Sulfobutyl Ether Beta-cyclodextrin Research Articles

Eco-friendly HPLC Method for the determination of Ranolazine using Cyclodextrin as a green additive to mobile phase

Background: Minimizing the amount of organic solvents is one of the main goals of green analytical chemistry; Therefore, a rapid, simple, sensitive, and environmentally benign method for the determination of ranolazine in bulk and pharmaceuticaldosage form was developed. Methods: The method based on using ethanol s a green solvent: (4mmol/L) sodium sulfobutyl ether-betacyclodextrin SBE-β-CD(pH in aqueous phase=4) (25:75)as a green mobile phase, C18 5𝞵 (4.6*150mm) InertSustain GL Sciences column at room temperature 35°C, the flow rate was 1mL/min, the photo diode array detector was set at 210nm and injection volume was 20μL. Results: The developed method was validated according to International Conference on Harmonization guidelines and showed good linear relationship over the concentration range of 50-150mg/L with the correlation coefficient was obtained R2 = 0.9999. The LOD and LOQ were found to be 1.91 and 5.81mg/L, respectively. The Precision was studied as intra- and inter-day with relative standard deviations not more than 2%, and the accuracy by mean recoveries ranged between100.1-101%. The percentage recoveries of active pharmaceutical ingredient from dosage forms ranged between 99.67 - 100.2%. Addition of cyclodexetrine derivative to the mobile phase, decreases the retention time tR of the compound by 64%, more over, it allowed the method to be greener by the ability to use high percentage of aqueous phase. GAPI and eco-scale were used to evaluate the greenness of the developed method. Conclusion: The results showed that the developed eco-friendly method is suitable for the precise, accurate and rapid determination of Ranolazine in bulk and tablet dosage forms.

Berberine and cyclodextrin based supramolecular assembly for the detection of a cancer biomarker in complex biomatrices via indicator displacement assay

Spermine, an aliphatic tetramine plays a vital role in the growth and proliferation of cells. When tissues undergo growth-promoting hormonal stimulation, the concentration of spermine increases within the body. However, an elevated level of spermine in biological matrices like urine and serum is considered to be an effective indicator of various physiological disorders, specially the presence of malignant tissues within the body. Therefore, it is highly rewarding to accurately determine the concentration of spermine by an instant, label free, user friendly method. Herein, we present a supramolecular assembly of berberine (BBR) and sulfobutylether beta cyclodextrin (SBE10βCD) as fluorescent probe for the quantification of spermine in complex bio-media. Formation of the BBR-SBE10βCD supramolecular assembly upon incorporation of BBR into the SBE10βCD cavity results in a significant increase in fluorescence intensity of the dye due to the reduction in its non-radiative decay channels. While spermine is introduced into the complex solution, it strongly binds with the polyanionic host, displacing BBR from the host cavity. This causes a dramatic reduction of the fluorescence intensity, which follows a linear trend as a function of spermine concentration. Thus, from the linear regression analysis of such fluorescence response, limit of detection (LOD) of spermine has been determined to be 0.8 µM and 1.49 µM, in 1% serum and 50% urine matrices respectively. This outcome showcases the practicality and suitability of the investigated system in the field of bio-sensing. Furthermore, excellent biocompatibility of both BBR and SBE10βCD, emission in the green region of the electromagnetic spectrum, well separated absorption and emission profiles make the studied supramolecular assembly a preferred choice for the initial diagnosis of malignant tissues within the body via indicator displacement assay (IDA).

Screening of Cyclodextrins in the Processing of Buserelin Dry Powders for Inhalation Prepared by Spray Freeze-Drying.

In this study, we prepared inhalable buserelin microparticles using the spray freeze-drying (SFD) method for pulmonary drug delivery. Raffinose as a cryoprotectant carrier was combined with two levels of five different cyclodextrins (CDs) and then processed by SFD. Dry powder diameters were evaluated by laser light scattering and morphology was determined by scanning electron microscopy (SEM). Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis were utilized for the determination of crystalline structures. The aerodynamic properties of the spray freeze-dried powders were evaluated by twin stage impinger (TSI) and the stability of prepared samples was assessed under normal and accelerated conditions. The prepared powders were mostly porous spheres and the size of microparticles ranged from 9.08 to 13.53 μm, which are suitable as spray-freeze dried particles. All formulations showed amorphous structure confirmed by DSC and XRD. The aerosolization performance of the formulation containing buserelin, raffinose and 5% beta-cyclodextrin (β-CD), was the highest and its fine particle fraction (FPF) was 69.38%. The more circular and separated structures were observed in higher concentrations of CDs, which were compatible with FPFs. The highest stability was obtained in the formulation containing hydroxypropyl beta-cyclodextrin (HP-β-16. CD) 5%. On the contrary, sulfobutylether beta-cyclodextrin (SBE-β-CD) 5% bearing particles showed the least stability. By adjusting the type and ratio of CDs in the presence of raffinose, the prepared formulations could effectively enhance the aerosolization and stability of buserelin. Therefore, they can be proposed as a suitable career for lung drug delivery.

