Rapamycin-cyclodextrin complexation: improved solubility and dissolution rate

The objective of this study was to improve poor aqueous solubility and dissolution properties of anticancer drug rapamycin through formation of inclusion complexes with natural and modified cyclodextrins. Of the cyclodextrins tested, ??-cyclodextrin and hydroxypropyl-??-cyclodextrin did not complex with rapamycin. However, complexes of rapamycin with ??-cyclodextrin, methyl-??-cyclodextrin and hydroxypropyl-??-cyclodextrin were prepared and characterized by techniques such as Fourier Transform infrared spectroscopy, differential scanning calorimetry, phase solubility analysis and in vitro dissolution studies. According to the characterization data for the complexes, rapamycin water solubility was highly enhanced by all three ??-cyclodextrins with methyl-??-cyclodextrin complex resulting in particularly higher solubility enhancement. FTIR spectra and DSC thermograms supported the formation of inclusion complexes. The complexes showed highly improved dissolution rate in water. Complexation with cyclodextrin derivatives such as methyl-??-cyclodextrin and hydroxypropyl-??-cyclodextrin can provide promising alternatives for the formulation of rapamycin.     

相溶解度法研究不同环糊精对丹皮酚的增溶作用

采用相溶解度法,通过测定丹皮酚在不同温度不同浓度的β-环糊精(β-CD)、羟丙基-β-环糊精(HP-β-CD)、羟乙基-β-环糊精(HE-β-CD)、取代度为4的磺丁基醚-β-环糊精(SBE4-β-CD)以及取代度为7的磺丁基醚-β-环糊精(SBE7-β-CD)中的溶解度,绘制相溶解度曲线,丹皮酚的溶解度均随5种环糊精浓度的增加而成线性增加,相溶解度曲线为AL型,说明丹皮酚与环糊精以1∶1包合,实验结果表明,5种环糊精对丹皮酚均有增溶作用且SBE7-β-CD的增溶效果最佳.     

Effect of hydrophilic polymer on complexing efficiency of cyclodextrins towards efavirenz-characterization and thermodynamic parameters

The present work describes the effect of PVP on the complexation efficiency of cyclodextrins towards efavirenz, a poorly soluble antiretroviral agent imparting irritating sensation to buccal cavity. The phase solubility study indicates 1:1 stoichiometry for binary and ternary systems. DSC and XRPD revealed complete inclusion only in the lyophilized systems. The ternary systems were autoclaved before being lyophilized for the best results. Proton NMR suggests that the chlorobenzene part of benzoxazinone ring of the drug is involved in inclusion and was confirmed by 2D-COESY. The thermodynamic parameters, indicative of complexation efficiency were calculated calorimetrically by determining the interaction enthalpy of efavirenz with cyclodextrins in the presence and absence of PVP. The value of stability constants increased in the order β-CD?<?HP-β-CD?<?M-β-CD and is still higher in the presence of PVP illustrating the facilitation of the inclusion. Molar enthalpy of interaction of autoclaved solid formulation determined calorimetrically indicated stronger interaction for efavirenz:M-βCD-PVP system (?12.20?kJ/mol) which showed highest solubility and dissolution rate. The in vitro measurement of permeability showed a ten fold increase in the flux for the autoclaved formulation containing efavirenz-M-β-CD-PVP. In conclusion, encapsulation by cyclodextrins increases the solubility and suppresses the oral irritation of efavirenz. PVP further increases the complexation efficiency and decreases the bulk of cyclodextrins.     

