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

Abstract

2-hydroxylpropyl-β-cyclodextrin (HP-β-CD) is an alternative to α-, β- and γ-cyclodextrin, with improved water solubility and may be more toxicologically benign. This paper reviews the toxicity of HP-β-CD, using both literature information and novel data, and presents new information. In addition, it includes a brief review from studies of the metabolism and pharmacokinetics of HP-β-CD in both humans and animals.

This review concludes that HP-β-CD is well tolerated in the animal species tested (rats, mice and dogs), particularly when dosed orally, and shows only limited toxicity. In short duration studies, there were slight biochemical changes whereas studies of a longer duration, up to three months, produced additional minor haematological changes but no histopathological changes. When dosed intravenously, histopathological changes were seen in the lungs, liver and kidney but all findings were reversible and no effect levels were achieved. The carcinogenicity studies showed an increase in tumours in rats in the pancreas and intestines which are both considered to be rat-specific. There were also non-carcinogenic changes noted in the urinary tract, but these changes were also reversible and did not impair renal function. There were no effects on embryo-foetal development in either rats or rabbits.

HP-β-CD has been shown to be well tolerated in humans, with the main adverse event being diarrhoea and there have been no adverse events on kidney function, documented to date.

Introduction

Cyclodextrins (CDs) are useful formulation vehicles, which increase the amount of drug that can be solubilised in aqueous vehicles, thus increasing delivery of many useful medicinal agents to a biological system. Without a successful delivery system, many drugs could not be developed.

Cyclodextrins are cyclic amylose-derived oligomers composed of a varying number of α-1-4-linked glucose units. These glucose chains form a cone-like cavity into which compounds may enter and form a water-soluble complex and thus change the drug’s physical–chemical properties. The number of units determines the size of the cone-like cavity and its corresponding name (Szetjli, 1998, Uekama et al., 1998). For example, the most common cyclodextrins used as formulation vehicles are α-, β- and γ-cyclodextrin, with the corresponding number of glucose units (α = 6, β = 7, γ = 8). These cyclodextrin molecules, although similar in their unit make-up, possess slightly different absorption rates, possibly due to differences in degradation processes (Antlsperger and Schmid, 1996).

α-, β- and γ-cyclodextrins are all used successfully to incorporate drugs into aqueous vehicles (Antlsperger and Schmid, 1996) and their toxicity profile has been studied extensively (WHO, 1993; reviewed by Antlsperger and Schmid, 1996). The toxicity profile of CDs can differ depending on the route of administration. For example, β-cyclodextrin administered orally, induces limited toxicity (Olivier et al., 1991, Bellringer et al., 1995) and in both rats and dogs is considered non-toxic at a daily dose of less than 600 mg/kg bw or 3% and less in the diet (Fromming and Szejtli, 1996). However, if β-cyclodextrin is administered at higher doses in animals via a subcutaneous route, it will cause a decrease in body weight gain, a decrease in liver weight, and nephrotoxicity, with an increase in kidney weight, proximal tubular nephrosis and cellular vacuolation (Perrin et al., 1978, Fromming and Szejtli, 1996). Parenteral administration also induces similar changes to the kidney proximal tubules (Frank et al., 1976).

2-hydroxylpropyl-β-cyclodextrin (HP-β-CD), a hydroxyalkyl derivative, is an alternative to α-, β- and γ-cyclodextrin, with improved water solubility properties (Uekama et al., 1998, Yoshida et al., 1988) and may be slightly more toxicologically benign.

This paper reviews the toxicity of HP-β-CD, using literature information together with novel in-house study data generated within AstraZeneca using HP-β-CD to assess the toxicology of a potential new drug with low water solubility. These new data add to the literature information regarding HP-β-CD and reduce the need for further assessments of this component in novel vehicles. A brief review of the metabolism and pharmacokinetics of HP-β-CD, with variants on the percentage administered and the route of administration is also included, as well as a limited review of human safety.