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R.J. Suverkrup, O. Krasichkova, M. Diestelhorst; Fast Precise Freeze Drying of Hyaluronic Acid / Dextran Ophthalmic Lyophilisate Carrier Systems (OLCS) . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5130.
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An OLCS is a freeze dried drop containing single dose of active pharmaceutical ingredient and hydrophilic polymer on a soft carrier membrane. OLCS are more stable, easier to administer, precisely dosed and better tolerated than aqueous solutions because they contain neither buffer salts nor preservatives. The bioavailability of fluorescein from OLCS was ten times higher than from equally dosed aqueous eye drops . For precise control of freeze drying conditions and minimization of the drying time, the FPFD technique was developed and applied to OLCS containing hyaluronic acid, which can be applied for symptomatic treatment of the dry–eye syndrome.
Key features of FPFD are: minimal volume of the drying chamber, snap freezing at a controlled rate, residual gas pressure <0.1 mbar, direct radiation heating, extreme temperature gradient between drop and condenser, and mechanical de–icing of condenser for quasi–continuous operation. Control parameters are: chamber pressure, surface temperature (external infrared thermometer), core temperature (thermocouple), water content (NIR spectroscopy). Adhesion force and structural strength were studied in a 33 full factorial design.
The differences between core and surface temperature exceed 15 K during primary drying, but all phases can be distinguished in both temperature profiles. Alternatively, the water content was measured by NIR transmission spectroscopy. The correlation is based on the first three principal components of the second derivatives of spectra between 1362 and 1420 nm. The influence of dextran and hyaluronic acid concentrations on adhesion force and structural strength are statistically highly significant .
The FPFD technique was developed for the lyophilization of small batches of products requiring precise control of process conditions. The use of small, flexible equipment, quasi continuous operation and real time control of critical process parameters are in–line with FDA PAT recommendations. The tolerability of hypromellose OLCS  was very good . Preliminary observations on hyaluronic acid OLCS indicate that the tolerability appears to be even better.
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