Dissolution Enhancement of Indomethacin through Binary and Ternary Solid dispersions and Inclusion Complexes – A Comparative Evaluation

Dissolution of drugs is a prerequisite in the development of their oral dosage forms with satisfactory bioavailability. In this investigation, solid dispersion of the model drug indomethacin in gelucire (50/13) and inclusion complexation in sulfobutyl ether beta cyclodextrin are employed to enhance the dissolution. Fast dissolving products (F1-F8) of indomethacin are prepared by different methods such as solvent evaporation, freeze drying and kneading and comparatively evaluated. The ternary and binary systems of the products are prepared and evaluated for their efficiency in increasing the dissolution. The dissolution efficiency values (DE30) were found to be higher for solid dispersions (73.34%) and inclusion complexes (53.12%) than the pure drug indomethacin (3.32%). The x ray diffraction and differential scanning calorimetry studies revealed that the crystalline drug is converted into an amorphous form in the dispersions and inclusion complexes. Soluplus and gelucire are employed as ternary components in the solid dispersions and inclusion complexes respectively and are found to be resulting in ternary systems which were found to be superior to the binary systems. A 22 full factorial experimental design in order to investigate the combined influence of method of preparation and nature of the product. It was observed that the method of preparation and nature of the product (a ternary system or a binary system) will influence the extent of improvement of dissolution of the drug.

Supramolecular modulation in photophysical features of berberine and its application towards ATP sensing

In this study we report supramolecular interaction of the cationic dye berberine (BBR) with the highly substituted polyanionic cyclodextrin derivative, sulfobutylether beta cyclodextrin (SBE10βCD). Though interaction of BBR with parent β-cyclodextrin (βCD) host is very weak, its interaction with SBE10βCD host is significantly strong with an association constant Ka as large as ∼2.67 × 105 M−1. Strong binding of BBR with SBE10βCD is governed by cooperative effect of electrostatic attraction and enhanced hydrophobic interaction caused by extended SBE10βCD cavity for bound BBR dye. In the BBR-SBE10βCD complex, lower micropolarity and rigid microenvironment of host cavity cause a large decrease both in structural agility and intramolecular charge transfer (ICT) state formation of bound BBR. Accordingly, the non-radiative de-excitation of excited BBR in the dye-host complex is reduced significantly, causing its emission intensity to increase quite largely. The BBR-SBE10βCD complex is found to be highly sensitive towards ionic strength of the medium. This property is further explored to form a ternary complex, BBR-SBE10βCD-Cd2+, with largely reduced fluorescence intensity. Interestingly, this ternary complex exhibits selective fluorescence turn-on in response to an important bio-analyte, adenosine triphosphate (ATP). Present study, thus, demonstrates a very strong supramolecular complex, BBR-SBE10βCD, which is found to be very useful in the ATP detection in the presence of Cd2+, involving the ATP responsive fluorescence.

Design of Besifloxacin HCl-Loaded Nanostructured Lipid Carriers: In Vitro and Ex Vivo Evaluation.

