Enhanced oral bioavailability of acyclovir by inclusion complex using hydroxypropyl-β-cyclodextrin

An alternative cyclodextrin based formulation for oral anticancer drug exemestane: In vitro and cell culture studies

The study was designed to investigate the effect of cyclodextrins (CDs) on the solubility, dissolution rate, and bioavailability of cilostazol by forming inclusion complexes. Natural CDs like beta-CD, gamma-CD, and the hydrophilic beta-CD derivatives, DM-beta-CD and HP-beta-CD, were used to prepare inclusion complexes with cilostazol. Phase solubility study was carried out and the stability constants were calculated assuming a 1:1 stoichiometry. Solid cilostazol complexes were prepared by coprecipitation and kneading methods and compared with physical mixtures of cilostazol and cyclodextrins. Prepared inclusion complexes were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC), and X-ray diffraction (XRD) studies. In vitro dissolution study was performed using phosphate buffer pH 6.4, distilled water, and HCl buffer pH 1.2 as dissolution medium. The optimized inclusion complex was studied for its bioavailability in rabbit and the results were compared with those of pure cilostazol and Pletoz-50. Phase solubility study showed dramatic improvement in the solubility of drug by formation of complexes, which was further increased by pH adjustment. The dissolution rate of cilostazol was markedly augmented by the complexation with DM-beta-CD. DSC and XRD curves showed sharp endothermic peaks indicating the reduction in the microcrystallinity of cilostazol. Selected inclusion complex was also stable at ambient temperature up to 6 months. The in vivo study revealed that DM-beta-CD increased the bioavailability of cilostazol with low variability in the absorption. Among all cilostazol-cyclodextrins complexes, cilostazol-DM-beta-CD inclusion complex (1:3) prepared by coprecipitation method showed 1.53-fold and 4.11-fold increase in absorption along with 2.1-fold and 2.97-fold increase in dissolution rate in comparison with Pletoz-50 and pure cilostazol, respectively.

Celecoxib is a non-steroidal anti-inflammatory drug (NSAID) used for the treatment of pain and inflammation. Celecoxib is included in class II in the Biopharmaceutis ClassificationAsystem drug (BCS) which has low solubility and high permeability. This study aims to increase the solubility and dissolution rate of celecoxib by characterizing the inclusion complex of celecoxib β-cyclodextrin. Inclusion complexes were prepared by the solvent evaporation method using a water-soluble polymer, β-cyclodextrin. The inclusion complexes were prepared in a 1: 1 ratio between celecoxib and β-cyclodextrins. As a comparison, a physical mixture with the same composition was made. Powder mixtures of physics and inclusion complexes characterized by physicochemical properties include: FT-IR spectroscopy analysis, DSC analysis, assay and dissolution test. The dissolution test was determined by the paddle method. The results of characterization of the inclusion complex using FT-IR spectrophotometry showed a shift in the wave number as well as the physical interaction between celecoxib and β-cyclodextrin. The results of the DSC (Differential Scanning Calorimetry) decreased the enthalpy and melting point between celecoxib, the physical mixture and the inclusion complex. The dissolution test showed an increase in dissolution rate at 60 minutes, namely Celecoxib 55.03%, physical mixture 61.58% and inclusion complex 67.53%.

SN-38, an active metabolite of irinotecan, is up to 1,000-fold more potent than irinotecan. But the clinical use of SN-38 is limited by its extreme hydrophobicity and instability at physiological pH. To enhance solubility and stability, SN-38 was complexed with different cyclodextrins (CDs), namely, sodium sulfobutylether β-cyclodextrin (SBEβCD), hydroxypropyl β-cyclodextrin, randomly methylated β-cyclodextrin, and methyl β-cyclodextrin, and their influence on SN-38 solubility, stability, and in vitro cytotoxicity was studied against ovarian cancer cell lines (A2780 and 2008). Phase solubility studies were conducted to understand the pattern of SN-38 solubilization. SN-38-βCD complexes were characterized by differential scanning calorimetry (DSC), X-ray powder diffraction analysis (XRPD), and Fourier transform infrared (FTIR). Stability of SN-38-SBEβCD complex in pH 7.4 phosphate-buffered saline was evaluated and compared against free SN-38. Phase solubility studies revealed that SN-38 solubility increased linearly as a function of CD concentration and the linearity was characteristic of an AP-type system. Aqueous solubility of SN-38 was enhanced by about 30-1,400 times by CD complexation. DSC, XRPD, and FTIR studies confirmed the formation of inclusion complexes, and stability studies revealed that cyclodextrin complexation significantly increased the hydrolytic stability of SN-38 at physiological pH 7.4. Cytotoxicity of SN-38-SBEβCD complex was significantly higher than SN-38 and irinotecan in both A2780 and 2008 cell lines. Results suggest that SBEβCD encapsulated SN-38 deep into the cavity forming stable inclusion complex and as a result increased the solubility, stability, and cytotoxicity of SN-38. It may be concluded that preparation of inclusion complexes with SBEβCD is a suitable approach to overcome the solubility and stability problems of SN-38 for future clinical applications.

