Phase Solubility Profiles Research Articles

Inclusion Complex of Ibuprofen-β-Cyclodextrin Incorporated in Gel for Mucosal Delivery: Optimization Using an Experimental Design

β-Cyclodextrin/ibuprofen inclusion complex was synthesized by freeze-drying method and characterized for phase solubility profiles, infrared spectra, thermal analysis, and X-ray powder diffractograms. The inclusion complex with HP-β-CD, as confirmed by molecular dynamics simulations, enhanced the aqueous solubility of ibuprofen by almost 30-fold compared to ibuprofen alone. Different grades of Carbopol (Carbopol 934P/Carbopol 974P/Carbopol 980 NF/Carbopol Ultrez 10 NF) and cellulose derivatives (HPMC K100M/HPMC K15M/HPMC K4M/HPMC E15LV/HPC) were evaluated for mucoadhesive gels incorporating the inclusion complex. The central composite design generated by Design-Expert was employed to optimize the mucoadhesive gel using two independent variables (a varying combination of two gelling agents) on three dependent variables (drug content and in vitro drug release at 6h and 12h). Except for the methylcellulose-based gels, most of the gels (0.5%, 0.75%, and 1% alone or as a mixture thereof) exhibited an extended-release of ibuprofen, ranging from 40 to 74% over 24h and followed the Korsmeyer-Peppas kinetics model. Using this test design, 0.95% Carbopol 934P and 0.55% HPC-L formulations were optimized to increase ibuprofen release, enhance mucoadhesion, and be non-irritating in ex vivo chorioallantoic membrane studies. The present study successfully developed a mucoadhesive gel containing the ibuprofen-β-cyclodextrin inclusion complex with sustained release.

Ternary Inclusion Complex of Sinapic Acid with Hydroxypropyl-β-cyclodextrin and Hydrophilic Polymer Prepared by Microwave Technology

Sinapic acid (SA) is a poorly water-soluble substance which could result in poor bioavailability. The aim of this study was to determine the “hydroxypropyl β-cyclodextrin (HPβCD)” solubilization of SA in the presence of the auxiliary substance hydroxypropyl methylcellulose (HPMC) and to evaluate the ternary inclusion complex prepared by microwave technology. Phase-solubility profiles showed that HPβCD exhibited the greatest solubilizing effect on SA in the presence of HPMC. The enhanced rate of SA dissolution was exhibited by a ternary complex. Outcomes of analyses such as “DSC, FTIR, NMR, and SEM” confirmed the embedding of SA into the cavity of the HPβCD and the formation of a ternary inclusion complex. The outcomes of antioxidant activity (ABTS and nitric oxide scavenging activity) demonstrated that SA ternary inclusion complex (TIC) presented strong antioxidant activity, which might be a result of the enhanced solubility of SA in the TIC prepared by microwave technology. Hence, SA-TIC formulation could be a better dosage form which may protect the body from free radical damage and oxidative stress. Microwave technology greatly boosted the interaction of SA with HPβCD and HPMC, and such findings are expected to contribute to raising the solubility of SA, thereby improving the bioavailability of SA.

Synthesis and characterization of ataluren-cyclodextrins complexes

An inclusion complex formation with cyclodextrin (CD) is a promising method for enhancing solubility and bioavailability of medicines. Ataluren (ALN) is a reading-through drug for overriding premature stop codons that is practically insoluble in water. By incresing the solubility of this molecule in aqueous media, its bioavailability in its oral dosage form may be improved. Inclusion complexes of ALN with alpha (αCD), beta (βCD), gamma (γCD), hydroxypropyl beta (HPβCD), randomly methylated beta (RMβCD) and sulfobutyl ether beta (SBECD) cyclodextrins were prepared. Phase solubility studies, Job's plot, Proton nuclear magnetic resonance (1HNMR), Differential scanning calorimetry (DSC), X-ray diffractometry (XRD), and Fourier transform Infrared (FTIR) analysis were used for the characterization of the inclusion complexes. The phase solubility profiles are AL type but each cyclodextrin behaves differently in interaction with ALN. The Job's plot revealed 1:1 stoichiometry in ALNCD complexes. The stability constants of ALN with αCD, βCD, γCD, HPβCD, RMβCD, and SBECD were 35 M − 1, 674 M − 1, 163 M − 1, 132 M − 1, 324 M − 1, and 232 M − 1 respectively. All CDs increased ALN solubility in aqueous media and RMβCD showed the maximun value of 121.0 times increment of ALN solubility in aqueous media.

