Cyclodextrin Solubilization of the Antibacterial Agents Triclosan and Triclocarban: Effect of Ionization and Polymers

The natural β-cyclodextrin (βCD) and its complexes have limited solubility in aqueous solutions. This low aqueous solubility, as well as low aqueous solubility of the guest molecule (i.e. triclosan or triclocarban (TCC)), can result in low complexation efficiency (CE). The purpose of this study was to enhance the apparent intrinsic solubility (S ₀) of the guest molecule and its βCD complexes through ionization and addition of auxiliary compounds such as polymers, amino acids and metal ions. Both triclosan (pK _a 7.9) and TCC (pK _a 12.7) are weak acids. Addition of ethanol to the complexation medium enhanced S ₀ of both triclosan and TCC but at the same time ethanol lowered the stability constant (K _c ) of their βCD complexes resulting in overall lowering of CE. Addition of small amount of water-soluble polymers enhanced the βCD solubilization of both guests, and addition lysine enhanced the solubilization of TCC. Ionization of triclosan resulted in significant enhancement of CE and enhanced triclosan release from tablets containing triclosan/βCD complex. The effect of ionization was not as pronounced in the case of TCC.This revised version was published online in July 2005 with a corrected issue number.     

The complexation efficiency

Studies have shown that cyclodextrins form both inclusion and non-inclusion complexes and that several different types of complexes can coexist in aqueous solutions. In addition, both cyclodextrins and cyclodextrin complexes are known to form aggregates and it is thought that these aggregates are able to solubilize drugs through micellar-type mechanism. Thus, stability constants determined from phase-solubility profiles are rarely true stability constants for of some specific drug/cyclodextrin complexes. A more precise method for evaluation of the solubilizing effects of cyclodextrins is to determine their complexation efficiency (CE). CE can be determined by measuring the solubility of a given drug at 2–3 cyclodextrin concentrations in pure water or a medium constituting the pharmaceutical formulation such as parenteral solution or aqueous eye drop formulation. Based on the CE value the drug:cyclodextrin ratio in the complexation medium can be determined as well as the increase in the formulation bulk in a solid dosage form. Determination of CE is a simple method for quick evaluating the solubilizing effects of different cyclodextrins and/or the effects of excipients on the solubilization. Here we report the CE of 43 different drugs with mainly 2-hydroxypropyl-β-cyclodextrin but also with randomly methylated β-cyclodextrin as well as few other cyclodextrins. Calculation of CE, drug:cyclodextrin molar ratio and the increase in the formulation bulk is discussed, as well as the influence of the intrinsic solubility and drug lipophilicity on the CE.     

Dexamethasone delivery to posterior segment of the eye

Due to anatomic barriers and lacrimal drainage it is difficult to obtain therapeutic drug concentrations in the posterior part of the eye after topical drug administrations. Lipophilic cyclodextrins, such as randomly methylated β-cyclodextrin (RMβCD), are known to act both as solubilizers of water-insoluble drugs in aqueous solutions and as penetration enhancers that reduce the barrier function of lipophilic membranes. The purpose of this study was to investigate the effects of RMβCD on dexamethasone delivery from aqueous eye drop solution into rabbit eyes. Dexamethasone (0.5 and 1.5% w/v) drops (50 μl) were administered to the left eye of rabbits (n = 6) and the drug levels measured in different eye tissues 2 h after administration. In aqueous humor dexamethasone levels were 1,190 ± 110 and 1,670 ± 630 ng/g (mean ± SD) after administration of the 0.5 and 1.5% dexamethasone eye drops, respectively. In the retina the levels were 33 ± 7 and 66 ± 49 ng/g, and in optic nerve 41 ± 12 and 130 ± 50 ng/g, respectively. In a previous study the dexamethasone concentration in aqueous humor after topical administration of 1.3% (w/v) dexamethasone eye drops in aqueous 2-hydroxypropyl-β-cyclodextrin (HPβCD) solution was determined to be 320 ± 230 ng/g and 66 ± 20 ng/g after administration of Maxidex^® eye drops. Both the hydrophilic HPβCD and the lipophilic RMβCD enhance topical dexamethasone delivery into the eye, but of the two, the lipophilic RMβCD results in higher dexamethasone concentrations.     

