Pekka Jarho

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.

Co-Administration of a Water-Soluble Polymer Increases the Usefulness of Cyclodextrins in Solid Oral Dosage Forms

AbstractPurpose. The aim of this study was to investigate the effect of cyclodextrins (β-CD, HP-β-CD and (SBE)7m-β-CD), and co-administration of a water-soluble polymer (HPMC) and cyclodextrins, on the oral bioavailability of glibenclamide in dogs. Methods. Effects of cyclodextrins on the aqueous solubility of glibenclamide, with and without hydroxypropylmethylcellulose (HPMC), were determined by a phase-solubility method. Solid inclusion complexes were prepared by freeze-drying. Glibenclamide was administered orally and intravenously to beagle dogs. Results. Aqueous solubility of glibenclamide increased as a function of cyclodextrin concentration, showing an AL-type diagram for β-CD and an Ap-type diagrams for both of the β-CD derivatives studied. HPMC enhanced the solubilising effect of cyclodextrins, but did not affect the type of phase-solubility diagram. Orally administered glibenclamide and its physical mixture with HP-β-CD showed poor absolute bioavailability, while orally administered glibenclamide/cyclodextrin-complexes significantly enhanced the absolute bioavailability of glibenclamide. Orally administered glibenclamide/β-CD/HPMC and glibenclamide/(SBE)7m-β-CD/HPMC complexes showed similar absolute bioavailability compared to formulations not containing HPMC, even though 80% (in the case of (SBE)7m-β-CD) or 40% (in the case of β-CD) less cyclodextrin was used. Conclusions. The oral bioavailability of glibenclamide was significantly increased by cyclodextrin complexation. HPMC increased the solubilising effect of cyclodextrins and, therefore, the amount of cyclodextrin needed in the solid dosage form was significantly reduced by their co-administration. In conclusion, the pharmaceutical usefulness of cyclodextrins in oral administration may be substantially improved by co-administration of a water-soluble polymer.

Ophthalmic arachidonylethanolamide decreases intraocular pressure in normotensive rabbits

Arachidonylethanolamide (AEA) was the first anandamide to be identified as an endogenous ligand for the cannabinoid receptor of porcine brain. Since cannabinoids have shown some value in the reduction of ocular hypertension, the title compound was evaluated in normotensive rabbits as a possible topically applied agent for reducing intraocular pressure. AEA was dissolved in an aqueous solution of 2-hydroxy-propyl-beta-cyclodextrin. Single eyedrops (25 microliters) containing 3.13, 6.25, 31.25, 62.5 or 125.0 micrograms of AEA were instilled unilaterally into eyes of normotensive albino and pigmented rabbits. The intraocular pressures (IOPs) of these rabbits were then measured at fixed time intervals. The effect of AEA on IOP in treated and untreated (contralateral) eyes was similar in both types of rabbits. Administration of 31.25 micrograms of AEA caused an immediate IOP reduction in the treated eyes. AEA doses of 62.5 micrograms caused an initial increase and subsequent decrease of IOP in the treated eyes. In the untreated eyes, a marginal ocular hypotensive response of limited duration occurred immediately after administration of AEA at doses 31.25 or 62.5 micrograms. A significant increase (without subsequent decrease below baseline) in IOP occurred in treated eyes after a dose of 125.0 micrograms. The lowest dose (3.13 micrograms) did not have an effect on IOP. This study constitutes the first published demonstration that topical, unilateral administration of AEA significantly decreases IOP in normotensive albino and pigmented rabbits. Although the mechanism of action by which this compound produces its hypotensive effect in the eye is not known, the results suggest that AEA may prove useful in the investigation of glaucoma therapy.

