Enhancement of levodopa stability when complexed with β-cyclodextrin in transdermal patches

Abstract

Levodopa is a promising candidate for administration via the transdermal route because it exhibits a short plasma half-life and has a small window of absorption in the upper section of the small intestine. The aim of this study was to prepare stable levodopa transdermal patches. Both xanthan gum and Carbopol 971 polymers were selected with ethylcellulose constituting the backing layer of the prepared patches. The effect of adding β-cyclodextrin on the prepared patches was investigated. The uniformity in thickness, weight and content of the studied patches was acceptable. Physicochemical characterization revealed that there was no interaction between levodopa and the applied polymer. The results proved that levodopa precipitated as an amorphous form in carbopol patches. Controlled drug release was achieved for all the tested patches over a 6?h period. However, increased permeation was achieved for the carbopol patches. Although cyclodextrin did not enhance levodopa permeation, the stability study confirmed that levodopa stability was enhanced when complexed with β-cyclodextrin. The cumulative amount of drug released from carbopol patches is slightly higher than that of xanthan patches. The optimal stability was achieved in the carbopol/levodopa:β-cyclodextrin patch. The levodopa-β-cyclodextrin complex was successfully characterized using X-ray diffraction, NMR analysis and molecular dynamics simulations. In conclusion, carbopol/levodopa:β-cyclodextrin patches can be considered as a promising stable and effective transdermal drug-delivery system.     

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.     

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.     

Inclusion complexation of amide-typed local anaesthetics with β-cyclodextrin and its derivatives. I. Physicochemical characterization

Qualitative aspects of the inclusion complexation of two local anaesthetics of the amide-type (LAs), bupivacaine (BVC) and lidocaine (LDC) with three cyclodextrins (CDs), β-cyclodextrin (βCD) and its alkylated derivatives 2-hydroxypropyl-β-cyclodextrin (HPβCD) and heptakis (2,6-di-o-methyl)-β-cyclodextrin (DMβCD), were studied in the solid state by infrared spectroscopy (IR) and differential scanning calorimetry (DSC). The LDC-βCD couple was also investigated in aqueous solution by nuclear magnetic resonance (¹H-NMR and ¹³C-NMR). This first part of a study dealing with improvement in LA administration provided clear indications about LA-CD complexation. Qualitative modifications in a number of peaks or bands obtained from spectral methods as well as thermal analysis signed the inclusion, showing that the freeze-drying method was suitable for obtaining inclusion complexes of LAs with CDs.     

Formation arid antimicrobial activity of complexes of β-cyclodextrin and some antimycotic imidazole derivatives

Complex formation between -cyclodextrin and six antimycotic imidazole derivatives has been studied. The solubility of all drugs was increased in the presence of -cyclodextrin. The smallest increase (approx. 5-fold) was observed for miconazol, and the largest increase (approx. 160-fold) was observed for bifonazol. Apparent I:I-complex constants were measured and found to decrease in the order: bifonazol > ketoconazol > tioconazol > miconazol > itraconazol > clotrimazol. The complexes appeared to possess a low, if any, antimicrobial activity. Measurement of inhibition zone sizes, with four test organisms was used to study the release of the antimycotic drugs from topical preparations. The antimycotic drugs were more readily released from topical preparations containing \-cyclodextrin than from the same vehicles without -cyclodextrin. The rationale of -cyclodextrin addition to antimycotic topical preparations is discussed.     

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.     

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.     

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.     

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.     

In vitro and in vivo evaluation of oral tablet formulations prepared with ketoconazole and hydroxypropyl-β-cyclodextrin

The objective of this study was to enhance the solubility, dissolution rate, and oral bioavailability of a very poorly water-soluble anti-fungal agent, ketoconazole (KET), by inclusion complexation with a highly-soluble cyclodextrin derivative, hydroxypropyl-β cyclodextrin (HP-β-CD). Two groups of tablets containing KET alone and KET:HP-β-CD (1:2) kneaded product (KP) including magnesium stearate and lactopress (anhydrous and spray-dried) as excipients were prepared by direct compression method. After the characterization studies, the in vitro dissolution studies of these tablets in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) were carried out. To evaluate the in vivo bioavailability, the tablets were administered orally to rabbits and drug levels in serum were determined by HPLC. Tablets containing the cyclodextrin complex showed a higher in vitro dissolution rate and bioavailability compared to the tablets containing KET alone.     

