Manufacturing and Examination of Vaginal Drug Delivery System by FDM 3D Printing
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.1.1. Used Polymer Filaments
2.1.2. Jellifying Agents
2.1.3. Model API’s
2.2. Methods
2.2.1. Design of the Drug Reservoirs and Printing of the Samples
2.2.2. Gel Formation and Sample Manufacturing
2.2.3. Weight Variation and Content Uniformity
2.2.4. Characterization
Thermogravimetric (TG) and Heatflow (DSC) Analysis
Contact Angle
Microcomputed Tomography (MicroCT)
2.2.5. In Vitro Dissolution Test
2.2.6. Biocompatibility Experiments
Cytotoxicity Experiments
- 1.
- Sterilization
- 2.
- Cell Culture
- 3.
- MTT Cell Viability Assay
- 4.
- Microbiological Evaluation
2.2.7. Statistical Analysis
3. Results
3.1. Design of the Drug Reservoirs and Printing of the Samples
3.2. Gel Formation and Sample Manufacturing
3.3. Weight Variation and Content Uniformity
3.4. Characterization
3.4.1. Thermogravimetric (TG) and Heatflow (DSC) Analysis
3.4.2. Contact Angle
3.4.3. Microcomputed Tomography (MicroCT)
3.5. In Vitro Dissolution Test
3.6. Biocompatibility Experiments
3.6.1. Cytotoxicity Experiments
3.6.2. Microbiological Evaluation
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
Appendix A
Sample | Chloramphenicol | Metronidazole | ||||||||||
2nd Formulation | 3rd Formulation | 4th Formulation | 2nd Formulation | 3rd Formulation | 4th Formulation | |||||||
Sampling Time (h) | Dissolved API (%) | ±SD | Dissolved API (%) | ±SD | Dissolved API (%) | ±SD | Dissolved API (%) | ±SD | Dissolved API (%) | ±SD | Dissolved API (%) | ±SD |
0 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
0.083 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.17 | 0.05 | 0.09 | 0.67 | 0.66 |
0.25 | 0.36 | 0.49 | 0.50 | 0.74 | 0.00 | 0.00 | 3.63 | 0.75 | 3.70 | 2.16 | 2.57 | 1.07 |
0.5 | 1.77 | 1.01 | 0.76 | 0.84 | 0.00 | 0.00 | 4.98 | 1.10 | 9.48 | 3.07 | 1.99 | 0.33 |
1 | 3.36 | 1.01 | 3.31 | 4.15 | 0.00 | 0.00 | 6.42 | 1.00 | 20.20 | 5.90 | 3.18 | 0.47 |
2 | 4.79 | 1.36 | 5.89 | 3.77 | 0.00 | 0.00 | 8.76 | 1.74 | 39.89 | 8.87 | 4.47 | 0.72 |
4 | 7.21 | 1.23 | 9.75 | 4.33 | 0.00 | 0.00 | 11.63 | 2.02 | 50.64 | 5.32 | 6.25 | 1.82 |
6 | 9.01 | 0.75 | 12.81 | 5.71 | 0.00 | 0.00 | 14.24 | 2.24 | 51.68 | 5.37 | 8.18 | 2.65 |
8 | 9.76 | 1.70 | 14.93 | 5.42 | 0.00 | 0.00 | 16.31 | 2.79 | 52.31 | 6.64 | 10.11 | 3.33 |
16 | 13.44 | 0.92 | 15.32 | 3.83 | 0.16 | 0.32 | 18.08 | 2.69 | 51.15 | 7.16 | 11.54 | 3.55 |
24 | 14.11 | 4.15 | 18.60 | 2.85 | 0.43 | 0.58 | 21.40 | 3.35 | 49.99 | 7.66 | 20.92 | 7.86 |
24.083 | 17.45 | 1.54 | 18.10 | 4.02 | 0.35 | 0.41 | 21.33 | 3.93 | 50.91 | 5.04 | 21.19 | 8.52 |
24.25 | 17.15 | 2.44 | 18.10 | 3.13 | 0.53 | 0.52 | 20.79 | 4.44 | 51.63 | 6.43 | 20.98 | 7.80 |
24.5 | 17.36 | 2.02 | 18.22 | 1.77 | 0.61 | 0.54 | 22.42 | 4.15 | 50.42 | 6.49 | 21.90 | 7.66 |
