Novel non-acidic formulations of haloperidol complexed with β-cyclodextrin derivatives

Haloperidol (Hal), a highly hydrophobic drug, was complexed with two β-cyclodextrin (β-CD) derivatives. Hal solubility was increased 20-fold in the presence of a 10-fold excess of methyl β-CD (Meβ-CD) and 12-fold in the presence of a 10-fold excess of 2-hydroxypropyl β-CD (HPβ-CD). The stoichiometries and stability constants of Hal–Meβ-CD (1:1 and 2345 M⁻¹ at 27°C) and Hal–HPβ-CD (1:1 and 2112 M⁻¹ at 27°C) complexes were calculated by the continuous variation and phase solubility methods respectively. Differential scanning calorimetry and ¹H-NMR were used to confirm the formation of inclusion complexes. Moreover, the enthalpy and entropy of the complexation process were calculated for both complexes in order to obtain such information as the main `driving force' and whether or not complex formation is thermodynamically favoured. This was achieved by monitoring the isothermic solubility lines at various temperatures.     

Enhancement of norfloxacin solubility via inclusion complexation with β-cyclodextrin and its derivative hydroxypropyl-β-cyclodextrin

The objectives of the study were to investigate the effects of β-cyclodextrin (βCD) and hydroxypropyl-β-cyclodextrin (HPβCD) on the solubility and dissolution rate of norfloxacin prepared using three different methods, at drug to cyclodextrin weight ratios of 1:1, 1:2, 1:4 and 1:8. All the methods increased the solubility and dissolution rate of norfloxacin via inclusion complexation with βCD and HPβCD. Norfloxacin was converted from crystalline to amorphous form through inclusion complexation. Solvent evaporation method was the most effective method in terms of norfloxacin solubilisation, while inclusion complex of HPβCD has higher solubility than βCD complex when prepared using the same procedure.     

Photochemical stability of the inclusion complexes formed by modified 1,4-dihydropyridine derivatives with β-cyclodextrin

The results of studies of photochemical stability of the derivatives of 1,4-dihydropyridine (NR) are reported. The NR with various substituents (-NO₂, -Cl, -F, CF₃) at different positions in the phenyl ring were identified by UV spectrophotometry. Photodegradation of NR in the inclusion complexes with β-cyclodextrin (β-CD) was studied in the liquid phase. The rate of photodegradation of NR derivatives was dependent on the position of -NO₂ group in the phenyl ring; for the ortho isomer it is ten times higher than for the meta one. The rate of photodegradation of 2-NO₂-NR (ortho isomer) in inclusion complex with β-CD was 200 times slower than that for this compound in the crystal phase. In the case of halogeno- and cyanoderivatives, the presence of β-CD caused a 4-fold increase in the photodegradation rate.     

Meloxicam β-cyclodextrin transdermal gel: physicochemical characterization and in vitro dissolution and diffusion studies

The aim of the study was to develop a Meloxicam (ME) transdermal gel formulations based on complexation with β-cyclodextrin. ME β-Cyclodextrin gel formulations were prepared using four different gel bases with different concentrations and different permeation enhancers. The developed formulations were examined for their in vitro characteristics and their diffusion through a mouse skin. The gel formulations were prepared successfully. Physicochemical characterization of ME β-CD complex in solution state by phase solubility revealed 1:1 M complexation of ME with β-Cyclodextrin. ME release profiles from the inclusion complex were superior over ME alone. Hydroxypropyl methyl cellulose 15% w/w gel base was proven to be a suitable base for ME inclusion complex formulation as it provides a high drug release than other studied bases. ME β-CD complex gel formulations containing oleic acid (1% w/w) or (5% w/w) cineol used as permeation enhancers in (15% w/w) HPMC gel base were proven to provide a higher diffusion rate of the drug through the mouse skin. This is very promising in providing analgesic activity of meloxicam via topical route of administration.     

Aqueous stability of leuprolide acetate: effect of temperature,dissolved oxygen,pH and complexation with β-cyclodextrin

In the present research, the aqueous stability of leuprolide acetate (LA) in phosphate buffered saline (PBS) medium was studied (pH?=?2.0–7.4). For this purpose, the effect of temperature, dissolved oxygen and pH on the stability of LA during 35 days was investigated. Results showed that the aqueous stability of LA was higher at low temperatures. Degassing of the PBS medium partially increased the stability of LA at 4?°C, while did not change at 37?°C. The degradation of LA was accelerated at lower pH values. In addition, complexes of LA with different portions of β-cyclodextrin (β-CD) were prepared through freeze-drying procedure and characterized by Fourier transform infrared (FTIR) and differential scanning calorimetry (DSC) analyses. Studying their aqueous stability at various pH values (2.0–7.4) showed LA/β-CD complexes exhibited higher stability when compared with LA at all pH values. The stability of complexes was also improved by increasing the portion of LA/β-CD up to 1/10.     