Evaluation of cholesterol depletion as a marker of nephrotoxicity in vitro for novel β-cyclodextrin derivatives

Cyclodextrins (CDs) have been shown to improve physicochemical and biopharmaceutical properties of drugs when low solubility and low safety limit their use in the pharmaceutical field. Recently, we have developed new multi-substituted-β-CDs, hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HPn-SBEm-β-CD). HPn-SBEm-β-CD exhibit low hemolysis, good solubility, strong inclusion ability, and an appropriate average molecular weight. In this study, we chose two products of HPn-SBEm-β-CD (HP₃-SBE₂-β-CD and HP₂-SBE₃-β-CD) and compared their effects to sulfobutyl ether-β-cyclodextrin (SBE₇-β-CD), methyl-β-cyclodextrin (M-β-CD) and 2,6-di-O-methyl-β-cyclodextrin (DM-β-CD). We evaluated viability, membrane damage, induction of apoptosis and necrosis, cholesterol depletion, and morphological changes in human embryonic kidney 293A cells (HEK293A) in vitro. CDs caused a reduction of cell viability and increased LDH levels in a concentration-dependent manner. The effect of HP₃-SBE₂-β-CD or HP₂-SBE₃-β-CD on cell viability, membrane damage, and the induction of apoptosis and necrosis resembled that of SBE₇-β-CD, whereas the effects were significantly lower for M-β-CD or DM-β-CD. HP₃-SBE₂-β-CD and HP₂-SBE₃-β-CD exhibited morphological changes at high concentrations. In conclusion, the results showed that cholesterol depletion may be as a marker for evaluating the cytotoxicity of novel β-CD derivatives. These results will provide useful information for HPn-SBEm-β-CD as a promising safe adjuvant for intravenous administration in the future.     

Analysis of triclosan inclusion complexes with β-cyclodextrin and its water-soluble polymeric derivative

Interaction in solution and in the solid state of triclosan (TR), a practically water-insoluble antimicrobial agent, with parent β-cyclodextrin (βCD) and its water-soluble epichlorohydrin polymer (EPI-βCD) was investigated by several analytical techniques, to evaluate the role of the carrier features on the physicochemical properties of the drug-cyclodextrin complex. Phase-solubility studies showed the higher solubilizing and complexing ability of EPI-βCD (K(s) =1 1,733 M(-1)) than parent βCD (K(s) = 2526 M(-1)). Actual inclusion complex formation between TR and both cyclodextrins tested was confirmed by 2D (1)H NMR studies (ROESY), which also gave insight into some different drug/cyclodextrin binding modes between polymeric and parent βCD. Addition of hydrophilic polymers (hydroxypropylcellulose, hypromellose or amidated pectin) to TR/βCD systems increased βCD solubilizing efficacy, but, unexpectedly, decreased its complexing ability towards the drug. Solid binary and ternary samples prepared by co-grinding of components in high energy mills were carefully characterised by Differential Scanning Calorimetry, X-ray powder diffractometry and Fourier transform infrared spectroscopy. The results pointed out the higher affinity of EPI-βCD than βCD for the interaction with TR even in the solid state, resulting in the formation of completely amorphous products with superior dissolution properties. Addition of hydrophilic polymers failed to effectively promote solid-state interactions between TR and βCD, while their positive influence on drug solubility, observed in phase-solubility studies, was absent in solid TR/βCD/polymer products. Finally, the time-kill analysis, used to evaluate the TR antimicrobial activity against Streptococcus mutans, demonstrated the significantly (p < 0.001) superior performance of both cyclodextrin complexes than drug alone, and confirmed the higher effectiveness (p < 0.05) of TR/EPI-βCD than TR/βCD complex.     

Release characteristics of freeze-dried eugenol encapsulated with β-cyclodextrin by molecular inclusion method

The study investigated the thermo-physical properties of eugenol encapsulated with β-cyclodextrin (β-CD) by molecular inclusion and eugenol release characteristics at various relative humidities and storage temperatures. Particle size, Zeta-potential, thermal transition and morphology of β-CD-Eugenol complex after freeze-drying measured using Nanosizer®, differential scanning calorimeter (DSC) and transmission electron microscopy (TEM), respectively. The particle size, Zeta-potential and inclusion efficiency of encapsulated eugenol presented ～340 nm, ?34.5 mV and 91.7% after freeze-drying, respectively. The relationship between retention rate of eugenol and time during release was described by a mathematical model of Avrami equation. In these events, the parameter of release mechanism and the release rate constant were rapidly elevated with increasing relative humidity and storage temperature. Furthermore, the Arrhenius activation energy for the release of eugenol decreases with increasing relative humidity and storage temperature.     

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.     

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.     

