Acute and Repeated Dose Toxicity Studies of Different β-Cyclodextrin-Based Nanosponge Formulations

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ABSTRACT

Nanosponges (NS) show promising results in different fields such as medicine, agriculture, water purification, fire engineering and so on. The present study was designed to evaluate toxicity of different NS formulations (namely, S1–S6) synthesized with different cross-linking agents such as carbonyl diimidazole, pyromellitic dianhydride and hexamethylene diisocynate; and preparation methods in experimental animals. Acute and repeated dose toxicity studies of formulations were carried out as per OECD guidelines 423 and 407, respectively. For acute toxicity study, formulations were administered to female rats at doses of 300 and 2000 mg/kg orally. The general behaviour of the rats was continuously monitored for 1 h after dosing, periodically during the first 24 h and daily thereafter for a total of 14 days. On day 14, animals were fasted overnight, weighed, and sacrificed. After sacrification, animals were subjected to necropsy. For repeated dose toxicity study, rats of either sex were orally administered with formulations at the dose of 300 mg/kg per day for a period of 28 days. The maximally tolerated dose of all formulations was found to be 2000 mg/kg. Repeated administration of formulations for 28 days did not show any significant changes in haematological and biochemical parameters in experimental animals. These results indicate that the formulations are safe, when tested in experimental animals.

Section snippets

INTRODUCTION

Cyclodextrin-based nanosponges (NS) are spherical, regular shape, cross-linked nanoparticles. NS emerge with promising results in different fields such as medicine as drug carrier, drug solubiliser, controlled-release matrix system; agriculture as longevity enhancing agent for fruits and flowers; water purification as adsorbing agent, fire engineering as smoke adsorbent and flame retardant and so on.1 NS are condensed, complexed and/or polymerised β-cyclodextrin (β-CD) with different

Materials

β-Cyclodextrin was gifted from Roquette Italia SpA (Cassano Spinola, Italy). CDI, PMDA, HMDI and potassium hydroxide were obtained from Sigma-Aldrich (Munich, Germany). Dichloromethane, dimethyl formamide (DMF), acetone, dimethyl sulfoxide (DMSO), triethyl amine (TEA) and ethanol were purchased from Sigma-Aldrich (Munich, Germany). All other chemicals and reagents were of analytical grade.

Preparation of Cross-Linked NS

The cross-linked NS were prepared in 1:8 molar ratio of β-CD and CDI or HMDI or PMDA (Table 1) by the

Particle Size

The particle sizes of NS formulations were between 400 and 550 nm in CM and 50 and 200 nm in NM (Table 2) with low polydispersity indices (data not shown). It suggests that particle size of NS depends on process of grinding as well as the preparation method. The particle sizes of NS were 450–550 nm by trituration and 40–60 nm by vibrational rod milling.4

Acute Toxicity Study

After single oral administration of NS samples at 300 and 2000 mg/kg dose levels, animals in all treated groups did not show any lethal effects or

DISCUSSION

Toxicological evaluation is an important step to determine safety of drugs and excipients; it also helps for selection of safe dose for their use in humans and animals.

It is worth of note that the fate of the parent cyclodextrins in the gastrointestinal tract differs based on the resistance to hydrolysis and enzymatic degradation. The β-CDs are practically resistant to stomach acid or salivary and pancreatic amylases and they are extensively hydrolyzed in the colon.11 A human study with healthy

CONCLUSIONS

All NS after oral administration to rats were found safe at selected doses in acute and repeated dose toxicity study. Thus, the study provides first systematic report on toxicity data of these hyper cross-linked cyclodextrin polymers after oral administration, showing a good biocompatibility with a potential negligible degradation during the gastrointestinal transit. Despite that, further investigations are needed to evaluate the fate of NS in the GI tract. On the basis of the results, β-CD NS

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