The influence of three different extrusion methods as well as extrusion temperature and screw speed on drug release from PLGA-based implants were investigated. Comparing biodegradable implants prepared with the Haake MiniLab under extrusion parameters of 85 °C/ 30 rpm and 105 °C/ 120 rpm, an increase in processing temperature and screw speed resulted in extrudates of uneven surface with a so-called “sharkskin effect”. The increased surface area led to a higher burst release of drug and ultimately resulted in a shorter release phase due to an increased PLGA-degradation. Biodegradable implants prepared with the ThreeTec ZE9 at a similar extrusion temperature of 105 °C/ 100 rpm had a lower burst and an even surface morphology. Due to the absence of mixing elements in ram-extrusion processes, the syringe-die method had a poor drug incorporation and thus a high burst release. Nevertheless, drug release phases from implants prepared with the syringe-die method were comparable to those of implants prepared with the ThreeTec ZE9, making it an attractive tool for formulation screening due to low processing times, small amounts of formulation blends needed, and the comparability to implants prepared with the ThreeTec ZE9. Therefore, the syringe-die method as a screening tool for hot-melt extruded implants was utilized.
For the establishment of an applicability map the influence on dexamethasone release from PLGA-based implants was investigated in terms of PLGA end groups, PLGA lactic acid to glycolic acid (L:G) ratio, polymer’s average molecular weight, and drug loading. Dexamethasone release from implants follows the typical drug release curve of PLGA-based drug delivery systems (DDS). A small burst release from excess drug on the implant’s surface, followed by a lag phase and the release phase, which is designated to the start of polymer degradation. Lag phases of dexamethasone release from implants prepared with 502H, 503H, and 502 were independent of the drug loading, while lag phases for dexamethasone release from 752S implants were influenced by drug loading. The release time after the lag phase was shorter for 752S implants containing higher drug loadings. Plotting the release phase over the lag phase, dexamethasone release was visualized in an applicability map. This applicability map was successfully utilized to develop a biodegradable dexamethasone implant with a desired release consisting of a lag phase of maximum 7 days and a release phase of approximately 14 days. This could be achieved by the preparation of a dexamethasone implant with 50%/ 60% drug loading and a PLGA mixture of 502H/ 502 in a 3:1 ratio.
Next, a formulation of a biodegradable implant for the application of brimonidine base was developed. The requirement for the implant was that it released the active substance to the same extend as dexamethasone was released from the already developed implant in order to possibly enable a simultaneous injection. Brimonidine release from biodegradable PLGA implants was investigated in terms of PLGA end groups, polymer molecular weight, L:G ratio, and drug loading. Release data was again collected in an applicability map, containing lag phase plotted against release phase, to develop the desired release implant as previously with dexamethasone implants. However, a biodegradable implant was successfully developed that released brimonidine from PLGA implants with a 1:1 mixture of 752S/ 503H with a 3-day longer lag phase and almost the same release time compared to the developed dexamethasone implant.
Combination implants with both drugs released brimonidine within several days, but dexamethasone release was incomplete for all formulations. Since simultaneous release from single dexamethasone and brimonidine implants was complete for both drugs, a drug – drug or drug – drug – PLGA interaction was assumed but not further investigated. Nevertheless, a combination implant containing both drugs could be possible using alternative preparation methods like co-extrusion.
In order to achieve a reliable release test method to obtain drug release curves from biodegradable implants after a short time period, an accelerated release test method was established by investigating the influence of temperature and pH of 106 the release medium on dexamethasone release from PLGA implants. The change of the release medium from aqueous sodium chloride (0.9%, saline) to phosphate buffered saline pH 2 (PBS, USP) did not accelerate PLGA degradation and thus dexamethasone release from the implants. The use of PBS pH 12 (USP) provides an accelerated PLGA degradation through basic catalyzed hydrolysis. PLGA implants degraded completely at temperatures of 37 °C, 45 °C, and 65 °C. Unfortunately, lag phases of dexamethasone release could not be observed at pH 12 due to the rapid PLGA degradation. This makes it difficult to compare different formulations or estimate drug releases under standard release test conditions. The best conditions for accelerated release tests of dexamethasone implants herein were at an elevated temperature of 45 °C in the standard release medium, saline. By increasing the temperature at release tests, dexamethasone release from PLGA implants took only half the time of drug release at 37 °C while still be able to observe differences between the formulations.
Dexamethasone release from 502H/ 502 implants was investigated in terms of implant sterilization by gamma irradiation and storage time at room temperature in a silica gel desiccator. The storage time of 2 years for implants prepared with the ThreeTec ZE9 resulted in a slight dexamethasone release during the lag phase but was declared as acceptable since the drug release was still similar to those of implants directly after HME. Dexamethasone release from implants prepared with the Haake MiniLab Compounder significantly changed after 3 years of storage. Although the typical sigmoidal release curve was still seen, the burst release increased, dexamethasone was released during the lag phase, and finally the release phase was decreased. Overall, a 2-years storage of gamma irradiated, PLGA-based dexamethasone implants was acceptable when it comes to drug release.
Ultimately, the mechanical properties of biodegradable PLGA implants were investigated in terms of drug loading, molecular weight of polymer matrix, implant dimensions such as length and diameter and moisture content. It was possible to measure and characterize the mechanical properties of biodegradable PLGA implants with a texture analyzer in terms of drug loading, polymer molecular weight, implant dimensions and moisture content by implementing an easy-to-use three-point bending test method. Especially peak forces, but also elongations, and AUC are sufficient parameters to describe differences in formulation properties while the slope of the curves have no beneficial correlations in terms of molecular weight and length of PLGA implants. Without the necessity of a complex method setup or converting measured parameters into tensile strengths, this method could be a simple alternative for the quality control of biodegradable implant formulations.