Chiral Recognition R- and RS- of New Antifungal: Complexation/Solubilization/Dissolution Thermodynamics and Permeability Assay

Novel potential antifungal of 1,2,4-triazole class have been synthesized as pure enantiomer (R-98) and racemic (RS-186). The effect of 2-hydroxypropyl-β-cyclodextrin (CD) on the solubility and permeability of RS-186 and R-98 in terms of chiral recognition was investigated. Phase solubility studies were carried out at 4 temperatures in 0–0.05 M CD concentration range for pH 2.0 and pH 7.4. - and -type phase-solubility profiles were obtained for both compounds in pH 2.0 and pH 7.4. The racemic formed more stable complexes with CD as compared to R-isomer. Disclosing of chiral discrimination was facilitated using the approach based on the complex consideration of the derived complexation/solubilization/inherent dissolution thermodynamic functions, including the differential parameters between the racemic compound and R-enantiomer. The differences in the thermodynamic parameters determined by the chirality were discussed in terms of the driving forces of the processes and the main interactions of the compounds with CD in solution. The membrane permeability of both samples in the presence of CD was accessed in order to evaluate the specificity of enantioselective transport through the lipophilic membrane. The solubility/permeability interrelation was disclosed. The investigated compounds were classified as medium permeable in pure buffers and low permeable in the presence of 0.01 M CD. The obtained results can be useful for the design of pharmaceutical products in the form of liquid formulations based on the investigated substances.

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

The inclusion complexation behavior, characterization and binding ability of sulfabenzamide (SBZ) with β-cyclodextrin (β-CD) and methyl-β-cyclodextrin (Mβ-CD) have been investigated both in solution and solid state by different experimental techniques. Sulfabenzamide drug having poor water solubility and slow dissolution. In order to improve its water solubility and thus dissolution, cyclodextrin complexation technique was followed. The spectral shifts revealed that part of aniline ring of SBZ is entrapped in the CD cavity. The association constants were determined by Benesi-Hildebrand plots and spectroscopic studies. The phase solubility studies were carried using two different types of cyclodextrins viz., β, methyl-β cyclodextrins. The phase solubility profiles with all the two cyclodextrins were classified as AL-type, indicating the formation of 1:1 stoichiometric inclusion complexes. Inclusion complexes exhibited higher rates of dissolution than the corresponding physical mixtures and pure drug. Characterization of inclusion complexes was done by solubility studies, in vitro dissolution studies, FTIR, 1HNMR, XRD and SEM studies. We investigated the interaction of the host–guest Mβ-CD/SBZ complex by means of molecular dynamics simulation using a density functional based tight-binding code (DFT).

Cyclodextrin-based Pickering nanoemulsions containing amphotericin B: Part I. evaluation of oil/cyclodextrin and amphotericin B/cyclodextrin inclusion complexes

