavailability of 38%, due to the first-pass effect, such that it belongs to class II of the Biopharmaceutics Classification System. Currently, studies are seeking to obtain new pharmaceutical formulations with an optimized biopharmaceutical profile. In this study, an inclusion complex of sildenafil citrate and 2-hydroxypropyl-beta-cyclodextrin in a molar ratio of 1:1 was obtained and its pharmaceutical compatibility with six pharmaceutical excipients was assessed. For three of these excipients, the presence of chemical interactions with sildenafil citrate has been presented in the literature, and for the other three, compatibility has not been evaluated. Methods: To certify the stoichiometry of the obtained inclusion complex molecular modeling, Job’s method and the Benesi–Hildebrand method were employed. Furthermore, we have described the inclusion complex and the obtained binary mixtures via ATR-FTIR and thermal (TG/DTG and DSC) analysis. Results: The results indicated a lack of chemical interactions between the inclusion complex and the six pharmaceutical excipients at ambient temperature (confirmed by ATR–FTIR investigations) and the presence of chemical interactions between the inclusion complex and three of the excipients when the mixture was heated under non-isothermal conditions (TG/DTG and DSC investigations). Conclusions: This study describes the inclusion complex between sildenafil citrate and 2-hydroxypropyl-beta-cyclodextrin in a molar ratio of 1:1 and its compatibility with several pharmaceutical excipients, results with further applications in the preformulation stage of novel delivery systems. Full article

Background/Objectives: Intrathecal drug delivery is essential for treating CNS disorders, but the safety of commonly used excipients such as citric acid/sodium citrate (SC) remains unclear. This study aims to systematically evaluate the potential neuropharmacological effects of repeated intrathecal SC administration. Methods: Multimodal approaches were applied across murine and lagomorph models. Doses ranged from 1.833–14.664 μg/g in mice and 0.104–3.290 mg/rabbit. Behavioral, neurophysiological, and fiber photometry analyses were conducted to assess sensorimotor function, cortical activity, and calcium dynamics. Results: SC induced dose-dependent sensorimotor deficits, including hypolocomotion (45.7% reduced distance, p < 0.001) and impaired coordination (latency reduction 48.3–64.1%, p < 0.001). Mortality increased with dosage and repeated exposure. Neurophysiological data revealed biphasic cortical modulation: acute c-Fos suppression followed by delayed hyperactivity. Fiber photometry confirmed calcium chelation-mediated attenuation and subsequent potentiation of Ca²⁺ signals. Rabbits exhibited similar neurological symptoms, correlating with transient CSF calcium/magnesium depletion, though no structural neural damage was observed. Conclusions: These results provide the first comprehensive evidence that SC buffers can significantly disrupt neuronal calcium homeostasis and induce functional impairments upon intrathecal delivery. The findings emphasize the need for reassessing excipient safety in CNS-targeted formulations. Full article

The stability of amorphous drug substances is a crucial issue in the pharmaceutical field. This study examines the influence of polyvinylpyrrolidone as an excipient on the stabilization of the amorphous drug substance bicalutamide. Solid dispersions of the active substance and the excipient were prepared in different weight ratios using ball milling, then packed into aluminum sachets and stored in a climate chamber for one year. The results indicate successful amorphization of bicalutamide, as confirmed by the absence of crystalline structure in the diffractograms and improved dissolution in the 1:1, 2:1, and 4:1 weight ratio systems. However, the 10:1 drug-to-excipient composition remained crystalline. Our findings demonstrate that PVP effectively stabilizes bicalutamide in its amorphous form. The solid dispersions prepared in weight ratios ranging from 1:1 to 4:1 remained stable under both tested storage conditions throughout the entire study period. Full article