Objective: In the treatment of severe cases of bacterial keratitis, conventional eye drops containing antibiotics should be applied daily and very frequently. The aim of this study is to develop low-dose high-effect formulations with the prepared nanostructured lipid carrier (NLC) formulations to reduce antibiotic resistance and increase patient compliance. Methods: NLC formulations were loaded with besifloxacin HCl (BHL) and the besifloxacin HCl: sulfobutyl ether beta-cyclodextrin (SBE-CD) complex. Positive charge was gained with chitosan, and corneal permeation and resolubility were increased with SBE-CD. In vitro characterization studies, permeability studies, and cytotoxicity and ex vivo transport studies were carried out. Results: In this study, it was found that SBE-CD increased BHL's solubility by 8-fold based on phase solubility studies. The optimized NLCs were small in size (13.63-16.09 nm) with a low polydispersity index (0.107-0.181) and adequate BHL drug loading efficiency. In vitro release studies showed that formulations were released approximately for 8 h and at levels over the minimum inhibitory concentration of Pseudomonas aeruginosa and Staphylococcus aureus. NLC formulations had a better corneal permeation rate than the marketed product during 6 h of ex vivo studies. Conclusions: According to in vitro and ex vivo data, it was determined that the most favorable NLC formulation was the formulation containing BHL/SBE-CD that was covered with chitosan. It has the highest drug loading capacity and one of the highest ex vivo corneal passage levels, along with desired drug release. The formulation containing BHL/SBE-CD and chitosan can be a potential alternative for the treatment of bacterial keratitis.

A combined molecular docking and molecular dynamics simulation approach to probing the host–guest interactions of Ataluren with natural and modified cyclodextrins

ABSTRACT The objective of this study was to apply molecular docking and molecular dynamics (MDs) simulation approaches to investigate the host–guest interactions between natural Cyclodextrins (CDs) (Alpha, Beta and Gamma Cyclodextrins) and some modified CDs (hydroxypropyl, sulfobutylether and randomly substituted methyl Beta Cyclodextrins) with Ataluren as a small molecule drug designed for diseases attributable to a nonsense mutation. Molecular docking results presented that randomly substituted methyl beta Cyclodextrin (RMBCD) has the highest binding affinity and Alpha Cyclodextrin (ACD) has the lowest binding affinity to Ataluren. According to the MDs simulation results, ACD and hydroxypropyl Cyclodextrin have not proper cavity for encapsulation of Ataluren. In contrast, Ataluren was totally included into the Beta Cyclodextrin (BCD), Gamma Cyclodextrin, sulfobutylether Beta Cyclodextrin (SBECD) and RMBCD due to appropriate interior capability. Moreover, MDs results showed that SBECD has the most conformational flexibility and BCD has the most conformational stability during simulation time. The results of this paper may open new paths to use this formulation for further researches in the delivery mechanism of hydrophobic pharmaceutical molecules.

A nephroprotective iodinated contrast agent with cardioprotective properties: A pilot study.

Background and PurposeEvaluation and treatment of acute ischemic syndromes, in the heart and brain, require vessel visualization by iodinated X‐ray contrast agents. However, these contrast agents can induce injury, in both the kidneys and target organs themselves. Sulfobutylether beta cyclodextrin (SBECD) added to iohexol (SBECD‐iohexol) (Captisol Enabled‐iohexol, Ligand Pharmaceuticals, Inc, San Diego, CA) is currently in clinical trials in cardiovascular procedures, to determine its relative renal safety in high‐risk patients. Preclinical studies showed that SBECD‐iohexol reduced contrast‐induced acute kidney injury in rodent models by blocking apoptosis. The current study was undertaken to determine whether SBECD‐iohexol is also cardioprotective, in the male rat ischemia‐reperfusion model, compared to iohexol alone.MethodsAfter anesthesia, the left coronary artery was ligated for 30 min and the ligation released and reperfusion followed for 2 h prior to sacrifice. Groups 1–4 were injected in the tail vein 10 min prior to ischemia with: (1) vehicle; (2) iohexol; (3) SBECD; and (4) SBECD‐iohexol. Infarct size, hemodynamics, and serum markers were measured.ResultsAn eight‐fold increase in serum creatine kinase in the iohexol‐alone group was observed, compared with no increase in the SBECD‐iohexol group. The mean arterial pressure and rate pressure product were depressed in the iohexol‐alone group, but not in the SBECD‐iohexol group, or controls. No difference in infarct size or serum creatinine among the groups was observed.ConclusionThe results of this study suggest that SBECD‐iohexol is superior to iohexol alone, for both the preservation of cardiomyocyte integrity and preservation of myocardial function in myocardial ischemia.