Cyclodextrin, an efficient tool for trans-anethole encapsulation: Chromatographic, spectroscopic, thermal and structural studies

The objective of the present research was to evaluate the physicochemical characteristics of berberine chloride and to assess the complexation of drug with 2-hydroxypropyl-β-cyclodextrin (HPβCD), a first step towards solution dosage form development. The parameters such as log P value were determined experimentally and compared with predicted values. The pH-dependent aqueous solubility and stability were investigated following standard protocols at 25°C and 37°C. Drug solubility enhancement was attempted utilizing both surfactants and cyclodextrins (CDs), and the drug/CD complexation was studied employing various techniques such as differential scanning calorimetry, Fourier transform infrared, nuclear magnetic resonance, and scanning electron microscopy. The experimental log P value suggested that the compound is fairly hydrophilic. Berberine chloride was found to be very stable up to 6 months at all pH and temperature conditions tested. Aqueous solubility of the drug was temperature dependent and exhibited highest solubility of 4.05 ± 0.09 mM in phosphate buffer (pH 7.0) at 25°C, demonstrating the effect of buffer salts on drug solubility. Decreased drug solubility was observed with increasing concentrations of ionic surfactants such as sodium lauryl sulfate and cetyl trimethyl ammonium bromide. Phase solubility studies demonstrated the formation of berberine chloride-HPβCD inclusion complex with 1:1 stoichiometry, and the aqueous solubility of the drug improved almost 4.5-fold in the presence of 20% HPβCD. The complexation efficiency values indicated that the drug has at least threefold greater affinity for hydroxypropyl-β-CD compared to randomly methylated-β-CD. The characterization techniques confirmed inclusion complex formation between berberine chloride and HPβCD and demonstrated the feasibility of developing an oral solution dosage form of the drug.

To prepare ecdysterone (ES)/hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complex, thus improving the water solubility and bioavailability of ES. Phase-solubility study was performed to study the mass ratio of ES and HP-β-CD. Then, the ES/HP-β-CD inclusion complex was prepared by the solvent evaporation method, and its physicochemical properties were characterised using the SEM, DSC, XRD, 1HNMR and FT-IR. In addition, in vitro dissolution and bioavailability (oral and transdermal) experiments were also conducted. The inclusion complex was formed with ES and HP-β-CD at the mass ratio of 1:1. ES existed in an amorphous form in the inclusion complex. The equilibrium solubility of ES/HP-β-CD inclusion complex in SGF (simulated gastric fluid) and SIF (simulated intestinal fluid) was 50.6 ± 0.11 mg/mL and 75.9 ± 0.38 mg/mL in SGF and SIF, which was 5.93 and 9.96 times higher than that of free ES, respectively. The ES/HP-β-CD inclusion complex had better dissolution ability and transdermal permeability than the free ES. The oral bioavailability and the transdermal bioavailability were respectively increased by 2.97 times and 1.92 times compared with the free ES. These data suggest that the ES/HP-β-CD inclusion complex can be developed as potential pharmaceutical product for future clinical applications.

Host-guest inclusion complexes of sulfabenzamide with β- and methyl-β-cyclodextrins: Characterization, antioxidant activity and DFT calculation

To study the effect of β-cyclodextrin (βCD) inclusion complex on the bioavailability of clotrimazole from poloxamer-based suppository, formulations composed of P 188, propylene glycol and different molar ratio of clotrimazole-βCD inclusion complex were prepared. Clotrimazole (1%) has been formulated in a suppository using the thermo sensitive polymer P188 (70%) together with propylene glycol (30%). To increase its aqueous solubility, clotrimazole was incorporated as its inclusion complex at various molar ratios with βCD (1:0.25, 1:0.5, 1:1, and 1:2). The inclusion complex was characterized by differential scanning calorimetry (DSC), XRD and phase solubility studies. It was observed that the complexation with βCD, particularly at high molar ratio (F3 (1:1) and F4 (1:2)) decreased the release profile of clotrimazole considerably. However, suppositories containing inclusion complex at low molar ratio (F1 (1:0.25) and F2 (1:0.5)) showed excellent release profile compared to control formulation. In vivo study in rats at 15 mg/Kg dose showed that the F1 and F2 (82.39 ± 15.40 and 67.05 ± 8.79, respectively) significantly increased the AUC compared to that of F3 (41.48 ± 11.51), F4 (23.34 ± 8.37) and control (46.7 ± 7.87) suppositories. Thus, the suppositories containing inclusion complexes prepared at low drug to βCD molar ratio (F1) could be a potential suppository formulation to increase the bioavailability of hydrophobic drugs such as clotrimazole.