Increase in aqueous solubility, stability and in vitro corneal permeability of anandamide by hydroxypropyl-β-cyclodextrin

Abstract Arachidonylethanolamide (AEA), an endogenous ligand for the cannabinoid receptor, has a low aqueous solubility and an instability which hinder its use in aqueous formulations. In the present study, the effect of cyclodextrins (CDs) on the aqueous solubility, stability and in vitro corneal permeability of AEA was studied. The corneal penetration of AEA in HP-β-CD formulations was investigated in vitro by using isolated corneas of rabbits. The phase solubility diagram with HP-β-CD was classified as Ap-type and stability constants (K1:1 and K1:2) for 1:1 and 1:2 inclusion complexes were calculated to be 39 419 M −1 and 12 M −1, respectively. The phase solubility diagram of AEA with DIME-β-CD and HP-γ-CD were of the A l -type, indicating the formation of 1:1-complexes. The stability constants for 1:1-complexes were 744 877 M−1 and 15 469 M−1, respectively. The complexation of AEA with HP-β-CD markedly increased the stability of AEA. The shelf-life (t90%) of AEA in 10.0% HP-β-CD solution at 50°C was determined to be 166 days. The complexation of AEA with HP-β-CD increased corneal penetration of AEA compared to a suspension of the compound. Maximum permeability was achieved with the lowest HP-β-CD concentration that dissolved AEA completely. The permeability of AEA correlated well with the concentration of free AEA in solution.

Hydroxypropyl-β-cyclodextrin and its combination with hydroxypropyl-methylcellulose increases aqueous solubility of Δ9-tetrahydrocannabinol

Abstract Δ9-tetrahydrocannabinol (THC) is the main psychoactive constituent of Cannabis sativa L. and its therapeutic effects are currently under intensive study. However, THC has a very low aqueous solubility (1–2 ( μg mL ), which restricts its use as a pharmaceutical. The present study demonstrates that THC forms a drug-cyclodextrin complex in an aqueous solution of hydroxypropyl-β-cyclodextrin (HP-β-CD), resulting in a thousand-fold increase in THC solubility. This improvement in solubility can be further increased by adding 0.1% hydroxypropylmethylcellulose to the HP-β-CD solution. The present results suggest that the use of cyclodextrins might be a simple and useful method to overcome the poor water solubility of THC.

Hydroxypropyl-β-cyclodextrin increases aqueous solubility and stability of anandamide

Anandamide (arachidonylethanolamide; AEA) is an endogenous ligand for the cannabinoid receptor and its pharmacological effects are under intensive study. However, AEA has a low aqueous solubility and stability which may restrict its use and may eventually endanger the reliability of the obtained results. In the present study, it was found that AEA forms inclusion complexes with cyclodextrins (CDs), resulting in greater aqueous solubility and stability of AEA as AEA/CD complex. Aqueous solubility increased 1 000 to 30 000-fold, depending on the type of CD (10% solution) used. The half-life of AEA in aqueous hydroxypropyl-beta-cyclodextrin solution (10%) at 50 degree C was 2.9 years. These results suggest that CD-technology will be a very useful method to overcome the solubility and stability problems of AEA.

Effects of topical alpha-substituted anandamides on intraocular pressure in normotensive rabbits

AbstractPurpose. Anandamides have been observed to lower intraocular pressure in the rabbit eye, preceded by a period of hypertension. Amidases are thought to catabolize these compounds into their component parts, including arachidonic acid. Direct application of arachidonic acid has been observed to cause a marked rise of intraocular pressure. Thus, anandamide analogs resistant to catabolism were thought possibly devoid of this initial hypertension, and their effects on rabbit IOP investigated. Methods. A series of chiral alpha-substituted anandamides were synthesized and studied for their effect on the intraocular pressure (IOP) of normotensive pigmented rabbits. Each test compound was dissolved in an aqueous 2-hydroxypropyl-β-cyclodextrin solution (containing 3% polyvinyl alcohol) and administered (62.5 μg) unilaterally to the eye. Results. The most promising compounds caused a statistically significant reduction of IOP (vs. vehicle) in the treated eyes. Of these, the R-alpha-isopropyl compound exhibited the best activity tested. Unlike the alpha-unsubstituted analogs previously studied, hypotensive effects were not preceded by an initial elevation of IOP and indomethacin pre-treatment (12.5 mg, s.c.) did not eliminate the IOP response, as demonstrated by administered R-alpha-isopropyl anandamide. Conclusions. Catabolism of alpha-unsubstituted anandamides may account for their observed intraocular hypertensive effects. The physiological mechanism by which alpha-substituted anandamides work apparently differs from that of the more easily metabolized alpha-unsubstituted compounds.

