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K. Gruner, R. Suverkrup, M. Diestelhorst; Latanoprost Ophthalmic Lyophilizate Carrier Systems (OLCS). Invest. Ophthalmol. Vis. Sci. 2009;50(13):5555.
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Latanoprost is the ester prodrug of a PFG2a -derivative and as such subject to pH- and temperature-dependent hydrolysis in aqueous solution. In conventional eye drops the risk of microbiological contamination is controlled by addition of 0.02 % BAC, which is known to cause long-term damage to the cornea. Ophthalmic lyophilizates contain less than 5 % water and no preservatives. Upon administration, the tear fluid serves as the physiologically optimal solvent, therefore they are well tolerated.
30 µl of a sterile aqueous solution containing 0.75 µg latanoprost (0.0025 %) and 1.5 mg mannitol (5 %) as bulking agent were pipetted onto an autoclaved PTFE membrane, shock frozen by immersion into the gas phase above liquid nitrogen and dried in a laboratory freeze-dryer. The residual water content was determined by thermogravimetry, water uptake was studied by dynamic vapor sorption, and the structure and porosity of the lyophilizates were visualized by scanning electron microscopy. Adhesion forces were measured by a micro-balance upon shearing and the content uniformity was assayed by HPLC.
The residual water content depends upon the duration and conditions of the secondary drying phase and is generally less than 1 %. At ambient temperature the vapor sorption is negligible up to a relative humidity of 80 % and increases steeply thereafter. The lyophilizates have an irregular honeycomb-like internal structure and a nearly closed and smooth surface. They dissolve instantaneously upon contact with small amounts of aqueous fluids. The force required to shear the dried droplets off the membrane ranged from 32 to 89 mN. Latanoprost OLCS meet pharmacopoeial requirements for content uniformity of single unit dosage forms.
Latanoprost OLCS are superior to conventional eye drops with respect to physiological tolerability, stability, dose uniformity and ease of administration. Experiences with fluorescein OLCS indicate that an enhanced bioavailability can also be expected in a forthcoming study. A process for volume production is under development.
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