Limits of cyclodextrin application in oral drug preparations

Cyclodextrins are applied to facilitate formulation problems, to improve stability and bioavailability. Following factors are determining whether or not cyclodextrins can be applied in oral pharmaceutical preparations:

- properties of the selected CD: solubility, price, specific catalytic properties,

- the drug to be complexed: molecular weight, polarity, solubility,

- drug dose

- solubility properties of the complex and the “super solubility” /temporary over-saturation/

- complex stability and possibility to shift the dissociation equilibrium toward the appropriate direction

- legislative procedures

     

Examples of the application of cyclodextrin in formulation of oral drug preparations

Fendiline hydrochloride [N-/1-phenylethyl/-3, 3-diphenylpropylamine. HCl] is a sparingly soluble and hardly absorbable coronary vasodilator. The fendiline base forms complex with -cyclodextrin in a molar ratio of 12. The enhanced solubility and dissolution rate of the complex resulted in a better bioavailability of the drug, which is represented by the elevated blood levels in rats. The -cyclodextrin complex of PGI₂Me /3% active ingredient content/ was prepared. The freeze-dried powder can be stored at 0°C for 1.5 years, while the pure substance only for 4 months. The biological effectiveness of the complex agrees well with that of the active ingredient. After oral administration the cytoprotective effect of the free and complexed drug on indomethacin induced ulcers in rats was similar in their order of magnitude, however the prolonged effect of the complex was detected in this case too.     

Prostaglandins and their cyclodextrin complexes

Generally, prostaglandins (PG) are unstable and insoluble in water, though they exhibit strong biological activities in minute amount. The most difficult problem in developing PG preparations is how to stabilize and solubilize PG without loss of their activities. We have successfully developed the pharmaceutical preparations contaning PG complexes with cyclodextrins (CD). These preparations are already on the market, namely PGE₂ ·-CD Tablet and PGE₁ ·-CD Injection. Moreover, PG and PGI₂ derivatives are now under development as a form of CD complex.     

An NMR study of cyclodextrin complexes of the steroidal neuromuscular blocker drug Rocuronium Bromide

The interaction of Rocuronium Bromide, and a model steroid Org 7402, with three cyclodextrins (β‐cyclodextrin, γ‐cyclodextrin and Org 25969) was studied by solution state NMR experiments. Stoichiometries and binding constants were determined from ¹H chemical shift titrations. All of the systems formed 1 : 1 complexes. Most of the complexes were in fast exchange with unbound species on the NMR time scale, but the most tightly bound complex (Rocuronium Bromide–Org 25969) was in the slow exchange regime. The geometry of the complexes was inferred from ¹H and ¹³C NMR shift changes upon complexation and from intramolecular NOE correlations. Rocuronium Bromide forms a weak complex with β‐cyclodextrin (K_a = 3.3 ± 0.5 × 10³ M ^?1) and no clear picture of the structure of the complex emerges. The complexes with γ‐cyclodextrin (K_a = 1.8 ± 0.2 × 10⁴ M ^?1) and Org 25969 (K_a > 10⁵ M ^?1) are true inclusion complexes with the steroid located inside the central void of the cyclodextrin. Copyright © 2002 John Wiley & Sons, Ltd.     

Zwitterion formation in gas-phase cyclodextrin complexes

Protonated complexes of amino acids and underivatized beta-cyclodextrin, produced by electrospray ionization and trapped in the Fourier transform mass spectrometer, undergo formation of ternary complexes when reacted with alkyl amine. Based on the reactivities of the protonated amino acid complexes with alkylamines, the reactivities of the corresponding amino acid esters, and partially derivatized beta-cyclodextrin hosts, we conclude that the ternary complexes are salt-bridge zwitterionic species composed of amino acid zwitterions and protonated alkylamine all interacting with the hydroxyl groups on the narrow rim of the cyclodextrin. Molecular modeling calculations and experimental results suggest that the interactions of the amino acids with the rims contribute greatly to the formation of the zwitterionic species.     

Self-assembled cyclodextrin nanoparticles and drug delivery

Drug/cyclodextrin complexes self-assemble in aqueous solutions to form nanosized aggregates or nanoparticles. These complex aggregates are responsible for many of the physicochemical and biological properties of cyclodextrin complexes. Due to the aggregate formation aqueous drug/cyclodextrin solutions can behave more like dispersed nanoscale systems, such as nano-suspensions and liposomes, rather than true solutions. The aggregation can result in enhanced cyclodextrin solubilization of poorly soluble lipophilic drugs; they can serve as building blocks for ternary or higher order complexes; they can be developed into nano- and microparticulated drug carriers for targeted drug delivery to, for example, hair follicles; they can be developed into sustained drug delivery systems; and they can possible be used as mucus-penetrating drug delivery vectors. All of this can be obtained without chemical modifications of the cyclodextrin monomers.     