Background/Objectives: The static in vitro permeability assay based on cell monolayers has been widely used in the pharmaceutical industry and recognized by regulatory agencies as a surrogate method for BCS classification. However, the application of such an experiment to study the effects of formulations is limited by the oversensitivity to the excipient effect on drug permeability. In this article, we studied the effects of common excipients on the permeability of moderately and poorly absorbed model compounds across cell monolayers, using two approaches to control said oversensitivity. Methods: Drug permeability across MDCK-wt was assessed in the absence (control) or presence (treatment) of excipients, using minoxidil as a high-permeability marker. The effects of excipients were parameterized as a permeability ratio (PR = treatment/control) without or with normalization (nPR) by minoxidil permeability. Metrics were compared by either ANOVA (p < 0.01) or confidence intervals (CI90, as per bioequivalence metrics) to identify excipient effects. Results: Acyclovir and hydrochlorothiazide showed the highest and lowest number of interactions, respectively. The most impactful excipients were sodium lauryl sulfate, microcrystalline cellulose, and sodium starch glycolate. Unexpectedly, nPR increased the number of excipient effects across model drugs (19 vs. 21). Alternatively, the CI90 approach was more sensitive than ANOVA in identifying excipient effects (41 vs. 32). Conclusions: Minoxidil was not able to control the anticipated oversensitivity of cell-based permeability experiments. Meanwhile, ANOVA was overall able to reduce oversensitivity to excipient effects on drug permeability compared to CI90. Nonetheless, there might be a niche for CI90 analysis when comparing the performance of two formulations on the permeability of moderately and poorly absorbed drugs. Full article

Background/Objectives: Drug products on the pharmaceutical market must meet a number of requirements that guarantee their quality, safety, and efficacy. Accordingly, periodic inspection of the content of active pharmaceutical ingredients (APIs) in marketed drug products is carried out, confirming that they meet all quality and quantity requirements for a given drug formulation before the expiration date. Therefore, the purpose of this study was to evaluate the suitability of the most commonly used thermal analysis methods, differential thermal analysis (DTA), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA), in the control of the composition of commercially available drug products. Results: Based on a review of the literature, it was shown that thermal methods can be useful in distinguishing drug products from different manufacturers, which guarantees their usefulness in quality control of finished drug products and detecting drug products from illegal manufacturers. They are also useful as tools for confirming the presence of APIs in dosage forms under investigation. The cited literature also indicates that DSC and TGA methods can be used in the quantification of APIs in marketed drug products and to detect non-compliant drug products. The use of chemometric techniques to interpret thermal data can eliminate the adverse effects of excipients on quantification results. Conclusions: Thermal methods are a good complement to chromatographic and spectroscopic methods, with the particular advantages of not needing any sample pretreatment, low sample weight, and short analysis time. Full article

Background/Objectives: Smart Formulation is an artificial intelligence-based platform designed to predict the Beyond Use Dates (BUDs) of compounded oral solid dosage forms. The study aims to develop a decision-support tool for pharmacists by integrating molecular, formulation, and environmental parameters to assist in optimizing the stability of extemporaneous preparations. Methods: A tree ensemble regression model was trained using a curated dataset of 55 experimental BUD values collected from the Stabilis database. Each formulation was encoded with molecular descriptors, excipient composition, packaging type, and storage conditions. The model was implemented using the KNIME platform, allowing the integration of cheminformatics and machine learning workflows. After training, the model was used to predict BUDs for 3166 APIs under various formulation and storage scenarios. Results: The analysis revealed a significant impact of excipient type, number, and environmental conditions on API stability. APIs with lower LogP values generally exhibited greater stability, particularly when formulated with a single excipient. Excipients such as cellulose, silica, sucrose, and mannitol were associated with improved stability, whereas HPMC and lactose contributed to faster degradation. The use of two excipients instead of one frequently resulted in reduced BUDs, possibly due to moisture redistribution or phase separation effects. Conclusions: Smart Formulation represents a valuable contribution to computational pharmaceutics, bridging theoretical formulation design with practical compounding needs. The platform offers a scalable, cost-effective alternative to traditional stability testing and is already available for use by healthcare professionals. Its implementation in hospital and community pharmacies may help mitigate drug shortages, support formulation standardization, and improve patient care. Future developments will focus on real-time stability monitoring and adaptive learning for enhanced precision. Full article

