Cyclodextrins: Improving Delivery of Hydrophobic Compounds

Beta-cyclodextrin derivatives have emerged as a useful tool for improving the stability and solubility problems of hydrophobic molecules. With steroid hormones, for example, as much as a 50-fold increase in solubility and bioavailability can be achieved through the use of beta-cyclodextrin derivatives (beta-CDs) as carrier molecules.1 Given the space limitations inherent in an implantable drug delivery system, beta-CDs are a viable option for use in ALZET ® Osmotic Pumps.

Cyclodextrins are conjoined glucose molecules forming a "donut" structure, or torus. The non-polar interior of the torus encapsulates hydrophobic molecules to increase solubility in aqueous solutions. The morphology of cyclodextrins encourages complexation, yet aqueous dilution elicits complete dissociation.2   beta-cyclodextrins occur naturally, but derivatives formed by substitution with hydroxyalkyl groups have reduced toxicity and optimized solvent action. One popular derivative is 2-hydroxypropyl-beta-cyclodextrin, which is sold as Trappsol ® by CTD, Inc., in either a powder or a pre-mixed solution.1,3

Optimizing Delivery

A drug's ability to form an inclusion complex with beta-CDs depends upon its size, shape, and lipid partition co-efficient.4 Even a polar molecule can be complexed if it contains non-polar side chains. An optimal cyclodextrin:drug ratio maximizes both dissolution and redistribution speed. Dr. Tony Yaksh et al . of the University of California at San Diego dissolved capsaicin, a lipid-soluble agent, in 20% 2-hydroxypropyl-beta-cyclodextrin. A "dramatic shift into the aqueous phase was observed," with the lipid partition coefficient of the capsaicin, inherently less than 0.01, rising to 2.05 when complexed with cyclodextrin.

Cyclodextrin derivatives are considered a relatively safe, benign vehicle. Natural cyclodextrins may form precipitable cholesterol complexes and should not be used parenterally. However, nephrotoxicity studies on the hydroxypropyl-beta derivative have shown it to be well tolerated.2   No production of unusual metabolites has been observed under normal physiological conditions.

Value in CNS Studies

The experimental utility of cyclodextrins is evident when delivering agents to the central nervous system (CNS). ALZET pumps are frequently used for CNS delivery of agents that do not cross the blood-brain barrier in systemic delivery. Intrinsically, this delivery route demands a stable, bioavailable solution with minimal volume and no vehicle effect. For these reasons, Dr. Tony Yaksh and his group highlighted the superior ability of cyclodextrins for CNS administration. Their results demonstrated normal motor function, nociception, EEG and general behavior in rats injected intrathecally with 20% hydroxypropyl-beta-cyclodextrin.4   Unlike DMSO, the beta-CD allowed the test agent to exert full biological effect without reducing the endogenous peptides being studied. Yaksh et al. concluded that cyclodextrin "represents a benign vehicle for solubilizing relatively insoluble materials and retains these agents in a bioavailable form after intracerebral and intrathecal administration."4  

Versatility for Agent Delivery

Cyclodextrins have been used in ALZET pumps to effectively deliver steroid hormones and other lipophilic molecules in a stable, bioactive form. Complexation "protects the guest molecule from loss by evaporation, from attack by oxygen, visible and uv light, and from intra- or intermolecular reactions." 5  Zhu et al. supplemented testosterone in hypogonadal rats using 45% 2-hydroxypropyl-beta-cyclodextrin for up to eight weeks. 6  Aditionally, Shrimpton et al. infused a cortisol:cyclodextrin complex to salmon in a receptor down-regulation study. 7  Interestingly, only the continuous administration method was capable of reducing the number and affinity of corticosteroid receptors without inducing stress. Lastly, Backensfeld et al . administered indomethacin, a non-steroidal anti-inflammatory agent with a water saturation solubility of 0.4 mg/ml that undergoes hydrolysis to form various acids. 8   The beta-CD vehicle augmented solubility by 175-875% depending on the pH and protected the indomethacin from chemical degradation. This finding, corroborated by NMR proton shift and HPLC data, led Backensfeld to conclude that, "B-CDs stabilize the indomethacin considerably better [than other vehicles]." 8

Cyclodextrins are fully compatible with ALZET pumps and are an appropriate option for some researchers trying to dissolve an agent for continuous infusion. Additional technical information available as follows:

Detailed technical information

  1. Pitha, J. Cyclodextrins: solutions to insolubility. Neurotransmissions 1989:5(1):1-4.
  2. Pitha, J. J Control Release 1987;6:309-313.
  3.   CTD, Inc. corporate website.
  4. Yaksh TL, Jang J, Nishiuchi Y, Braun KP, Ro S & Goodman M. Life Sci 1991;48(7):623-633.
  5. Pagington JS. Chemistry in Britain 1987;23:455-458.
  6. Zhu et al. Biol Reprod 2000;63(2):368-376.
  7. Shrimpton JM & Randall DJ. Am J Physiol 1994;267(36):R432-R438.
  8. Backensfeld et al. Pharm Res 1990;7(5):484-490.


Pump Advantages

  • Ensure around-the-clock exposure to test agents at predictable levels
  • Permit continuous administration of short half-life proteins and peptides
  • Provide a convenient method for the chronic dosing of laboratory animals
  • Minimize unwanted experimental variables and ensure reproducible, consistent results
  • Eliminate the need for nighttime or weekend dosing
  • Reduce handling and stress to laboratory animals
  • Small enough for use in mice or very young rats
  • Allow for targeted delivery of agents to virtually any tissue
  • Cost-effective research tool


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Researchers are saying...

“CsA and RAD were administered by ALZET minipumps, which we prefer because of the well-defined drug exposure. It avoids the daily peaks and troughs of oral drug administration, which in many animal studies are not well defined.” Matsumoto et al., Trasplantation 2003;76:166-1170.