26 | 16.31 | 2.03 | 19.17 | 3.06 | 0.53 | 0.57 | 22.34 | 5.01 | 49.63 | 6.55 | 22.51 | 7.98 |
28 | 17.69 | 2.42 | 18.08 | 4.19 | 0.98 | 0.79 | 25.71 | 4.43 | 49.73 | 6.56 | 23.98 | 8.26 |
30 | 17.49 | 1.86 | 18.91 | 3.59 | 1.40 | 0.95 | 28.65 | 6.32 | 48.55 | 6.87 | 24.13 | 10.07 |
32 | 17.94 | 2.96 | 19.06 | 3.20 | 1.52 | 0.68 | 29.34 | 7.08 | 47.61 | 5.57 | 25.57 | 9.22 |
40 | 19.03 | 3.60 | 18.04 | 2.14 | 1.96 | 0.64 | 32.15 | 7.38 | 48.05 | 7.92 | 27.16 | 9.51 |
48 | 15.86 | 5.10 | 18.57 | 2.51 | 2.14 | 0.92 | 34.12 | 7.97 | 47.98 | 7.42 | 29.67 | 6.50 |
Appendix B
Pairwise Comparison of Dissolution Profiles | |||
Sample 1 vs. | Sample 2 | f1 | f2 (%) |
Chloramphenicol 2nd formulation | Chloramphenicol 3rd formulation | 13.32 | 76.07 |
Chloramphenicol 2nd formulation | Chloramphenicol 4th formulation | 2156.98 | 39.86 |
Chloramphenicol 2nd formulation | Metronidazole 2nd formulation | 35.74 | 50.57 |
Chloramphenicol 2nd formulation | Metronidazole 3rd formulation | 71.56 | 19.96 |
Chloramphenicol 2nd formulation | Metronidazole 4th formulation | 24.55 | 61.43 |
Chloramphenicol 3rd formulation | Chloramphenicol 4th formulation | 2434.11 | 37.36 |
Chloramphenicol 3rd formulation | Metronidazole 2nd formulation | 27.84 | 53.95 |
Chloramphenicol 3rd formulation | Metronidazole 3rd formulation | 68.07 | 21.20 |
Chloramphenicol 3rd formulation | Metronidazole 4th formulation | 24.88 | 63.33 |
Chloramphenicol 4th formulation | Metronidazole 2nd formulation | 97.15 | 30.20 |
Chloramphenicol 4th formulation | Metronidazole 3rd formulation | 98.74 | 13.00 |
Chloramphenicol 4th formulation | Metronidazole 4th formulation | 96.53 | 33.80 |
Metronidazole 2nd formulation | Metronidazole 3rd formulation | 55.75 | 24.62 |
Metronidazole 2nd formulation | Metronidazole 4th formulation | 22.79 | 62.45 |
Metronidazole 3rd formulation | Metronidazole 4th formulation | 176.28 | 21.99 |
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Properties | Method | PLA | PLA Gypsum | PLA Foam | TPU |
---|---|---|---|---|---|
Specific gravity (g/cm3) | D792 | 1.24 | 1.25 | 1.00 | 1.2 |
Heat distortion temperature at 0.45 MPa (°C) | D790 | 55 | 55 | 55 | 106 |
Glass Trans. temperature (°C) | D3418 | 55–60 | 55–60 | 55–60 | 150–230 |
Tensile strength (MPa) | ISO 527 | 60 | 54 | 53 | No break |
Tensile modulus (MPa) | ISO 527 | 3800 | 3200 | 6040 | No break |
Notched Izod impact (kJ/m2) | ISO 180 | 16 | 14 | 12 | No break |
Properties | Method | PLA | PLA Gypsum | PLA Foam | TPU |
---|---|---|---|---|---|
Tensile strength (MPa) | ISO 527 | 31.6 | 25.0 | 20.0 | No break |
Tensile modulus (GPa) | ISO 527 | 1.8 | 1.4 | 5.1 | No break |
Notched Izod impact (kJ/m2) | ISO 180 | 2.6 | 2.9 | 2.2 | No break |
Filament Type | PLA | PLA Gypsum | PLA Foam | TPU |
---|---|---|---|---|
Filament Diameter (mm) | 1.75 | 1.75 | 1.75 | 1.75 |
Extruder Nozzle Diameter (µm) | 400 | 400 | 400 | 400 |