Retention properties of cyclodextrins and modified cyclodextrins in reversed phase HPLC

Summary In the course of systematic studies on the solubility, hydrophobicity and complexation properties of cyclodextrins and modified cyclodextrins, the retention behavior of , , and of some glycosylated cyclodextrins has been examined by means of reverse phase HPLC. Mobile phase mixtures containing large amounts of water have been used because of the possible application of such systems to biological studies. Mobile phase mixtures with both methanol and acetonitrile show a linear relationship between the volume fraction of the organic part of the mobile phase and the logarithm of the capacity factor. The extrapolation of capacity factors to a total aquous system are used and compared to other techniques (including solubility) in order to evaluate the hydrophobic properties of the cyclodextrins. In particular, the solubility of cyclodextrins has been explored for a wide range of organic solvent/water mixtures. Whilst cyclodextrins are definitely the most hydrophobic, followed by glycosylated cyclodextrins, the others behave differently in the two mobile phase systems. The differences observed in the results are related to the chemical nature of the organic phase. Comparisons between chromatographic and solubility methods are given and interpretations are proposed. Some cyclodextrins have been modified to increase or modify not only the hydrophobicity but also the solubility, the complexation and the molecular recognition of drugs. The most important aim of this study was to define conditions and rules for further drug vectorization by cyclodextrin-drug complexation.     

Computational Prediction for the Slopes of AL-type Phase Solubility Curves of Organic Compounds Complexed With α-, β-, or γ-cyclodextrins Based on Monte Carlo Docking Simulations

A Monte Carlo (MC) docking method was introduced in order to predict the aqueous solubility of inclusion complexes composed of small organic compounds and various cyclodextrins. The slope (S) of the A_L-type phase solubility curve was accurately predicted by a combination of the interaction energy and nonpolar solvation free energy for each of the docked complexes. The regression equation for S, the slope of the phase solubility curve gives a fine correlation coefficient, r ², of 0.913 and standard error of 0.028 for the 63 organic compounds complexed with cyclodextrins.     

Solubilization of itraconazole as a function of cyclodextrin structural space

Cyclodextrins are functional pharmaceutical excipients, which can dynamically include poorly water-soluble drugs and drug candidates resulting in improved solubility, stability and oral bioavailability. A number of formulations containing “natural” and chemically modified cyclodextrins have reached the market and are enjoying widespread attention and use. One such example is itraconazole, a broad-spectrum antifungal agent which is available in an aqueous hydroxypropyl-β-cyclodextrin (HPβCD) vehicle for both oral and parenteral use (Sporanox Oral Solution and Sporanox Intravenous Injection^®). While the interaction of itraconazole and HPβCD is well described, its ability to form complexes with other cyclodextrins is less understood. This creates an intriguing opportunity of screening the structural space of available cyclodextrin derivates by assessing their complexation with a single chemical probe, in this case itraconazole. To this end, a number of cyclodextrin derivatives were assess with regard to their ability to improve the water solubility of the test substrate. In some instances, more detail assessments including the effect of pH and the physical form of the drug probe were also completed. The various cyclodextrins solubilized itraconazole to varying extents (micrograms to milligrams) and by varying inclusion mechanisms and stoichiometries.     

Preparation,physicochemical characterization and biological activity evaluation of some inclusion complexes containing artesunate

Journal of Thermal Analysis and Calorimetry - The use of cyclodextrins as carrier molecules is currently highly researched since they can improve not only the apparent water solubility and...     

Berberine/γ‐Cyclodextrin Inclusion Structure Studied by 1H‐NMR Spectroscopy and Molecular‐Dynamics Calculations

To understand the increased solubility and decreased bitter taste of berberine, a clinically important isoquinoline alkaloid, in the presence of cyclodextrins, the interaction with γ‐cyclodextrin (γ‐CD) in aqueous solution was studied by a combination of ¹H‐NMR analyses and molecular‐dynamics calculations. The proposed complexation mode of berberine by γ‐CD could explain the increased solubility in water. No difference in germicidal activity between berberine alone and its inclusion complex with γ‐ or β‐CD was observed, which is important to further develop the pharmacological application of berberine.     