Inclusion complexes with cyclodextrin and usnic acid

Molecular inclusion complexes of usnic acid (UA) with β-cyclodextrin (β-CD) and 2-hydroxypropyl β-cyclodextrin (HP β-CD) were prepared by the co-precipitation method in the solid state in the molar ratio of 1:1. Structural complexes characterization was based on different methods, FTIR, ¹H NMR, XRD and DSC. Parallel to the complex by the above methods, corresponding physical mixtures of UA with cyclodextrins and complexing agents (β-CD, HP β-CD and UA) were analyzed. The results of DSC analysis showed that, at around 200 °C, the endothermal peak in the complexes with cyclodextrins originating from the UA melting has disappeared. Complex diffractogram patterns do not contain peaks characteristic for the pure UA. They are more appropriate to cyclodextrin diffractogram. This fact points to the molecular encapsulation of UA in the cyclodextrin cavity. Chemical shifts in ¹H NMR spectra after the inclusion of UA into the cyclodextrin cavity, especially H-3 protons (0.0012 and 0.0102 ppm in the β-CD and HP β-CD, respectively) and H-5 and H-6 (0.0134 ppm) and hydrogen from CH₃ (0.0073 ppm) HP β-CD also points to the formation of molecular inclusion complexes. The improved solubility of UA in water was achieved by molecular incapsulation. In the complex with β-CD the solubility is 0.3 mg/cm³, with HP β-CD 4.2 mg/cm³ while the uncomplexed UA solubility is 0.06 mg/cm³. The microbial activity of UA and both complexes was tested against eight bacteria and two fungi and during the test no reduced activity of UA in the complexes was observed.     

人参皂苷与环糊精包合物的研究进展

人参皂苷是从人参、西洋参和三七中提取的主要活性成分,其药效价值相当高,但因其在水中几乎不溶,生物利用度极低,因此极大的限制了其在临床上的应用.环糊精具有独特的性质,其"腔内疏水、腔外亲水",可以选择性的包合人参皂苷等客体分子.环糊精与人参皂苷形成包合物后可以改变客体分子的某些物理化学性能,如水溶性、稳定性以及光学性质等,以此来提高其生物利用度.     

Separation ability and stoichiometry of cyclodextrin complexes

Gas-liquid chromatography has been applied to search relations between selectivity towards isomers and stoichiometry of cyclodextrin complexes. The model tested compounds were: dimethylnaphthalenes and alpha- and beta-pinenes as constitutional isomers; cis/trans decalins, anetholes and isosafroles as diastereomers and as enantiomers (+/-)-alpha-pinenes and (+/-)-camphenes. Experimental retention data are used to confirm a simple theoretical model that allows distinguishing formation of G x CD complexes (1:1) and G x CD2 complexes (1:2). Based on the experimental data, stability constants K were evaluated. It has been found that remarkable selectivity factor alpha may appear both within the range of 1:1 stoichiometry (beta-CD complexes of decalins and of alpha- and beta-pinenes) and 1:2 stoichiometry (alpha-CD complexes with (+/-)-alpha-pinenes and (+/-)-camphenes). Occasionally selectivity arises from a different composition, when one isomer forms a 1:1 stoichiometry complex while another forms a 1:2 complex (dimethylnaphthalenes, cis/trans-anetholes and cis/trans-isosafroles).     

Physicochemical characterization of cholesterol-beta cyclodextrin inclusion complexes

Study and characterization of molecular complexes between cholesterol and beta cyclodextrin has been done using X-ray diffraction, thermogravimetric analysis (TG), differential scanning calorimetry (DSC) and nuclear magnetic resonance spectroscopy (¹³C NMR). Whatever the value of the molar ratio cholesterol/βCD used during the preparation, the same compound is always obtained. Corresponding to a molar ratio 1/3 (cholesterol/βCD), this compound is a stable hydrate which, contrary toβCD, contains at room temperature a large amount of molecules of water. It can be dehydrated under low pressure but the thermal degradation occurs at 200°C (250°C forβCD). This implies that cholesterol is strongly bounded toβCD.     