Prior to developing cyclodextrin (CD) stabilized Pickering nanoemulsions (NEs) containing amphotericin B (AmB) for fungal keratitis therapy, the AmB solubility and the effect of CDs on complex formation of medium chain triglyceride (MCT) oils and AmB was investigated. The phase-solubility profiles of AmB in various aqueous CD solutions were determined. The AmB solubilization in oils and surfactants was also examined. Two CDs, γ-cyclodextrin (γCD) and 2-hydroxypropyl-γCD (HPγCD), along with MCT oil and lecithin were chosen because of their high solubilization ability for AmB. The solution- and solid-state characterizations of their inclusion complexes were investigated. Proton nuclear magnetic resonance studies demonstrated the formation of MCT oil/α-cyclodextrin (αCD), AmB/γCD, and AmB/HPγCD complexes. Some interactions between AmB and CDs were observed by solid-state characterizations using Fourier-transform infrared (FT-IR) spectroscopy, powder X-ray diffractometry and differential scanning calorimetry. The interfacial tension at the oil-water interface, the analysis of dissolved CD content in saturated MCT oil, and FT-IR confirmed the affinity of αCD for MCT oil. Scanning electron microscopy revealed that the MCT oil/αCD complexes can transformed into the precipitated solid complexes at high αCD concentration. Thus, the MCT oil/αCD complexes will be used as solid particles to stabilize Pickering NEs for further studies.

Preparation, Characterization, and Bioavailability of Host-Guest Inclusion Complex of Ginsenoside Re with Gamma-Cyclodextrin.

This work aimed at improving the water solubility of Ginsenoside (G)-Re by forming an inclusion complex. The solubility parameters of G-Re in alpha (α), beta (β), and gamma (γ) cyclodextrin (CD) were investigated. The phase solubility profiles were all classified as AL-type that indicated the 1:1 stoichiometric relationship with the stability constants Ks which were 22 M−1 (α-CD), 612 M−1 (β-CD), and 14,410 M−1 (γ-CD), respectively. Molecular docking studies confirmed the results of phase solubility with the binding energy of −4.7 (α-CD), −5.10 (β-CD), and −6.70 (γ-CD) kcal/mol, respectively. The inclusion complex (IC) of G-Re was prepared with γ-CD via the water-stirring method followed by freeze-drying. The successful preparation of IC was confirmed by powder X-ray diffraction (XRD), Fourier transform-infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). In-vivo absorption studies were carried out by LC-MS/MS. Dissolution rate of G-Re was increased 9.27 times after inclusion, and the peak blood concentration was 2.7-fold higher than that of pure G-Re powder. The relative bioavailability calculated from the ratio of Area under the curve AUC0–∞ of the inclusion to pure G-Re powder was 171%. This study offers the first report that describes G-Re’s inclusion into γ-CD, and explored the inclusion complex’s mechanism at the molecular level. The results indicated that the solubility could be significantly improved as well as the bioavailability, implying γ-CD was a very suitable inclusion host for complex preparation of G-Re.

Effect of salt formation on γ-cyclodextrin solubilization of irbesartan and candesartan and the chemical stability of their ternary complexes

Angiotensin II receptor blockers (ARBs) are unstable compounds and have relatively low aqueous solubility, which may hamper their bioavailability. The present study aimed to increase the aqueous solubility of ARBs by the formation of cyclodextrin (CD) inclusion complex and determine their chemical stability in aqueous solutions. The pH- solubility of drugs and their phase-solubility profiles were determined, and the results showed that the solubility of drugs increased by forming inclusion complexes with γ-cyclodextrin (γCD) and by increasing their intrinsic solubility in phosphate buffer (pH 7.5). The formation of irbesartan/γCD (IRB/γCD) and candesartan cilexetil/γCD (CAC/γCD) inclusion complexes was confirmed by molecular docking. To enhance the γCD solubilization of drugs, salt formation using various organic salts was also investigated. Of these, Tris was the most powerful, followed by sodium acetate, as they significantly increased the γCD solubilization of IRB and CAC. However, chemical instability was observed, particularly at high salt concentrations, where they provided a higher IRB and CAC solubility. Thus, the balance of optimum drug solubility and its chemical stability in aqueous solutions should be considered in formulation development.

