Cyclodextrins and their uses: a review

https://onlinelibrary.wiley.com/doi/pdf/10.1021/js950534b

Pharmaceutical Applications of Cyclodextrins. 1. Drug Solubilization and Stabilization

Cyclodextrin Drug Carrier Systems.

The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson9s and Huntington9s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB 1 receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB 1 receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB 2 receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients9 need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.

http://www.phytecs.com/wp-content/uploads/2015/02/Pharmacol-Rev-2006-Pacher-389-462.pdf

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

Cyclodextrins as pharmaceutical solubilizers.

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 approximately 30 different pharmaceutical products worldwide containing drug/cyclodextrin complexes on the market.

Cyclodextrins in drug delivery

The aim of this study was to investigate the effect of cyclodextrins (s-CD, HP-s-CD and (SBE)7m-s-CD), and coadministration of water-soluble polymer (hydroxypropyl-methylcellulose; HPMC) and cyclodextrins (CDs) on aqueous solubility and oral bioavailability of glibenclamide (GBA). GBA was administered orally and intravenously to dogs. GBA showed AL-type diagram for s-CD and Ap-type diagrams for both s-CD derivatives studied. HPMC (0.05 %) enhanced the solubilizing effect of CDs but did not affect the type of phase-solubility diagram. Orally administered GBA and its physical mixture with HP-s-CD showed poor absolute bioavailability while GBA/s-CD, GBA/HP-s-CD and GBA/(SBE)7m-s-CD enhanced significantly the absolute bioavailability of GBA. Orally administered GBA/s-CD/HPMC and GBA/(SBE)7m-s-CD/HPMC showed similar absolute bioavailability compared to formulations not containing HPMC even though 80 % (in the case of (SBE)7m-s-CD) or 40 % (in the case of s-CD) less CD was used. In conclusion, the oral bioavailability of GBA was significantly increased by CD-complexation and the amount of CD needed was significantly reduced by co-administration of HPMC.

Co-administration of a water-soluble polymer increases the usefulness of cyclodextrins in solid oral dosage forms.

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.

Ophthalmic arachidonylethanolamide decreases intraocular pressure in normotensive rabbits.

The complexation of pilocarpine prodrug, O,O'-dipropionyl-(1,4-xylylene) bispilocarpate, with various beta-cyclodextrin (beta-CyD) derivatives was studied by the phase solubility method. The effects of coadministered sulphobutyl ether beta-CyD (SBE7-beta-CyD) with and without poly(vinyl alcohol) (PVA) on the miotic response and eye irritation of the prodrug were investigated in pigmented rabbits. The pilocarpine prodrug formed 1:1 inclusion complexes with variably substituted sulphobutyl ether derivatives of beta-CyD (SBE4-beta-CyD and SBE7-beta-CyD), and 1:1 and 1:2 complexes with hydroxypropyl-beta-CyD (HP-beta-CyD) at pH 7-4. Coadministered SBE7-beta-CyD eliminated the eye irritation due to the pilocarpine prodrug, but also decreased the miotic response. Ocular absorption of the prodrug was improved by increasing the viscosity of prodrug/SBE7-beta-CyD solution with PVA without inducing any eye irritation. Eye irritation due to viscous prodrug/SBE7-beta-CyD solutions was comparable with isotonic NaCl solution. We conclude that administration of pilocarpine prodrug in viscous SBE7-beta-CyD solution decreases substantially eye irritation while ocular absorption is not affected.

Pekka Jarho

Papers

Cyclodextrins in drug delivery

Co-administration of a water-soluble polymer increases the usefulness of cyclodextrins in solid oral dosage forms.

Ophthalmic arachidonylethanolamide decreases intraocular pressure in normotensive rabbits.

Modified β-Cyclodextrin (SBE7-β-CyD) with Viscous Vehicle Improves the Ocular Delivery and Tolerability of Pilocarpine Prodrug in Rabbits

In vitro toxicity and permeation of cyclodextrins in Calu-3 cells.