Crystal packing patterns of cyclodextrin inclusion complexes

Cyclodextrin inclusion complexes crystallize in two basically different patterns, the cage and the channel type. The cage type occurs when cyclodextrins are packed crosswise (fishbone) or, if they are packed side-by-side, in layers and adjacent layers are displaced by about one half molecule. In each case, the internal cavity of one cyclodextrin is closed on both sides by neighbouring cyclodextrins. On the other hand, channel complexes are formed if cyclodextrins are stacked like coins in a roll so that cavities line up to produce long channels. In these crystal structures, cyclodextrins can be arranged in head-to-head or head-to-tail mode. In the smaller -cyclodextrin, cage type structures are formed with small, molecular guests whereas long molecular guests and ionic guest molecules induce channel type structures. The latter are generally preferred with the - and -cyclodextrin series which is probably due to the higher tendency for self aggregation in these two members of the cyclodextrin family.Part XXII of the series Topography of Cyclodextrin Inclusion Complexes. For part XXI, see ref. 6.     

Dissolution properties of cypermethrin/cyclodextrin complexes

Cypermethrin—a very effective pyrethroid-type insecticide—has been complexed with β-cyclodextrin and peracetylated-β-cyclodextrin with different guest content. Dissolution measurements by reversed phase HPLC method, together with UV-spectrophotometry, differential scanning calorimetry and thermogravimetry were applied to prove the inclusion complex formation and characterize the complexes. With the help of the thermal analysis the really complexed (strongly bound) and surface-bound guests were distinguished. All of the β-cyclodextrin complexes show better dissolution rate than the pure guest. In case of inclusion complexes an oversaturated solution was formed with extremely high concentration of active substance (6–19 mg L^?1) during the first couple of minutes then the concentration decreased gradually until it reached the equilibrium solubility value of the complex (2 mg L^?1). The cypermethrin/peracetylated-β-cyclodextrin complexes prepared with organic solvent method showed slightly retarded dissolution profile compared to the pure guest. The area under the dissolution curves was introduced for quantitative characterization of the dissolution rate. The release was found to depend on the complexed guest content of the samples. The continuous variation plots used first for this parameter gave information on the stoichiometry of the complexes: 1:2 cypermethrin/β-cyclodextrin and 1:1.25 cypermethrin/peracetylated-β-cyclodextrin.     

Comparison of inter- and intramolecular cyclodextrin complexes

Abstract

We present the first comparative steady-state and time-resolved fluorescence studies of inter- and intramolecular cyclodextrin complexes. Specifically, we report equilibrium and kinetic results for dansyl-glycine complexed with β-cyclodextrin (intermolecular) and the dansyl-glycine-β-cyclodextrin adduct (intramolecular). The fluorescence intensity decay profile for the intermolecular system is best described by a discrete triple exponential decay law. This is consistent with stepwise 1:1 and 2:1 (β-cyclodextrin:guest) inclusion complexation. Equilibrium constants are in line with previous results on similar species. In contrast, we found that the intramolecular case was described by a doubly exponential decay law—consistent with a single intramolecular inclusion complex. Displacement experiments, with borneol, confirm the simplicity of the intramolecular complex. In all cases, continuous distribution models failed to fit the experimental data.     

Developments in cyclodextrin applications in drug formulations

With regard to recent developments in cyclodextrin (CD) applications in drug formulations, here will be described on the basis mainly of (a) novel preparative methods of CD inclusion complexes, (b) effects of CDs on bioavailability and disposion of drugs and (c) absorption enhancement by CD derivatives in transdermal application. (a) When inclusion complex of cinnarizine (CN) with -CD was prepared by a spray-drying method, it was very stable under heating and highly humid conditions. (b-1) CDs gave influence on hypnotic potency and disposition of barbiturates in intravenous and intraperitoneal administrations. (b-2) The bioavailability of CN on oral administration of the complex, which was comparable with that of CN alone, was enhanced by simultaneous administration of competing agents, such as DL-phenylalanine. (c) When tolnaftate (TOL), antifungal drug, was administered percutaneously in the form of the complex with dimethyl--CD and water-soluble -CD polymer, it was absorbed in the skin, and the concentration was kept high compared with the case of TOL alone.     

Electrospinning of polymer-free nanofibers from cyclodextrin inclusion complexes

The electrospinning of polymer-free nanofibers from highly concentrated (160%, w/v) aqueous solutions of hydroxypropyl-β-cyclodextrin (HPβCD) and its inclusion complexes with triclosan (HPβCD/triclosan-IC) was achieved successfully. The dynamic light scattering (DLS) and rheology measurements indicated that the presence of considerable HPβCD aggregates and the high solution viscosity were the key factors in obtaining electrospun HPβCD and HPβCD/triclosan-IC nanofibers without the use of any polymeric carrier. The HPβCD and HPβCD/triclosan-IC solutions containing 20% (w/w) urea yielded no fibers but only beads and splashes because of the depression of the self-aggregation of the HPβCD. The inclusion complexation of triclosan with HPβCD was studied by isothermal titration calorimetry (ITC) and turbidity measurements. The characteristics of the HPβCD and HPβCD/triclosan-IC nanofibers were investigated by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), X-ray diffraction (XRD), and differential scanning calorimetry (DSC). It was found that the electrospinning of HPβCD/triclosan-IC solution having a 1:1 molar ratio was optimal for obtaining nanofibers without any uncomplexed guest molecules.     