Background: Fixed-dose combinations have advanced in many therapeutic areas, including otorhinolaryngology, where hearing disorders are increasingly prevalent. Objectives: The present study focuses on developing and evaluating a new capsule combining nicergoline (NIC), piracetam (PIR), and hawthorn extract (HE) for the management of sensorineural hearing loss. Methods: The first phase methodology comprised preformulation studies (DSC, FTIR, and PXRD) to assess compatibility among active substances and excipients. Subsequently, four formulations were prepared and tested for flowability, dissolution behavior in acidic and neutral media, and stability under oxidative, thermal, and photolytic stress. Quantification of the active substances and flavonoids was performed using validated spectrophotometric and HPLC-UV methods. Results: Among the tested variants, the F1 formulation (4.5 mg NIC, 200 mg PIR, 50 mg HE, 2.5 mg magnesium stearate, 2.5 mg sodium starch glycolate, and 240.5 mg monohydrate lactose per capsule) displayed optimal technological properties, superior dissolution in acidic media, and was further selected for evaluation. The antioxidant activity of the formulation was confirmed through the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, Trolox Equivalent Antioxidant Capacity (TEAC), and iron chelation tests, and was primarily attributed to the flavonoid content of the HE. Acute toxicity tests in mice and rats indicated a high safety margin (LD₅₀ > 2500 mg/kg), while ototoxicity assessments showed no adverse effects on auditory function. Conclusions: The developed formulation displayed good stability, safety, and therapeutic potential, while the applied workflow could represent a model for the development of future fixed-dose combinations. Full article

Background: Precision medicine refers to the formulation of personalized drug regimens according to the individual characteristics of patients to achieve optimal efficacy and minimize adverse reactions. Additive manufacturing (AM), also known as three-dimensional (3D) printing, has emerged as an optimal solution for precision drug delivery, enabling customizable and the fabrication of multifunctional structures with precise control over morphology and release behavior in pharmaceutics. However, the influence of 3D printing parameters on the printed tablets, especially regarding in vitro and in vivo performance, remains poorly understood, limiting the optimization of manufacturing processes for controlled-release profiles. Objective: To establish the fabrication process of 3D-printed controlled-release tablets via comprehensively understanding the printing parameters using fused deposition modeling (FDM) combined with hot-melt extrusion (HME) technologies. HPMC-AS/HPC-EF was used as the drug delivery matrix and carbamazepine (CBZ) was used as a model drug to investigate the in vitro drug delivery performance of the printed tablets. Methodology: Thermogravimetric analysis (TGA) was employed to assess the thermal compatibility of CBZ with HPMC-AS/HPC-EF excipients up to 230 °C, surpassing typical processing temperatures (160–200 °C). The formation of stable amorphous solid dispersions (ASDs) was validated using differential scanning calorimetry (DSC), hot-stage polarized light microscopy (PLM), and powder X-ray diffraction (PXRD). A 15-group full factorial design was then used to evaluate the effects of the fan speed (20–100%), platform temperature (40–80 °C), and printing speed (20–100 mm/s) on the tablet properties. Response surface modeling (RSM) with inverse square-root transformation was applied to analyze the dissolution kinetics, specifically t_50% (time for 50% drug release) and Q_4h (drug released at 4 h). Results: TGA confirmed the thermal compatibility of CBZ with HPMC-AS/HPC-EF, enabling stable ASD formation validated by DSC, PLM, and PXRD. The full factorial design revealed that printing speed was the dominant parameter governing dissolution behavior, with high speeds accelerating release and low speeds prolonging release through porosity-modulated diffusion control. RSM quadratic models showed optimal fits for t_50% (R² = 0.9936) and Q_4h (R² = 0.9019), highlighting the predictability of release kinetics via process parameter tuning. This work demonstrates the adaptability of polymer composite AM for tailoring drug release profiles, balancing mechanical integrity, release kinetics, and manufacturing scalability to advance multifunctional 3D-printed drug delivery devices in pharmaceutics. Full article

