Cyclodextrin complexed drugs

ABSTRACT. The application of cyclodextrin complexed drugs in non-oral dosage forms results in the folio-wing advantages ... 

The magnitude of association between a drag compound and various cyclodextrins depends critically on the details of the fit of the substrate into the cyclodextrin cavity. As shown in Table 6, the experimental compound RS-82856 forms the strongest complexes with /3-cyclodextrin, while maximal solubility is reached with y-cyclodextrin [62], Formation of the /8-cyclodextrin complex dramatically increased the dissolution rate of the compound as well. For RS-82856 itself, 20% dissolved within 20 minutes, while more than 80% of the drug-/3-cyclodextrin complex was found to be dissolved at the same time point. 

III. APPLICATION OF CAPILLARY ELECTROPHORESIS FOR DETERMINATION OF ENANTIOSELECTIVE BINDING CONSTANTS OF CHIRAL DRUG/CYCLODEXTRIN COMPLEXES... 

Let us compare the methods applied by Pedersen for establishing the complex formation with a modern approach. Today tedious solubility studies are carried out almost exclusively with practical applications in mind, but they are not performed to prove the complex formation. For instance, one ofthe main reasons for the use of cyclodextrin complexes in the pharmaceutical industry is their solubilizing effect on drugs [8]. There, and almost only there, solubility studies are a must. As concerns spectroscopic methods, at present the NMR technique is one ofthe main tools enabling one to prove the formation of inclusion complex, carry out structural studies (for instance, making use of the NOE effect [9a]), determine the complex stability [9b, c] and mobility of its constituent parts [9d]. However, at the time when Pedersen performed his work, the NMR method was in the early stage of development, and thus inaccurate, and its results proved inconclusive. UV spectra retained their significance in supramolecular chemistry, whilst at present the IR method is used to prove the complex formation only in very special cases. 

A novel cyclodextrin reversal drug, sugammadex, has been submitted for FDA approval. It can rapidly inactivate steroidal neuromuscular blocking drugs by forming an inactive complex, which is excreted in the urine. This process allows the practitioner to rapidly reverse even profound degrees of neuromuscular blockade produced by rocuronium and vecuronium at the end of the surgical procedure. 

Figure 5 Solubilization and effect of dilution drug-cyclodextrin complex or drug cosolvent formulation.

Muller, B.W. and Albers, E. (1991). Effect of hydrotropic substances on the complexation of sparingly soluble drugs with cyclodextrin derivatives and the in uence of cyclodextrin complexation on the pharmacokinetics. Pharm. Sci., 80, 599. 

Redenti, E., L. Szente, and J. Szejtli (2001). Cyclodextrin complexes of salts of acidic drugs. Thermodynamic properties, structural features, and pharmaceutical applicatloFffearm. Sci., 90 979-986. 

FIGURE 6 Representation of drag in-cyclodextrin in liposome technique for encapsulation of lipophilic drugs in aqueous interior of vesicles. Drag molecules have low aqueous solubility and thus cannot be encapsulated in the aqueous compartment of the vesicle. However, the drug-cyclodextrin complex has high aqueous solubility and can thus be encapsulated in high concentrations in the vesicles. 

Fatouros, D. G, Hatzidimitirou, K., and Antimisiaris, S. G. (2001), Liposomes encapsulating prednisolone and prednisolone-cyclodextrin complexes Comparison of membrane integrity and drug release, Eur. J. Pharm. Sci., 13, 287-296. 

Complexation Drug is entrapped or complexed with excipients that can mask the lipophilic groups of the drug and enhance drug solubility in water. Cyclodextrins are commonly used to entrap hydrophobic drugs in the core, while the hydrophilic groups on the periphery help to solubilize the drug. 

Incorporation of Drug-Cyclodextrin Complexes in Nanoparticulate Delivery Systems... 