Improvement of water solubility and in vitro dissolution rate of aceclofenac by complexation with β-cyclodextrin and hydroxypropyl-β-cyclodextrin

The present study deals with the inclusion complexation of aceclofenac with β-cyclodextrin by grinding, microwave and spray-drying techniques. A derivative of β-cyclodextrin, hydroxypropyl-β-cyclodextrin, was also subjected to the complexation process with aceclofenac by spray-drying technique. The samples were subjected to in-vitro dissolution studies, fourier transform infra-red spectroscopy, differential scanning calorimetry, nuclear magnetic resonance spectroscopy and x-ray diffraction studies. The in-vitro dissolution of aceclofenac-hydroxypropyl-β-cyclodextrin complex was faster as compared to the aceclofenac- β-cyclodextrin complex and aceclofenac alone. Spray-dried aceclofenac-β-cyclodextrin complex were subjected to anti-inflammatory and analgesic activity and showed significant anti-inflammatory and analgesic activity.     

Halogenation effects of pheniramines on the complexation with β-cyclodextrin

This study investigated the inclusion complexes of β-cyclodextrin with pheniramine and its halogenated derivatives chlorpheniramine and brompheniramine both experimentally and theoretically to characterize the effects of a halogenated phenyl ring on the intermolecular interactions. Fourier transform infrared and nuclear magnetic resonance (NMR) experiments provided evidence of the formation of inclusion complexes and NMR were conducted to evaluate the apparent binding constants. The two-layered hybrid ONIOM method, ONIOM(B3LYP/6-31G(d):PM3), was adopted to optimize the geometry. The linear relationships between the calculated and experimental values for frequencies (with a scaling factor of 0.96) and for magnetic properties (with a scaling factor of 1.05) demonstrate that the quantum chemical calculations were consistent with the experimental spectra. Additionally, the calculated binding energies were consistent with the experimental results: the stability order of the complexes and the trend of the binding energy is: brompheniramine > chlorpheniramine > pheniramine; S-enantiomer > R-enantiomer. Natural Bond Orbital analysis further demonstrated three major electronic delocalizations—from the substituent on the phenyl moiety of pheniramine to β-CD and from β-CD to the phenyl and amine moieties in pheniramine—which were the dominant intermolecular forces that were responsible for the substantially different binding strengths. Geometrical data and the partial charge distribution obtained by NBO analysis are provided as supplementary data.     

NMR Studies of the Inclusion Complex of Cloprostenol Sodium Salt with β-cyclodextrin in Aqueous Solution

Purpose Cloprostenol sodium salt (referred as cloprostenol) may be used for the synchronization of estrous cycles in farm animal species. Cyclodextrins (CDs) have potential as drug delivery systems through the formation of inclusion complexes between CDs and drugs. This is the first study of the inclusion complex of cloprostenol with β-cyclodextrin (β-CD) in aqueous solution using NMR and 3D molecular dynamics simulations. Methods 1D proton NMR spectra of β-CD, a complex of cloprostenol with β-CD, and cloprostenol in D₂O were assigned and confirmed. The cross relaxation interactions from ROESY were used as constraints for 3D molecular modeling studies. Results In the 2D ROESY of the complex, cross-peaks were observed between the aromatic protons of cloprostenol and protons of the β-CD as well as between aliphatic protons and protons of the β-CD. The stoichiometry of the complex was found that β-CD forms a 1:1 inclusion complex with cloprostenol. The association constant K was 968 ± 120 M⁻¹ at 298 K. Conclusions Aromatic side and/or aliphatic side chains of the cloprostenol is included in the β-CD while aliphatic side and/or aromatic side chains wraps around β-CD, respectively. The molecular modeling also confirms that β-CD forms a 1:1 inclusion complex with cloprostenol. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Study of the dissolution characteristics of oxazepam via complexation with β-cyclodextrin

Complex formation of oxazepam and β-cyclodextrin in solution was studied by phase solubility and spectral shift methods. The value of the apparent stability constant, K_c, calculated using these techniques, was 205 and 498 M⁻¹, respectively. Solid complexes of oxazepam and β-CD were prepared using the kneading and spray-drying methods. These complexes led to an improvement in the dissolution rate over free oxazepam, spray-drying being the most efficient technique. These complexes were characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and X-ray diffraction.     