Sulfobutylether-beta-cyclodextrin-enabled antiviral remdesivir: Characterization of electrospun- and lyophilized formulations

Veklury™ by Gilead Sciences, Inc., containing antiviral drug, remdesivir (REM) has received emergency authorization in the USA and in Europe for COVID-19 therapy. Here, for the first time, we describe details of the non-covalent, host-guest type interaction between REM and the solubilizing excipient, sulfobutylether-beta-cyclodextrin (SBECD) that results in significant solubility enhancement. Complete amorphousness of the cyclodextrin-enabled REM formulation was demonstrated by X-ray diffraction, thermal analysis, Raman chemical mapping and electron microscopy/energy dispersive spectroscopy. The use of solubilizing carbohydrate resulted in a 300-fold improvement of the aqueous solubility of REM, and enhanced dissolution rate of the drug enabling the preparation of stable infusion solutions for therapy. 2D ROESY NMR spectroscopy provided information on the nature of REM–excipient interaction and indicated the presence of inclusion phenomenon and the electrostatic attraction between anionic SBECD and nitrogen-containing REM in aqueous solution.

Cyclodextrin Diethyldithiocarbamate Copper II Inclusion Complexes: A Promising Chemotherapeutic Delivery System against Chemoresistant Triple Negative Breast Cancer Cell Lines.

Diethyldithiocarbamate Copper II (DDC-Cu) has shown potent anticancer activity against a wide range of cancer cells, but further investigations are hindered by its practical insolubility in water. In this study, inclusion complexes of DDC-Cu with hydroxypropyl beta-cyclodextrin (HP) or sulfobutyl ether beta-cyclodextrin (SBE) were prepared and investigated as an approach to enhance the apparent solubility of DDC-Cu. Formulations were prepared by simple mixing of DDC-Cu with both cyclodextrin (CDs) at room temperature. Phase solubility assessments of the resulting solutions were performed. DDC-Cu CD solutions were freeze-dried for further characterisations by DSC, thermogravimetric analysis (TGA) and FT-IR. Stability and cytotoxicity studies were also performed to investigate the maintenance of DDC-Cu anticancer activity. The phase solubility profile deviated positively from the linearity (Ap type) showing significant solubility enhancement of the DDC-Cu in both CD solutions (approximately 4 mg/mL at 20% w/w CD solutions). The DSC and TGA analysis confirmed the solid solution status of DDC-Cu in CD. The resulting solutions of DDC-Cu were stable for 28 days and conveyed the anticancer activity of DDC-Cu on chemoresistant triple negative breast cancer cell lines, with IC50 values less than 200 nM. Overall, cyclodextrin DDC-Cu complexes offer a great potential for anticancer applications, as evidenced by their very positive effects against chemoresistant triple negative breast cancer cells.

Inclusion Complexation in Sulfobutyl Ether Beta Cyclodextrin and Dispersion in Gelucire for Sustained Release of Nifedipine Employing Almond Gum

In the present research investigation, the utility of employing high dissolving forms of nifedipine for sustained release from matrix tablets with almond gum as major release retardant is explored. A poorly soluble BCS class II drug nifedipine is chosen as a model drug. Efforts were made to alter the dissolution characteristics of the drug before it is entrapped in the polymer matrix of almond gum. Inclusion complexation in sulfobutyl ether beta cyclodextrin or solid dispersion in gelucire (50/13) resulted in enhanced dissolution of nifedipine. The high dissolving forms are characterized by x-ray diffraction, differential scanning calorimetry and infra-red spectroscopy. The matrix tablets prepared employing the high dissolving forms exhibited satisfactory characteristics such as hardness, friability, swelling index. The drug release is found to be slow and spread over a period of 12 hours and the release could be modified with changes in nature of high dissolving form and the proportion of almond gum as the major release retardant. Employing high dissolving forms in matrix tablets of almond gum is found to be a novel approach in obtaining slow and complete release of poorly soluble drug such as nifedipine.
 Keywords: sulfobutyl ether beta cyclodextrin, solid dispersion, nifedipine

Utility of Sulfobutyl Ether beta-Cyclodextrin Inclusion Complexes in Drug Delivery: A Review

