Phase Solubility Analysis Research Articles

Computational and experimental analysis of Luteolin-β-cyclodextrin supramolecular complexes: Insights into conformational dynamics and phase solubility

Investigating the structural stability of poorly-soluble luteolin (LuT) after encapsulation within cyclodextrins (CDs) is crucial for unlocking the therapeutic potential of LuT bioactive molecule. Herein, native and modified β-CD were employed to investigate LuT inclusion complex formation. Molecular mechanics (MM) and quantum mechanics (QM) were utilized for structural dynamics analysis. Microsecond timescale MD simulations yielded insights into LuT-CD interactions. The binding affinity between LuT and selected β-CDs was assessed by calculating the binding free energy using MM-PBSA and umbrella sampling simulations. The MM-PBSA results indicated that Heptakis-O-(2-hydroxypropyl)-β-CD (HP-β-CD) (−82.59+/-11.67 kJ/mol) and Di-O-methyl-β-CD (DM-β-CD) (−54.01+/-11.07 kJ/mol) exhibited good binding affinity for LuT. Subsequently, derivative screening of HP-β-CD revealed that only 2-HP-β-CD (HP-β-CD-1)/LuT (−21.38 kJ/mol) displayed a superior binding free energy (obtained from umbrella sampling) than HP-β-CD/LuT (−16.55 kJ/mol) inclusion complex. We conducted QM calculations on the top three inclusion complexes namelly HP-β-CD, DM-β-CD, and HP-β-CD-1 employing wB97X-D/6–311 + G(d,p) model chemistry to strengthen the MM results. The computational analysis aligns with experimental findings (phase solubility analysis), validating HP-β-CD-1 as most effective cavitand molecule for improving the solubility of LuT. This study offers critical structural insights for developing novel HP-β-CD derivatives with enhanced host capacity to encapsulate guest molecules efficiently.

Preparation, characterization, and in vitro cytogenotoxic evaluation of a novel dimenhydrinate-β-cyclodextrin inclusion complex.

Dimenhydrinate (DMH), used to alleviate motion sickness symptoms such as nausea, vomiting, dizziness, and vertigo, encounters limitations in oral pharmaceutical formulations due to its poor water solubility and bitter taste. Our research hypothesized that inclusion complexation with β-cyclodextrin (β-CD) might address these drawbacks while ensuring that the newly formed complexes exhibit no cytotoxic or genotoxic effects on peripheral blood mononuclear cells (PBMCs). Inclusion complexes were prepared using the kneading method and the solvent evaporation method. The phase solubility analysis, attenuated total reflectance-fourier transform infrared spectroscopy (ATR-FTIR), and differential scanning calorimetry (DSC) were conducted to evaluate the complexation efficacy and stability constant of the new binary systems. The results demonstrated that both methods provided complete and efficient complexation. Cytogenotoxic analysis, including the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, alkaline comet assay, and cytokinesis-block micronucleus cytome (CBMN-cyt) assay, was conducted to assess the cytogenotoxic potential of DMH-β-CD inclusion complexes, a topic previously unexamined. No cytotoxic or genotoxic effects were observed within the concentration range of 36.36 to 109.09 ng/mL. Cell viability of treated PBMCs exceeded 85% for all tested concentrations. No significant increases in DNA strand breaks were observed at any dose, and tail intensity of all complexes remained lower or up to 2.2% higher than the negative control. Parameters indicating genotoxic effects, as well as cytotoxic and cytostatic potential in the CBMN-cyt assay, did not significantly differ from untreated controls. These results suggest that inclusion complexation with β-CD might be a safe and promising solution to overcome the limitations of poor solubility and unpleasant taste of DMH, potentially providing opportunities for new and improved oral pharmaceutical dosage forms.

Fabrication of Uniform Melatonin Microparticles Potentially for Nasal Delivery: A Comparison of Spray Drying and Spray Freeze Drying.