Structure and spectroscopic properties of cyclodextrin inclusion complexes

We compare spectroscopic properties of higher order complexes of organic guests (e.g. naphthalene, phenols, indole, C₆₀ fullerene) with cyclodextrins (CDx) to results of molecular modeling investigations. Naphthalene 1:2 complexes with -CDx show high spectral resolution and peculiar triplet properties. Molecular simulations and calculation of the experimentally measured induced circular dichroism (ICD) provide detailed structural information.     

Crystal structures of cyclodextrin complexes with chiral molecules

The chiral recognition by cyclodextrins and permethylated cyclodextrins have been investigated on the basis of the X-ray data of crystalline inclusion complexes. The macrocyclic ring of - and -cyclodextrin shows a round and symmetrical structure. -Cyclodextrin includes racemic 1-phenylethanol with the statistical disorder of the hydroxyl group. A pair of the R- and S-isomers of flurbiprofen are included within the cylindrical cavity formed by dimeric -cyclodextrin molecules with a head-to-head arrangement. The macrocyclic ring of permethylated cyclodextrins is remarkably distorted from the regular polygonal symmetry and has more flexibility in the conformational change than cyclodextrins. Owing to the distorted conformation and steric hindrance involving methyl groups, permethylated cyclodextrins do not equally include both isomers, as demonstrated by the permethylated -cyclodextrin complexes with mandelic acids. Permethylated -cyclodextrin binds D-mandelic acid more tightlyvia a host-guest hydrogen bond and induced-fit conformational change. Permethylated -cyclodextrin forms a hydrated crystalline complex with R-flurbiprofen, but S-flurbiprofen forms a non-hydrated crystalline complex. Significant differences between the two complexes are found in the orientation of the phenyl group and hydrogen-bond formation involving the carboxyl group.     

Investigation of ternary cyclodextrin complexes by fluorescence spectrometry

Ternary complexes of cyclodextrin are apparently formed in the presence of saturated alcohols, glycols and acids. The role of third components in these complexes is investigated. Pyrene is used as a probe to determine the degree of compartmentalization, the change in the hydrophobicity of the microenvironment, and the formation constant.     

Chitosan/cyclodextrin nanoparticles as drug delivery system

One of the most attractive areas of research in drug delivery is the design of nanomedicines consisting of nanosystems that are able to deliver drugs to the right place, at appropriate time. Natural polysaccharides, due to their outstanding merits, have received more and more attention in the field of drug delivery systems. In particular, polysaccharides seem to be the most promising materials in the preparation of nanometric carriers. The main goal of the present study was to investigate the potential of a recent generation of hybrid polysaccharide nanocarriers, composed of chitosan (CS) and an anionic cyclodextrin, carboxymethyl-β-cyclodextrin (CM-β-CD), for the encapsulation of a model drug, sulindac. CS and CM-β-CD were processed to nanoparticles (NPs) via the ionotropic gelation technique. The stoichiometric ratio between these two polymers was found to influence particle size and zeta potential. Decreasing CS:CM-β-CD ratio led to an increase in particle size and decrease in zeta potential. DSC and FTIR analyses confirmed formation of NPs and encapsulation of sulindac inside them. Release profiles indicate a continuous release of the drug throughout 24?h. However, the rate of release was more rapid during the first hours; about 55–90% of the drug being released after 3?h.     

Influence oftert-butyl alcohol on cyclodextrin inclusion complexes of pyrene

The effect oftert-butyl alcohol on complexes of pyrene and various cyclodextrins is investigated. The equilibrium constant for the complexation is derived from the fluorescence decay parameters. A greater than twofold enhancement of pyrene lifetime is observed in the presence oftert-butyl alcohol and -cyclodextrin or -cyclodextrin. As the number of hydroxyl groups decreases, substituted -cyclodextrins show smaller enhancements to both the fluorescence lifetime and the formation constant. These observations are explained by proposing that alcohol molecules are associated with the inclusion complex. This association increases the apparent hydrophobicity of the cyclodextrin cavity, protects the molecule from collisional quenching and deactivation, and provides additional rigidity to the system.