Cyclodextrins and the liquid-liquid phase distribution of progesterone, estrone and prednicarbate

The purpose of the present work was to investigate the interaction of drugs and octanol with hydroxypropyl β- (HPβCD) and γ- (HPγCD) cyclodextrin, sulfobutyl ether β-cyclodextrin (SBEβCD) and randomly methylated-β-cycoldextrin (RMβCD) and to describe the interaction by theoretical models. The poorly soluble steroid drugs progesterone, estrone and prednicarbate were used as model compounds in this study. Hexane and chloroform were also investigated in combination with HPβCD. Octanol formed a complex with all cyclodextrins and the saturation of the aqueous solution with this solvent therefore had a significant effect on the solubilization and extraction potential of cyclodextrins. Hexane had less affinity for cyclodextrins, but the drugs were poorly soluble in this solvent and it could therefore not be used in phase-distribution investigations. Previously we have derived equations that can be used to account for the competitive interaction between two guest compounds that compete for space in the cyclodextrin cavity. These equations were rearranged to calculate the complexation efficacy from phase-solubility data. An equation was derived that obtains intrinsic solubility (S ₀) and intrinsic partition coefficient (P) from the slopes of the phase-solubility and phase-distribution profiles. Investigation of the data showed that the results could not be sufficiently explained by the “classical” drug/cyclodextrin complex model that recognizes the possibility of competitive interactions but ignores any contribution from higher order complexes or aggregation of the cyclodextrin complexes. Relative difference in solubilization potential of different cyclodextrins cannot be translated to relative differences in extraction efficacy. Thus, for these three steroid compounds, RMβCD and SBEβCD gave the best solubilization potential whereas the best extraction efficacy was observed with HPγCD.     

Determination of the Inclusion Constants for the Inclusion Complexes between meso-Tetrakis (4-sulfonatophenyl) Porphyrin and Cyclodextrins by Three Methods

In this paper, the interactions of meso-Tetrakis (4-sulfonatophenyl) porphyrin (TPPS 4 ) and six cyclodextrins have been studied, respectively, by fluorescence spectroscopy, polarography and thin-layer chromatography. The inclusion constants of different methods are determined and the comparison of inclusion capacity of various cyclodextrins indicates that for the ionic cyclodextrins the charge interaction plays an important role in the inclusion procedure. The thermodynamic parameters of interaction imply that the inclusion process shows the enthalpy-entropy compensation effect. Cyclodextrin, being regarded as an artificial analogue of proteinoid of heme, provides a protective sheath for porphyrin. However, the TPPS 4 , encapsulated within this saccharid-coated barrier, its solubility is enhanced prominently, which exhibits that this interaction may modify the biological properties of TPPS 4 that owned the similar properties as hematoporphyrin.     

Physicochemical characterization of finasteride:PEG 6000 and finasteride:Kollidon K25 solid dispersions, and finasteride: ��-cyclodextrin inclusion complexes

Finasteride is a practically insoluble in water drug that belongs to the Class II of the BCS (poor solubility and high permeability). Solid dispersions are solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. Solid dispersions are a successful strategy to improve drug release of poorly water-soluble drugs such as finasteride. Natural cyclodextrins are doughnut-shaped molecules with an internal hydrophobic cavity and a hydrophilic external surface. The lipophilic cavity enables cyclodextrins to form non-covalent inclusion complexes with a wide variety of poorly water-soluble drugs such as finasteride. The aim of this study was to investigate the formation of finasteride:PEG 6000 and finasteride:Kollidon K25 solid dispersions and finasteride:??-cyclodextrin inclusion complexes by solvent evaporation method using a mixture of water:ethanol (1:1). The formation of finasteride:PEG 6000 and finasteride:Kollidon K25 solid dispersions and finasteride:??-cyclodextrin inclusion complexes was investigated and characterized by differential scanning calorimetry (DSC), infrared (IR) spectroscopy, and dissolution studies from capsules containing a quantity equivalent to 5 mg of finasteride. The DSC thermograms revealed the transformation of finasteride into the amorphous state in solid dispersions with PEG 6000 and Kollidon K25, and in inclusion complexes with ??-cyclodextrin. The IR spectra demonstrated molecular interaction in solid dispersions of finasteride with PEG 6000, and in inclusion complexes with ??-cyclodextrin. Dissolution rate of solid dispersions and inclusion complexes was significantly greater than that of corresponding physical mixtures and pure drug, indicating that the formation of solid dispersions and inclusion complexes increased the solubility of the poorly soluble drug, finasteride.     