Insomnia is a major health concern, and melatonin (MLT) is key for initiating sleep. Delivering MLT nasally can enhance brain bioavailability by targeting the olfactory region. This study aimed to fabricate MLT embedded microparticles for nasal delivery. MLT-cyclodextrin (CD) derivatives complex microparticles (MCCMPs) were fabricated by spray drying and spray freeze drying MLT and CD derivative solutions. Phase solubility and 1H-1H ROSEY NMR analysis assessed MLT-CD assembly. The effects of formulation compositions and process parameters on microparticle structural attributes were investigated. The in vitro nasal release and deposition performances were evaluated by a modified paddle-over-disk apparatus and 3D-printed nasal cavity cast, respectively. Sodium sulphobutylether-β-cyclodextrin (SBE-β-CD) exhibited the best complexation ability with MLT, with the indole structure of MLT included in its cavity. Spray dried MCCMPs showed dense structure with high density, while the spray freeze dried counterpart showed the brittle and porous structure with low density. Despite the porous structure may promote the release rate of spray freeze dried samples, the high hydrophilicity of the CD derivative overshadows this advantage. Samples prepared by spray drying not only exhibited rapid release rates but also could deposit more effectively in the olfactory region, as they avoid breakage due to their higher mechanical strength. The optimal sample showed ~ 86.70% of the MLT released at 20min and ~ 10.57% of the deposition fraction in the olfactory region. This work compares MCCMPs fabricated by spray drying and spray freeze drying, providing the optimal formulation and process combinations.

Design and development of a chitosan-based nasal powder of dimethyl fumarate-cyclodextrin binary systems aimed at nose-to-brain administration. A stability study

The nasal administration route has been studied for the delivery of active molecules directed to the Central Nervous System, thanks to the anatomical connection between the nasal cavity and the brain.Dimethyl fumarate is used to treat relapsing-remitting multiple sclerosis, with a role as an immunomodulator towards T- T-cells and a cytoprotector towards neurons and glial cells. Its use in therapy is hindered by its low aqueous solubility, and low stability, due to hydrolysis and sublimation at room temperature. To overcome this limitation, in this study we evaluated the feasibility of using two amorphous β-cyclodextrin derivatives, namely hydroxypropyl β-cyclodextrin and methyl β-cyclodextrin, to obtain a nasally administrable powder with a view to nose-to-brain administration.Initially, the interaction product was studied using different analytical methods (differential scanning calorimetry, Fourier transform infrared spectroscopy and powder X-ray diffraction) to detect the occurrence of binary product formation, while phase solubility analysis was used to probe the complexation in solution.The dimethyl fumarate-cyclodextrin binary product showing best solubility and stability properties was subsequently used in the development of a chitosan-based mucoadhesive nasally administrable powder comparing different preparative methods. The best performance in terms of both hydrolytic stability and DMF recovery was achieved by the powder obtained via freeze-drying.

Silibinin solubilization: combined effect of co-solvency and inclusion complex formation

Objective Belonging to the class II drugs according to the biopharmaceutics classification system, silibinin (SLB) benefits from high permeability but suffers poor solubility that negatively affects the development of any delivery system. This research aimed to improve SLB solubility by combined use of co-solvency and complexation phenomena. Methods Solubility studies were performed using the phase solubility analysis according to the shake-flask method in the presence of ethanol and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) as a co-solvent and inclusion complexing agent, respectively. SLB release studies from chitosan nanoparticles were carried out in double-wall, diffusion cells using the optimized drug release medium. Results SLB solubility was mathematically optimized constraining to using the lowest concentrations of ethanol and HP-β-CD. SLB solubility increased linearly with the increase of HP-β-CD concentration. The solubility in PBS-ethanol mixtures followed a log-linear model. SLB solubility in the presence of the ethanol co-solvent and HP-β-CD complexing agent was optimized by adopting a genetic algorithm suggesting the phosphate buffer saline solution supplemented by 6%v/v ethanol and 8 mM HP-β-CD as an optimized medium. The optimized solution was examined to study SLB release from chitosan nanoparticles (4.5 ± 0.2% drug loading) at 37 °C under static conditions. The sigmoidal release profile of SLB from the particles indicated a combination of erosion and diffusion mechanisms governing drug release from the nanoparticles. Conclusion SLB solubility in a buffered solution supplemented by ethanol co-solvent and HP-β-CD complexing agent is a function of free drug present in the semi-aqueous media, the drug-ligand binary complex, and the drug/ligand/co-solvent ternary complex.