Background/Objectives: Hot-melt extrusion (HME) has gained prominence for the manufacture of sustained-release oral dosage forms, yet the application of wax-based matrices and their resilience to alcohol-induced dose dumping (AIDD) remains underexplored. This study aimed to develop and characterise wax-based sustained-release felodipine formulations, with a particular focus on excipient functionality and robustness against AIDD. Methods: Felodipine sustained-release formulations were prepared via HME using Syncrowax HGLC as a thermally processable wax matrix. Microcrystalline cellulose (MCC) and lactose monohydrate were incorporated as functional fillers and processing aids. The influence of wax content and filler type on mechanical properties, wettability, and drug release behaviour was systematically evaluated. Ethanol susceptibility testing was conducted under simulated co-ingestion conditions (4%, 20%, and 40% v/v ethanol) to assess AIDD risk. Results: MCC-containing tablets demonstrated superior sustained-release characteristics over 24 h, showing better wettability and disintegration. In contrast, tablets formulated with lactose monohydrate remained structurally intact during dissolution, overly restricting drug release. This limitation was effectively addressed through granulation, where reduced particle size significantly improved surface accessibility, with 0.5–1 mm granules achieving a satisfactory release profile. Ethanol susceptibility testing revealed divergent behaviours between the two filler systems. Unexpectedly, MCC-containing tablets showed suppressed drug release in ethanolic media, likely resulting from inhibitory effect of ethanol on filler swelling and disintegration. Conversely, formulations containing lactose monohydrate retained their release performance in up to 20% v/v ethanol, with only high concentrations (40% v/v) compromising matrix drug-retaining functionality and leading to remarkably increased drug release. Conclusions: This study highlights the pivotal role of excipient type and constitutional ratios in engineering wax-based sustained-release formulations. It further contributes to the understanding of AIDD risk through in vitro assessment and offers a rational design strategy for robust, alcohol-resistant oral delivery systems for felodipine. Full article

Preservatives are essential for ensuring the stability, safety, and efficacy of pharmaceuticals, cosmetics, and food products. However, synthetic preservatives often raise toxicity concerns. This study evaluated Rosmarinus officinalis (rosemary) leaf extracts and coffee by-products from Coffea arabica and Coffea canephora as potential natural preservatives for emulsions. Antimicrobial activity was assessed against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans, along with cytotoxicity tests on human keratinocytes and antioxidant activity. The most effective extracts were incorporated into an oil-in-water emulsion for evaluation. C. arabica extracts showed the best results among coffee samples, with 43.53 mg GAE/g (gallic acid equivalents) and 2.32 mg QE/g of total phenolics (quercetin equivalents) and flavonoids, and minimum inhibitory concentrations (MICs) of 12.5 mg/mL against Escherichia coli, and 25 mg/mL against Staphylococcus aureus and Pseudomonas aeruginosa. Rosemary extract showed 158.01 ± 23.67 mg GAE/g and 1.95 ± 0.05 mg QE/g, with MICs of 2.5 mg/mL against E. coli, 1.25 mg/mL against P. aeruginosa, 0.3 mg/mL against S. aureus, and 0.08 mg/mL against Candida albicans. However, rosemary extracts displayed complete inhibition of keratinocyte growth at 20 µg/mL. A combination of both extracts had synergistic effects against S. aureus and P. aeruginosa. The emulsion met microbial safety standards in the challenge test for bacteria but not yeast. The results suggest that rosemary extracts enhance the potential of coffee by-product as a preservative system, and as a multifunctional excipient system in cosmetics, offering preservation and antioxidant protection. However, further strategies, such as adding other ingredients or adjusting the formulation pH, are required to ensure yeast inhibition. Full article

