Már Másson

Studies of curcumin and curcuminoids. XXVII. Cyclodextrin complexation: solubility, chemical and photochemical stability

Cyclodextrin complexes of the natural compound curcumin were prepared in order to improve the water solubility and the hydrolytic and photochemical stability of the compound. Complex formation resulted in an increase in water solubility at pH 5 by a factor of at least 10(4). The hydrolytic stability of curcumin under alkaline conditions was strongly improved by complex formation, while the photodecomposition rate was increased compared to a curcumin solution in organic solvents. The cavity size and the charge and bulkiness of the cyclodextrin side-chains influenced the stability constant for complexation and the degradation rate of the curcumin molecule.

Cyclodextrins in drug delivery

Cyclodextrins are a family of cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity. Cyclodextrin molecules are relatively large with a number of hydrogen donors and acceptors and, thus, in general they do not permeate lipophilic membranes. In the pharmaceutical industry cyclodextrins have mainly been used as complexing agents to increase aqueous solubility of poorly soluble drugs, and to increase their bioavailability and stability. Studies in both humans and animals have shown that cyclodextrins can be used to improve drug delivery from almost any type of drug formulation. However, the addition of cyclodextrins to existing formulations without further optimisation will seldom result in acceptable outcome. Currently there are ~ 30 different pharmaceutical products worldwide containing drug/cyclodextrin complexes on the market.

Cyclodextrins in topical drug formulations: theory and practice

Cyclodextrins are cyclic oligosaccharides with a hydrophilic outer surface and a somewhat lipophilic central cavity. Cyclodextrins are able to form water-soluble inclusion complexes with many lipophilic water-insoluble drugs. In aqueous solutions drug molecules located in the central cavity are in a dynamic equilibrium with free drug molecules. Furthermore, lipophilic molecules in the aqueous complexation media will compete with each other for a space in the cavity. Due to their size and hydrophilicity only insignificant amounts of cyclodextrins and drug/cyclodextrin complexes are able to penetrate into lipophilic biological barriers, such as intact skin. In general, cyclodextrins enhance topical drug delivery by increasing the drug availability at the barrier surface. At the surface the drug molecules partition from the cyclodextrin cavity into the lipophilic barrier. Thus, drug delivery from aqueous cyclodextrin solutions is both diffusion controlled and membrane controlled. It appears that cyclodextrins can only enhance topical drug delivery in the presence of water.

Role of cyclodextrins in improving oral drug delivery

The use of high-throughput screening and similar techniques in drug discovery has put a number of evolutionary pressures on drug candidates such that over time there is a tendency for them to increase in molecular weight, increase in log K(octanol/water) and decrease in water solubility. These trends provide an ever-increasing series of challenges for the drug formulator to generate effective, orally bioavailable dosage forms. An important tool in this regard is the use of cyclodextrins, especially chemically modified cyclodextrins. These starch derivatives interact via dynamic complex formation and other mechanisms in a way that camouflages undesirable physicochemical properties, including low aqueous solubility, poor dissolution rate and limited drug stability. Through these effects, cyclodextrins and their derivatives have become popular modalities for increasing oral bioavailability and absorption rate. These actions have positioned cyclodextrins as important enabling and functional excipients. This review aims to assess the use of cyclodextrins in oral and other administration routes in the context of the Biopharmaceutical Classification Systems (BCS), a US FDA-based characterization approach that bins drugs based on solubility and permeability features. Specifically, a framework based on Fickian theory as well as the Noyes-Whiney relationship is constructed to assess where cyclodextrins are likely to be useful and where their use is probably not justified. This working model is examined in the context of a number of published examples in which cyclodextrins have been applied to class I, II, III, and IV drugs and drug candidates.

Cyclodextrins as permeation enhancers: some theoretical evaluations and in vitro testing

It is well known that cyclodextrins can enhance the permeation of poorly soluble drugs through biological membranes. However, the permeability will decrease if cyclodextrin is added in excess of the concentration needed to solvate the drug. The mechanism of cyclodextrin effect on drug permeability has not been fully explained. The effect of cyclodextrins can not be explained as solely due to increased solubility of the drug in the aqueous donor phase nor can it be explained by assuming that cyclodextrins act as classical permeation enhancers, i.e. by decreasing the barrier function of the lipophilic membrane. In the present work we have modeled the effect of cyclodextrins in terms of mixed barrier consisting of both diffusion and membrane controlled diffusion, where the diffusion of the drug in the aqueous diffusion layer is significantly slower than in the bulk of the donor. This diffusion model is described by simple mathematical equation where the properties of the system are expressed in terms of two constants P(M)/Kd and M1/2. Data for the permeation of hydrocortisone through hairless mouse skin in the presence of various cyclodextrins, and cyclodextrin polymer mixtures, were fitted to obtain values for these two constants. The rise in flux with increased cyclodextrin complex concentration and fall with excess cyclodextrin was accurately predicted. Data for the permeation of drugs through semi-permeable cellophane membrane could also be fitted to the equation. It was concluded that cyclodextrins act as permeation enhancers carrying the drug through the aqueous barrier, from the bulk solution towards the lipophilic surface of biological membranes, where the drug molecules partition from the complex into the lipophilic membrane.