Introduction: Selexipag, a selective prostacyclin receptor (IP) agonist used in pulmonary arterial hypertension, suffers from poor aqueous solubility, limiting its oral bioavailability. Cyclodextrin complexation is a widely accepted technique to improve solubility and dissolution properties of hydrophobic drugs. This study aimed to enhance the solubility and dissolution rate of Selexipag by forming inclusion complexes with β-cyclodextrin. Methods: Inclusion complexes of Selexipag were prepared using three techniques: physical mixing, kneading, and solvent evaporation, each in 1:1 and 1:2 molar ratios with β-cyclodextrin. Phase solubility studies were performed to determine the stability constant. The prepared complexes were evaluated for drug content and in vitro dissolution using UV spectrophotometry and paddle method, USP Type II apparatus in 0.1 N HCl. Results: The phase solubility diagram exhibited an AL-type profile with a 1:1 stoichiometry and a stability constant of 164.56 M–¹. All formulations demonstrated acceptable drug content (98.3–102.2 %). Among the tested complexes, the kneading method at a 1:2 ratio (SK2) showed the highest drug release, achieving 94.2 % dissolution in 60 minutes, compared to 29.63 % for pure Selexipag. This enhancement is attributed to increased wettability, amorphization, and reduced crystallinity of the drug. Conclusion: Inclusion complexation of Selexipag with β-cyclodextrin markedly improved its solubility and dissolution rate. The kneading method with a 1:2 molar ratio proved most effective, offering a promising strategy for improving the oral delivery of poorly soluble drugs.

Purpose: To evaluate the effect of the preparation method on the inclusion complex of curcumin and hydroxypropyl-β-cyclodextrin (HP- β -CD).Methods: HP-β-CD was selected to prepare an inclusion complex with curcumin at a molar ratio of 1:1. The inclusion complexes were prepared using three different methods: common solvent evaporation (CSE), freeze drying (FD), and pH shift. The inclusion complexes were characterized by differential scanning calorimetry (DSC) and fourier transform infrared (FTIR) spectroscopy. The content, solubility, dissolution, and stability of the complexes were evaluated and compared with curcumin and their physical mixture.Results: Formation of inclusion complexes was confirmed by DSC and FTIR results. CSE and FD methods gave a high content of curcumin in the inclusion complexes (> 88.39 %), while pH shift gave a lower content (64.04 %). All three methods significantly (p < 0.05) increased curcumin solubility (> 276.43-fold). However, higher stability complexes were obtained using CSE and FD methods.Conclusion: Among the three preparation methods (CSE, FD and pH shift) used for the inclusion complexes, CSE is the most suitable method for preparation of curcumin-HP-β-CD inclusion complex for increased curcumin solubility and stability.Keywords: Curcumin, Cyclodextrin, Inclusion complex, Solubility, Stability, Common solvent evaporation, Freeze drying, pH shift

The formation of hydrochlorothiazide inclusion complexes has been carried out to improve the physicochemical properties and increase the dissolution rate of hydrochlorothiazide. Inclusion complexes were made by co-grinding using ß cyclodextrin at a ratio of 1:1 mol, with variations in milling time, namely 30 minutes (F1), 1 hour (F2), and 2 hours (F3). The inclusion complexes formed were characterized by X-ray diffraction analysis, differential scanning calorimetry (DSC), Fourier transforms infrared (FT-IR), scanning electron microscopy, and dissolution tests. X-ray diffraction results showed a decrease in hydrochlorothiazide intensity, the DSC thermogram showed a decrease in endothermic peaks and enthalpy values, and FT-IR spectrum analysis showed that there was a chemical interaction between hydrochlorothiazide and ß-cyclodextrin. All characterization checks carried out met the requirements and confirmed an increase in the dissolution rate. The dissolution yield of hydrochlorothiazide was 41.711%, the physical mixture was 57.135%, the F1 inclusion complex was 59.52%, the F2 inclusion complex was 79.17%, and the F3 inclusion complex was 103.62%. This proves that the formation of inclusion complexes with the addition of ß-cyclodextrin can significantly increase the dissolution