Background/Objectives: Early diagnosis and oral or, in severe cases, intravenous antibiotics are usually effective for Lyme disease, but some patients have persistent symptoms unresponsive to standards of care, requiring alternative therapies. Disulfiram (DIS), a drug for alcoholism, is under investigation as a potential adjunctive treatment, but its low bioavailability, rapid metabolism, and safety concerns urge the development of improved formulations for clinical translation. Methods: Screening dissolution and permeation studies were investigated for vehicle and excipient selection, following the pharmacopeia perspectives to develop and optimize the low-dose DIS rectal suppository intended for application in post-treatment Lyme disease syndrome (PTLDS). Further characterizations were carried out by differential scanning calorimetry, X-ray diffraction, and infrared spectroscopy. Results: Cyclodextrin (CD) encapsulation was investigated to improve the aqueous solubility of the hydrophobic drug. The dissolution of DIS from fatty base suppository was very slow; it was remarkably improved by the molecular encapsulation of the drug with CDs. The dissolution of DIS from a water-soluble base was more favorable, but incomplete. In the polyethylene glycol (PEG) based suppositories, the addition of CDs already in a physical mixture ensured the dissolution of the drug. The presented drug delivery system relates to a novel preparation for rectal administration comprising a low-dose disulfiram with improved solubility and permeability by the PEG and hydroxypropyl-β-cyclodextrin (HPBCD) synergistic matrix. Conclusions: The rectal dosage form containing the drug and CD in the physical mixture is advantageous, avoiding the hepatic first-pass effect, minimizing dose-limiting toxicity, simplifying production, and fasting the availability of the repositioned drug. Full article

The recent advancement of 3D-printed drugs is an emerging technology that has the potential for effective and safe oral delivery of personalized treatment regimens to patients, replacing the current “one size fits all” philosophy. The objective of this literature review is to highlight the importance of 3D-printing technology in the development of personalized treatments, focusing on Levetiracetam, the first FDA-approved 3D-printed drug, for the treatment of epilepsy. Levetiracetam serves as an ideal paradigm for exploring how precision medicine and 3D printing can be applied to improve treatment outcomes for other complex diseases such as diabetes, cardiovascular diseases, and cancer. 3D printing enables precise dosage and time-release profiles by modifying factors such as shape and size, and the combination of active pharmaceutical ingredients (APIs) and excipients, ensuring consistent therapeutic levels over the treatment period. Design of oral tablets with multiple compartments allows for simultaneous treatment with multiple APIs, each one with a different release profile, minimizing drug–drug interactions and side effects. This technology also supports on-demand production, making it particularly beneficial in resource-limited or urgent situations, and offers the flexibility to customize dosage forms. Additive manufacturing could be an important tool for developing personalized treatments to address the diverse medical needs of patients with complex diseases. Therefore, there is a need for more 3D-printed FDA-approved drugs in the biopharmaceutical industry to enable personalized treatment, improved patient compliance, and precise drug release control. Full article

Background/Objectives: Levocetirizine (LCZ) is a second-generation antihistamine with minimal central nervous system effects. However, its short half-life necessitates daily dosing, potentially reducing adherence in pediatric populations. This study aimed to develop a long-acting injectable LCZ formulation by synthesizing lipophilic prodrugs and evaluating their physicochemical stability, enzymatic hydrolysis, and pharmacokinetics in vivo. Methods: Two prodrugs of LCZ, LCZ decanoate (LCZ-D) and LCZ laurate (LCZ-L), were synthesized via esterification with alkyl alcohols. The compounds were characterized using NMR, FT-IR, and DSC. Prodrugs were formulated with an oil-based vehicle (castor oil and benzyl benozate), and their hydrolysis was evaluated using porcine liver esterase (PLE) and rat plasma. Pharmacokinetic profiles were assessed in Sprague Dawley rats after oral or intramuscular administration. Stability was tested at 25 °C, 40 °C, and 60 °C for 6 weeks. Results: LCZ-D and LCZ-L exhibited first-order hydrolysis kinetics, with rates following the order of PLE (2.0 > 0.5 units/mL) > plasma > PLE (0.2 units/mL). The C_max of LCZ-D and LCZ-L were 13.95 and 5.12 ng/mL, respectively, with corresponding AUC_0–45d values of 6423.12 and 2109.22 h·ng/mL. Formulations containing excipients with lower log P values led to increased systemic exposure. All formulations maintained therapeutic plasma concentrations for over 30 days. The inclusion of the antioxidant BHT (0.03% v/v) improved oxidative stability, reducing degradation at 60 °C from 4.72% to 1.17%. Conclusions: All formulations demonstrated potential for the long-acting delivery of LCZ, maintaining therapeutic plasma levels for over 30 days. Moreover, the release behavior and systemic exposure could be effectively modulated by excipient selection. Full article