Application of Biomaterials in the Development of Hydrogel-Forming Microneedles Integrated with a Cyclodextrin Drug Reservoir for Improved Pharmacokinetic Profiles of Telmisartan.

Telmisartan (TEL) is a promising antihypertensive agent among other angiotensin receptor blockers. However, its oral application is limited by its poor water solubility. This study presents the successful utilization of biomaterial-based hydrogel-forming microneedles integrated with a direct compressed tablet reservoir (HFMN-DCT) for the transdermal delivery of telmisartan in the treatment of hypertension. The combination of PVP, PVA, and tartaric acid was used in the HFMN formulation. A range of cross-linking temperatures and times were employed to optimize the characteristics of the HFMN. The HFMN exhibited excellent swelling capacity, mechanical strength, and insertion properties. Additionally, the poorly soluble characteristic of TEL was improved by the inclusion complex formulation with β-cyclodextrin (βCD). Phase solubility analysis showed an Ap-type diagram, indicating a higher-order complex between TEL and βCD, with respect to βCD. A ratio of TEL:βCD of 1:4 mM demonstrates the highest solubility enhancement of TEL. The inclusion complex formation was confirmed by FTIR, XRD, DSC, and molecular docking studies. A significantly higher release of TEL (up to 20-fold) from the inclusion complex was observed in the in vitro release study. Subsequently, a DCT reservoir was developed using various concentrations of sodium starch glycolate. Essentially, both the HFMN and DCT reservoir exhibit hemocompatibility and did not induce any skin irritation. The optimized combination of the HFMN-DCT reservoir showed an ex vivo permeation profile of 83.275 ± 2.405%. Notably, the proposed system showed superior pharmacokinetic profiles in the in vivo investigation using male Wistar rats. Overall, this study highlights the potential of HFMN-DCT reservoir systems as a versatile platform for transdermal drug delivery applications.

Development and Evaluation of Solid Dispersion Formulations of Olanzepine

The purpose of present study was to enhance the aqueous solubility of olanzapine by using the Solid dispersion technique. Solid dispersions of olanzapine were prepared by the dispersion method using PGS and SSG as carriers. Drug-carrier ratios such as 1 : 1, 1 : 2, 1 : 4, 1 : 6, 1: 8 and 1 : 10 were tried for optimization. Characterization was done by phase solubility, in-vitro release, saturation solubility, permeation, wettability, XRD and FTIR analysis. Solid dispersions showed higher solubility and an improved drug release profile than the pure drug. Solid dispersion and physical mixture with a drug-polymer ratio of 1 : 10 showed the best release profile in comparison with the other samples. Phase solubility results verified the solubilization effect of the carrier. XRD and NIR analysis confirmed the reduction of crystallinity in the samples. The release study findings were well supported by the results of wettability, saturation solubility and permeability studies. IR analysis substantiated the inertness of the carrier. It was concluded that pregelatinised starch (PGS) and sodium starch glycollate (SSG) could be utilized as effective carriers to improve the aqueous solubility of poorly soluble drugs.
 Keywords: Olanzapine, solid dispersion, solubility, evaluation.

Tunable structure of chimeric isomaltomegalosaccharides with double α-(1 → 4)-glucosyl chains enhances the solubility of water-insoluble bioactive compounds

Isomaltomegalosaccharides with α-(1 → 4) and α-(1 → 6)-segments solubilize water-insoluble ligands since the former complexes with the ligand and the latter solubilizes the complex. Previously, we enzymatically synthesized isomaltomegalosaccharide with a single α-(1 → 4)-segment at the reducing end (S-IMS) by dextran dextrinase (DDase), but the chain length [average degree of polymerization (DP) ≤ 9] was insufficient for strong encapsulation. We hypothesized that the conjugation of longer α-(1 → 4)-segment afforded the promising function although DDase is incapable to do so. In this study, the cyclodextrin glucanotransferase-catalyzed coupling reaction of α-cyclodextrin to S-IMS synthesized a new α-(1 → 4)-segment at the nonreducing end (N-4S) of S-IMS to form D-IMS [IMS harboring double α-(1 → 4)-segments]. The length of N-4S was modulated by the ratio between α-cyclodextrin and S-IMS, generating N-4Ss with DPs of 7–50. Based on phase-solubility analysis, D-IMS-28.3/13/3 bearing amylose-like helical N-4S with DP of 28.3 displayed a water-soluble complex with aromatic drugs and curcumin. Small-angle X-ray scattering revealed the chain adapted to rigid in solution in which the radius of gyration was estimated to 2.4 nm. Furthermore, D-IMS with short N-4S solubilized flavonoids of less-soluble multifunctional substances. In our research, enzyme-generated functional biomaterials from DDase were developed to maximize the hydrophobic binding efficacy towards water-insoluble bioactive compounds.