Solubility enhancement of poorly water soluble domperidone by complexation with the large ring cyclodextrin

The water solubility of domperidone (DMP) could be improved by complexation with large ring cyclodextrins (LR-CDs). LR-CDs contain a relatively hydrophobic cavity that is capable of entrapping the molecules to form inclusion complexes. The complex formation capability of mixture LR-CDs having a degree of polymerization (DP) of 22–48, with DMP was investigated. The phase solubility profile of mixture LR-CD/DMP was classified as AN-type, resulting in increased DMP solubility in water by 3-fold. Various physicochemical techniques confirmed the mixture LR-CD/DMP complex formation. Single LR-CD with DP of 26, 27, 28, 29, 30, 33 and 34 (CD26 ~ CD34) were isolated from LR-CD mixtures using ODS column for HPLC separation. The CD33/DMP complex has demonstrated the most significant improvement compared to other single LR-CD complexes with a 2.7-fold increase in DMP solubility. The molecular dynamic result revealed that DMP formed stable complexes with CD33 by positioned fully encapsulated inside the cavity and covered by 13–14 subunits of CD33.

Використання полімерних композиційних матеріалів для підвищення біодоступності гесперидина

Purpose. Investigation of the influence of the composition of polymeric solubilizers on the phase solubilization in water of the model active pharmaceutical ingredient of flavonoid nature hesperidin.Methods. Hesperidin was chosen as a model substance of characteristic chemical structure. Pharmaceutically acceptable high molecular weight polymers based on polyvinylpyrrolidone (PVP) with a molecular weight of from 2500 to 58000 D were used for research; cetylpyridinium chloride; β-cyclodextrin. Phase solubilization of hesperidin was investigated by the method of Higuchi and Connors. The concentration of hesperidin was determined spectrophotometrically by absorption at 284 nm. The phase solubility diagram was constructed as the dependence of the concentration of hesperidin in solution on the concentration of the polymer. The obtained phase solubility profiles of hesperidin were compared with standard curves. For different compositions at the experiment temperature of 37 ± 0.5 °C, the stability constant and the dissociation constant of intermolecular complexes were calculated.Scientific novelty. The influence of the composition of polymer solubilizers on the phase solubilization in water of the model API of flavonoid nature of hesperidin was established. Practical significance. The optimal composition of the polymer composite material with hesperidin in the form of a solid dispersed system to maximize the solubility of flavonoids in water is substantiated. Results. The influence of the composition of polymer solubilizers on the phase solubilization in water of the model API of flavonoid nature of hesperidin was investigated. Based on the results of graphical analysis of the obtained data, it was concluded that the solubility of hesperidin increases with increasing number of polymers with different molecular weights and surfactants. The increase in solubility depends on the composition. When adding several polymers or a combination of a polymer with a surfactant, the solubility increases significantly more than when adding one compound. It is shown that the maximum value of solubility increase is observed in the system with polymer C and K surfactant - 42.7 times. It was found that the stability constants of polymeric composite materials of hesperidin based on polyvinylpyrrolidones are in the range from 161.87 to 219.88 M-1, which indicates favorable conditions for the formation of complexes.

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.

Cold nitrogen plasma modified cuminaldehyde/β-cyclodextrin inclusion complex and its application in vegetable juices preservation

E. coli O157:H7 is one of the most common food-borne pathogens and usually related to contaminated vegetables. This study was to prepare an effective antibacterial agent and applied in vegetable juices. In this study, β-cyclodextrin inclusion complexof CUM (CUM /βCD-IC) was prepared using ultrasonication technique and then treated with cold nitrogen plasma (CNP) to observe its effect in the physicochemical and antibacterial properties of CUM/βCD-IC. Various characterization techniques such as fluorescence, fourier transform infrared spectroscopy (FT-IR), thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-ray diffraction (XRD) confirmed the formation of IC between CUM and βCD. Phase solubility and double reciprocal profiles studies proved the enhanced solubility of CUM with increasing amount of βCD and the guest/host stoichiometry of 1:1. Computational modeling and FT-IR indicated that the phenyl ring with isopropyl chain of CUM is inserted in the hydrophobic βCD. Investigations of thermal properties proved that the βCD-IC formation improved the stability of CUM. Antibacterial test results indicated that CNP-CUM/βCD-IC exhibited better antibacterial activity than CUM/βCD-IC. After CNP-CUM/βCD-IC treatment, it was observed by TEM that the cell membrane of E. coli O157:H7 was broken. In addition, the antibacterial activity of CNP-CUM/βCD-IC in vegetable juices was carried out and the findings revealed that CNP-CUM/βCD-IC has an excellent antibacterial effect on vegetable juices.