The potential of beta-cyclodextrins as a pharmaceutical aid has been established through several decades of research. However, some beta-cyclodextrins are reported to be toxic causing deleterious effects on long term usage. In the recent past, sulfobutyl ether beta-cyclodextrin, a modified beta-cyclodextrin has captured interest as a comparatively safer and effective beta-cyclodextrin for increasing the solubility and the bioavailability of biopharmaceutical classification system class II drugs. Sulfobutyl ether beta-cyclodextrin has demonstrated immense potential in addressing solubility and stability issues associated with formulation of drugs. Till date no comprehensive report on their utility in drug development has been published. Hence, this review focusses on the structure, properties, preparation techniques and applications of sulfobutyl ether beta-cyclodextrin inclusion complexes. Investigation of the feasibility of forming stable inclusion complexes of sulfobutyl ether beta-cyclodextrin and various drugs as guest molecules using molecular modelling techniques have been elaborated in the review. Incorporation of sulfobutyl ether beta-cyclodextrin complexes into novel drug delivery systems (liposomes and nanoformulations) have been summarized along with various methods of preparation and the clinical safety. Molecular modelling approach discussed in this review, coupled with wet-lab validation of the complexes, will enable a faster transit of the delivery systems into the clinical setting.

In silico prediction coupled with in vitro experiments and absorption modeling to study the inclusion complex of telmisartan with modified beta-cyclodextrin

Telmisartan (TEL) is a poorly bioavailable antihypertensive drug candidate owing to its low solubility in all the biofluids. The present study is aimed to enhance the solubility of TEL by forming an inclusion complex with sulfobutylether beta-cyclodextrin (SBE-β-CD), discover its mode of inclusion and predict the bioavailability of the prepared complexes. The formation of the inclusion complex is explained based on the hydrogen bond propensities and molecular dynamics simulations. Freeze-drying method was employed for the preparation of inclusion complexes. These complexes were subsequently characterized by powder X-ray diffraction, differential scanning calorimetry, and Fourier transform-infrared spectroscopy. The spatial configuration of the drug inside the cyclodextrin cavity is probed using 1H and 13C NMR. The in silico docking results are in good agreement with the experimental data and reveal that the hydrogen bond is formed as a part of the guest molecule enters from the broader end of the ring and the protons at the interior portion of the molecule interact with the carboxylic acid (–COOH) group of TEL leading to the formation of a hydrogen bond. The phenyl moiety of TEL occupies the central core and forms multiple Van-der-Waals interactions with the glucopyranose units of the SBE-β-CD. The inclusion complex demonstrates significantly higher in vitro dissolution profile as compared with plain TEL. The GastroPlus™ simulation software generated parameters of inclusion complex in comparison to plain TEL show a seven fold increase in Cmax and 18 fold increase in bioavailability.

Intravenous delivery of a liposomal formulation of voriconazole improves drug pharmacokinetics, tissue distribution, and enhances antifungal activity

Voriconazole (VCZ), a triazole with a large spectrum of action is one of the most recommended antifungal agents as the first line therapy against several clinically important systemic fungal infections, including those by Candida albicans. This antifungal has moderate water solubility and exhibits a nonlinear pharmacokinetic (PK) profile. By entrapping VCZ into liposomes, it is possible to circumvent certain downsides of the currently available product such as a reduction in the rate of its metabolization into an inactive form, avoidance of the toxicity of the sulfobutyl ether-beta-cyclodextrin (SBECD), vehicle used to increase its solubility. PKs and biodistribution of VCZ modified by encapsulation into liposomes resulted in improved antifungal activity, due to increased specificity and tissue penetration. In this work, liposomal VCZ resulted in AUC0–24/MIC ratio of 53.51 ± 11.12, whereas VFEND® resulted in a 2.5-fold lower AUC0–24/MIC ratio (21.51 ± 2.88), indicating favorable antimicrobial systemic activity. VCZ accumulation in the liver and kidneys was significantly higher when the liposomal form was used. Protection of the drug from biological degradation and reduced rate of metabolism leads to a 30% reduction of AUC of the inactive metabolite voriconazole-N-oxide (VNO) when the liposomal drug was administered. Liposomal VCZ presents an alternative therapeutic platform, leading to a safe and effective treatment against systemic fungal infections.

Ready-to-use parenteral amiodarone: a feasibility study towards a long-term stable product formulation

ObjectivesTo determine the feasibility of preparing a long-term stable ready-to-use parenteral amiodarone formulation using cyclodextrins as dissolution enhancer.MethodsA preformulation study was performed with different molar ratios of hydroxypropyl-beta-cyclodextrin (HP-BCD) or...

