Coenraad F. Lerk

The effect of parenterally administered cyclodextrins on cholesterol levels in the rat

The inclusion complex formation of intravenously administered hydroxypropyl-β-cyclodextrin and β-cyclodextrin with endogenous lipids was studied. We tested the hypothesis that complex formation of endogenous cholesterol with cyclodextrins in the bloodstream leads to extraction of cholesterol from the large lipoprotein particles. The relatively small cholesterol–cyclodextrin complexes then leave the bloodstream via capillary pores, and dissociation of the complex in the extravascular compartment finally causes redistribution of cholesterol from blood to tissue. This hypothesis is supported by the following experimental findings. Intravenous administration of cyclodextrins led to a transient decrease in plasma cholesterol levels in a dose-dependent manner, and in vitro cholesterol-cyclodextrin complexes passed dialysis membranes with a molecular weight cutoff of 6000–8000. Further, cyclodextrins increased protein binding of the steroidal drug spironolactone, probably through removal of cholesterol from plasma protein binding sites. Finally, extravascular redistribution was directly demonstrated in histological studies of the kidneys. Glomerular filtration of the cholesterol–cyclodextrin complex is followed by dissociation of the complex in the ultrafiltrate, resulting in cholesterol accumulation in the proximal tubule cells. The cholesterol-β-cyclodextrin complex has a limited aqueous solubility. Crystallization of this complex in renal tissue might explain the nephrotoxicity of parenterally administered β-cyclodextrin. The absence of such crystallization might explain the lower nephrotoxicity of hydroxypropyl-β-cyclodextrin after intravenous administration.

The pharmacokinetics of β-cyclodextrin and hydroxypropyl-β-cyclodextrin in the rat

Hydroxypropyl-β-cyclodextrin was analyzed by HPLC using postcolumn complexation with phenolphthalein and negative colorimetric detection, with a detection limit of 20 µg/ml. The pharmacokinetics of β-cyclodextrin and of hydroxypropyl-β-cyclodextrin were studied after intravenous administration to permanently cannulated rats. The pharmacokinetic behavior of both cyclodextrins was similar to that of inulin, showing rapid distribution over extracellular fluids. Elimination occurred through glomerular filtration. When a dose of 200 mg/kg β-cyclodextrin was administered the elimination rate was decreased, probably as a result of nephrotoxicity of β-cyclodextrin. Within 24 hr after administration most of the cyclodextrin dose was recovered unchanged in urine. After oral administration, only insignificant amounts of intact β-cyclodextrin were absorbed from the gastrointestinal tract.

The effects of cyclodextrins on drug absorption II. In vivo observations

Complex formation of diazepam and of naproxen with β-cyclodextrin results in increased aqueous solubility of the drug. The complex stability constants found were 179 and 2146 M−1, respectively. To study the effect of complex formation of drugs with β-cyclodextrin in vivo, micro-enemas containing diazepam or naproxen with and without β-cyclodextrin were administered to human volunteers. Plasma levels of the drug were determined for the investigation of the absorption of the two drugs. The results demonstrated that absorption neither of cyclodextrin nor of the drug-cyclodextrin complex took place, and that a decrease in the rate of absorption of the drug did not occur when administered as the drug-cyclodextrin complex. The absence of absorption deceleration was explained by the fact that complexed drug is displaced from the complex by lipids in the mucus adjacent to the absorption membrane. The ability of mucus and bile samples to displace eomplexed drug was shown in vitro in displacement studies with phenolphthalein. Especially bile was shown to possess a high capacity for displacement. The micro-enemas in which all drug was dissolved through complexation showed much faster absorption as compared with those in which the drug was suspended.

The effects of cyclodextrins on the disposition of intravenously injected drugs in the rat

Naproxen and flurbiprofen form complexes with hydroxypropyl-β-cyclodextrin; with stability constants of 2207 and 12515 M−1 respectively. However, only small fractions of the drug remain complexed when the drug–cyclodextrin complex is added to plasma in vitro. This result can be explained by albumin effectively competing with cyclodextrin for drug binding and by the simultaneous displacement of the drug from cyclodextrins by plasma cholesterol. Naproxen and flurbiprofen were administered intravenously to rats as cyclodextrin complexes. The disposition in the body of naproxen was not significantly altered by the complexation. This indicates that immediately after administration all drug is removed from the cyclodextrin complex. However, the initial distribution of flurbiprofen was changed upon complexation. Drug concentrations in liver, brain, kidney, and spleen were increased, indicating that hydroxypropyl-β-cyclodextrin may improve the presentation of the flurbiprofen to biomembranes, as compared with plasma proteins. The effect was transient; 60 min after injection the differences in tissue concentration compared with controls were dissipated. Finally, the importance of protein binding in determining the mode of interaction of cyclodextrins on drug disposition is discussed.

Increased podophyllotoxin production in Podophyllum hexandrum cell suspension cultures after feeding coniferyl alcohol as a β-cyclodextrin complex

SummaryCell suspension cultures, derived from roots of Podophyllum hexandrum Royle (Berberidaceae), accumulate podophyllotoxin. In this study the use of β-cyclodextrin in feeding the poorly water-soluble precursor coniferyl alcohol to these cultures is described. By complexation with β-cyclodextrin, a solution of 3 mM coniferyl alcohol could be fed, resulting in enhanced podophyllotoxin accumulation. The same concentration of non-complexed suspended coniferyl alcohol had only little effect on the podophyllotoxin accumulation. β-Cyclodextrin itself was proven to be non-toxic for the cells. It did not influence the podophyllotoxin content and it was not metabolized or used as a carbon source by the cells. For comparison, coniferin, the water-soluble β-D-glucoside of coniferyl alcohol, was also fed in the same concentration. The effect of coniferin on the podophyllotoxin accumulation was stronger than that of coniferyl alcohol complexed with β-cyclodextrin, but coniferin is not commercially available.