Evaluation of the phase solubility of inclusion complexes of diisopropylphenol (INN) with hydroxypropyl-β-cyclodextrin

The paper presents the results of a study of the stability of aqueous solutions of inclusion complexes of hydroxypropyl-β-cyclodextrin with diisopropylphenol in various systems by the Higuchi-Connors phase solubility method. The phase solubility profiles for each system corresponding to the AN type are determined graphically, and the stability constants of the resulting inclusion complexes are calculated. An aqueous solution containing 0.2 % Tween 80 and 0.2 % mannitol was selected as the optimal condition for obtaining the hydroxypropyl-β-cyclodextrin inclusion complex with diisopropylphenol.

The investigation of binary and ternary sulfobutylether-β-cyclodextrin inclusion complexes with asiaticoside in solution and in solid state

Asiaticoside (AS) is poorly water-soluble compound that can lead to low the bioavailability. The aims of this study were to determine the cyclodextrin (CD) solubilization of AS and characterize binary AS/CD and ternary AS/CD/polymer complexes in solution- and solid-state. Thermal stability of AS through heating process was determined and found that It could withstand by heating through sonication method. Phase-solubility profiles showed that β-cyclodextrin (βCD) exhibited the greatest solubilizing effect but sulfobutylether-βCD (SBEβCD) was selected for further investigations due to its relatively high complexation efficiency (CE) value. The effect of polymers that were poloxamer 407 (P407) and chitosan (CS) on CD solubilization were investigated. It was found that the increment of CE was resulted from the formation of ternary complexes or complex aggregates with confirmed by dynamic light scattering and transmission electron microscopy. Proton nuclear magnetic resonance (1H NMR) data indicated that the cyclohexane moiety of AS was totally inserted into the hydrophobic inner cavity of SBEβCD in the presence or absence of polymer. The molecular modeling study displayed the binding orientation of such complex which correlated to 1H NMR result. The solid state characterized by Fourier transform infra-red, differential scanning calorimetry and powder X-ray diffraction demonstrated the formation of binary AS/SBEβCD and ternary AS/SBEβCD/polymer inclusion complexes. The enhancement of AS dissolution was achieved in both binary and ternary complexes. The permeation study showed that ternary AS/SBEβCD/CS nanoparticles exhibited a promising controlled drug release nanocarrier.

Effects of the preparation technique on the physicochemical characteristics and dissolution improvement of ketoprofen-SBE7-β-CD binary inclusion complexes

