Search Results (51)

This study presents a methodology for developing a cyclodextrin-based delivery system for ceftobiprole, a poorly water-soluble and amphoteric drug, chemically stable in acidic conditions. Ceftobiprole is a broad-spectrum cephalosporin antibiotic administered clinically as its water-soluble prodrug, ceftobiprole medocaril, due to limited aqueous solubility of the parent compound. Solubility enhancement was achieved through complexation with anionic sulfobutylether-β-cyclodextrin (SBE-β-CD). At a pH below 3, ceftobiprole is protonated and cationic, which facilitates electrostatic interactions with the anionic cyclodextrin. An optimised high-performance liquid chromatography (HPLC) method was used to assess solubility, the impurity profile, and long-term chemical stability. X-ray powder diffraction (XRPD) confirmed the amorphous nature of the system and the absence of recrystallization. Nuclear magnetic resonance (NMR) and attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy supported the formation of a host–guest complex. The freeze-dried system prepared from 0.1 M formic acid solution contained negligible residual acid due to nearly complete sublimation. The most promising formulation was a ternary system of ceftobiprole, maleic acid, and SBE-β-CD (1:25:4 molar ratio), showing ~300-fold solubility improvement, low levels of degradation products, and stability after eight months at −20 °C. After pH adjustment to a parenterally acceptable level, the formulation demonstrated solubility and a pH comparable to the marketed drug product. Full article

Background/Objectives: Proteolysis-targeting chimeras (PROTACs) have shown significant potential in the treatment of intractable diseases. However, their clinical applications are limited by poor water solubility and permeability. In this study, the cyclodextrin inclusion method was employed for the first time to prepare the PROTAC-CD complex with the aim of improving the dissolution of a PROTAC drug (LC001). Methods: Initially, sulfobutyl ether-β-cyclodextrin (SBE-β-CD) was selected to improve the solubility of LC001. The polymer TPGS was screened based on the phase solubility method to enhance the efficiency of complexation and solubilization capacity, and its ratio with SBE-β-CD was optimized. The ternary complex was prepared by lyophilization with an SBE-β-CD/TPGS molar ratio of 1:0.03. Differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy results confirmed the formation of an amorphous complex. Fourier-transform infrared and molecular docking simulations indicated the formation of hydrogen bond interactions between components. Results: The results showed that the ternary complexes significantly improved the dissolution rate and release amount of LC001 in PBS (pH 6.8) and were unaffected by changes in gastric pH compared to the binary complexes and physical mixtures. The lack of crystal structure in the lyophilized particles and the formation of nano aggregates in solution may be the reasons for the improved dissolution of the ternary complex. Conclusions: In conclusion, the addition of TPGS to the LC001-SBE-β-CD binary system has a synergistic effect on improving the solubility and dissolution of LC001. This ternary complex is a promising formulation for enhancing the dissolution of LC001. Full article

Cyclodextrins (CDs) enhance the solubility of poorly water-soluble drugs like ibuprofen (IBU), making them promising carriers for pulmonary drug delivery. This route lowers the required dose, minimizing side effects, which could be beneficial in treating cystic fibrosis. In this study, a nano-spray-drying technique was applied to prepare CD/IBU complexes using sulfobutylether-β-cyclodextrin (SBECD) or (2-Hydroxy-3-N,N,N-trimethylamino)propyl-beta-cyclodextrin chloride (QABCD) as carriers as well as mannitol (MAN) and leucine (LEU) as aerosolization excipients. Various investigation techniques were utilized to examine and characterize the samples, including a Master Sizer particle size analyzer, scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy (FT-IR). We applied in vitro Andersen Cascade Impactor measurements and in silico simulation analysis to determine the sample’s aerodynamic properties. We also performed in vitro dissolution and diffusion tests. Applying formulations with optimal aerodynamic properties, we achieved an improved ~50% fine particle fraction values based on the Andersen Cascade Impactor measurements. The in vitro dissolution and diffusion studies revealed rapid IBU release from the formulations; however, the QABCD-based sample exhibited reduced membrane diffusion compared to SBECD due to the formation of electrostatic interactions. Full article

