Cyclodextrin Drug Carrier Systems.

Pharmaceutical applications of cyclodextrins. 2. In vivo drug delivery

https://onlinelibrary.wiley.com/doi/pdf/10.1021/js960213f

Pharmaceutical applications of cyclodextrins. III. Toxicological issues and safety evaluation

2-Hydroxypropyl-β-cyclodextrin (HP-β-CD): A toxicology review

Cyclodextrins (CyDs) are cyclic carbohydrates derived from starch. The parent CyDs contain six, seven and eight glucopyranose units and are referred as α-, β- and γ-CyD, respectively. The most important property of the CyDs is the ability to establish specific interactions - molecular encapsulation - with various types of molecules through the formation of non-covalently bonded entities, either in the solid phase or in aqueous solution. These nano-encapsulating agents may form inclusion complexes with essential oils and volatiles, or their components, in order to improve their characteristics, such as transformation of liquid compounds into crystalline form; masking unpleasant smells and tastes of some compounds; improving the physical and/or chemical stability; and stabilizing volatile compounds by reducing or eliminating any losses through evaporation. Complexation has been used to avoid the destruction of certain flavours by processing or, on storage, allowing the use of minor amounts of flavours. The guest molecule is released in the warm moisture of the mouth. Examples are spices, essential oils of vegetable origin and plant flavours, chamomile oil and extract, eucalyptus oil, fennel oil, lemon oil, onion and garlic oil, camphor, menthol, thymol, etc. There are several methods for the preparation of inclusion complexes; kneading, co-precipitation, freeze-drying and spray-drying the most commonly used. Evidence for a guest inclusion into the apolar CyD cavity may be proved by various analytical techniques, including NMR spectroscopy, UV-visible absorption spectroscopy, optical rotatory dispersion and circular dichroism, fluorescence, infrared/FT-IR spectroscopy, thermo-analysis, TLC, mass spectromety, and powder X-ray diffractometry. Copyright © 2010 John Wiley & Sons, Ltd.

A review on cyclodextrin encapsulation of essential oils and volatiles

Pharmaceutical evaluation of hydroxyalkyl ethers of β-cyclodextrins

3-Hydroxypropyl- and 2,3-dihydroxypropyl-beta-cyclodextrins (3-HP- and DHP-beta-CyDs) with different degrees of substitution (D.S.) were prepared and their pharmaceutical properties were investigated. The aqueous solubility of 3-HP- and DHP-beta-CyDs was much higher than that of the parent beta-CyD and the dissolution of DHP-beta-CyD in water was endothermic. The acid- and alpha-amylase-catalyzed hydrolysis rates of 3-HP- and DHP-beta-CyDs were slower than those of the parent beta-CyD. The hemolytic activity (human erythrocytes) and local irritancy (rabbit muscle) of DHP-beta-CyD were considerably less than those of natural, methylated or other hydroxyalkylated beta-CyDs, and decreased with increasing D.S. The ability of the hydroxyalkylated beta-CyDs to remove cholesterol and proteins from human erythrocytes decreased with increasing D.S., and correlated well with their hemolytic activity. 3-HP-beta-CyD was a more effective solubilizer for poorly water-soluble drugs than the parent beta-CyD, and its stabilizing effect on chemically instable drugs was higher than that of the parent beta-CyD. The above data suggest a considerable pharmaceutical potential of 3-HP- and DHP-beta-CyDs as parenteral carriers.

Some Pharmaceutical Properties of 3-Hydroxypropyl- and 2, 3-Dihydroxypropyl-β-cyclodextrins and Their Solubilizing and Stabilizing Abilities

Some physicochemical properties of branched β-cyclodextrins and their inclusion characteristics

Possible utility of hydroxyalkylated beta-cyclodextrin (beta-CyD) derivatives as parenteral drug carriers was investigated, using nimodipine, a dihydropyridine derivative with calcium antagonistic action, as a model drug. The aqueous solubility of nimodipine increased linearly with increase in the concentration of hydroxyalkylated beta-CyDs, showing an AL-type phase solubility diagram. The stability constant of nimodipine--hydroxyalkylated beta-CyD complexes was in the order of 2,3-dihydroxypropyl-beta-CyD less than beta-CyD less than 2-hydroxyethyl-beta-CyD less than 3-hydroxypropyl-beta-CyD less than 2-hydroxypropyl-beta-CyD, and the solubilizing ability of the beta-CyDs was also in that order. The results of powder X-ray diffractometry and thermal analysis suggested 1:3 (guest:host) complex formation of nimodipine with 2-hydroxypropyl-beta-CyD in the solid state. The dissolution rate of nimodipine-2-hydroxypropyl-beta-CyD complex was much faster than that of the drug alone. Nimodipine-2-hydroxypropyl-beta-CyD complex gave higher plasma levels of the drug after intramuscular administration to rabbits, i.e., the area under the plasma concentration--time curve and the maximum plasma concentration of the complex were about 2.5 times higher than those of the drug alone. The muscular damage after the injection of nimodipine was reduced by the administration of the complexed form.

Utility of 2-Hydroxypropyl-β-cyclodextrin in an Intramuscular Injectable Preparation of Nimodipine

Inclusion complexation of digitoxin with β-cycIodextrin (β-CyD) derivatives, such as 2, 6-di-Omethyl-β-CyD (DM-β-CyD), 2, 3, 6-tri-O-methyl-β-CyD (TM-β-CyD), hydroxypropyl-β-CyD (HPβ-CyD, substitution degree 4.3) and hydroxyethyl-β-CyD (HE-β-CyD, substitution degree 4.0) was studied by the solubility method. The apparent 1: 1 stability constant (Kc) of the complexes in water at 25 -C was in the order of DM-β-CyD (84000 m-1)> HP-β-CyD (18000 m-1) =HE-β-CyD (17000 m-1) =β-CyD (17000 M-1)> TM-β-CyD (5600 M -1). From the high-performance liquid chromatographic tracing of each of the four components (digitoxin, bisdigitoxoside, monodigitoxoside, digitoxigenin) in the reaction mixtures, the individual hydrolysis rate constants (K1-K6) were determined by the non-linear least-squares method.β-CyDs suppressed the hydrolysis rates of digitoxin species in an acidic medium (pH 1.2), particularly the appearance of digitoxigenin, the final hydrolysis product, and the inhibitory effect was generally in the order of DM-β-CyD >β-CyD=HP-β-CyD=HE-β-CyD> TM-β-CyD. By analyzing the concentration dependency of the hydrolysis rate, DM-β-CyD was found to decelerate the appearance rate of digitoxigenin more than 2400 times.

https://www.jstage.jst.go.jp/article/cpb1958/36/10/36_10_4075/_pdf

Atsuya Yoshida

Papers

Pharmaceutical evaluation of hydroxyalkyl ethers of β-cyclodextrins

Some Pharmaceutical Properties of 3-Hydroxypropyl- and 2, 3-Dihydroxypropyl-β-cyclodextrins and Their Solubilizing and Stabilizing Abilities

Some physicochemical properties of branched β-cyclodextrins and their inclusion characteristics

Utility of 2-Hydroxypropyl-β-cyclodextrin in an Intramuscular Injectable Preparation of Nimodipine

Improvement of Chemical Instability of Digitoxin in Aqueous Solution by Complexation with β-Cyclodextrin Derivatives