In vitro degradation and erosion behavior of commercial PLGAs used for controlled drug delivery

Walker, Jennifer L.; Albert, Jason; Liang, Desheng; Sun, Jing; Schutzman, Richard; Kumar, Raj; White, Cameron; Beck-Broichsitter, Moritz; Schwendeman, Steven P.

doi:10.1007/s13346-022-01177-8

Cited by 19 publications

(7 citation statements)

References 48 publications

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“…The total residual monomer was notably higher in the Akina polymers compared with the Evonik polymers. However, all samples had a total residual monomer content of ≤0.5%, in line with the total residual monomer content of other commercially available 50:50 PLGAs …”

Section: Resultssupporting

confidence: 74%

Role of PLGA Variability in Controlled Drug Release from Dexamethasone Intravitreal Implants

Costello,

Liu,

Kuehster

et al. 2023

Mol. Pharmaceutics

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Long-acting injectable formulations based on poly-(lactide-co-glycolide) (PLGA) have been commercialized for over 30 years in at least 20 FDA-approved products. These formulations offer several advantages, including reduced dosing frequency, improved patient compliance, and maintenance of therapeutic levels of drug. Despite extensive studies, the inherent complexity of the PLGA copolymer still poses significant challenges associated with the development of generic formulations having drug release profiles equivalent to those of the reference listed drugs. In addition, small changes to PLGA physicochemical properties or the drug product manufacturing process can have a major impact on the drug release profile of these long-acting formulations. This work seeks to better understand how variability in the physicochemical properties of similar PLGAs affects drug release from PLGA solid implants using Ozurdex (dexamethasone intravitreal implant) as the model system. Four 50:50, acid-terminated PLGAs of similar molecular weights were used to prepare four dexamethasone intravitreal implants structurally equivalent to Ozurdex. The PLGAs were extensively characterized by using a variety of analytical techniques prior to implant manufacture using a continuous, hot-melt extrusion process. In vitro release testing of the four structurally equivalent implants was performed in both normal saline and phosphate-buffered saline (PBS), yielding drastically different results between the two methods. In normal saline, no differences in the release profiles were observed. In PBS, the drug release profiles were sensitive to small changes in the residual monomer content, carboxylic acid end group content, and blockiness of the polymers. This finding further underscores the need for a physiologically relevant in vitro release testing method as part of a robust quality control strategy for PLGA-based solid implant formulations.

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Section: Resultssupporting

confidence: 74%

Role of PLGA Variability in Controlled Drug Release from Dexamethasone Intravitreal Implants

Costello,

Liu,

Kuehster

et al. 2023

Mol. Pharmaceutics

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“…However, a complete degradation of PLGA was observed at a LA/GA ratio of 1.8 to 2. The continuous increase in the LA/GA ratio suggests the preferential hydrolytic cleavage of glycolic acid block within the PLGA matrix, which is due to the higher affinity of water molecules to the hydrophilic nature of GA . Thus, the rate of PLGA degradation was found to be in agreement with the rate of change in the LA/GA ratio.…”

Section: Resultsmentioning

confidence: 71%

“…In the case of the 502H formulation, a continuous influx of water in the PLGA implant (owing to the hydrophilic nature of the acid-terminated PLGA) results in the hydrolytic degradation of PLGA. This allows the formation of nano-/microchannels, which is required to diffuse out the dissolved DM and degradation products of PLGA in a sustained manner. − However, in the case of 502 formulations, due to the hydrophobic nature, a limited amount of water (entered from 1 to 21 d) entered within the PLGA matrix (Figure ). The limited water content in the 502 formulations could be sufficient to initiate the autocatalytic PLGA degradation, however, insufficient to develop nano-/microchannels.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, up to 21 d, the dissolved DM (in supersaturated conditions) and degraded PLGA products in the core of the implant could have created a sufficient osmotic pressure gradient across the PLGA implant, resulting in the collapse of the PLGA backbone (accompanied by a significant increase in water uptake, Figure 9). 36,40 Interestingly, after 21 d, in spite of the PLGA collapse, a marginal DM release was observed, which could be due to the precipitation of supersaturated drug or/followed by the encapsulation of precipitated/crystalline DM via the remaining hydrophobic PLGA. Interestingly, a complete DM release (or release to the level of DM saturation) was observed, when more than ∼80% w/w PLGA was degraded (38 d for 502 and 42 d for 502H and 502H:502 (3:1) formulations), suggesting at least 20% w/w PLGA is required to limit the dose dumping from 40% w/w DM-loaded PLGA formulations.…”

Section: H-qnmr Studies Formentioning

confidence: 99%

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

et al. 2023

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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 endcapped 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 quantitative 1 H 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 °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 μCT, 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.

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“…Polymeric nanoparticles also share advantages such as an increment in drug stability and a slow and steady release of drugs into the lungs and mucosal system. In clinical applications, cationic lipid nanoparticles have more advantages over polymeric nanoparticles, but the application of cationic polymeric nanoparticles in drug delivery to the lungs cannot be discarded [ 119 , 120 , 121 ].…”

Section: Application Of Nanotechnology In Covid-19 Therapeuticsmentioning

confidence: 99%

Aspects of Nanotechnology for COVID-19 Vaccine Development and Its Delivery Applications

et al. 2023

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Coronavirus, a causative agent of the common cold to a much more complicated disease such as “severe acute respiratory syndrome (SARS-CoV-2), Middle East Respiratory Syndrome (MERS-CoV-2), and Coronavirus Disease 2019 (COVID-19)”, is a member of the coronaviridae family and contains a positive-sense single-stranded RNA of 26–32 kilobase pairs. COVID-19 has shown very high mortality and morbidity and imparted a significantly impacted socioeconomic status. There are many variants of SARS-CoV-2 that have originated from the mutation of the genetic material of the original coronavirus. This has raised the demand for efficient treatment/therapy to manage newly emerged SARS-CoV-2 infections successfully. However, different types of vaccines have been developed and administered to patients but need more attention because COVID-19 is not under complete control. In this article, currently developed nanotechnology-based vaccines are explored, such as inactivated virus vaccines, mRNA-based vaccines, DNA-based vaccines, S-protein-based vaccines, virus-vectored vaccines, etc. One of the important aspects of vaccines is their administration inside the host body wherein nanotechnology can play a very crucial role. Currently, more than 26 nanotechnology-based COVID-19 vaccine candidates are in various phases of clinical trials. Nanotechnology is one of the growing fields in drug discovery and drug delivery that can also be used for the tackling of coronavirus. Nanotechnology can be used in various ways to design and develop tools and strategies for detection, diagnosis, and therapeutic and vaccine development to protect against COVID-19. The design of instruments for speedy, precise, and sensitive diagnosis, the fabrication of potent sanitizers, the delivery of extracellular antigenic components or mRNA-based vaccines into human tissues, and the administration of antiretroviral medicines into the organism are nanotechnology-based strategies for COVID-19 management. Herein, we discuss the application of nanotechnology in COVID-19 vaccine development and the challenges and opportunities in this approach.

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In vitro degradation and erosion behavior of commercial PLGAs used for controlled drug delivery

Cited by 19 publications

References 48 publications

Role of PLGA Variability in Controlled Drug Release from Dexamethasone Intravitreal Implants

Role of PLGA Variability in Controlled Drug Release from Dexamethasone Intravitreal Implants

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

Aspects of Nanotechnology for COVID-19 Vaccine Development and Its Delivery Applications

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