Effects of Drug Physicochemical Properties on In-Situ Forming Implant Polymer Degradation and Drug Release Kinetics

Joiner, Jordan B.; Prasher, Alka; Young, Isabella C.; Kim, Jessie; Shrivastava, Roopali; Maturavongsadit, Panita; Benhabbour, S. Rahima

doi:10.3390/pharmaceutics14061188

Cited by 22 publications

(13 citation statements)

References 34 publications

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“…During optimization and building on our prior work, all CAB ISFI formulations were generated using an FDA-approved biodegradable polymer consisting of 50:50 PLGA, which enables ultra-long release of antiretrovirals from ISFIs 20,21,29 and has a favorable degradation profile including eliciting complete degradation within a few months 30,31 . This degradation profile is ideal to ensure complete polymer degradation prior to subsequent ISFI injections to prevent polymer accumulation.…”

Section: Optimization Of Cab Isfi and In Vitro Drug Releasementioning

confidence: 99%

“…Implant microstructures were evaluated by scanning electron microscopy (SEM) as previously described 20,30 . In brief, to assess the microstructure of in vitro ISFIs, 30 ± 3 mg of ISFI solution or suspension was injected into 200 mL of 0.01 M PBS, pH 7.4 with 2% Solutol at 37 °C.…”

Section: Scanning Electron Microscopy (Sem) Imaging and Sem Energy Di...mentioning

confidence: 99%

“…GPC was performed as previously described 30 . In brief, GPC was utilized to evaluate polymer degradation of placebo ISFIs post-storage as well as polymer degradation in CAB ISFIs that were retrieved 30-, 60-, and 90-days post-injection from BALB/c mice.…”

Section: Gel Permeation Chromatography (Gpc)mentioning

confidence: 99%

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Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection

et al. 2023

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Ultra-long-acting delivery platforms for HIV pre-exposure prophylaxis (PrEP) may increase adherence and maximize public health benefit. We report on an injectable, biodegradable, and removable in-situ forming implant (ISFI) that is administered subcutaneously and can release the integrase inhibitor cabotegravir (CAB) above protective benchmarks for more than 6 months. CAB ISFIs are well-tolerated in female mice and female macaques showing no signs of toxicity or chronic inflammation. In macaques, median plasma CAB concentrations exceed established PrEP protection benchmarks within 3 weeks and confer complete protection against repeated rectal SHIV challenges. Implant removal via a small incision in 2 macaques at week 12 results in a 7- to 48-fold decrease in plasma CAB levels within 72 hours. Modeling to translate CAB ISFI dosing suggests that a 3 mL injection would exceed protective benchmarks in humans for over 5 months post administration. Our results support the clinical advancement of CAB ISFIs for ultra-long-acting PrEP in humans.

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Section: Optimization Of Cab Isfi and In Vitro Drug Releasementioning

confidence: 99%

Section: Scanning Electron Microscopy (Sem) Imaging and Sem Energy Di...mentioning

confidence: 99%

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Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection

et al. 2023

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“…Meanwhile, the case II transport is dominant when the relaxation process is very slow compared with the diffusion [66]. Normally, hydrophilic drugs liberate much more rapidly than hydrophobic drugs, particularly at the initial time with burst release while the ISG is still solidifying [67]. Nevertheless, gradual drug release was achieved from these zein-based ISGs without burst release.…”

Section: Drug Content and In Vitro Drug Release Studymentioning

confidence: 99%

Levofloxacin HCl-Incorporated Zein-Based Solvent Removal Phase Inversion In Situ Forming Gel for Periodontitis Treatment

