212
After the small-scale laboratory experiments for optimizing the reaction conditions in order to get the product of proper shape, size, and swelling, the scaling up
was started in Organic Chemistry Development Co. (SzVF, Budapest) in 1983.
Instead of paraffin oil, dichloroethane was used as water-immiscible solvent and
ethylcellulose as protecting colloid for stabilizing the emulsion. The diepoxy coupling agent in the second step of cross-linking was very expensive; therefore epichlorohydrin was used in this step, too. To improve the flowing properties of the dry
beads, they were silylated. Fractionation was performed by a wet technology to
replace sieving, and fluid bed dryer was used for drying. In a further development,
dichloroethane was replaced by 1-butanol, thus improving the environmental footprint of the technology, and a proper surfactant was selected for stabilizing the
emulsion during polymerization.
In-house acute toxicity study on mice and rats in 3000 mg/kg and 5000 mg/kg
dose per os demonstrated no toxicity. Dermal toxicity study in Chinoin Toxicological
Department showed no irritation when used in 5000 mg/kg dose on depilated skin
of male and female rats. According to preliminary microbiological studies, the bead
polymer, unlike to starch usually applied in topical powder formulations, was not a
substrate for fungi causing dermatomycosis. The tissue compatibility studies by
intramuscular injection of bead polymer into rats resulted in no pathological
reactions.
In vivo experiments on rats proved the wound healing effect without detecting
inflammatory cell reactions. In human trials, therapy-resistant ulcers were treated
successfully on nine patients (Felméray et al. 1996). The overinfected, coated
wounds became clear on the average in 5 days. Both the depth and the basic area of
the ulcers were reduced quickly.
Approximately 130 kg bead polymers of 200–400 μm grain size, 4.7–5.6 mL/g
swelling, and 48–62% cyclodextrin content were produced in 16 batches. Instructions
for production were compiled, and specification set and methods for qualification
worked out. The microscopic photo on the beads (Fig. 4.16) shows the regular shape
and narrow size distribution of the product. Option for production and selling was
granted to Wacker Chemie (Consortium für elektrochemische Industrie, Germany)
by Chinoin based on an agreement in 1986, but it was not realized.
In 1987, the product with 2% iodine content was selected for development under
the trade name Chinoderm as wound healing powder for veterinary application by
Chinoin. A 3-year expiry date was established based on stability studies which
showed no change in iodine content after 30-day storage at 40 and 50 °C, and only
12% decrease at 60 °C. In Chinoin (Nagytétény unit), 20 kg cyclodextrin bead polymer with 2% iodine content was prepared for toxicological and efficacy studies.
These studies showed the beneficial effects of the iodine-releasing beads in wound
healing on dogs by the University of Veterinary Medicine, Budapest.
É. Fenyvesi et al.
After the small-scale laboratory experiments for optimizing the reaction conditions in order to get the product of proper shape, size, and swelling, the scaling up
was started in Organic Chemistry Development Co. (SzVF, Budapest) in 1983.
Instead of paraffin oil, dichloroethane was used as water-immiscible solvent and
ethylcellulose as protecting colloid for stabilizing the emulsion. The diepoxy coupling agent in the second step of cross-linking was very expensive; therefore epichlorohydrin was used in this step, too. To improve the flowing properties of the dry
beads, they were silylated. Fractionation was performed by a wet technology to
replace sieving, and fluid bed dryer was used for drying. In a further development,
dichloroethane was replaced by 1-butanol, thus improving the environmental footprint of the technology, and a proper surfactant was selected for stabilizing the
emulsion during polymerization.
In-house acute toxicity study on mice and rats in 3000 mg/kg and 5000 mg/kg
dose per os demonstrated no toxicity. Dermal toxicity study in Chinoin Toxicological
Department showed no irritation when used in 5000 mg/kg dose on depilated skin
of male and female rats. According to preliminary microbiological studies, the bead
polymer, unlike to starch usually applied in topical powder formulations, was not a
substrate for fungi causing dermatomycosis. The tissue compatibility studies by
intramuscular injection of bead polymer into rats resulted in no pathological
reactions.
In vivo experiments on rats proved the wound healing effect without detecting
inflammatory cell reactions. In human trials, therapy-resistant ulcers were treated
successfully on nine patients (Felméray et al. 1996). The overinfected, coated
wounds became clear on the average in 5 days. Both the depth and the basic area of
the ulcers were reduced quickly.
Approximately 130 kg bead polymers of 200–400 μm grain size, 4.7–5.6 mL/g
swelling, and 48–62% cyclodextrin content were produced in 16 batches. Instructions
for production were compiled, and specification set and methods for qualification
worked out. The microscopic photo on the beads (Fig. 4.16) shows the regular shape
and narrow size distribution of the product. Option for production and selling was
granted to Wacker Chemie (Consortium für elektrochemische Industrie, Germany)
by Chinoin based on an agreement in 1986, but it was not realized.
In 1987, the product with 2% iodine content was selected for development under
the trade name Chinoderm as wound healing powder for veterinary application by
Chinoin. A 3-year expiry date was established based on stability studies which
showed no change in iodine content after 30-day storage at 40 and 50 °C, and only
12% decrease at 60 °C. In Chinoin (Nagytétény unit), 20 kg cyclodextrin bead polymer with 2% iodine content was prepared for toxicological and efficacy studies.
These studies showed the beneficial effects of the iodine-releasing beads in wound
healing on dogs by the University of Veterinary Medicine, Budapest.
É. Fenyvesi et al.