Microwave Irradiation Technique: A Green Chemistry Approach for Dissolution Enhancement of Ritonavir

This research was focused on improvement of aqueous solubility of Ritonavir (RIT), Antiretroviral (ART) drug by preparing solid dispersion (SD) through solvent methodology and microwave irradiation (MWI) technique as a green chemistry approach. In MWI different batches of SD were formulated by 32 factorial approach with time of exposure (X1) and power of radiation (X2) as variable quantity and dissolution rate as response (Y1). β-CD was used as hydrophilic carriers. Drug carrier magnitude relation of 1:1 resolve by phase solubility analysis and SD were assessed for drug content, percentage dissolution rate studies, FTIR, XRD, DSC and SEM analysis. The FTIR, XRD, DSC and SEM studies exhibited no interaction between RIT and excipient. In Physical mixture (PM) it shows less intensity and disappearance of sharp peaks while in SD indicates the conversion of crystalline state of RIT to amorphous state that discovered the dissolution enhancing, so the SD prepared by MWI proved to be a promising approach to increasing the dissolving rate of BCS class II drug RIT. Hence, from the all analysis studies, it absolutely was evident that factorial batch F2 was the higher. F2 coded batch (RIT: β-CD within the magnitude relation of 1:1 with time of exposure (4 min) and power of radiation (450 Watt), shows 06 folds increase i.e. 58% compared with drug discharged inside 60 min to plane RIT and SD i.e. 9 % only and 47 % respectively.

Complexation between the Antioxidant Pterostilbene and Derivatized Cyclodextrins in the Solid State and in Aqueous Solution.

Inadequate aqueous solubilities of bioactive compounds hinder their ability to be developed for medicinal applications. The potent antioxidant pterostilbene (PTB) is a case in point. The aim of this study was to use a series of modified water-soluble cyclodextrins (CDs), namely, hydroxypropyl β-CD (HPβCD), dimethylated β-CD (DIMEB), randomly methylated β-CD (RAMEB), and sulfobutyl ether β-CD sodium salt (SBECD) to prepare inclusion complexes of PTB via various solid, semi-solid, and solution-based treatments. Putative CD-PTB products generated by solid-state co-grinding, kneading, irradiation with microwaves, and the evaporative treatment of CD-PTB solutions were considered to have potential for future applications. Primary analytical methods for examining CD-PTB products included differential scanning calorimetry and Fourier transform infrared spectroscopy to detect the occurrence of binary complex formation. Phase solubility analysis was used to probe CD-PTB complexation in an aqueous solution. Complexation was evident in both the solid-state and in solution. Complex association constants (K1:1) in an aqueous solution spanned the approximate range of 15,000 to 55,000 M-1; the values increased with the CDs in the order HPβCD < DIMEB < RAMEB < SBECD. Significant PTB solubility enhancement factors were recorded at 100 mM CD concentrations, the most accurately determined values being in the range 700-fold to 1250-fold.

