Intraocular Pressure Effects and Mechanism of Action of Topical Versus Sustained-Release Bimatoprost.

PURPOSE: To assess the intraocular pressure (IOP)-lowering effects of bimatoprost sustained-release implant (BimSR) in normotensive monkeys receiving topical bimatoprost. METHODS: Six eyes from six female, normotensive, cynomolgus monkeys were treated with once-daily topical latanoprost 0.005% plus twice-daily fixed-combination dorzolamide 2%/timolol 0.5%. At week 5, topical latanoprost was switched to once-daily topical bimatoprost 0.03% and twice-daily dorzolamide 2%/timolol 0.5% was continued. At week 8, BimSR 20 µg was administered intracamerally to three eyes and topical therapy was continued in all eyes. At week 12, all topical therapy was discontinued and animals were monitored for another 4 weeks. IOP was measured with a TonoVet rebound tonometer in nonsedated animals weekly for 16 weeks. RESULTS: Average mean (standard deviation) IOP was 19.8 (1.6) mm Hg at baseline, 15.7 (0.9) mm Hg during treatment with topical latanoprost/dorzolamide/timolol from weeks 1 to 5, and 14.2 (0.5) mm Hg during weeks 6 to 8 after topical latanoprost was switched to topical bimatoprost. After BimSR was added, average mean IOP during weeks 9 to 12 was 10.8 (1.3) mm Hg, a decrease of 3.9 mm Hg compared with the topical-only arm. When topical therapy was discontinued, IOP in BimSR-treated eyes remained below that in unmedicated eyes (15.8 [0.9] vs. 20.2 [0.2] mm Hg at weeks 14-16). CONCLUSIONS: Intracameral BimSR has IOP-lowering effects additive to those of topical bimatoprost, suggesting an additional mechanism of action with intracameral drug delivery. TRANSLATIONAL RELEVANCE: Compared with topical bimatoprost, intracameral BimSR may have an additional mechanism of action of IOP lowering.

Use of surfactants as plasticizers in preparing solid dispersions of poorly soluble API: selection of polymer-surfactant combinations using solubility parameters and testing the processability.

Formation of solid dispersions as a means to enhance the dissolution rate of poorly soluble Active pharmaceutical ingredients (APIs) typically employs hydrophilic polymer systems and surfactants. While the utility of the surfactant systems in solubilization is well known, the secondary effects of the same on processing and subsequent physical stability of the solid dispersions needs to be studied further. Physical blends of the poorly soluble API and hydrophilic polymers such as PVP-K30, Plasdone-S630, HPMC-E5, HPMCAS, and Eudragit L100 with mass ratio 1:1 were prepared. The surfactants tested in this study included Tween-80, Docusate sodium, Myrj-52, Pluronic-F68 and SLS. Thermal analysis of the API-polymer-surfactant blends suggested that the surfactants caused solvation/plasticization, manifesting in reduction of (i) the melting (T(m)) of API (ii) T(g) of the polymers and (iii) the combined T(g) of the solid dispersion formed from quench cooling. Explanation of these effects of surfactants is attempted based on their physical state (at the temperature of interest), HLB values and similarity of their solubility parameter values with respect to drug-polymer systems. Furthermore, extruded matrices containing different API-polymer (PVP-K30, Plasdone-S630, and HPMC-E5) mixtures prepared with and without surfactants, were produced by feeding the powder blend through a hot-melt extruder. The melt viscosity of the polymer blends was assessed by torque rheometry using a Haake Rheomix. The physicochemical properties of the extruded API-polymer-surfactant were characterized by differential scanning calorimetry, X-ray diffraction, Raman spectroscopy, and polarized microscopy. The results demonstrated that the glass transition temperature of the carrier polymers decreased as direct result of the surfactants in the extrudate, due to an increase in the chain mobility of polymers. A decrease in the melt viscosity was seen due to a plasticization of the polymer. The drug release profiles of the extruded solid dispersions containing intra granular surfactants were found to fit the dispersions with extra granularly added surfactants.

Use of surfactants as plasticizers in preparing solid dispersions of poorly soluble API: stability testing of selected solid dispersions.

PURPOSE: The purpose of the study is to evaluate the effect of surfactant-plasticizers on the physical stability of amorphous drug in polymer matrices formed by hot melt extrusion. METHOD: Solid dispersions of a poorly soluble drug were prepared using PVP-K30, Plasdone-S630, and HPMC-E5 as the polymeric carriers and surfactants as plasticizers. The solid dispersions were produced by hot melt extrusion at temperatures 10 degrees C above and below the glass transition temperature (Tg) of the carrier polymers using a 16 mm-Haake Extruder. The surfactants tested in this study included Tween-80 and Docusate Sodium. The particle size of the extrudate was reduced to have mean of 100-200 micron. The physical stability of the solid dispersions produced was monitored at 30 degrees C/60% for six-months and at 60 degrees C/85% for two-months in open HDPE bottles. Modulated differential scanning calorimetry, polarized light microscopy, powder X-ray diffraction and dissolution testing was performed to assess the physical stability of solid dispersions upon stress testing. RESULTS: The dispersions containing HPMC-E5 were observed especially to be susceptible to physical instability under an accelerated stress conditions (60 degrees C/85%RH) of the solid dispersion. About 6% conversion of amorphous drug to crystalline form was observed. Consequently, the system exhibits similar degree of re-crystallization upon addition of the surfactant. However, under 30 degrees C/60%RH condition, the otherwise amorphous Drug-HPMC-E5 system has been destabilized by the addition of the surfactant. This effect is much more reduced in the extruded solid dispersions where polymeric carriers such as Plasdone S-603 and PVP-K30 (in addition to surfactants) are present. Furthermore, the drug release from the solid dispersions was unaffected at the stress conditions reported above. CONCLUSIONS: Possible reasons for the enhanced stability of the dispersions are due to the surfactants ability to lower the viscosity of the melt, increase the API solubility and homogeneity in the carrier polymer. In contrast, while it is possible for the surfactants to destabilize the system by lowering the Tg and increasing the water uptake, the study confirms that this effect is minimal. By and large, the surfactants appear to be promising plasticizers to produce solid dispersions by hot melt extrusion, in so doing improving dissolution rate without compromising the physical stability of the systems.