Cyclodextrins as actives - the origins from 1983

The whole story of using cyclodextrins as active ingredients started by the groundbreaking research conducted by Josef Pitha and Lajos Szente in 1983, which explored the use of cyclodextrins to treat hypervitaminosis A. Their work not only shed light on potential therapeutic applications but also paved the way for further investigations.

The Study

Pitha and Szente investigated the complexation of retinoids (vitamin A and its derivatives) with cyclodextrins, in particular 2,6-di-O-methyl-beta-cyclodextrin (dimethyl-BCD). The researchers found that dimethyl-BCD could form inclusion complexes with retinoids, effectively sequestering them and altering their pharmacokinetics.

Results

A synthetic derivative of beta-cyclodextrin in which all 2, 6 hydroxy groups were converted to methoxy groups (dimethyl-BCD), considerably accelerated the dissolution and increased the solubility of all-trans retinoic acid. Dimethyl-BCD affected the toxicity of retinoic acid in mice in a manner depending on the method of administration: (a) when dimethyl-BCD was administered simultaneously with retinoic acid, the toxic effects were increased and set in rapidly without symptoms of hypervitaminosis A, (b) when dimethyl-BCD was administered alone, after the hypervitaminosis A had been established, the survival rate was improved.

The key findings were twofold:

• Toxicity Mitigation: When administered orally, dimethyl-BCD reduced the toxicity of retinoids. Hypervitaminosis A, characterized by tissue damage, weight loss, and bone fragility, occurs due to excessive vitamin A intake. dimethyl-BCD complexation prevented the direct interaction of retinoids with tissues, thereby mitigating toxicity.
• Potentiation of Retinoid Toxicity: Intravenous administration of dimethyl-BCD-retinoid complexes, however, potentiated retinoid toxicity. This unexpected result highlighted the importance of route of administration. The complexed retinoids reached target tissues more efficiently, leading to enhanced toxicity.

Implications and Further Research

Pitha and Szente’s work sparked interest in cyclodextrin-based drug delivery systems. Researchers explored various cyclodextrin derivatives, including hydroxypropyl-β-cyclodextrin (HP-β-CD), sulfobutylether-β-cyclodextrin (SBE-β-CD), and others. These derivatives improved solubility, stability, and bioavailability of poorly water-soluble drugs. Cyclodextrins found applications in pharmaceuticals, cosmetics, and food industries.

In summary, Pitha and Szente’s pioneering study not only addressed hypervitaminosis A but also catalyzed research into cyclodextrin-based drug formulations. Their findings continue to influence drug development and delivery strategies, emphasizing the critical role of molecular encapsulation in pharmacology. 🌟

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In the coming weeks, we will continue focusing on using cyclodextrins as active ingredients, disease by disease. Stay tuned!

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