Structure-based in silico model profiles the binding constant of poorly soluble drugs with β-cyclodextrin

Cyclodextrin inclusion complexation technique is the key method to enhance the solubility and absorption of poorly soluble drugs in the early development stage, and thus it is essential to predict the binding constant between drug molecules and cyclodextrin. Structure-based in silico model was constructed for a data set of 86 poorly soluble drugs and used to profile the binding constant of drug-β-cyclodextrin inclusion complex. The stepwise regression was employed to select the optimum subset of the independent variables. The in silico model was built by the multiple linear regression method and validated by the residual analysis, the normal Probability–Probability plot and Williams plot. For the entire data set, the R² and Q² of the model were 0.78 and 0.67, respectively. The results indicated that the fitted model is robust, stable and satisfies all the prerequisites of the regression models. The chemical space position and important contributors were compared between selected drug molecules and organic compounds available in the literature. It was suggested that the binding behavior of drug molecules with β-CD should differ from that of the common organic compounds. Focusing on structurally diverse drugs, the in silico model can be used as an efficient tool to rapidly screen the drug-β-cyclodextrin inclusion complex stability and to rationally design the new drug delivery system of poorly soluble drugs.     

Study of the complexation behaviour of gliclazide with partially methylated β-cyclodextrin in solution and solid state

The complexation of Gliclazide (GL) with a partially methylated β-cyclodextrin was studied. Phase-solubility and ¹H NMR spectroscopy were employed to investigate the complexation behaviour in solution and to demonstrate the complexation in liquid medium with the participation of both azabicyclooctyl and tolyl moieties of GL in the inclusion process. Solid systems prepared by kneading, co-grinding and spray drying have also been checked, using DSC and HSM, for assessing the formation of the inclusion compound. Experimental evidence of the complexation between drug and cyclodextrin was reported for the co-ground and spray-dried systems.     

Pharmacokinetics and β-blocking effects of transdermal timolol

Summary The pharmacokinetic profiles of transdermal timolol 6 and 24 mg (as 5 and 20% w/v patches) was studied in four healthy young volunteers. To assess its bioavailability, the pharmacokinetics of an IV infusion of timolol maleate 5 mg was also determined in the same subjects. When the 20% (w/v) timolol patch was applied, the mean bioavailability was 74.4%.Plasma timolol concentrations were below the detection limit when a 5% patch was applied to the same skin area in all four subjects, except for one in whom the bioavailability was 23.6%. Weak erythema developed at the application site in all of the volunteers after application of the 20% (w/v) patch. However, erythema did not develop in any volunteer when the 5% patch was applied. The -blocking effect was determined by exercise testing.Similar plasma levels generated similar changes in exercise-induced heart rate after the transdermal and intravenous administration of timolol.     

Linalool and linalool complexed in β-cyclodextrin produce anti-hyperalgesic activity and increase Fos protein expression in animal model for fibromyalgia

The analgesic activity of (?)-linalool (LIN), a monoterpene present in essential oils of Lamiaceae species, has been previously demonstrated in rodents. However, its possible use in the treatment of fibromyalgia (FM) was never demonstrated. Additionally, as a short half-life is a limitation for the LIN medicinal application, the employment of drug delivery systems has been used to improve pharmaceutical properties of this compound. We investigated the anti-nociceptive effect of LIN, isolated or in β-cyclodextrin complex (LIN–CD), in an animal model of chronic non-inflammatory muscle pain (a FM animal model), as well as its effect on the central nervous system (CNS). Male Swiss mice were subjected to two injections of acidic saline (pH 4; 20 μL/gastrocnemius) and were treated on alternate days, with LIN–CD (25 mg/kg, p.o.), LIN (25 mg/kg, p.o.), tramadol (TRM 4 mg/kg, i.p.), or vehicle (neutral saline). After 60 min, they were screened for mechanical hyperalgesia (von Frey), motor coordination (rotarod), and muscle strength (grip strength meter) for 27 days. The CNS areas involved in the anti-hyperalgesic activity were evaluated by immunofluorescence. LIN or LIN–CD produced a significant reduction (p?p?相似文献   