Effects of aqueous solubility and dissolution characteristics on oral bioavailability of entacapone

Entacapone is a new catechol‐O‐methyltransferase (COMT) inhibitor used clinically in a triple combination therapy for Parkinsons disease (PD). The bioavailability of entacapone after oral administration is low and subject to large interindividual variation. The purpose of this study was to evaluate aqueous solubility/dissolution profiles of entacapone in vitro, and to evaluate their role in the poor oral bioavailability of entacapone in rats. The effect of the novel pharmaceutical excipient hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) on the aqueous solubility and dissolution of entacapone, and on entacapone bioavailability in rats, was also studied.

The use of cyclodextrins in ophthalmic formulations of dipivefrin

Abstract Dipivefrine (dipivalyl epinephrine, DPE) is a dipivalic acid ester prodrug of epinephrine. The present study evaluates the possible use of hydroxypropyl- β -cyclodextrin (HP- β -CD) or sulfobutyl ether β -cyclodextrin ((SBE) 7m - β -CD) in ophthalmic formulations of DPE in order to increase the aqueous stability of DPE. The solubility of DPE was determined by phase-solubility method at pH 7.4 while the stability of DPE was investigated as a function of temperature (37–70°C) and CD concentrations at pH 5.0 and 7.4. The effect of HP- β -CD and (SBE) 7m - β -CD on the aqueous phase to organic phase transfer kinetics was studied with an aqueous buffer/ n -octanol system, while the effect of (SBE) 7m - β -CD on (in vitro) corneal uptake of DPE was studied with isolated rabbit corneas in order to predict the ophthalmic bioavailability of DPE in the presence of CD. The negatively charged (SBE) 7m - β -CD formed significantly stronger inclusion complexes with the positively charged DPE (p K a =9.01) and enhanced the aqueous stability of DPE significantly more compared to the neutral cyclodextrin HP- β -CD. At room temperature and at pH values of 5.0 and 7.4, 9.2 mM (SBE) 7m - β -CD increased the aqueous stability of DPE about 20- and 100-fold, respectively, while 9.2 mM HP- β -CD increased the stability about four to five times. The phase-transfer and in vitro corneal uptake studies suggested that the complexation of DPE with both CDs may decrease the ophthalmic availability of DPE.

Hydroxypropyl-beta-cyclodextrin increases the aqueous solubility and stability of pilocarpine prodrugs.

AbstractPurpose. The effects of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) on the aqueous solubility and stability of two lipophilic bispilocarpine prodrugs were investigated at pH 7.4. Methods. The solubility of prodrugs was studied by phase-solubility method (0–72.5 mM HP-β-CD). The stability of one of the prodrugs was investigated as a function of temperature (40°C–70°C) and HP-β-CD concentration (0–72.5 mM). The apparent rate constants (k1, k2) for degradation of prodrug in 1:1 and 1:2 inclusion complexes and apparent stability constants (K1:1, Kl:2) were calculated by the curve-fitting method. Results. The phase-solubility diagrams were classified as Ap-type and the apparent stability constants (Kl:l, Kl:2) for 1:1- and 1:2-inclusion complexes were calculated to be 143–815 M−l and 29–825 M−1, respectively. The stability of prodrug increased as a function of HP-β-CD concentration over the studied temperature range. The shelf-life (t90%, calculated by the Arrhenius equation) of the prodrug in 72.5 mM HP-β-CD solution increased 5.1-fold and 6.1-fold at 25°C and 4°C, respectively. Conclusions. The solubility of the prodrugs was shown to increase markedly in phase-solubility studies. The degradation rate of prodrug in stability studies was shown to be slower in the l:2-complex than in the l:l-complex and the relative amounts of complex species were found to be dependent on CD concentration.