Angiotensin converting enzyme inhibitors/cyclodextrin inclusion complexes: solution and solid-state characterizations and their thermal stability

Angiotensin converting enzyme (ACE) inhibitors have recently gained attention as a new class of drug in the therapeutic management of glaucoma. However, the application of eye drops is limited because of their chemical instability in aqueous solutions. To overcome such a problem, cyclodextrins (CDs) were introduced to form inclusion complexes. Three ACE inhibitors, namely, captopril, quinapril and fosinopril (FOS), were chosen and the effect of CDs on their thermal stability in aqueous solutions was investigated. All three drugs formed inclusion complexes of 1:1 stoichiometry with all three natural CDs and the FOS/γCD inclusion complex possessed the highest stability constant, resulting in thermal stability enhancement. Furthermore, the addition of antioxidants could greatly enhance the thermal stability of FOS in the presence of γCD in aqueous solutions. The inclusion complex formation of FOS/γCD was further examined by computational and experimental characterizations. All these characterization results confirmed that FOS and γCD formed a true inclusion complex that provided drug stabilization in the aqueous eye drop medium.

     

Surface activity and self-aggregation ability of three cationic quaternized aminocalix[4]arenes

The self-aggregation ability of three amphiphilic cationic calix[4]arenes possessing four quaternary amino groups (aminoCAs) was investigated using a variety of methods. All of the studied compounds possess high aggregation ability. Their critical aggregation concentration (CAC) values in water are in the 0.0009–0.04 % (w/v) concentration range. Several size populations of aggregates were detected by DLS for all three CAs, and restructuring of aggregates was observed to be dependent on concentration. Particles formed above CAC were attributed to formation of vesicular structures (vesicles). The coexistence of other type of aggregates (presumably micelles) with vesicles was observed in the aqueous solution of CAs 2 and 3 from concentrations of 0.5 and 0.8 % (w/v), respectively. The filtration procedure was found to be a significant factor since the obtained data from filtered and unfiltered samples was different. The particle sizes obtained by TEM measurements were somewhat correlated with the DLS data for unfiltered CAs solutions. An analysis of the aggregate composition was undertaken by a size-exclusion method using semi-permeable cellophane membranes with different MWCO. A negative deviation from linearity of permeability flux profile starting from 0.8 % (w/v) concentration of donor phase indicated that the fraction of large aggregates at this point is significant enough that the molecules could not easily permeate through the membranes.     

Mössbauer spectroscopy for determining phase stability in the ferrosilicon system

We present studies of phase dynamics of the silicon rich part of the Fe?Si system performed with Mössbauer spectroscopy. Standard spectra are obtained in very pure samples and these are applied to the studies of commercial 75& ferrosilicon. We find that the semistable high temperature alpha phase, known for considerable concentration of vacancies, needs multiple quadrupole doublets to fit the data. Finally it is shown how the Mössbauer effect can be applied to quality control in ferrosilicon production.     

Investigation of drug-cyclodextrin complexes by a phase-distribution method: some theoretical and practical considerations

The purpose of the study was to evaluate an octanol-water phase distribution method for investigation of drug/cyclodextrin (D/CD) complexes and to compare stability constant values obtained by this method to values obtained by the phase solubility method. A general equation for determination of 1 : 1 D/CD complex stability constant (K1 : 1) from the slope of a phase-distribution diagram (a diagram of the reciprocal of the apparent partition coefficient vs. the total CD concentration) was derived. The equation accounted for the possible inclusion of the organic solvent in the CD cavity and the gradual saturation of the CD binding with increasing concentration of the guest compound. This method was used to determine K1 : 1 for 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) complexes of hydrocortisone, prednisolone, diazepam, beta-estradiol and diethylstilbestrol. These values were comparable to K1 : 1 values determined by the phase-solubility method. The phase-distribution method could also be applied to determine stability constants for the neutral and ionic forms of the weakly acidic drugs, naproxen and triclosan and the weakly basic drug lidocaine. The phase-distribution method is a very versatile and fast method and has the advantage, compared to the phase-solubility method, that it only requires very small drug samples. Thus, this method would be suitable for screening of new drug candidates.     

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.     

Synthesis of Cyclic Glycerol Ether Cyclodextrin Derivatives and Investigation of their Binding Properties with Drugs

Epichlorohydrin was reacted with cyclodextrins to form the non-cyclic and cyclic glycerol ethers of - and -cyclodextrin (abbreviated as glyc-CD). Cyclic substitution extends the cyclodextrin cavity in a way that is as rigid and non-polar as the cavity of the parent cyclodextrin. Derivatives with extended cavities should better accommodate large or odd shaped molecules. The binding of drugs to the new cyclodextrin derivatives was investigated, through degradation rate studies and solubilization studies, and compared to that of -cyclodextrin, -cyclodextrin and hydroxypropyl--cyclodextrin. The inclusion binding of small molecules such as acetazolamide, ethoxyzolamide and chlorambucil, in the glyc-CDs was either increased or decreased compared to the other cyclodextrins. However, larger molecules, such as indomethacin and hydrocortisone, always bound better to the glyc-CDs with up to 180% increase in the stability constant. The degradation rate within the cyclodextrin cavity was not affected by the above derivation.