Ketoprofen (KTF) is classified as a biopharmaceutics classification system (BCS) class II drug owing to low aqueous solubility. To improve the solubility and dissolution profile of pure ketoprofen its inclusion complexes with sulfobutylether7-beta-cyclodextrin (SBE7-β-CD) were prepared by kneading (KD) and freeze-drying (FD) technique. The effects of the preparation technique on the physicochemical characteristics and dissolution improvement of binary inclusion complexes were investigated by comparing with pure ketoprofen and drug-polymer physical mixture. The phase solubility studies of ketoprofen with the carrier revealed the existence of the AL-type phase solubility profile. The characterization of the formed binary systems was carried out through Fourier transform-infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder X-ray diffractometry (PXRD). Scanning electron microscope (SEM) used to determine the morphology of the binary systems prepared by different techniques revealed that the rectangular crystalline morphology of ketoprofen was absent and further approve the realization of inclusion complexes. The dissolution profiles of inclusion complexes were estimated and compared with those of pure ketoprofen. The marked dissolution improvement of ketoprofen was observed in freeze-dried binary systems (∼99 % release in 120 min) rather than the kneaded systems. Percentage dissolution efficiency of the inclusion complexes followed the following order: FD-1:5 > FD-1:3 > FD-1:1 > KD-1:5 > KD-1:3 > KD-1:1. Therefore, it can be concluded that the preparation technique played significant roles in the dissolution improvement of the prepared binary systems. In conclusion, the negative docking energy (-4.4 kcal/mol) obtained in the molecular docking study suggests the formation of a stable configuration of the drug-polymer conjugate. Finally, we can suggest that SBE7-β-CD can be an efficient alternative for enhancing the solubility of ketoprofen by the formation of an inclusion complex.

Aqueous solubility of kinase inhibitors: III the effect of acidic counter ion on the dovitinib/γ-cyclodextrin complexation

Dovitinib, a hydrophobic kinase inhibitor (KI), is lipophilic anticancer agent that forms water-soluble complexes with cyclodextrins (CDs). However, dovitinib’s very low intrinsic solubility hampers the complex formation and, consequently, the CD solubilization. The aim of the study was to enhance the CD solubilization through formation of more water soluble dovitinib salts. When dovitinib is unionized (i.e. at pH above its pKa value) the phase-solubility profile of the binary dovitinib/γCD complex is of Bs-type with K1:1 of 684 M−1. Then the complex has limited solubility in water. Upon protonization, (i.e. at pH below the pKa value) the solubility of dovitinib was increased but the increase was dependent on the negatively charged counter ion. Citrate, acetate, EDTA and chloride resulted in the greatest solubility enhancement and, thus, were selected to further studies. The ternary phase-solubility profiles of dovitinib/γCD/counter ion were also of Bs-type while those of dovitinib/HPγCD/counter ion and dovitinib/SBEγCD/counter ion were of AN-type. The counter ions had greater solubilizing effect in SBEγCD solutions than in γCD and HPγCD solutions. This is due to the influence of charge-charge interaction between the positively charged dovitinib and negatively charged SBEγCD. Citrate was the most effective counter ion particularly in aqueous SBEγCD solutions. The complexation was verified by NMR. The highest dovitinib flux through semi-permeable membrane was observed from medium containing dovitinib/CDs/citrate complexes. In conclusion, citrate provided the highest dovitinib solubilization and complexation.

Cyclodextrin Complexation for Enhanced Stability and Non-invasive Pulmonary Delivery of Resveratrol-Applications in Non-small Cell Lung Cancer Treatment.

Pulmonary drug delivery is a noninvasive therapeutic approach that offers many advantages including localized drug delivery and higher patient compliance. As with all formulations, the low aqueous solubility of a drug often poses a challenge in the formulation development. Thus, strategies such as cyclodextrin (CD) complexation have been utilized to overcome this challenge. Resveratrol (RES), a natural stilbene, has shown abundant anti-cancer properties. Due to many drawbacks of conventional chemotherapeutics, RES has been proposed as an emerging alternative with promising pharmacological effects. However, RES has limited therapeutic applications due to low water solubility, chemical stability, and bioavailability. This study was aimed at developing an inhalable therapy that would increase the aqueous solubility and stability of RES by complexation with sulfobutylether-β-cyclodextrin (SBECD). Phase solubility profiles indicated an optimal stoichiometric inclusion complex at 1:1 (SBECD:RES) ratio for formulation considerations. Physiochemical characterizations were performed to analyze CD-RES. Stability studies at pH7.4 and in plasma indicated significant improvement in RES stability after complexation, with a much longer half-life. The mass median aerodynamic diameter (MMAD) of CD-RES was 2.6 ± 0.7μm and fine particle fraction (FPF) of 83.4 ± 3.0% are suitable for pulmonary delivery and efficient deposition. Lung cancer was selected as the respiratory model disease, owing to its high relevance as the major cause of cancer deaths worldwide. Cell viability studies in 5 non-small-cell-lung-cancer (NSCLC) cell lines suggest CD-RES retained significant cytotoxic potential of RES. Taken together, CD-RES proves to be a promising inhalation treatment for NSCLC.