Inclusion complex of erlotinib with sulfobutyl ether-β-cyclodextrin: Preparation, characterization, in silico, in vitro and in vivo evaluation

The aim of the study was to investigate the impact of erlotinib sulfobutyl ether beta-cyclodextrin complex (ERL-SBE-β-CD) on ERL dissolution rate and oral bioavailability. Preliminary comparative phase solubility study indicated ERL exhibited maximum solubility in SBE-β-CD solution. Optimal experimental design confirmed freeze drying of SBE-β-CD:ERL in 1:1.05 molar ratio as the optimum method. Differential scanning calorimetry (DSC), Fourier transformation infrared spectroscopy (FT-IR), powder X-ray diffractometry (PXRD), proton nuclear magnetic resonance (1H NMR) and two-dimensional rotating-frame Overhauser effect spectroscopy (2D ROESY NMR) confirmed the inclusion complexation. The in silico computational study, employed to analyze the comparative interactions of ERL with SBE-β-CD and β-CD, indicated ease of ERL-SBE-β-CD complexation. In vitro dissolution and in vivo bioavailability studies further confirmed the ERL-SBE-β-CD as a valuable approach to enhance ERL oral bioavailability with 3.6-fold increase in relative oral bioavailability with higher Cmax (134.29±36.51 vs. 42.36±1.75μg/ml) and AUC0–∞ (2103.47±156.75 vs.580.43±71.91μg/mlh) over the free drug. The complex exhibited 3.2-fold increase in Cmax with 5.4-fold decrease in Tmax (0.5±0.2 vs. 2.7±0.8h) in comparison to pure ERL. Thus, ERL-SBE-β-CD complexation exhibits a potential to enhance oral bioavailability of ERL leading to reduce dose and dose-related side effects.

Safety and Tolerability of Voriconazole in Patients with Baseline Renal Insufficiency and Candidemia

Acutely ill patients with candidemia frequently suffer from renal insufficiency. Voriconazole's intravenous formulation with sulfobutylether beta-cyclodextrin (SBECD) is restricted in patients with renal insufficiency. We evaluated the use of intravenous voriconazole formulated with SBECD in candidemic patients with renal insufficiency and compared treatment outcome and safety to those who received a short course of amphotericin B deoxycholate followed by fluconazole. We reviewed data on treatment outcome, survival, safety, and tolerability from the subset of patients with moderate (creatinine clearance [CrCl], 30 to 50 ml/min) or severe (CrCl, <30 ml/min) renal insufficiency enrolled in a trial of voriconazole compared to amphotericin B deoxycholate followed by fluconazole for treatment of candidemia in 370 patients. Fifty-eight patients with renal impairment were identified: 41 patients on voriconazole and 17 on amphotericin B/fluconazole. The median duration of treatment was 14 days for voriconazole (median, 7 days intravenous) and 11 days for amphotericin B/fluconazole, 3 days of which were for amphotericin B. Despite the short duration of exposure, worsening of renal function or newly emerged renal adverse events were reported in 53% of amphotericin B-treated patients compared to 39% of voriconazole-treated patients. During treatment, median serum creatinine decreased in the voriconazole arm, whereas creatinine increased in the amphotericin B/fluconazole arm, before return to baseline at week 3. All-cause mortality at 14 weeks was 49% in the voriconazole arm compared to 65% in the amphotericin B/fluconazole arm. Intravenous voriconazole formulated with SBECD was effective in patients with moderate or severe renal insufficiency and candidemia and was associated with less acute renal toxicity than amphotericin B/fluconazole.

EFFECT OF SULFOBUTYL ETHER BETA-CYCLODEXTRIN MODIFIER ON SELECTIVITY OF REVERSED PHASE HPLC SEPARATIONS

Selectivity changes imparted by sulfobutyl ether beta-cyclodextrin (SBECD) modifier were evaluated in reversed phase HPLC separations. The mixed mode capabilities of SBECD, including cation exchange and an orthogonal hydrophobic interaction (i.e., via inclusion complex), altered the typical retention properties of a C18 column. This enabled several racemates (fenoterol, idazoxan hydrolyzate, orciprenaline, terbutaline, tranylcypromine, and imazalil) to be resolved. The selectivity of SBECD is distinct, as the related sulfated beta-cyclodextrin (SCD) modifier separated different racemates (1-aminoindane, fenoterol, both idazoxan and its hydrolyzate, nefopam, terbutaline, and tranylcypromine). The SBECD modifier also improved main peak resolution or altered impurity profiles for the fermentation-derived drug substances A40926, ramoplanin, teicoplanin, and vancomycin. Selectivity changes from SBECD were shown to be beneficial for chiral and chemical purity separations. Moreover, cyclodextrin modifier may enable a combined chiral and overall chemical purity method to be developed, which is not feasible by only using current chiral or reversed phase C18 columns alone. This study demonstrated that cyclodextrins and their derivatives are underutilized for HPLC and warrant consideration as a viable alternative to commercially available chiral or mixed mode columns.