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

Cilostazol is a phosphodiesterase III inhibitor characterized by poor solubility. This limitation can be overcome by using a drug carrier capable of delivering the drug to the target site. Cyclodextrins are essential as drug carriers because of their outstanding complexation abilities and their capacity to improve drug bioavailability. This study comprises two stages: The first involves verifying different cyclodextrins and their complexation abilities towards cilostazol. This was accomplished using molecular docking simulations (MDS) and density functional theory (DFT). Both techniques indicate that the largest Sulfobutyl Ether-β-Cyclodextrin forms the most stable complex with cilostazol. Additionally, other important parameters of the complex are described, including binding sites, dominant interactions, and thermodynamic parameters such as complexation enthalpy, Gibbs free energy, and Gibbs free energy of solvation. The second stage involves a binding study between cilostazol and Phosphodiesterse3 (PDE3). This study was conducted using molecular docking simulations, and the most important energetic parameters are detailed. This is the first such report, and we believe that the results of our predictions will pave the way for future drug development efforts using cyclodextrin–cilostazol complexes as potential therapeutics. Full article

The encapsulation of sodium sulfobutylether-β-cyclodextrin (SBE-β-CD) is influenced not only by the degree of substitution (DS) but also by the presence of strong-bonded water (SBW). Guests compete with SBW for positions within the cavity of SBE-β-CD. However, the correlation between DS and SBW was not clear. This study revealed a positive correlation between DS and SBW utilizing Karl Fischer titration. The mechanism may be attributed to molecular polarizability. To explore the impact of SBW inside SBE-β-CD with different DS on encapsulation, density functional theory was employed. Throughout the release process, an increase in enthalpy is unfavorable, while an increase in entropy favors spontaneous reaction occurrence. For SBE-β-CD (DS = 2, 3), enthalpy increase is the primary factor, leading to the retention of SBW within the cavities and consequently hindering guest entry. In contrast, for SBE-β-CD (DS = 4, 7), the situation differs. For SBE₁₀-β-CD, the influence of SBW is minimal. This study aims to elucidate the relationship between DS and SBW, as well as the effect of SBW inside SBE-β-CD with different DS on encapsulation. It is crucial for a comprehensive understanding of the factors affecting the encapsulation of SBE-β-CD, thereby promoting quality control and functional development of SBE-β-CD. Full article

Riluzole (RLZ), a sodium channel-blocking benzothiazole anticonvulsant BCS class II drug, is very slightly soluble in aqueous medium. To improve aqueous solubility and modulate dissolution rate and membrane permeability, complex formation of RLZ with two cyclodextrin, α-cyclodextrin (α-CD) and sulfobutylether-β-cyclodextrin (SBE-β-CD), was studied. The stability constants demonstrated a greater affinity of SBE-β-CD towards RLZ compared to α-CD. A solubility growth of 1.7-fold and 3.7-fold with α-CD and SBE-β-CD, respectively, was detected in the solutions of 1% cyclodextrins and accompanied by the permeability reduction. For 1% CD solutions, several biopolymers (1% w/v) were tested for the membrane permeability under static conditions. The synergistic positive effect of α-CD and polymer on the solubility accompanied by unchanged permeability was revealed in RLZ/α-CD/PG, RLZ/α-CD/PEG400, and RLZ/α-CD/PEG1000 systems. Solid RLZ/CD complexes were prepared. Dynamic dissolution/permeation experiments for the solid samples disclosed the characteristic features of the release processes and permeation rate through different artificial membranes. The maximal permeation rate was determined across the hydrophilic semi-permeable cellulose membrane followed by the lipophilic PermeaPad barrier (model of intestinal and buccal absorption) and polydimethylsiloxane-polycarbonate membrane (simulating transdermal delivery way). Different mode of the permeation between the membranes was estimated and discussed. Full article

New oral tablets of nebivolol have been developed aiming to improve, by cyclodextrin (CD) complexation, its low solubility/dissolution properties—the main reason behind its poor/variable oral bioavailability. Phase-solubility studies, performed using βCD and highly-soluble βCD-derivatives, indicated sulfobutylether-βCD (SBEβCD) as the best solubilizing/complexing agent. Solid drug-SBEβCD systems were prepared by different methods and characterized for solid-state and dissolution properties. The coevaporated product was chosen for tablet development since it provided the highest dissolution rate (100% increase in dissolved drug at 10 min) and almost complete drug amorphization/complexation. The developed tablets reached the goal, allowing us to achieve 100% dissolved drug at 60 min, compared to 66% and 64% obtained, respectively, with a reference tablet without CD and a commercial tablet. However, the percentage dissolved after 10 min from such tablets was only 10% higher than the reference. This was ascribed to the potential binding/compacting abilities of SBEβCD, reflected in the greater hardness and longer disintegration times of the new tablets than the reference (7.64 vs. 1.06 min). A capsule formulation with the same composition of nebivolol-SBEβCD tablets showed about a 90% increase in dissolved drug after 5 min compared to the reference tablet, and reached 100% dissolved drug after only 20 min. Full article

