Formulation of sustained release lipid-based matrix system for vaginal delivery using the twin-screw hot-melt extrusion method

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The development of sustained-release formulations for vaginal delivery of certain drugs has a big potential toward the increase of the treatment efficiency and patient compliance. One of the possible strategies to formulate sustained release dosage form for vaginal delivery is the incorporation of sustained-release microparticles into the bio-adhesive gel. Objectives of this study were to assess the possibility to formulate matrix system microparticles for vaginal delivery using lipid-based excipient SyncrowaxTM HGLC and optionally Gelucire® 50/13 (G-50/13), Avicel® PH-101 (MCC) or hypromellose type K100M excipients. As model drugs for this purpose were chosen antiretroviral zidovudine (known as azidothymidine; AZT) and antimicrobial metronidazole (MTZ).
The mixture of C18-36 acid triglycerides (SyncrowaxTM HGLC; Croda Europe Ltd., UK). Stearoyl macrogol-32 glycerides which are comprising mono-, di- and triglycerides mixed with mono- and diesters of fatty acids (palmitic/C16 and stearic/C18) and polyethylene glycol (Gelucire® 50/13 (G-50/13); Gattefosse, France). Microcrystalline cellulose (MCC; Avicel® PH-101; FMC BioPolymer, USA). Hypromellose (HPMC) type K100M and K4M (Coloron, UK). Hard gelatine capsules size #3 with capsule body volume of 0.27 ml (Coni-Snap®; Capsugel, Belgium).
Ternary mixing diagram was used for the experimental design. Twin-screw hot melt extrusion (TS HME; Rondol 10mm twin-screw extruder with 2mm die; Rondol Industries SAS, France) and molten-liquid filling of hard gelatin capsules methods were used for the preparation of drug-loaded microparticles and placebo formulations, correspondently. Thermal methods as thermogravimetric analysis (TGA), differentiating scanning calorimetry (DSC) and polarized-light hot-stage microscopy (PLHSM) were used for investigation of thermal stability components and model drug dissolution in the excipients. Tensile strength determination, water uptake/ weight loss (WU/WL) test with electronic scanning microscopy (ESM) observation were used for screening purpose. The solubility of model drugs at biorelevant pH 4.5 was investigated using the shake-flask method and the sustained release potential of dug loaded microparticles was assessed with the dissolution test in the sodium acetate buffer at pH 4.5.
Tensile strength testing didn’t reduce the experimental space (Figure 1), while the placebo samples testing with WU/WL test allowed to reduce the experimental space with SyncrowaxTM HGLC not less than 80% w/w because of high weight loss kinetics of other formulations (Figure 2).
Figure 1. The effect of HGLC substitution with second excipient on the tensile strength of binary placebo formulations
Figure 2. Ternary diagram for investigated drug-loaded formulations.
Sustained release microparticles were successfully prepared with TS HME using conditions intended to minimize the effect on the model drug particle size reducing and to avoid the solid-state change of the drug. The possibility of AZT dissolution in Gelucire® 50/13 (Figure 3) and hypromellose, as well as MTZ dissolution in the hypromellose at the temperature range between 90 and 190℃, were established with the DSC method.
Figure 3. DSC-profiles of AZT with HGLC and G-50/13 (1:2:2) and MZT with HGLC and G-50/13 (1:2:2) in comparison with HGLC and G-50/13 (1:1).
Additionally, the development of the cracks during the cooling down of lipid-based formulations was detected with PLHSM (Figure 4).
Figure 4. The cracks appearance after heating up and cooling down until RT.
Drug release from microparticles was investigated as a function of drug loading and diluent type (Figure 5).
Figure 5. Effect of diluents on the drug release from HGLC matrix.
The number of drug-loaded experimental formulations in accordance with the ternary mixing diagram were successfully reduced due to the screening of placebo formulations with WU/WL test. Insoluble matrix system sustained-release microparticles for vaginal delivery based on the insoluble lipid SyncrowaxTM HGLC in the concentration not less than 80% (w/w) and loaded with model drugs AZT or MTZ was successfully prepared using the tween-screw hot melt extrusion method. The addition of diluents Avicel® PH-101 or hypromellose type K100M (at the 10% w/w level) can be used for the adjustment of drug release profile. The development of cracks in the SyncrowaxTM HGLC lipid matrix during the cooling down stage could be considered as an additional aspect of drug release facilitation.
Original languageEnglish
Number of pages2
Publication statusAccepted - 06 Feb 2020
Event12th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology - Vienna, Austria
Duration: 23 Mar 202026 Mar 2020


Conference12th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology
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