Fabrication of fucoxanthin/2-hydroxypropyl-β-cyclodextrin inclusion complex assisted by ultrasound procedure to enhance aqueous solubility, stability and antitumor effect of fucoxanthin

Fucoxanthin (Fx) possesses multiple bioactivities such as antitumor, antioxidant and anti-inflammatory activities, but its application is limited due to the poor water solubility, low bioavailability, and instability to some external harsh conditions. In this study, a stable inclusion complex of Fx and 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) was prepared with the aid of ultrasound, which was characterized by scanning electron microscope, Fourier transform infrared spectroscopy, powder X-ray diffraction, and differential scanning calorimetry techniques. The phase solubility analysis and absorption spectroscopy results showed that Fx formed stoichiometry 1:2 inclusion complex with 2-HP-β-CD, and this could be well proved by molecular simulation. Structural analyses and molecular docking study indicated that Fx was successfully encapsulated into the cavity of 2-HP-β-CD, promoting it soluble in water and stable against heat, storage and gastrointestinal environments. In addition, Fx/2-HP-β-CD inclusion complex exhibited excellent antitumor activity against HCT116 and Caco-2 cell lines with IC50 values of 12.0 μΜ and 14.86 μΜ, respectively. Therefore, it could be a potentially promising way to promote the application of Fx in pharmaceuticals and functional foods by HP-β-CD encapsulation strategy.

ENCAPSULATION OF EXEMESTANE WITH β-CYCLODEXTRIN AND TERNARY AGENT: FORMULATION, EVALUATION AND ANTICANCER ACTIVITY

Objective: A potent aromatase inhibitor, Exemestane, is well known for its anticancer action in breast neoplasm. The vital problem of this medicament is its poor aqueous solubility, which hinders its dissolution in body fluids. Therefore, the present study targets to enhance the water solubility of Exemestane by means of its complexation with β-cyclodextrin and a suitable ternary agent. Methods: Inclusion complexes of Exemestane with β-cyclodextrin and ternary agent were prepared by kneading and lyophilization technique. Different hydrophilic polymers and organic acids were screened for their influential ability as a co-complex with a carrier; β-cyclodextrin. The validation of complex formation was carried out by various solid-state techniques. The geometry of Exemestane in the β-cyclodextrin cavity was picturized in docking studies. The in vitro anticancer activity of prepared inclusion complex formulations carried out using MCF-7 cell lines Results: Phase solubility analysis proved HPMC E5 as the best ternary agent for complexation of Exemestane with β-cyclodextrin as it improved the stability constant of the drug from 665.92 M-1 to 1238.38 M-1. The synthesized binary and ternary inclusion complexes exhibited 2.74 and 4.62 times enhanced solubilization of Exemestane. Likewise, the dissolution characteristics of Exemestane were improved, and drug release was increased by 1.18 and 1.42 times with binary and ternary freeze-dried formulations. Differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD) study results presented the formation of binary and ternary complexes with significantly drooped crystallinity. Docking studies predicted encapsulation of rings A, B, and C of Exemestane in the cavity of β-cyclodextrin. In-line results were obtained in Fourier transform infrared (FTIR) studies. The cell growth inhibition of 62.78 % was achieved with a ternary complex of Exemestane which was far superior than the pure active moiety that showed mere 44.56 % of inhibition. Conclusion: Altogether, it can be concluded that the inclusion complex of Exemestane boosted its aqueous solubility, resulting in its increased dissolution and in vitro anticancer activity in a breast cancer MCF-7 cell line.

Aurisin A Complexed with 2,6-Di-O-methyl-β-cyclodextrin Enhances Aqueous Solubility, Thermal Stability, and Antiproliferative Activity against Lung Cancer Cells.

Aurisin A (AA), an aristolane dimer sesquiterpene isolated from the luminescent mushroom Neonothopanus nambi, exhibits various biological and pharmacological effects. However, its poor solubility limits its use for further medicinal applications. This study aimed to improve the water solubility of AA via complexation with β-cyclodextrin (βCD) and its derivatives (2,6-di-O-methyl-βCD (DMβCD) and 2-hydroxypropyl-βCD (HPβCD). A phase solubility analysis demonstrated that the solubility of AA linearly enhanced with increasing concentrations of βCDs (ranked in the order of AA/DMβCD > AA/HPβCD > AA/βCD). Notably, βCDs, especially DMβCD, increased the thermal stability of the inclusion complexes. The thermodynamic study indicated that the complexation between AA and βCD(s) was a spontaneous endothermic reaction, and AA/DMβCD possesses the highest binding strength. The complex formation between AA and DMβCD was confirmed by means of FT-IR, DSC, and SEM. Molecular dynamics simulations revealed that the stability and compactness of the AA/DMβCD complex were higher than those of the DMβCD alone. The encapsulation of AA led to increased intramolecular H-bond formations on the wider rim of DMβCD, enhancing the complex stability. The antiproliferative activity of AA against A549 and H1975 lung cancer cells was significantly improved by complexation with DMβCD. Altogether, the satisfactory water solubility, high thermal stability, and enhanced antitumor potential of the AA/DMβCD inclusion complex would be useful for its application as healthcare products or herbal medicines.

