Influence of PLGA End Groups on the Release Profile of Dexamethasone from Ocular Implants

被引：12

作者：

Saraf, Isha ^{[1
]}

Kushwah, Varun ^{[1
]}

Alva, Carolina ^{[1
]}

Koutsamanis, Ioannis ^{[1
]}

Rattenberger, Johannes ^{[2
]}

Schroettner, Hartmuth ^{[2
,6
]}

Mayrhofer, Claudia ^{[2
]}

Modhave, Dattatray ^{[1
,5
]}

Braun, Michael ^{[4
]}

Werner, Bernd ^{[3
]}

Zangger, Klaus ^{[3
]}

Paudel, Amrit ^{[1
,7
]}

机构：

[1] Res Ctr Pharmaceut Engn, A-8010 Graz, Austria

[2] Graz Ctr Electron Microscopy ZFE, A-8010 Graz, Austria

[3] Karl Franzens Univ Graz, Inst Chem, A-8010 Graz, Austria

[4] Boehringer Ingelheim Pharm GmbH & Co KG, Pharmaceut Dev, D-88397 Biberach, Germany

[5] Galapagos NV, B-2800 Mechelen, Belgium

[6] Graz Univ Technol, Inst Electron Microscopy & Nanoanal FELMI, NAWI Graz, A-8010 Graz, Austria

[7] Graz Univ Technol, Inst Proc & Particle Engn, A-8010 Graz, Austria

来源：

MOLECULAR PHARMACEUTICS | 2023年

关键词：

PLGA; PLGA end capping; dexamethasone; in vitro long-term release; digital release profile; N?hot melt extrusion; intravitreal implant; INTRAVITREAL IMPLANT; POLY(LACTIDE-CO-GLYCOLIDE) PLGA; HYDROLYTIC DEGRADATION; MICROCLIMATE PH; MACULAR EDEMA; IN-VIVO; MICROSPHERES; ACID); FORMULATION; GENTAMICIN;

D O I：

10.1021/acs.molpharmaceut.2c00945

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

The present study deals with the development of dexamethasone (DM)-loaded implants using ester end-capped Resomer RG 502 poly(lactic acid-co-glycolic acid) (PLGA) (502), acid end-capped Resomer RG 502H PLGA (502H), and a 502H:502 mixture (3:1) via hot melt extrusion (HME). The prepared intravitreal implants (20 and 40% DM loaded in each PLGA) were thoroughly investigated to determine the effect of different end-capped PLGA and drug loading on the long-term release profile of DM. The implants were characterized for solid-state active pharmaceutical ingredient (APIs) using DSC and SWAXS, water uptake during stability study, the crystal size of API in the implant matrix using hot-stage polarized light microscopy, and in vitro release profile. The kinetics of PLGA release was thoroughly investigated using quantitative1H NMR spectroscopy. The polymorph of DM crystal was found to remain unchanged after the extrusion and stability study. However, around 3 times reduction in API particle size was observed after the HME process. The morphology and content uniformity of the RT-stored samples were found to be comparable to the initial implant samples. Interestingly, the samples (mainly 502H) stored at 40 degrees C and 75% RH for 30 d demonstrated marked deformation and a change in content uniformity. The rate of DM release was higher in the case of 502H samples with a higher drug loading (40% w/w). Furthermore, a simple digital in vitro DM release profile derived for the formulation containing a 3:1 ratio of 502H and 502 was comparable with the experimental release profile of the respective polymer mixture formulation. The temporal development of pores and/or voids in the course of drug dissolution, evaluated using mu CT, was found to be a precursor for the PLGA release. Overall, the release profile of DM was found to be dependent on the PLGA type (independent of subtle changes in the formulation mass and diameter). However, the extent of release was found to be dependent on DM loading. Thus, the present investigation led to a thorough understanding of the physicochemical properties of different end-capped PLGAs and the underlying formulation microstructure on the release profile of a crystalline water-insoluble drug, DM, from the PLGA-based implant.

引用

页码：1307 / 1322

页数：16

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