Cyclodextrin solubilization of benzodiazepines: formulation of midazolam nasal spray

The cyclodextrin solubilization of three benzodiazepines, i.e. alprazolam, midazolam and triazolam, was investigated. The cyclodextrin solubilization was enhanced through ring-opening of the benzodiazepine rings and ionization of the ring-open forms. Additional enhancement was obtained through interaction of a water-soluble polymer with the cyclodextrin complexes. The ring-opening was pH-dependent and completely reversible, the ring-open forms dominating at low pH but the ring-closed forms at physiologic pH. The ring-closed forms were rapidly regenerated upon elevation of pH. In freshly collected human serum in vitro at 37 degrees C, the half-life for the first-order rate constant for the ring-closing reaction was estimated to be less than 2 min for both alprazolam and midazolam. Midazolam (17 mg/ml) was solubilized in aqueous pH 4.3 nasal formulation containing 14% (w/v) sulfobutylether beta-cyclodextrin, 0.1% (w/v) hydroxypropyl methylcellulose, preservatives and buffer salts. Six healthy volunteers received 0.06 mg/kg midazolam intranasally and 2 mg intravenously, and blood samples were collected up to 360 min after the administration. Midazolam was absorbed rapidly reaching maximum serum concentrations of 54.3+/-5.0 ng/ml at 15+/-2 min. The elimination half-life of midazolam was 2.2+/-0.3 h and the absolute availability was 73+/-7%. All mean values+/-SEM.

The effects of water-soluble polymers on cyclodextrins and cyclodextrin solubilization of drugs

For a variety of reasons, including cost, formulation bulk and toxicology, the amounts of cyclodextrin (CD) that can be included in drug formulations is limited. This is further complicated by the fact that the complexation efficacy of CDs is, in general, very low and their molecular weight is rather high. Here we review studies which have shown that complexation efficacy of CDs can be significantly enhanced by including a small amount of water-soluble polymer in the aqueous complexation medium. The polymers increase the apparent stability constant of the drug/CD complexes through formation of ternary drug/CD/polymer complexes. Thus, in average 40 to 50% less CD is needed when a polymer is present. Furthermore, some studies have shown that drug bioavailability from formulations containing a ternary drug/CD/polymer complex is greater than from a comparable drug/CD binary complex. In general, the water-soluble polymers improve both pharmaceutical and biological properties of drug/CD complexes.

The effects of organic salts on the cyclodextrin solubilization of drugs.

Previous studies have indicated that conventional description of drug/cyclodextrin complexes in aqueous solutions as inclusion complexes are not as unambiguous as one might think. It has been shown that in some cases drug/cyclodextrin complexes consist of a mixture of inclusion and non-inclusion complexes. Furthermore it has been shown that drug/cyclodextrin complexes can form aggregates containing up to couple of hundred complexes. In this present study beta-cyclodextrin (betaCD) solubilization of hydrocortisone is enhanced by including short-chain anionic and cationic species in the aqueous complexation medium. For example, maximum hydrocortisone solubility in pure aqueous betaCD solutions or suspensions is 2.2 mg/ml. Addition of 1% (w/v) sodium acetate to the complexation medium increases this value to 7.1 mg/ml (or over 220%). Further addition of 0.25% (w/v) hydroxypropyl methylcellulose to the medium increased the hydrocortisone solubility to over 9 mg/ml. Similar results were obtained when sodium salicylate or benzalkonium chloride were added to the complexation medium. It is also shown that cyclodextrin complexes of lipophilic compounds that have good affinity for the cyclodextrin cavity can be used to enhance cyclodextrin solubilization of drugs that have low affinity for the cavity. All these observations can be explained by formation of drug/cyclodextrin complex aggregates.

Cyclodextrins and drug permeability through semi-permeable cellophane membranes

Determinations of drug fluxes through semi-permeable cellophane membranes are used to evaluate cyclodextrin complexes and cyclodextrin containing drug formulations. In the present study we investigated how the cyclodextrin concentration, the membrane thickness and the molecular weight cut off (MWCO) of the membrane influence drug fluxes. The cyclodextrin used was 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) and the sample drug was hydrocortisone. The MWCO of the membranes ranged from 500 to 14,000 and the HPbetaCD concentration ranged from 0 to 25% (w/v). The hydrocortisone flux from saturated solutions through the MWCO 500 membrane was unaffected by the cyclodextrin concentration. When MWCO of the membrane was greater than the molecular weight of the complex the flux from solutions saturated with hydrocortisone increased with increasing HPbetaCD concentration. This increase showed negative deviation from linearity. When the flux was corrected for the viscosity increase with increasing HPbetaCD concentration then the flux pattern could be described on the basis of Ficks first law and Stokes-Einstein equation. However, the flux did not correlate with the viscosity when it was increased by adding polymer to the saturated drug solutions. It was shown that the observed flux pattern was consistent with self-association of cyclodextrin complexes in the aqueous donor phase.

Role of H-bond formation in the photoreactivity of curcumin ∗

Curcumin is the main constituent of curry. In its ground state it shows chemo-preventive, chemo-therapeutic and anti-inflammatory effects. For its immunostimulating action it has been considered for the development of drugs suitable for treating AIDS and cystic fibrosis. Further biological action is induced in curcumin by photoactivation: in suitable environmen- tal conditions electronically excited curcumin can act as a singlet oxygen generator. Moreover, cytotoxicity is enhanced by light exposure and antibacterial effects are photosensitized. This work is aimed to understand the photobiological action of curcumin by elucidating the deactivation mechanisms of its first excited singlet state. In particular we find evidence of the role of tautomerization in the excited state by measuring fluorescence lifetimes and quantum yields for such compound dissolved in solvents of different polarity and H-bonding capability. Degradation quantum yield and singlet oxygen generation efficiency were also measured in acetonitrile and methanol. The results emphasize the strong dependence of the deactivation processes from the environment. The deactivation phenomenology can be fully explained by postulating intramolecular proton transfer in the cis enol conformer to be the leading non-radiative deactivation pathway.