BEPO®: Bioresorbable diblock mPEG-PDLLA and triblock PDLLA-PEG-PDLLA based in situ forming depots with flexible drug delivery kinetics modulation

Roberge, Christophe; Cros, Jean-Manuel; Serindoux, Juliette; Cagnon, Marie-Emérentienne; Samuel, Rémi; Vrlinič, Tjaša; Berto, Pierre; Rech, Anthony; Richard, J.; López-Noriega, Adolfo

doi:10.1016/j.jconrel.2020.01.022

Cited by 37 publications

(22 citation statements)

References 41 publications

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“…The injectable long-acting formulation of IVM was prepared by Medincell using their proprietary drug delivery platform BEPO Ò [23,37]. A diblock (PEG-PLA) and a triblock (PLA-PEG-PLA) bioresorbable copolymer were allowed to dissolve overnight in a biocompatible solvent, dimethyl sulfoxide (DMSO), with gentle mixing on a roller mixer at room temperature.…”

Section: Treatment Descriptionmentioning

confidence: 99%

Effects of an injectable long-acting formulation of ivermectin on Onchocerca ochengi in zebu cattle

Boussinesq

Enyong²,

Chounna-Ndongmo³

et al. 2020

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The availability of a safe macrofilaricidal drug would help to accelerate onchocerciasis elimination. A trial was conducted in Cameroon to evaluate the effects of a subcutaneous injectable long-acting formulation of ivermectin (LAFI) on the microfilariae (mf) and adult stages of Onchocerca ochengi. Ten zebu cattle naturally infected with the parasite were injected subcutaneously with either 500 mg (group A, N = 4), or 1000 mg long-acting ivermectin (group B, N = 4) or the vehicle (group C, N = 2). Skin samples were collected from each animal before, and 6, 12, and 24 months after treatment to measure microfilarial densities (MFDs). Nodules excised before, and 6 and 12 months after treatment were examined histologically to assess the adult worms’ viability and reproductive status. Blood samples were collected at pre-determined time-points to obtain pharmacokinetic data. Before treatment, the average O. ochengi MFDs were similar in the three groups. Six months after treatment, all animals in groups A and B were free of skin mf, whereas those in group C still showed high MFDs (mean = 324.5 mf/g). Only one ivermectin-treated animal (belonging to group A) had skin mf 12 months after treatment (0.9 mf/g). At 24 months, another animal in group A showed skin mf (10.0 mf/g). The histologic examination of nodules at 6 and 12 months showed that LAFI was not macrofilaricidal but had a strong effect on embryogenesis. The new LAFI regimen might be an additional tool to accelerate the elimination of human onchocerciasis in specific settings.

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Section: Treatment Descriptionmentioning

confidence: 99%

Effects of an injectable long-acting formulation of ivermectin on Onchocerca ochengi in zebu cattle

Boussinesq

Enyong²,

Chounna-Ndongmo³

et al. 2020

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“…Interestingly, it was observed that the solvent diffused very rapidly to the surrounding medium and that, additionally, the kinetics of release of DMSO were similar independently of the polymeric composition. These observations differ from the behavior noticed in ISFD LAI formulated with PEG-polyesters, where the solvent exchange timespan could be tuned with the utilization of copolymers with different PEG:polyester ratios [ 20 ]. This quick solvent exchange on (m)PEG–PTMC based injectables may be explained by the high hydrophobicity of the aliphatic polycarbonate chains, which forces the diffusion of the polar DMSO to the surrounding aqueous medium [ 32 ].…”

Section: Discussionmentioning

confidence: 72%

“…These tests were conceived since solvent-exchange-based ISFD technologies offer a wide range of tunable parameters to achieve diverse release profiles and kinetics. Hence, some of the studies described in this manuscript were designed to assess whether the utilization of different ratios of hydrophilic PEG and hydrophobic PTMC within (m)PEG:PTMC could be used as a way to tune the drug release kinetics, similarly to other amphiphilic-based controlled delivery systems [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…One way to overcome this limitation would be the utilization of polycarbonate-based copolymers with a hydrophilic block such as poly(ethylene glycol) (PEG). Similar to other copolymers such as PEG-polyesters, formulating with amphiphilic PEG–polycarbonate block copolymers would yield increased flexibility to ultimately achieve a wider range of delivery duration and kinetics; the hydrophilic:hydrophobic ratio within the copolymers would be an additional parameter to leverage in order to further adjust the final functionality of the drug product [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Poly(ethylene glycol)-b-poly(1,3-trimethylene carbonate) Copolymers for the Formulation of In Situ Forming Depot Long-Acting Injectables