Effect of porcine pancreatic α-amylase on dexamethasone release from aqueous solution containing natural γ-cyclodextrin.

Dexamethasone release from natural γ-cyclodextrin (γCD) complexes was investigated in presence of porcine pancreatic α-amylase (PPA). The phase-solubility of dexamethasone in aqueous γCD solutions was determined, PPA degradation of γCD was investigated, and permeation studies were performed in simulated tear fluid. The phase-solubility profile was of Bs type and the stability constant (K1:1) of the dexamethasone/γCD complex determined from the initial linear section of the profile was relatively high or 12887M-1. The high K1:1 value indicates that dexamethasone has high affinity for γCD under the test condition. From the PPA catalyzed γCD degradation studies the Michaelis-Menten constant (Km) and Vmax were determined to be 3.24mM and 9.79×10-3 mM/min, respectively. The permeation studies performed at low γCD concentrations, showed that dexamethasone is released from the complex solutions at faster rate when PPA was present than when no PPA was present.

Solubilization and in vitro permeation of dovitinib/cyclodextrin complexes and their aggregates

Dovitinib (DOV) is a tyrosine kinase inhibitor affecting the vascular endothelial growth factor and antiangiogenic activity. It has been studied in tumor and carcinoma treatment. However, its therapeutic usefulness is hampered by its very low aqueous solubility. In this present study, cyclodextrins (CDs) and polymers were used to solubilize DOV. The DOV/CD complexes were characterized by 1H-NMR, and formation of nano- and microparticles by dynamic light scattering and in vitro permeation studies. In aqueous CD media DOV was stable during autoclaving at low γCD concentrations. In aqueous γCD solutions DOV displayed Bs-type phase solubility profile. Water-soluble polymers enhanced DOV solubility in aqueous CD solutions through ternary complex formations and formation of complex aggregates. CD derivatives were also able to increase the DOV solubility but the concentration of complex nanoparticles was relatively low. In comparison to the binary DOV/γCD complexes, the permeation flux of ternary DOV/γCD/polymer complexes increased while their apparent permeability coefficient values decreased.

Aqueous solubility of kinase inhibitors: I the effect of hydrophilic polymers on their γ-cyclodextrin solubilization

Most small-molecule protein kinase inhibitors (KIs) are neutral or weakly basic lipophilic compounds with very poor solubility in aqueous media that decreases their ability to permeate biological membranes from an aqueous exterior and consequently bestow them with low bioavailability after oral and topical administration. Cyclodextrin (CD) complexation can increase water-solubility of poorly soluble drugs without affecting their ability to permeate biological membranes. The aim of the present study was to enhance aqueous solubility of six KIs that is axitinib, cediranib, dovitinib, motesanib, pazopanib and regorafenib, through formation of drug/γ-cyclodextrin (γCD)/polymer ternary complexes. The complexes were prepared in an aqueous environment by heating technique. The phase-solubility profiles showed formation of binary KI/γCD complexes of Bs-type. γCD alone had significant solubilizing effect on dovitinib (stability constant (K1:1) = 684 M−1 and complexation efficacy (CE) = 0.011). The aqueous solubility of the binary KI/γCD complexes was pH-dependent. Hexadimethrine bromide (HDMBr) was the most effective polymer of the ones tested. The ternary complexes formed nano-sized aggregates with diameter between 200 and 400 nm. Osmolarity and pH were also monitored. TEM study showed formation of complex aggregates in aqueous media.