et al. 2023

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Zein is composed of nonpolar amino acids and is a water-insoluble protein used as the matrix-forming agent of localized in situ forming gel (ISG). Therefore, this study prepared solvent removal phase inversion zein-based ISG formulations to load levofloxacin HCl (Lv) for periodontitis treatment using dimethyl sulfoxide (DMSO) and glycerol formal (GF) as the solvents. Their physicochemical properties were determined, including viscosity, injectability, gel formation, and drug release. The topography of dried remnants after drug release was revealed using a scanning electron microscope and X-ray computed microtomography (μCT) to investigate their 3D structure and % porosity. The antimicrobial activities were tested against Staphylococcus aureus (ATCC 6538), Escherichia coli ATCC 8739, Candida albicans ATCC 10231, and Porphyromonas gingivalis ATCC 33277 with agar cup diffusion. Increasing zein concentration or using GF as the solvent notably enhanced the apparent viscosity and injection force of the zein ISG. However, its gel formation slowed due to the dense zein matrix barrier’s solvent exchange: the higher loaded zein or utilization of GF as an ISG solvent prolonged Lv release. The SEM and μCT images revealed the scaffold of dried ISG in that their % porosity corresponded with their phase transformation and drug release behavior. In addition, the sustainability of drug diffusion promoted a smaller antimicrobial inhibition clear zone. Drug release from all formulations was attained with minimum inhibitory concentrations against pathogen microbes and exhibited a controlled release over 7 days. Lv-loaded 20% zein ISG using GF as a solvent exhibited appropriate viscosity, Newtonian flow, acceptable gel formation and injectability, and prolonged Lv release over 7 days with efficient antimicrobial activities against various test microbes; thus, it is the potential ISG formulation for periodontitis treatment. Consequently, the Lv-loaded solvent removal zein-based ISGs proposed in this investigation offer promising potential as an efficacious drug delivery system for periodontitis treatment by local injection.

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“…Furthermore, implants in general tend to be more susceptible to local inflammation when compared to injectable alternatives. 19,20 Conventional injectable platforms such as microparticles, and in situ-forming implants (ISFI) have been documented to achieve prolonged release of hydrophobic drugs but have poor ability to achieve similar long-term release of hydrophilic drugs [21][22][23][24] . In the case of ISFI, which typically consist of a hydrophobic polymer, poly(lactic-co-glycolic acid) (PLGA) dissolved in N-methyl-2-pyrrolidone (NMP), efflux of the solvent during phase conversion tends to release a significant amount of drug as initial burst, which increases with the hydrophilicity of the drug.…”

Section: Introductionmentioning

confidence: 99%

An injectable in situ crosslinkable platform for ultra-long-acting delivery of hydrophilic therapeutics

Lee,

Zhao,

Chen

et al. 2023

Preprint

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Although hydrophilic drugs represent a large proportion of all therapeutics used to treat and manage chronic diseases, achieving their ultra-long-term delivery via an injectable system remains a major challenge. Implants have demonstrated potential for long-term delivery of both hydrophobic and hydrophilic drugs; however, they require invasive insertion process in a sterile setting, which restricts their suitability for resource-limited settings. Furthermore, implants tend to be more susceptible to local inflammation when compared to injectable alternatives. Here we report a solvent free, injectable, biodegradable, and in situ crosslinking depot (ISCD) platform for ultra-long term release of hydrophilic drugs. ISCD consists of a low molecular weight liquid pre-polymer methacrylated polycaprolactone (PCL). Both hydrophilic and hydrophobic drugs can be suspended/dissolved in the liquid polymer, and when injected along with a radical initiator and an accelerator, the polymer crosslinksin situ, resulting in a solid monolithic and degradable depot, integrating the unique advantages of injectability and retrievability. Low molecular weight PCL forms a dense mesh, which limits water influx/efflux and hence reduces the drug release. Liquid state of the polymer obviates the need for solvent, minimizing initial burst release due to the solvent exchange process, as observed within situforming implants. Drug release and ISCD degradation can be tailored by modifying their polymer network via altering the concentration of accelerator and initiator, molecular weight of methacrylated PCL, or by incorporation of a hydrophilic polymer or a non-crosslinking polymer. We demonstrated sustained release of seven hydrophilic drugs with varying solubility or drug combinations for over seven monthsin vitro. Ultra-long term drug release and depot degradation was also demonstrated in rats for at least six months without any evidence of local inflammation or fibrosis. Excitingly, the platform also enabled ultra-long term release of a model hydrophobic drug – tacrolimus for at least six months. To the best of our knowledge, this marks the first successful demonstration of an ultra-long term delivery of hydrophilic drugs using an injectable formulation. This platform holds promise for developing ultra-long acting therapies across a wide range of diseases.

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Effects of Drug Physicochemical Properties on In-Situ Forming Implant Polymer Degradation and Drug Release Kinetics

Cited by 22 publications

References 34 publications

Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection

Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection

Levofloxacin HCl-Incorporated Zein-Based Solvent Removal Phase Inversion In Situ Forming Gel for Periodontitis Treatment

An injectable in situ crosslinkable platform for ultra-long-acting delivery of hydrophilic therapeutics

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