Retinal vascular diseases and consequential metabolic disturbances in the eye are major concerns for healthcare systems all around the world. BGP-15, a drug candidate small-molecule [O-(3-piperidino-2-hydroxy-1-propyl) nicotinic amidoxime dihydrochloride], has been formerly demonstrated by our workgroup to be retinoprotective both in the short and long term. Based on these results, the present study was performed to investigate the efficacy of BGP in an eyedrop formulation containing sulfobutylether-β-cyclodextrin (SBECD), which is a solubility enhancer as well. Electroretinographical evaluations were carried out and BGP was demonstrated to improve both scotopic and photopic retinal a- and b-waves, shorten their implicit times and restore oscillatory potentials after ischemia–reperfusion. It was also observed to counteract retinal thinning after ischemia–reperfusion in the eyes of Sprague Dawley rats. This small-molecule drug candidate is able to compensate for experimental global eye ischemia–reperfusion injury elicited by ligation of blood vessels in rats. We successfully demonstrated that BGP is able to exert its protective effects on the retina even if administered in the form of eyedrops. Full article

Cataract surgery interventions are constantly increasing, particularly among adult and elderly patients. This type of surgery can lead to inflammatory states of the ocular anterior segment (AS), usually healed via postoperative treatment with dexamethasone (DEX)-containing eye drops. The application of eye drops is challenging due to the high number of daily administrations. In this study, mucoadhesive nanoparticles (NPs) were formulated to improve the residence time of DEX on the corneal mucosa, enhancing the drug’s solubility and bioavailability. The NPs were generated using an ionotropic gelation technique, exploiting the interaction between the cationic group of chitosan (CS) and the anionic group of sulfobutylether-β-cyclodextrin (SBE-β-CD). The formation of the inclusion complex and its stoichiometry were studied through phase solubility studies, Job’s plot method, and Bi-directional transport studies on MDCKII-MDR1. The obtained NPs showed good chemical and physical characteristics suitable for drug loading and subsequent testing on animal mucosa. The DEX-loaded CS/SBE-β-CD NPs exhibited a prolonged residence time on animal mucosa and demonstrated enhanced drug permeability through the corneal membrane, showing a sustained release profile. The developed NPs posed no irritation or toxicity concerns upon local administration, making them an optimal and innovative drug delivery system for inflammatory AS diseases treatment. Full article

Ocular pathologies present significant challenges to achieving effective therapeutic results due to various anatomical and physiological barriers. Natural products such as flavonoids, alone or in association with allopathic drugs, present many therapeutic actions including anticancer, anti-inflammatory, and antibacterial action. However, their clinical employment is challenging for scientists due to their low water solubility. In this study, we designed a liquid formulation based on rutin/sulfobutylether-β-cyclodextrin (RTN/SBE-β-CD) inclusion complex for treating ocular infections. The correct stoichiometry and the accurate binding constant were determined by employing SupraFit software (2.5.120) in the UV-vis titration experiment. A deep physical–chemical characterization of the RTN/SBE-β-CD inclusion complex was also performed; it confirmed the predominant formation of a stable complex (K_c, 9660 M⁻¹) in a 1:1 molar ratio, with high water solubility that was 20 times (2.5 mg/mL) higher than the free molecule (0.125 mg/mL), permitting the dissolution of the solid complex within 30 min. NMR studies revealed the involvement of the bicyclic flavonoid moiety in the complexation, which was also confirmed by molecular modeling studies. In vitro, the antibacterial and antibiofilm activity of the formulation was assayed against Staphylococcus aureus and Pseudomonas aeruginosa strains. The results demonstrated a significant activity of the formulation than that of the free molecules. Full article