Ono, N. Hirayama, F. Arima, H. Uekama, K. Determination of stability constant of P-cyclodextrin complexes using the membrane permeation technique and the permeation behavior of drug-competing agent-P-cyclodextrin ternary systems. Eur. J. Pharm. Sci. 1999, 8 (2), 133-139. 

Ammar, H.O. El-Nahhas, S.A. Improvement of some pharmaceutical properties of drugs by cyclodextrin complexation. 2. Colchicine. Pharmazie 1995, 50 (4), 269-272. 

In this study, the foregoing methodology of dimensional analysis was applied to a kneading process of drug-cyclodextrin complexation. Aoustin kneader with dual Z blades was instrumented for torque measurements and multiple runs were made at two scales (2.5 and 5L). 

Stella VJ, Rao VM, Zannou EA, Zia V. Mechanisms of drug release from cyclodextrin complexes. Adv Drug Delivery Rev 1999 36(1) 3-16. 

Figure 5.8 Schematic representation of the dissolution-dissociation-recrystallisation process of a cyclodextrin complex with a poorly soluble guest. The complex rapidly dissolves, and a metastable oversaturated solution is obtained. The anomalously high level of dissolved guest drops bock but remains higher than the level that can be obtained with noncomplexed drug. Solid curve = complexed drug broken curve = noncomplexed drug.

Pitha J, Teruhiko H, Torres-Labandeira J, and Irie T. Preparation of Drug-Hydroxypropyl Cyclodextrin Complexes by a Method Using Ethanol or Aqueous Ammonium Hydroxide as Cosolubilizers. IntJPharm 1992 80 253-258. 

Figure 14 Danazol is a drug with an aqueous solubility of 10 ttg/mL. Here danazol plasma levels are plotted as a function of time after administration of three forms of the drug including a nanoparticle dispersion and a hydroxypropyl-P-cyclodextrin complex, using a suspension with a mean particle size of 10 pm as a comparator. Source From Ref. 83.

Otagiri, M., Imai, T., Uekama, K. Enhanced oral bioavailability of anti-inflammatory drug flurbiprofen in rabbits by tri-O-methyl-p-cyclodextrin complexation. J. Pharmacobio-Dynam. 1982, 5, 1027-1029. 

Cyclodextrin complexation (See Chapter 40) can also represent a way to improve the stability and the solubility of sensitive drugs such as thalidomide. Thalidomide is currently in clinical use for the treatment and prevention of graft-versus-host disease in leukemia patients after bone marrow transplant. However, this drug is sparingly soluble in aqueous solutions (50 Kig/mL) and is readily hydrolyzed. Complexation with hydroxypropyl (3-cyclodextrin increases the solubility to 1700 Kig/mL and extends the half-life of a dilute solution from 2.1 to 4.1 h. Other vulnerable and sparingly soluble drugs stabilized by means of cyclodextrin complexation are the non-steroidal antiinflammatory drugs diclofenac, piroxicam, and indomethacin and the anthra-cycline antibiotic daunorubicin. ... 

Other studies have included the formation of complexes using spray-drying techniques, including the preparation of cyclodextrin complexes. DSC may be used to determine the extent of drug inclusion within the cyclodextrin ring system, again via monitoring of the decrease in the heat of fusion (97). 

Pharmaceutical applications of the titration experiment include receptor-enzyme, protein-membrane, and other biomaterial interactions. There are many microcalorimetry publications on binding of drugs to cyclodextrins (e.g., 37,38) however, a real limitation of this approach is that to minimize the heat of dilution and heat of mixing effects, the cyclodextrin and the drug must be dissolved in the same solvent as each other. It would be unusual to have an interest in drug-cyclodextrin complexes in circumstances where both the drug and the cyclodextrin are freely soluble in water. 

T Loftsson. Increasing the cyclodextrin complexation of drugs and drug bioavailability through addition of water-soluble polymers. Pharmazie 53 733-740, 1998. 

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