et al. 2021

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This article describes the utilization of (methoxy)poly(ethylene glycol)-b-poly(1,3-trimethylene carbonate) ((m)PEG–PTMC) diblock and triblock copolymers for the formulation of in situ forming depot long-acting injectables by solvent exchange. The results shown in this manuscript demonstrate that it is possible to achieve long-term drug deliveries from suspension formulations prepared with these copolymers, with release durations up to several months in vitro. The utilization of copolymers with different PEG and PTMC molecular weights affords to modulate the release profile and duration. A pharmacokinetic study in rats with meloxicam confirmed the feasibility of achieving at least 28 days of sustained delivery by using this technology while showing good local tolerability in the subcutaneous environment. The characterization of the depots at the end of the in vivo study suggests that the rapid phase exchange upon administration and the surface erosion of the resulting depots are driving the delivery kinetics from suspension formulations. Due to the widely accepted utilization of meloxicam as an analgesic drug for animal care, the results shown in this article are of special interest for the development of veterinary products aiming at a very long-term sustained delivery of this therapeutic molecule.

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“…ISFI presents several significant advantages such as the avoidance of the first-pass metabolism, higher bioavailability for poorly water-soluble drugs, avoiding the escape of the treatment by the patients, which is especially relevant in indications where the lack of adherence to oral treatment may lead to incapacity and loss of autonomy [17][18][19]. Furthermore, ISFI utilizes bioresorbable polymers to control the drug release after parenteral administration.…”

Section: Introductionmentioning

confidence: 99%

Optimization and in Vitro Evaluation of Injectable Sustained-Release of Levothyroxine Using PLGA-PEG-PLGA

et al. 2020

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Purpose In situ-forming gels (semi-solid state) (ISFGs) are widely used as sustained drug delivery, but they show a high burst release as well. The purpose of the current study is to make triblock that can make a quick gel on injection with a minimum burst release. Methods In this study, to control the release of levothyroxine from ISFG, PLGA-PEG-PLGA (triblock) polymer was used. The melting method was employed to synthesize the triblock via ring-opening polymerization (ROP). Different weight percentages of triblock in the formulation were investigated to reach the minimum initial burst release of levothyroxine from ISFGs. Furthermore, the results of the in-situ forming implant (solid-state) (ISFI) of levothyroxine prepared from PLGA 504 H polymers were compared with ISFG. Results The melting method employed in this study showed a successful ROP of the triblock. As the % triblock concentration was increased from 30 to 50%, the initial burst release decreased significantly. The initial burst release levothyroxine from ISFG (6.52 ± 0.30%) was much lower than the amount of levothyroxine released from ISFI (14.15 ± 0.79%). No cytotoxicity was observed for the sustained-release formulation containing ISFG 50% according to the MTT assay. Conclusion The results indicated that this formulation was safe to be administered subcutaneously. As the synthesized triblock has thermosensitive properties, and also has the hydrogen bonding between the N-methyl pyrrolidone molecules and PEG, therefore, these properties make ISFG formulation to have a smaller initial burst release compared to ISFI formulation.

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BEPO®: Bioresorbable diblock mPEG-PDLLA and triblock PDLLA-PEG-PDLLA based in situ forming depots with flexible drug delivery kinetics modulation

Cited by 37 publications

References 41 publications

Effects of an injectable long-acting formulation of ivermectin on Onchocerca ochengi in zebu cattle

Effects of an injectable long-acting formulation of ivermectin on Onchocerca ochengi in zebu cattle

Poly(ethylene glycol)-b-poly(1,3-trimethylene carbonate) Copolymers for the Formulation of In Situ Forming Depot Long-Acting Injectables

Optimization and in Vitro Evaluation of Injectable Sustained-Release of Levothyroxine Using PLGA-PEG-PLGA

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