The effect of cyclodextrin mixtures on aqueous solubility of beclomethasone dipropionate

The aim of present study was to evaluate the effect of natural, synthetic cyclodextrins (CDs) and CD mixtures on aqueous solubility of beclomethasone dipropionate (BDP). The phase solubility studies were done in the presence of 6 CDs. Furthermore, aqueous solubility of BDP was tested in the presence of CD mixtures. The solubility of BDP in water was increased by 30, 77, 155 and 30 folds in the solution containing 20%?w/v α-CD, hydroxylpropyl β-CD (HP-β-CD), hydroxypropyl γ-CD (HP-γ-CD) and sulphobutylether β-CD (SBE-β-CD), respectively. CD mixtures had remarkable effect on the aqueous solubility of BDP so that solubility in water increased between 200 and 1,500 times in the presence of different CD mixtures. Further addition of sodium acetate to the solubilisation medium reduced the aqueous solubility. In conclusion, CD complexation was able to improve the aqueous solubility of BDP. The synergistic effect of cyclodextrin mixture was observed.     

Increasing the solubility characteristics of D-norgestrel with cyclodextrins

Levonorgestrel dissolves only slightly in water. Attempts were made to increase the solubility properties of this drug by complexing with cyclodextrins. The products were investigated with a dissolution tester and a Sartorius resorption model. X-ray and NMR spectra of the inclusion complexes were analysed.     

Host–Guest Interaction Study of Resveratrol With Natural and Modified Cyclodextrins

The aim of this work is to increase the stability and water solubility of resveratrol by complexation with different cyclodextrins. Furthermore, physical–chemical properties of each inclusion compound were investigated. Complexes of resveratrol with cyclodextrins both native (α, β, γ) and modified (2-hydroxypropyl-β-cyclodextrin, dimethyl-β-cyclodextrin) were obtained by using the suspension method. An inclusion complex with β-cyclodextrin was also prepared by using the microwave. Solid state characterization of the products was carried out using Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray diffraction (DRX); solution studies were performed by UV–Vis spectrophotometry and ¹H-NMR spectroscopy. Phase solubility profiles with all cyclodextrins employed were classified as A_N type, indicating the formation of 1:1 stoichiometric inclusion complexes. Stability constants (K _c) from the phase solubility diagrams were calculated. Stability studies in the solid state and in solution were performed; the photodegradation by UV–Vis spectrophotometry was monitored. The isomerization rate trans to cis, in ethanol solution, decreased with inclusion. The dissolution studies revealed that resveratrol dissolution rate was improved by the formation of inclusion complexes.     

Fatty acid-cyclodextrin complexes: Properties and applications

The complexation of fatty acids (both saturated and unsaturated) with various cyclodextrins and cyclodextrin derivatives greatly modifies their properties. Inclusion complex formation — depending upon the type of host cyclodextrin — may result in protection against the environment, in improved water solubility and bioavailability. Thus lipid complexation enables the preparation of more reliable diagnostic reagents, better chromatographic separations and higher yields in biotechnological processes. The relevant literature is reviewed with particular emphasis on the practical utility of the molecular encapsulation of fatty acids with cyclodextrins.     

Interactions of xanthine and its derivatives with cyclodextrins in aqueous solutions

Using calorimetry, ¹H NMR, UV spectroscopy, and solubility methods, the interactions of natural and hydroxypropylated 6h-, β-, and γ-cyclodextrins with xanthine and its methylated derivatives (theophylline, theobromine, and caffeine) were studied in aqueous solutions at 298.15 K. Cyclodextrins revealed low complexation ability toward xanthine and its methylated derivatives. Hydroxypropyl-γ-cyclodextrin with the largest internal cavity is the most effective solubilizing agent for this type of compounds. The calculated thermodynamic parameters are discussed in terms of structural effects of cyclodextrins and purine alkaloids on the character of their intermolecular interactions in aqueous medium.     