Sustained release of edaravone from (2-hydroxypropyl)-β-cyclodextrin mediated tamarind kernel powder/kappa-carrageenan hydrogel: Microwave-assisted synthesis and optimization using experimental design

In the current study, a sustained release formulation made of natural polysaccharide tamarind kernel powder/kappa-carrageenan and (2-hydroxypropyl)-β-cyclodextrin (2-Hp-β-CD) was chosen to increase drug effectiveness. A kappa-carrageenan and tamarind kernel powder 3-D hydrogel network was synthesized with the aid of microwave irradiations. The ICs complexes were prepared using a physical mixture (PM), kneading (KM), and microwave (MW) approach and were then successfully loaded into the hydrogel. The synthesis of ICs was verified as a true IC using DSC, SEM, FTIR, 1H NMR, and 2D NMR ROESY. A study on the in vitro sustained release of EV at pH 2, 7, and 7.4 was conducted at 37 °C. The microwave (MW) method was the most effective method for preparing true ICs of EV and 2-Hp-β-CD for sustained drug release, as evidenced by the drug release data, which indicated that PM and KM displayed a burst release of the drug. Ritger-Peppas and Peppas-Sahlin were essential models for drug release. A phase solubility analysis was done to evaluate the IC's stoichiometry and complexation constant. Studies on drug release have shown that 2-Hp-β-CD was effective at causing pH-responsive sustained drug release.

Microwave Irradiation Technique, a Green Chemistry Approach for Dissolution Enhancement of Lopinavir

Aim: This research was focused on improvement of aqueous solubility of Lopinavir (LPO), Antiretroviral (ART) drug by preparing solid dispersion (SD) through microwave irradiation (MWI) technique as a green chemistry approach.&#x0D; Place and Duration of Study: Department of Pharmaceutics, M. C. E. Society’s Allana College of Pharmacy, CIF-SPPU, Pune, between June 2018 and July 2021&#x0D; Methodology: In MWI different batches of SD were formulated by 32 factorial approach with time of exposure (X1) and power of radiation (X2) as variable quantity and dissolution rate as response (Y1). β-CD was used as hydrophilic carriers. Drug carrier magnitude relation of 1:1 resolve by phase solubility analysis and SD were assessed for drug content, percentage dissolution rate studies, FTIR, XRD, DSC and SEM analysis.&#x0D; Results: The FTIR, XRD, DSC and SEM studies exhibited no interaction between LPO and excipient. In Physical mixture (PM) it shows less intensity and disappearance of sharp peaks while in SD indicates the conversion of crystalline state of LPO to amorphous state that discovered the dissolution enhancing, so the SD prepared by MWI proved to be a promising approach to increasing the dissolving rate of BCS class II drug LPO.&#x0D; Conclusion: Hence, from the all analysis studies, it absolutely was evident that factorial batch F1 was the higher. F1 coded batch (LPO: β-CD within the magnitude relation of 1:1 with time of exposure (4 min) and power of radiation (300 Watt), shows 07 folds increase i.e. 84% compared with drug discharged inside 60 min to plane LPO and SD i.e. 12 % only and 84% respectively.