Cyclodextrins possess the ability to increase the apparent solubility and dissolution rate of poorly water soluble drugs. The objectives of the study were to investigate the effect of β-cyclodextrin, hydroxypropyl-β-cyclodextrin and sulfobutyl ether7 β-cyclodextrin on solubility and dissolution rate of docetaxel. Four different methods (physical mixture, kneading, freeze drying and solvent evaporation) were employed for inclusion complexation, at varying drug to cyclodextrin ratios 1:1, 1:2 and 1:4. The inclusion complexes of docetaxel with β-cyclodextrin, hydroxypropyl-β-cyclodextrin and sulfobutyl ether7 β-cyclodextrin at molar ratios 1:1 were characterized by fourier transform infrared spectroscopy (FTIR), X-ray diffractometry (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and proton nuclear magnetic resonance (1H NMR). The dissolution profiles of inclusion complexes were compared with pure drug. The results revealed formation of inclusion complexes between drug and β-cyclodextrin, hydroxypropyl-β-cyclodextrin and sulfobutyl ether7 β-cyclodextrin as confirmed by FTIR. 1H NMR revealed inclusion of drug within cyclodextrin cavity with appearance of proton shifts. Drug crystallinity was reduced with physical mixing and kneading method while amorphous form was attained by freeze drying and solvent evaporation method as revealed by XRD. The DSC and TGA confirmed the formation of inclusion complexes with the absence of melting peak of drug. The effect on solubility and dissolution rate of docetaxel was greater with sulfobutyl ether7 β-cyclodextrin than hydroxypropyl-β-cyclodextrin and β-cyclodextrin when prepared with similar methods. Drug to cyclodextrin ratio 1:1 was the optimum ratio to increase the solubility and dissolution of docetaxel irrespective of the method. It is concluded that sulfobutyl ether7 β-cyclodextrin had greater effect on solubility and dissolution rate of docetaxel than β-cyclodextrin and hydroxypropyl-β-cyclodextrin at molar ratios 1:1.

Objective: Diacerein (DCN) is a new anti-inflammatory analgesic and antipyretic drug developed specially for the treatment of osteoarthritis. DCN is a poorly water-soluble drug with relatively low bioavailability. Therefore, the purpose of this study was to enhance the solubility and dissolution of DCN by complexation with polyethylene glycol 6000 (PEG).Methods: Solid dispersions (SDs) of DCN were prepared in weight ratios of 60:40, 40:60, 20:80, and 5:95 by the melting method using PEG as carrier. These SDs were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared (FTIR) spectroscopy to ascertain whether there were any physicochemical interactions between drug and carrier that could affect dissolution. Solubility and dissolution studies were conducted with pure DCN, physical mixtures (PMs) and SDs.Results and discussion: Solubility studies indicated that PEG significantly increased the solubility of DCN in water. The Gibbs free energy (ΔGtr°) values were negative, indicating the spontaneous nature of DCN solubilization. Phase solubility studies indicated complex with a possible stoichiometry of 1:1.Conclusion: FTIR, DSC and PXRD studies indicate that there is no chemical interaction between DCN and PEG in solid state. In contrast to slow dissolution rate of pure DCN, the dispersion of drug in PEG considerably enhanced the dissolution rate. Even PMs of DCN prepared with PEG also showed better dissolution profiles compared with that of DCN, indicating the solubilization effect of PEG. Therefore, it is concluded that the preparation of SDs of DCN with PEG provides a promising way to increase its solubility and dissolution rate.

Cannabinoids can save paediatric patients from harmful psychological conditions caused by epilepsy. However, the limited aqueous solubility of the drug presents a limitation to oral absorption and bioavailability. Previous studies have shown the enhancement of oral bioavailability for poorly water-soluble drugs using milk or milk-based products like infant formula as a novel lipid-based formulation, due to digestion of the lipids to enhance drug solubility that is particularly well suited to infants and in low economy settings. Therefore, this study has investigated the in vitro solubilisation enhancement of cannabidiol (CBD) in milk-based products during digestion using synchrotron small angle X-ray scattering, followed by pharmacokinetic studies to determine the relative oral bioavailability. The in vitro results, coupled with in vivo data, demonstrate a two-fold increase in the oral bioavailability of CBD in bovine milk as well as infant formula. The results of this study indicate the potential for infant formula to be considered as a novel formulation approach for CBD. Further study is encouraged for more drugs with infant formula to strengthen the correlation between the solubilisation of drug and their oral bioavailability.