Cyclodextrins in Eye Drop Formulations

Ideally, eye drop formulations are aqueous solutions. Many drugs that are useful in topical application to the eye are not sufficiently water soluble to be dissolved in simple aqueous solutions. This problem is approached through hydrophilic prodrugs, suspensions, lipid based solutions and excipients such as cyclodextrins. Cyclodextrins can be used to form aqueous eye drop solutions with lipophilic drugs, such as steroids. The cyclodextrins increase the water solubility of the drug, enhance drug absorption into the eye, improve aqueous stability and reduce local irritation. Cyclodextrins are useful excipients in eye drop formulations of various ophthalmic drugs, including steroids of any kind, carbonic anhydrase inhibitors, pilocarpine and cyclosporins. Their use in ophthalmology has already begun and it is likely to expand the selection of drugs available as eye drops. In this paper we review the use of cyclodextrins in eye drop formulations. The use of cyclodextrins to formulate dexamethasone eye drops is an example of their usefulness. Cyclodextrins have been used to formulate eye drops containing corticosteroids, such as dexamethasone, with concentration and ocular absorption, which in human and animal studies is many fold that seen with presently available formulations. Such formulations offer the possibility of once a day application of corticosteroid eye drops after eye surgery, and more intensive topical steroid treatment in severe inflammation.     

Development of a formulation of Pirodavir using 2-hydroxypropyl-β-cyclodextrin

Pirodavir, 4-[2-[1-(6-Methyl-3-pyridazinyl)-4-piperidinyl]ethoxy]benzoic acid ethyl ester, is an antiviral compound which has low aqueous solubility (<0.01 mg/ml). The compound is a weak base (pKa 5.8) with high lipophicity (logP 4.44). Ionization of the compound increases the solubility in acidic medium to 2.3 mg/ml at pH 2.4. However, a low pH is not acceptable for nasal application as this would induce irritation. Extensive solubility studies were performed using different types of substituted cyclodextrins in order to select an appropriate derivate capable of increasing solubility to an acceptable level for formulations for nasal application. Aqueous solubility of pirodavir increased in a linear fashion with increasing concentration of most of the substituted cyclodextrins. However, using 2-hydropropyl-β-cyclodextrin (HPBCD) the solubility increased in a non-linear fashion. Based on these studies HPBCD was selected as the most appropriate excipient. To support a clinical study on the treatment of rhinovirus cold by intranasal Pirodavir formulations were developed containing up to 5 mg/ml of pirodavir and up to 10% of HPBCD. Stability of the formulations was studied and found to be acceptable.     

Investigation on the Interaction of Bendazac with β-, Hydroxypropyl-β-, and γ-, yclodextrins

The interactions of Bendazac, a topical non-steroidal anti-inflammatory drug, with-cyclodextrin, hydroxypropyl--cyclodextrin and -cyclodextrinwere investigated to evaluate possibilities to improve the drug's poor water solubilityand eventually to enhance the topical delivery of Bendazac. Phase solubility studiesdemonstrated the ability of the selected cyclodextrins to complex with Bendazac andincrease drug solubility. The amount of solubilized Bendazac increased linearly withthe addition of each cyclodextrin according toA_L type plots. ¹³C-NMR studiesshowed that the Bendazac A-ring was included in the cavity of the three cyclodextrins.The -cyclodextrin was also able to include the B-ring of Bendazac, forminga complex where one drug molecule fitted into two cyclodextrin molecules. Equimolarsolid systems of the drug with each cyclodextrin carrier were prepared using varioustechniques (physical mixing, spray-drying and freeze-drying). The results of differential scanning calorimetry and Fourier transform infrared analysis, performed on the solid systems, demonstrated that freeze-dried and spray-dried products had a high degree of amorphization and agreed with the hypothesis of the existence of drug–cyclodextrin interaction in the solid state. The cyclodextrins tested were able to improve the dissolution of Bendazac. The dissolution profile of the drug was also affected by the physico-chemical properties of each solid system, the freeze-dried products being the most rapidly dissolving forms.