Infill Percentage (%) | 0 | 0 | 0 | 0 |
Extrusion Temperature (°C) | 215 | 215 | 215 | 233 |
Bed Temperature (°C) | 60 | 60 | 60 | 65 |
Layer Thickness (µm) | 100 | 100 | 100 | 100 |
Sample | Weight | Content Uniformity | |||
---|---|---|---|---|---|
Average (g) | ±SD | Average (g) | ±SD | ||
2nd formulation | Chloramphenicol | 2.83 | 0.42 | 1.51 | 0.20 |
3rd formulation | 2.82 | 0.38 | 1.49 | 0.14 | |
4th formulation | 2.86 | 0.24 | 1.52 | 0.23 | |
2nd formulation | Metronidazole | 2.81 | 0.41 | 1.52 | 0.01 |
3rd formulation | 2.84 | 0.12 | 1.48 | 0.25 | |
4th formulation | 2.84 | 0.36 | 1.50 | 0.11 |
Sample | 2 h | 8 h | 48 h | ||||
---|---|---|---|---|---|---|---|
Dissolved API Amount (%) | ±SD | Dissolved API Amount (%) | ±SD | Dissolved API Amount (%) | ±SD | ||
Chloramphenicol | 2nd formulation | 4.79 | 1.36 | 9.76 | 1.70 | 15.86 | 5.10 |
3rd formulation | 5.89 | 3.77 | 14.93 | 5.42 | 18.57 | 2.51 | |
4th formulation | 0.00 | 0.00 | 0.00 | 0.00 | 2.14 | 0.92 | |
Metronidazole | 2nd formulation | 8.76 | 1.74 | 16.31 | 2.79 | 34.12 | 7.97 |
3rd formulation | 39.89 | 8.87 | 52.31 | 6.64 | 47.98 | 7.42 | |
4th formulation | 4.47 | 0.72 | 10.11 | 3.33 | 29.67 | 6.50 |
Sample | Zero-Order Kinetics | First-Order Kinetics | Zero-Order Kinetics | First-Order Kinetics | Zero-Order Kinetics | First-Order Kinetics | |
---|---|---|---|---|---|---|---|
0–48 h | 0–48 h | 0–8 h | 0–8 h | 8–48 h | 8–48 h | ||
Chloramphenicol | 2nd formulation | 0.808 | 0.806 | 0.922 | 0.925 | 0.177 | 0.176 |
3rd formulation | 0.730 | 0.726 | 0.967 | 0.971 | 0.215 | 0.214 | |
4th formulation | 0.765 | 0.763 | 0.000 | 0.000 | 0.870 | 0.871 | |
Metronidazole | 2nd formulation | 0.921 | 0.944 | 0.891 | 0.978 | 0.902 | 0.910 |
3rd formulation | 0.410 | 0.361 | 0.796 | 0.818 | 0.635 | 0.632 | |
4th formulation | 0.896 | 0.896 | 0.950 | 0.973 | 0.465 | 0.473 |
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Arany, P.; Papp, I.; Zichar, M.; Regdon, G., Jr.; Béres, M.; Szalóki, M.; Kovács, R.; Fehér, P.; Ujhelyi, Z.; Vecsernyés, M.; et al. Manufacturing and Examination of Vaginal Drug Delivery System by FDM 3D Printing. Pharmaceutics 2021, 13, 1714. https://doi.org/10.3390/pharmaceutics13101714
Arany P, Papp I, Zichar M, Regdon G Jr., Béres M, Szalóki M, Kovács R, Fehér P, Ujhelyi Z, Vecsernyés M, et al. Manufacturing and Examination of Vaginal Drug Delivery System by FDM 3D Printing. Pharmaceutics. 2021; 13(10):1714. https://doi.org/10.3390/pharmaceutics13101714
Chicago/Turabian StyleArany, Petra, Ildikó Papp, Marianna Zichar, Géza Regdon, Jr., Mónika Béres, Melinda Szalóki, Renátó Kovács, Pálma Fehér, Zoltán Ujhelyi, Miklós Vecsernyés, and et al. 2021. "Manufacturing and Examination of Vaginal Drug Delivery System by FDM 3D Printing" Pharmaceutics 13, no. 10: 1714. https://doi.org/10.3390/pharmaceutics13101714