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A unique intellectual property situation with hydroxypropyl-beta-cyclodextrins
resulted a long interference process. At the National Institutes of Health, Josef Pitha
filed a patent in early 1984 with quite broad claims on the preparation and pharmaceutical use of hydroxypropylated cyclodextrins emphasizing the unobvious amorphousness of the composite products, their enhanced water solubility, and
complex-forming characteristics together with the solubilizing potency and low
toxicity of these cyclodextrin derivatives (Pitha 1988).
Nearly at the same time, a patenting process started in Germany and in the
USA. Company Hoechst disclosed the process of making hydroxypropyl cyclodextrins (Brandt and Felcht 1986; filed in 1983 in Germany). At the Christian-Albrecht
University in Kiel was simply claimed the improvement of drug solubility and stability using cyclodextrin derivatives, in particular hydroxypropyl-beta- cyclodextrins
(Müller and Brauns 1985, filed in 1983 in Germany and in 1985 in the USA,
assigned to Janssen). The co-existence of US patent applications of NIH and Janssen
caused a decade-long interference process, since US and European patent policies
considered the patents differently: while US NIH patent by Pitha was considered the
“first to invent,” Müller’s patent by Janssen was the “first to file” type. The longlasting interference process was finally settled, and after 35 years of intellectual
protection of hydroxypropyl cyclodextrins’ use in the USA, in May 2019, (these
days) the use of hydroxypropyl-beta-cyclodextrin as a drug solubility improving
excipient becomes free worldwide. No such a turbulent intellectual property situation hampers any more the application of this great multifunctional excipient.
Much later, an unexpected function of hydroxypropyl-beta-cyclodextrin was discovered: it turned out to be more than just an excipient. In 2008, it was accidentally
discovered that solubilizing excipient hydroxypropyl-beta-cyclodextrin showed
remarkable potency in improving the lifespan of mice suffering from a rare, lysosomal storage disorder, called Niemann-Pick type C disease (Liu et al. 2008, 2009).
These early observations were then further supported by other research teams
searching for therapies to treat Niemann-Pick type C disease (e.g., Davidson
et al. 2009).
Based on these encouraging results, the favorable safety profile, and 20-yearlong pharmaceutical application as an excipient in human injectable products, regulatory orphan drug designation was given to hydroxypropyl-beta-cyclodextrin in the
USA and in EU for the treatment of Niemann-Pick type C disease. This means that
this cyclodextrin derivative today can be considered as safe and efficient solubilizing excipient, as well as an orphan drug for treatment of a rare, lysosomal lipid
storage disease. However, the demand is very small for orphan drug applications,
although extremely high quality/purity is required, but huge amounts of
hydroxypropyl- beta-cyclodextrin have been used in the household toiletries: for
deodorizing fabrics especially those dried in drying machines (Trinh et al. 1996).
4 History of Cyclodextrin Production in Hungary
A unique intellectual property situation with hydroxypropyl-beta-cyclodextrins
resulted a long interference process. At the National Institutes of Health, Josef Pitha
filed a patent in early 1984 with quite broad claims on the preparation and pharmaceutical use of hydroxypropylated cyclodextrins emphasizing the unobvious amorphousness of the composite products, their enhanced water solubility, and
complex-forming characteristics together with the solubilizing potency and low
toxicity of these cyclodextrin derivatives (Pitha 1988).
Nearly at the same time, a patenting process started in Germany and in the
USA. Company Hoechst disclosed the process of making hydroxypropyl cyclodextrins (Brandt and Felcht 1986; filed in 1983 in Germany). At the Christian-Albrecht
University in Kiel was simply claimed the improvement of drug solubility and stability using cyclodextrin derivatives, in particular hydroxypropyl-beta- cyclodextrins
(Müller and Brauns 1985, filed in 1983 in Germany and in 1985 in the USA,
assigned to Janssen). The co-existence of US patent applications of NIH and Janssen
caused a decade-long interference process, since US and European patent policies
considered the patents differently: while US NIH patent by Pitha was considered the
“first to invent,” Müller’s patent by Janssen was the “first to file” type. The longlasting interference process was finally settled, and after 35 years of intellectual
protection of hydroxypropyl cyclodextrins’ use in the USA, in May 2019, (these
days) the use of hydroxypropyl-beta-cyclodextrin as a drug solubility improving
excipient becomes free worldwide. No such a turbulent intellectual property situation hampers any more the application of this great multifunctional excipient.
Much later, an unexpected function of hydroxypropyl-beta-cyclodextrin was discovered: it turned out to be more than just an excipient. In 2008, it was accidentally
discovered that solubilizing excipient hydroxypropyl-beta-cyclodextrin showed
remarkable potency in improving the lifespan of mice suffering from a rare, lysosomal storage disorder, called Niemann-Pick type C disease (Liu et al. 2008, 2009).
These early observations were then further supported by other research teams
searching for therapies to treat Niemann-Pick type C disease (e.g., Davidson
et al. 2009).
Based on these encouraging results, the favorable safety profile, and 20-yearlong pharmaceutical application as an excipient in human injectable products, regulatory orphan drug designation was given to hydroxypropyl-beta-cyclodextrin in the
USA and in EU for the treatment of Niemann-Pick type C disease. This means that
this cyclodextrin derivative today can be considered as safe and efficient solubilizing excipient, as well as an orphan drug for treatment of a rare, lysosomal lipid
storage disease. However, the demand is very small for orphan drug applications,
although extremely high quality/purity is required, but huge amounts of
hydroxypropyl- beta-cyclodextrin have been used in the household toiletries: for
deodorizing fabrics especially those dried in drying machines (Trinh et al. 1996).
4 History of Cyclodextrin Production in Hungary