Therapeutic efficacy of an injectable formulation of purinostat mesylate in SU-DHL-6 tumour model

Background: Previous studies have proven that Purinostat Mesylate (PM) is a new HDAC inhibitor and exhibits significant antitumor efficacy. However, the clinical application of PM was greatly limited by its poor solubility in water and low bioavailability. Objective:To increase the solubility of PM through pharmaceutical research, and prepare it into an injection that meets the needs of intravenous use to promote its clinical application. MethodsThe prepared PM/HP-β-CD inclusion complex was studied by computer simulation, fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (1H-NMR spectroscopy), and scanning electron microscopy (SEM). Then, the antitumor effects of PM/HP-β-CD inclusion complex were studied by in vitro cytotoxicity assay, apoptosis assay, pharmacokinetic study and in vivo antitumor assay. Results:Phase Solubility Analysis revealed that PM and HP-β-CD were compatible and the solubility of PM increased almost 220 times, to 2.02 mg/mL. The interaction mechanism studies revealed that PM could be embedded into the cavity of HP-β-CD through the side of the aminobenzene ring. Cell viability and apoptosis assays showed that PM/HP-β-CD complex maintained the good anti-cancer activity of PM, and PM/HP-β-CD complex has a better anti-tumor effect and lower toxicity than LBH589 and Hyper-CVAD/RTX in vivo. All the results suggest that HP-β-CD can solve the problem of PM administration and provide a way for clinical application of PM. Conclusions: In this study, an injectable formulation of PM in HP-β-CD (10% w/v) was prepared to improve its water solubility. Our research provides a way for clinical administration of PM, which has been under phase I clinical trial for the treatment of relapsed or refractory B-cell-related hematologic malignancies in China and the USA. KEY MESSAGES We developed a preparation of Purinostat Mesylate that can be administered intravenously, reducing the toxicity associated with oral administration. This preparation has an outstanding therapeutic effect on SU-DHL-6 xenograft tumour, indicating its clinical value, which has been under phase I clinical trial for the treatment of relapsed or refractory B-cell-related haematologic malignancies in China and the USA.

Enhanced solubility of curcumin by complexation with fermented cyclic β-1,2-glucans

Curcumin (CUR) is a low-solubility polyphenolic compound with many physiological functions. Cyclic β-1,2-glucans (cyclosophoraoses [Cys]), which contain rings of different sizes with degrees of polymerization ranging from 17 to 23, were obtained from Rhizobium radiobacter ATCC 1333, a soil microorganism. The complexation ability and solubility enhancement of cyclic β-1,2-glucans with insoluble curcumin were investigated. Phase-solubility analysis revealed that the stoichiometric ratio of the inclusion complexes was 1:1. The stability constant of Cys was 930 M−1, which was 7.68 times that of α-cyclodextrin (α-CD) and 2.09 times that of β-cyclodextrin (β-CD). The characteristics of the curcumin/Cys inclusion complexes were successfully determined by using Fourier transform infrared (FTIR) spectrometry, differential scanning calorimetry (DSC), nuclear magnetic resonance (1H NMR) spectroscopy, and scanning electron microscopy (SEM). Moreover, a 1:1 molecular model of the curcumin/Cys inclusion complexes was established through molecular docking analysis. These findings indicated that cyclic β-1,2-glucans successfully formed complexes with curcumin, which suggested that they could be used as solubility-increasing agents. To the best of our knowledge, this is the first report in which curcumin has been embedded into cyclic β-1,2-glucans resulting in an increase in its aqueous solubility.

Inclusion Complexes of Rifampicin with Native and Derivatized Cyclodextrins: In Silico Modeling, Formulation, and Characterization.

Inclusion complexation of rifampicin (RIF) with several types of cyclodextrins (βCD, hydroxypropyl-βCD, γCD, hydroxypropyl-γCD) in aqueous solutions at different pH values was investigated to assess the interactions between RIF and cyclodextrins (CDs). Molecular modeling was performed to determine the possible interactions between RIF and CDs at several pH values. The inclusion complexes were characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, powder X-ray diffractometry, and scanning electron microscopy. Moreover, this study evaluated the dissolution profile and antibacterial activity of the formed complexes. Phase solubility analysis suggested the formation of RIF-CD affirmed 1:1 stoichiometry at all pH values (except RIF-βCD at pH 4.0 and both βCD and γCD at pH 9.0). The inclusion complexation of RIF with CD successfully increased the percentage of RIF released in in vitro studies. The inclusion complexes of RIF exhibited more than 60% of RIF released in 2 h which was significantly higher (p < 0.05) than release of pure RIF, which was only less than 10%. Antibacterial activity of RIF-CD complexes (measured by the minimum inhibitory concentration of RIF against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus) was lower for both RIF-βCD and RIF-HPγCD at pH 7.0 to pure RIF suspension. In conclusion, this work reports that both βCD and γCD can be used to enhance the solubility of RIF and thus, improve the effectivity of RIF by decreasing the required daily dose of RIF for the treatment of bacterial infections.