Novel sulfobutyl ether cyclodextrin gradient leads to highly active liposomal irinotecan formulation

Liposomal delivery of irinotecan could provide protection against drug hydrolysis, deliver more active lactone form to tumours and prolong irinotecan exposure time. Nevertheless, conventional drug-loading technologies have typically resulted in undesired drug retention properties. To resolve the problem, a modified gradient loading method was developed and the resulting formulations were evaluated in a systemic manner. Irinotecan was loaded into liposomes using a novel sulfobutyl ether beta-cyclodextrin (sbe-CD) gradient. The effect of drug-to-lipid ratio (D/L) and polyethylene glycol (PEG) grafting density were investigated. Drug release experiments were performed in ammonium-containing medium based on the fluorescence dequenching phenomenon of irinotecan. Pharmacokinetic studies were performed in normal balb/c mice treated with different formulations. To compare the anti-tumour effect of different formulations, an RM-1 prostate cancer model was used. Acute toxicity studies were performed in healthy female c57 mice. Irinotecan could be encapsulated into liposomes with >90% loading efficiency at a high drug-to-lipid mass ratio (>0.5). In-vitro release experiments revealed that sbe-CD anion was more able to retain irinotecan than sulfate. Moreover, the elevated D/L ratio elicited decreased drug release kinetics. Both trends had also been observed when the effects of anions and D/L ratio on half-life of irinotecan were assessed. Pegylated liposomal irinotecan loaded with sbe-CD/triethylammonium gradient had irinotecan half-life values ranging from 9.4 to 13.1 h, surpassing vesicles prepared by the triethylammonium sulfate method (∼4.5 h). In the RM-1 tumour model, all the liposomal irinotecan formulations were more therapeutically active than free irinotecan and the formulation with a high D/L ratio was the most efficacious. Moreover, the high D/L formulation might be less toxic than free irinotecan based on acute toxicity studies. The novel sbe-CD gradient could mediate effective irinotecan loading and improve irinotecan retention, thus resulting in highly active liposomal irinotecan formulations. The improvement in drug retention might be associated with the formation of complicated aggregates inside vesicles.

Development and validation of a nylon6 nanofibers mat-based SPE coupled with HPLC method for the determination of docetaxel in rabbit plasma and its application to the relative bioavailability study

A simple and sensitive HPLC method was established and validated for the determination of docetaxel (DTX) in rabbit plasma. Biosamples were spiked with paclitaxel (PCX) as an internal standard (I.S.) and pre-treated by solid-phase extraction (SPE). The SPE procedure followed a simple protein digestion was based on nylon6 electrospun nanofibers mats as sorbents. Under optimized conditions, target analytes in 500 μL of plasma sample can be completely extracted by only 2.5 mg nylon6 nanofibers mat and eluted by 100 μL solvent. The HPLC separation was obtained on C18 column and UV detector was used to quantify the target analytes. The extraction recovery was more than 85%; the standard curve was linear over the validated concentrations range of 10–5000 ng/mL and the limit of detection was 2 ng/mL. The inter-day coefficient of variation (CV%) of the calibration standards was below 5.0% and the mean accuracy was in the range of 92.8–113.4%. Moreover, analysing quality control plasma samples in 3 days, the results showed that the method was precise and accurate, for the intra- and inter-day CV% within 10% and the accuracy from 96.0% to 114.0%. The developed and validated method was successfully applied to relative bioavailability study for the preclinical evaluation of a new injectable DTX–sulfobutyl ether beta-cyclodextrin (DTX–SBE-β-CD) inclusion complex freeze-dried powder (test preparation), compared with the reference preparation (DTX injection, Taxotere ®) in healthy rabbits. On the basis of the mean AUC(0– t) and AUC(0–infinity), the relative bioavailability of the test preparation was found to be 113.1%.