Determination of stability constants of the inclusion complexes of β-blockers in heptakis (2,3-dimethyl-6-sulfato)-β-cyclodextrin

The beta-blockers possess at least one chiral center and the S(-)-enantiomer shows higher affinity for binding to the beta-adrenergic receptors than antipode. The stability constants of acebutolol, celiprolol, propranolol and terbutaline in the inclusion complexes with single-isomer heptakis (2,3-dimethyl-6-sulfato)-beta-cyclodextrin (HDMS-beta-CD) were determined by capillary electrophoresis. The approximation and linear double reciprocal methods were adapted with comparable results. Among the beta-blockers studied, propranolol had the lowest stability constant but the highest enantioselectivity, indicating that the magnitudes of the stability constants carried little information about enantioseparation. The magnitudes of enantioselectivities between the enantiomer pair were in the order of propranolol > celiprolol > terbutaline > acebutolol.     

The aggregative stability of β-lactoglobulin in glassy mixtures with sucrose, trehalose and dextran

The aim of this study was to investigate the effect of the addition of different carbohydrates on the thermally induced aggregation of a model globular protein, β-lactoglobulin (BLG), in the glass state. Amorphous mixtures of BLG with trehalose, sucrose and dextran were prepared by freeze-drying, their glass behaviour was characterised using calorimetry and thermally induced aggregation was measured using size exclusion chromatography. Pure BLG shows increasing levels of aggregation when heated in the temperature range 70-100 °C for 48-144 h. The addition of the disaccharides sucrose and trehalose both resulted in a decrease in aggregation rate which approached negligible rates at 50 wt.% carbohydrate. The effect of dextran addition was similar to that of the disaccharides when preparations containing 9 wt.% carbohydrate were heated at 70 °C for 2 days. However, when the concentration exceeded 23 wt.%, the reaction temperature was 70 °C or above or the reaction time was longer than 48 h, the addition of the polysaccharide did not protect the protein from thermally induced aggregation, suggesting that protein-polymer phase separation could have occurred during freeze-drying. Overall the results support the proposal that one aspect of carbohydrate additive functionality is as a diluent with the added condition that the carbohydrate remains miscible with the protein during processing.     

Solubilization of ibuprofen with β-cyclodextrin derivatives: energetic and structural studies

The aim of this work was to investigate the complexation of ibuprofen as model drug with various β-cyclodextrins (native β-cyclodextrin, hydroxypropyl-β-cyclodextrin with two different molar degrees of substitution, and methyl-β-cyclodextrin). Solutions of the commercially available β-cyclodextrins were prepared in phosphate buffer (73mM). The pH value was adjusted to 7.4 and the solutions were isotonized with NaCl. A solution of ibuprofen was prepared in the same way. A thermal activity monitor was used for isothermal titration calorimetry (ITC). (1)H NMR analysis was employed to investigate the structures of the complexes. ITC analysis showed that each type of β-cyclodextrin had its characteristic values of both enthalpy and mass equilibrium constant for the complexation processes with the drug molecules. (1)H NMR spectroscopy of the complexes showed through significant differences in chemical shifts that the physical interaction between the cyclodextrins and ibuprofen molecules were also different, probably due to different three-dimensional arrangements of ibuprofen in the cyclodextrin cavity, induced by the different substituents bonded to the glucose rings. These differences were connected to the thermodynamic parameters of the complexes.     

Mechanical complex formation of tolbutamide with β-cyclodextrin by solid phase roll mixing

The mechanical complexing behavior of tolbutamide (TB) and β-cyclodextrin (βCD) was closely examined from measurements of the time-course curve of the complex yield, the complexing ratio of βCD to TB and the phase solubility diagrams of roll mixing systems in the solid phase. The crystalline equimolar mixture of TB and βCD was readily transformed to an amorphous form by roll mixing. The roll mixture exhibited above 90% conversion in the complex yield for 10 min roll mixing periods. The complex yield increased with increasing shear rates between two rotating rollers. The roll mixing products were estimated stoichiometrically to be an equimolar ratio complex of βCD and TB. It was obtained from the phase solubility diagram that an apparent stability constant of the TBβCD complex in the roll mixture system was enhanced about four times over TB roll mixed without βCD. The equimolar ratio complex changed to an inclusion compound with complex ratio 2.5, when it was kept on 97% relative humidity for 48 h. The equimolar ratio complex was proposed to be a metastable amorphous solid form.