Spray dried nanospheres for inclusion complexes of cefpodoxime proxetil with β-cyclodextrin, 2-hydroxypopyl-β-cyclodextrin and methyl-β-cyclodextrin: improved dissolution and enhanced antibacterial activity

Objective The aim of the current research was the development hard cellulose capsules containing cefpodoxime proxetil (CEF) (BCS-Class II) encapsulated nanospheres of inclusion complexes with β-CD, HP-β-CD and M-β-CD for efficient antibacterial therapy. Significance The reason for this phenomenon is to bring an innovative approach to effective oral antimicrobial therapy with hard cellulose capsules containing spray dried nanospheres of CEF with β-CD, HP-β-CD and M-β-CD by means of increased solubility, dissolution rate and improved antibacterial efficiency with lower oral dose. Methods Phase solubility analyses was performed to evaluate the drug/CD interaction, involving the stoichiometry and apparent stability constant. Following the preparation of inclusion complexes by spray-drying method, complexes were characterized for physical, solid-state and microbiological analyses. In vitro dissolution from hard cellulose capsules containing CEF and CEF/β-CD, CEF/HP-β-CD and CEF/M-β-CD complexes were performed. Results According to AL type phase solubility curves, complexes were formulated as 1:1 molar ratio. The solubility of pure CEF was determined as 0.241 ± 0.002 mg mL−1, the solubility of inclusion complexes increased solubility from 3 to 5 times. The strong host–guest interaction was confirmed for CEF/HP-β-CD and CEF/M-β-CD complexes with SEM, DSC, FT-IR and 1H-NMR analyses. Inclusion complexes were more efficient on bacterial cells (2–4 fold) than pure CEF both Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae. Hard-cellulose capsules filled with inclusion complexes exhibited significantly faster release than unprocessed CEF. Conclusion Hard-cellulose capsules containing CEF/HP-β-CD and CEF/M-β-CD complexes appear to be superior alternative to commercially available CEF tablets for effective antibacterial therapy.

Differential mode of cholesterol inclusion with 2-hydroxypropyl-cyclodextrins increases safety margin in treatment of Niemann-Pick disease type C.

Niemann-Pick disease type C (NPC) is a lysosomal storage disorder with disrupted intracellular cholesterol trafficking. A cyclic heptasaccharide, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), is a cholesterol solubilizer that is being developed to treat NPC, but its ototoxicity and pulmonary toxicity remain important issues. We have characterized 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD), a cyclic octasaccharide with a larger cavity than HP-β-CD, as a candidate drug to treat NPC. However, the molecular target of HP-γ-CD with respect to NPC and its potential for clinical application are still unclear. We investigated the mode of interaction between HP-γ-CD and cholesterol by phase-solubility analysis, proton NMR spectroscopy and molecular dynamics simulations. We then evaluated the therapeutic effects of HP-γ-CD compared with HP-β-CD using cellular and murine NPC models. Mouse auditory and pulmonary function tests were also conducted. HP-γ-CD solely formed a 1:1 inclusion complex with cholesterol with an affinity similar to that of HP-β-CD. In vitro, HP-γ-CD and HP-β-CD amelioration of NPC-related manifestations was almost equivalent at lower concentrations. However, at higher concentrations, the cholesterol inclusion mode of HP-β-CD shifted to the highly soluble 2:1 complex whereas that of HP-γ-CD maintained solely the 1:1 complex. The constant lower cholesterol solubilizing ability of HP-γ-CD conferred it with significantly reduced toxicity compared with HP-β-CD, but equal efficacy in treating a mouse model of NPC. HP-γ-CD can serve as a fine-tuned cholesterol solubilizer for the treatment of NPC with a wider safety margin than HP-β-CD in terms of ototoxicity and pulmonary toxicity.