Formulation and evaluation of pH sensitive hydrogel of camptothecin with enhanced solubility by using β-cyclodextrin

The use of a novel injectable biocompatible and biodegradable camptothecin (CPT) formulation for controlled intra-tumoral release of CPT is described. The drug delivery vehicle is an autogelling pH sensitive formulation, which is based on the natural biopolymer chitosan. The formulation was prepared by Crosslinking methods. The formulations were characterized by Fourier transform infrared spectroscopy, X-ray diffraction, gelation time and viscosities were investigated for controlled release hydrogel formulation. The formulation, containing homogeneously dispersed CPT, was studied by MTT assay on tumor cell MCF-7. The effectiveness of treatment was measured in terms of percentage control tumor growth inhibition (TGI). The hydrogel formulation of CPT showed good release profile with polymer [chitosan (C)/glyceryl monooleate (GMO)/β-cyclodextrin (β-CD)] compare to without polymer. The gelation pH of the formulation PF, PF4, PF6, PF10 and PF12 were found to be 6.58, 7.42, 7.20, 6.98 and 7.30 respectively and calculated values of viscosity in centipoises of the formulation PF, PF4, PF6, PF10 and PF12 were 3,413.3, 5,843.1, 6,948.8, 5,212.6 and 6,972.6 respectively at 25 °C. It was found that cumulative percentage drug release for formulations prepared PF, PF4, PF6, PF10 and PF12 were released 48.48, 76.92, 83.72, 78.97 and 59.23 % respectively. The formulation PF6 showed maximum cumulative percentage drug release which has 3 % w/v chitosan, 3 % w/v GMO and 1.5 % w/v β-CD. The TGI was found that for formulations CPT, PF, PF4, PF6, PF10 and PF12 were 10.2 ± 1.22, 10.4 ± 0.85, 14.92 ± 1.06, 16.42 ± 1.11, 13.58 ± 1.21 and 11.71 ± 1.14 % respectively. The formulation PF6 showed maximum TGI in comparison to other formulation. The system formulated with CPT was found to be stable and the release profiles of a formulation with chitosan, GMO and β-CD showed all most effective release kinetics. These findings show chitosan/GMO/β-CD hydrogel to be a safe, effective, homogeneous, injectable and stable formulation for delivery of CPT and this approach represents an attractive technology platform for the delivery of other clinically important hydrophobic drugs.     

Development of machine learning models of β-cyclodextrin and sulfobutylether-β-cyclodextrin complexation free energies

A new set of 142 experimentally determined complexation constants between sulfobutylether-β-cyclodextrin and diverse organic guest molecules, and 78 observations reported in literature, were used for the development of the QSPR models by the two machine learning regression methods - Cubist and Random Forest. Similar models were built for β-cyclodextrin using the 233-compound dataset available in the literature. These results demonstrate that the machine learning regression methods can successfully describe the complex formation between organic molecules and β-cyclodextrin or sulfobutylether-β-cyclodextrin. In particular, the root mean square errors for the test sets predictions by the best models are low, 1.9 and 2.7 kJ/mol, respectively. The developed QSPR models can be used to predict the solubilizing effect of cyclodextrins and to help prioritizing experimental work in drug discovery.     

Enhanced anti-tumor effect of 9-nitro-camptothecin complexed by hydroxypropyl-β-cyclodextrin and safety evaluation

The aim of this study was to evaluate the safety and anti-tumor effect of 9-nitro-camptothecin/hydroxypropyl-β-cyclodextrin (9-NC/HP-β-CD) complex on tumor-bearing mice. The in vitro anti-tumor activity was tested by MTT assay. Our study revealed that the 9-NC/HP-β-CD complex showed significant anti-tumor activity towards Skov-3, MCF-7, HeLa and S180 cell lines with IC(50) values of 0.24 ± 0.09, 0.59 ± 0.20, 0.83 ± 0.11, and 6.30 ± 2.42 μg/ml, respectively, significantly superior to the free 9-NC. The in vivo therapeutic efficacy was investigated in ICR mice bearing mouse sarcoma S180. Both the high (3mg/kg) and low (1mg/kg) doses of 9-NC/HP-β-CD complex demonstrated high inhibition ratio of tumor growth (>75%). The subacute toxicity test was performed by measuring the body weight, histopathology, blood cell counts and clinical chemistry parameters (total bilirubin, alanine transferase, aspartate transferase, blood urea nitrogen and creatinine), and the results indicated the good safety profile of the complex. Taken together, the results suggested that the 9-NC complexed in HP-β-CD, instead of dissolved in the organic solvent, presented significant anti-tumor activity and low toxicity for the treatment of cancer.