Background/Objectives: Chronic lung diseases are among the leading causes of death worldwide. In the treatment of these diseases, non-steroidal anti-inflammatory drugs can be effective. We have previously developed an excipient formulation alongside a modern manufacturing protocol, which we aim to further investigate. We have chosen two new model drugs, meloxicam (MX) and its water-soluble salt, meloxicam-potassium (MXP). The particles in dry powder inhaler (DPI) formulation were expected to have a spherical shape, fast drug release, and good aerodynamic properties. Methods: The excipients were poloxamer-188, mannitol, and leucine. The samples were prepared by spray drying, preceded by solution preparation and wet grinding. Particle size was determined by laser diffraction, shape by scanning electron microscopy (SEM), crystallinity by powder X-ray diffraction (PXRD), interactions by Fourier-transform infrared spectroscopy (FT-IR), in vitro drug dissolution by paddle apparatus, and in vitro aerodynamic properties by Andersen cascade impactor and Spraytec^® device. Results: We achieved the proper particle size (<5 μm) and spherical shape according to laser diffraction and SEM. The XRPD showed partial amorphization. FT-IR revealed no interaction between the materials. During the in vitro dissolution tests, more than 90% of MX and MXP were released within the first 5 min. The best products exhibited an aerodynamic diameter of around 4 µm, a fine particle fraction around 50%, and an emitted fraction over 95%. The analysis by Spraytec^® supported the suitability for lung targeting. Conclusions: The developed preparation process and excipient system can be applied in the development of different drugs containing DPIs. Full article

The mRNA vaccine has protected humans from the Coronavirus disease 2019 (COVID-19) and has taken the lead in reversing the epidemic efficiently. However, the Centre of Disease Control (CDC) reported and raised the alarm of allergic or acute inflammatory adverse reactions after vaccination with mRNA-LNP vaccines. Meanwhile, the US Food and Drug Administration (FDA) has added four black-box warnings in the instructions for mRNA-LNP vaccines. Numerous studies have proven that the observance of side effects after vaccination is indeed positively correlated to the level of anti-PEG antibodies (IgM or IgG), which are enhanced by PEGylated preparations like LNP vaccine and environmental exposure. After literature research and review in the past two decades, it was found that the many clinical trial failures (BIND-014, RB006 fell in phase II) of PEG modified delivery system or PEGylated drug were related to the high expression of anti-PEG IgM and IgG. In the background of shooting multiple mRNA-LNP vaccines in billions of people around the world in the past three years, the level of anti-PEG antibodies in the population may have significantly increased, which brings potential risks for PEG-modified drug development and clinical safety. This review summarizes the experience of using mRNA-LNP vaccines from the mechanism of the anti-PEG antibodies generation, detection methods, clinical failure cases of PEG-containing products, harm analysis of abuse of PEGylation, and alternatives. In light of the increasing prevalence of anti-PEG antibodies in the population and the need to avoid secondary injuries, this review article holds greater significance by offering insights for drug developers. It suggests avoiding the use of PEG excipients when designing PEGylated drugs or PEG-modified nano-formulations and provides references for strategies such as utilizing PEG-free or alternative excipients. Full article