The present study reports the effects of two pharmaceutical excipients of differing natures—non-ionic surfactant pluronic F127 (F127) and anionic sulfobutylether-β-cyclodextrin (SBE-β-CD)—on the permeation of the model compound, carbamazepine (CBZ). The permeability coefficients of CBZ at three concentrations of the excipients were measured through two different artificial barriers: hydrophilic cellulose membrane (RC) and lipophilic polydimethylsiloxane–polycarbonate membrane (PDS). The equilibrium solubility of CBZ in F127 and SBE-β-CD solutions was determined. The micellization, complexation, and aggregation tendencies were investigated. Systemically increasing the solubility and the reduction of permeation upon the excipients’ concentration growth was revealed. The quantitative evaluation of the permeability tendencies was carried out using a P_ratio parameter, a quasi-equilibrium mathematical mass transport model, and a correction of permeability coefficients for the free drug concentration (“true” permeability values). The results revealed the mutual influence of the excipient properties and the membrane nature on the permeability variations. Full article

This paper presents the theoretical calculations of the inclusion complex formation between native ceftobiprole, a promising antibiotic from the cephalosporin group, and selected cyclodextrins (CDs) approved by the European Medicines Agency. Ceftobiprole was studied in three protonation states predicted from pK_a calculations, along with three selected CDs in a stoichiometric ratio of 1:1. It was introduced into the CD cavity in two opposite directions, resulting in 18 possible combinations. Docking studies determined the initial structures of the complexes, which then served as starting structures for molecular dynamics simulations. The analysis of the obtained trajectories included the spatial arrangement of ceftobiprole and CD, the hydrogen bonds forming between them, and the Gibbs free energy (ΔG) of the complex formation, which was calculated using the Generalised Born Surface Area (GBSA) equation. Among them, a complex of sulfobutyl ether- (SBE-) β-CD with protonated ceftobiprole turned out to be the most stable (ΔG = −12.62 kcal/mol = −52.80 kJ/mol). Then, experimental studies showed changes in the physiochemical properties of the ceftobiprole in the presence of the CDs, thus confirming the validity of the theoretical results. High-performance liquid chromatography analysis showed that the addition of 10 mM SBE-β-CD to a 1 mg/mL solution of ceftobiprole in 0.1 M of HCl increased the solubility 1.5-fold and decreased the degradation rate constant 2.5-fold. Full article

Permeability has an important effect on drug absorption. In this study, the effect of different concentrations of sodium sulfobutyl ether-β-cyclodextrin (SBE-β-CD) on the absorption of ranitidine was investigated to examine the mechanism of permeability changes. The results of a parallel artificial membrane permeability assay (PAMPA) showed that increasing the concentration of sodium sulfobutyl ether-β-cyclodextrin, 0, 0.12% (w/v), 0.36% (w/v) and 3.6% (w/v), respectively, caused the apparent permeability coefficient of ranitidine to decrease to 4.62 × 10⁻⁵, 4.5 × 10⁻⁵, 3.61 × 10⁻⁵ and 1.08 × 10⁻⁵ in Caco-2 cells, respectively. The same results were obtained from an oral pharmacokinetic study in rats. Further studies indicated that SBE-β-CD significantly increased the zeta potential of ranitidine. SBE-β-CD interacted with ranitidine charges to form a complex that reduced ranitidine permeability, and SBE-β-CD should be chosen with caution for drugs with poor permeability. Full article

Valacyclovir (VACV) was developed as a prodrug of the most common anti-herpetic drug Acyclovir (ACV), aiming to enhance its bioavailability. Nevertheless, prolonged VACV oral treatment may lead to the development of important side effects. Nanotechnology-based formulations for vaginal administration represent a promising approach to increase the concentration of the drug at the site of infection, limiting systemic drug exposure and reducing systemic toxicity. In this study, VACV-loaded nanodroplet (ND) formulations, optimized for vaginal delivery, were designed. Cell-based assays were then carried out to evaluate the antiviral activity of VACV loaded in the ND system. The chitosan-shelled ND exhibited an average diameter of about 400 nm and a VACV encapsulation efficiency of approximately 91% and was characterized by a prolonged and sustained release of VACV. Moreover, a modification of chitosan shell with an anionic cyclodextrin, sulfobutyl ether β-cyclodextrin (SBEβCD), as a physical cross-linker, increased the stability and mucoadhesion capability of the nanosystem. Biological experiments showed that SBEβCD-chitosan NDs enhanced VACV antiviral activity against the herpes simplex viruses type 1 and 2, most likely due to the long-term controlled release of VACV loaded in the ND and an improved delivery of the drug in sub-cellular compartments. Full article