Stress relaxation of compacts produced from viscoelastic materials

Stress relaxation of tablets is a phenomenon that is known to be related to elastic deformation of particles. Expressions of stress relaxation are tablet expansion and capping. It has been shown that there is a direct relation between the changes in volume of the tablet and the amount of stored energy, calculated from the elastic modulus and the yield strength of the material. The relations are, however, different for the different materials. On the basis of the assumption that the increase in tablet volume is an expression of stress relaxation and stored energy is the driving force for it, there should be a counteracting force that prevents a compact from expansion. This paper shows that the counteracting force is determined by particle bonding, quantified by the Ryshkewitch-Duckworth relation and friction of the tablet with the die wall, quantified by the ejection pressure. The data presented here suggest that the final tablet porosity is unequivocally determined by stored energy, particle attraction and friction of the tablet with the die wall. All tablets that were capped showed both high stored energies and large particle bonding. From this observation it is concluded that porous and capped tablets suffer from the same problem, but the expression stress relaxation is different for the different materials.

Effect of molecular weight and glass transition on relaxation and release behaviour of poly(DL-lactic acid) tablets

Different molecular weight grades of poly(DL-lactic acid) were applied as release controlling excipients in tablets for oral drug administration. The role of molecular weight and glass transition in the mechanism of water-induced volume expansion and drug release of PDLA tablets was investigated. Modulated differential scanning calorimetry (MDSC) was used to determine the glass transition temperature of both dry and hydrated PDLA samples. The absorption rate and total amounts of sorbed water by the polymer were determined by dynamic vapour sorption (DVS). Expansion behaviour of PDLA tablets was measured using thermal mechanical analysis (TMA). At 95% relative humidity all molecular weight grades of PDLA sorbed 1.1-1.3% w/w water, as was determined with DVS. MDSC showed glass transition temperature reductions of 10-11 degrees C for all molecular weight grades of PDLA in water. Volume expansion studies using TMA showed that the molecular relaxation time and equilibrium porosity of the tablets increased with molecular weight. The mean relaxation time increased exponentially with the temperature interval T(g)-T. The onset temperature of shape recovery of hydrated tablets was approximately 8 degrees C lower than for dry samples. Drug release was only slightly affected by molecular weight. It is concluded that volume expansion of compressed PDLA tablets is related to the glass transition behaviour, originates from water-induced and thermally stimulated shape memory behaviour and is therefore highly dependent on the molecular weight of PDLA.

The polymorphism of sulphathiazole

Abstract Three crystalline modifications and one amorphous form of sulphathiazole have been characterized using differential scanning calorimetry, X-ray diffraction and infrared spectroscopy. The melting points of polymorphs I, II and III are 201.0°C, 196.5°C and 173.6°C, respectively. Complete melting of the polymorphs I and II was only observed if the crystalline modifications were very pure. Methods for the preparation of these very pure substances are described. The amorphous form shows a glass transition at 62°C. Dissolution studies have shown that the polymorphs I and II are very unstable in water and are rapidly converted into polymorph III of sulphathiazole.

Effect of water on deformation and bonding of pregelatinized starch compacts

This paper evaluates the tabletting process of pregelatinized starch with different moisture contents on the basis of the stress deformation curve. Simplification of the stress deformation curve enables the amount of elastically stored energy to be calculated. That stored energy, which is the driving force for relaxation of tablets, increases with compaction speed and decreases with increasing water activity of the material. This paper suggests a relation between absorbed water and stored energy. Interparticle bonding, however, also decreases with increasing amounts of adsorbed water. The decrease in stored energy with increasing water activity of the pregelatinized starch tends to produce stronger tablets at higher water activities, whereas the decrease of particle bonding with increasing water activity tends to produce weaker tablets at higher water activities. Given these two counteracting effects, the final tablet strength is a balance between viscoelasticity and bonding, resulting in a water activity where tablet strength has a maximum. In this case, the optimum water activity is about 0.70.

Cyclodextrin-facilitated bioconversion of 17β-estradiol by a phenoloxidase from Mucuna pruriens cell cultures

After complexation with beta-cyclodextrin, the phenolic steroid 17 beta-estradiol could be ortho-hydroxylated into a catechol, mainly 4-hydroxyestradiol, by a phenoloxidase from in vitro grown cells of Mucuna pruriens. By complexation with beta-cyclodextrin the solubility of the steroid increased from almost insoluble to 660 microM. The bioconversion efficiency after 72 hr increased in the following order: freely suspended cells (0%), immobilized cells (1%), cell homogenate (6%), phenoloxidase preparation (40%). Mushroom tyrosinase converted 17 beta-estradiol, as a complex with beta-cyclodextrin, solely into 2-hydroxyestradiol, with a maximal yield of 30% after 6-8 hr. Uncomplexed 17 beta-estradiol was not converted at all in any of these systems.