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Poly(lactic-co-glycolic acid) (PLGA) long-acting release depots are effective for extending the duration of action of peptide drugs. We describe efficient organic-solvent-free remote encapsulation based on the capacity of common uncapped PLGA to bind and absorb into the polymer phase net positively charged peptides from aqueous solution after short exposure at modest temperature. Leuprolide encapsulated by this approach in low-molecular-weight PLGA 75/25 microspheres slowly and continuously released peptide for over 56 days in vitro and suppressed testosterone production in rats in an equivalent manner as the 1-month Lupron Depot®. The technique is generalizable to encapsulate a number of net cationic peptides of various size, including octreotide, with competitive loading and encapsulation efficiencies to traditional methods. In certain cases, in vitro and in vivo performance of remote-loaded PLGA microspheres exceeded that relative to marketed products. Remote absorption encapsulation further removes the need for a critical organic solvent removal step after encapsulation, allowing for simple and cost-effective sterilization of the drug-free microspheres before encapsulation of the peptide. Encapsulation of bioactive peptides in slow-release particles is complex and relies on organic solvents. Here, the authors absorb peptides in a polymer phase from water, creating a simple low-cost encapsulation process in a class of polymer depot.

Most pharmaceuticals are given using short-acting formulations that require frequent administration, which can negatively affect patient compliance and increase failure risks associated with inconsistent use. By contrast, long-acting release formulations can achieve sustained release of drugs for weeks, months or years. In this Review, we discuss long-acting drug delivery formulations that release drugs for at least 1 month and that have received approval from the US Food and Drug Administration (FDA), with an emphasis on materials used in their formulation. We highlight different slow-release mechanisms, including dissolution-based, biodegradation-based (preformed and in situ-formed), non-degradable implantable and hydrogel-based formulations, and investigate the clinical applications of long-acting drug delivery formulations, including long-acting contraceptives, extended sex hormone suppression, opioid and alcohol addiction treatments and localized drug delivery to the eye. Finally, we summarize release mechanisms, delivery duration, pharmaceutical forms, administration routes, indications, manufacturers and inactive ingredients of 63 FDA-approved long-acting drug products. We conclude by looking at the future challenges and opportunities for long-acting drug delivery formulations. Long-acting drug delivery formulations enable sustained and prolonged drug release at the site of action or for systemic delivery, overcoming the need for frequent and repeated drug administration. This Review discusses US Food and Drug Administration (FDA)-approved long-acting drug delivery formulations, highlighting different slow-release mechanisms and delivery platforms, and the materials used to achieve them.

Purpose The acidic microclimate pH (µpH) distribution inside poly(lactic- co -glycolic acid) (PLGA) microspheres was monitored quantitatively as a function of several formulation variables. Methods A ratiometric method by confocal laser scanning microscopy with Lysosensor yellow/blue® dextran was adapted from those previously reported, and µpH distribution kinetics inside microspheres was examined during incubation under physiologic conditions for 4 weeks. Effects of PLGA molecular weight (MW) and lactic/glycolic acid ratio, microspheres size and preparation method, and polymer blending with poly(ethylene glycol) (PEG) were evaluated. Results µpH kinetics was accurately sensed over a broadly acidic range (2.8 < µpH < 5.8) and was more acidic and variable inside PLGA with lower MW and lactic/glycolic acid ratio. Lower µpH was found in larger microspheres of lower MW polymers, but size effects for lactic-rich polymers were insignificant during 4 weeks. Microspheres prepared by the oil-in-oil emulsion method were less acidic than those prepared by double emulsion, and blending PLGA 50/50 with 20% PEG increased µpH significantly (µpH > 5 throughout incubation). Conclusions Coupling this method with that previously developed (SNARF-1® dextran for µpH 5.8–8.0) should provide microclimate pH mapping over the entire useful pH range (2.8–8.0) for optimization of PLGA delivery of pH-sensitive bioactive substances.

Controlled release from biodegradable polymers is a novel approach to replace daily painful injections of protein drugs. A major obstacle to development of these polymers is the need to retain the structure and biological activity of encapsulated proteins during months of incubation under physiological conditions. We encapsulated bovine serum albumin (BSA) in injectable poly(DL-lactide- co -glycolide) (PLGA) 50/50 cylindrical implants and determined the mechanism of BSA instability. Simulations of the polymer microclimate revealed that moisture and acidic pH (<3) triggered unfolding of encapsulated BSA, resulting in peptide bond hydrolysis and noncovalent aggregation. To neutralize the acids liberated by the biodegradable lactic/glycolic acid-based polyester, we coincorporated into the polymer an antacid, Mg(OH) 2 , which increased microclimate pH and prevented BSA structural losses and aggregation for over one month. We successfully applied this stabilization approach in both cylinder- and microsphere-injectable configurations and for delivery of angiogenic basic fibroblast growth factor and bone-regenerating bone morphogenetic protein-2.

Women often have limited access to contraception, and barrier methods have low acceptance and a high failure rate, mostly due to incorrect use, which can result in unplanned pregnancies. Sustained-release formulations of contraceptive hormones are available, yet typically require their administration by trained personnel. Here, we report the design of a microneedle patch with rapidly separable biodegradable polylactic acid and polylactic-co-glycolic acid needles, and its application for the continuous release of levonorgestrel—a contraceptive hormone. Bubble structures between each microneedle and the patch backing allow the microneedles to efficiently penetrate skin under compression, and to snap off under shear within five seconds after patch administration. In rats, the microneedle patch was well tolerated, leaving little visible evidence of use, and maintained plasma concentrations of the hormone above the human therapeutic level for one month. Further development of the rapidly separable microneedle patch for self-administered, long-acting contraception could enable women to better control their fertility. A microneedle skin patch with rapidly separable, biodegradable polymer needles continuously releases the contraceptive levonorgestrel for over one month in rats.

Challenges to discovery and preclinical development of long‐acting release systems for protein therapeutics include protein instability, use of organic solvents during encapsulation, specialized equipment and personnel, and high costs of proteins. We sought to overcome these issues by combining remote‐loading self‐healing encapsulation with binding HisTag protein to transition metal ions. Porous, drug‐free self‐healing microspheres of copolymers of lactic and glycolic acids with high molecular weight dextran sulfate and immobilized divalent transition metal (M2+) ions were placed in the presence of proteins with or without HisTags to bind the protein in the pores of the polymer before healing the surface pores with modest temperature. Using human serum albumin, insulin‐like growth factor 1, and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), encapsulated efficiencies of immunoreactive protein relative to nonencapsulation protein solutions increased from ~41%, ~23%, and ~9%, respectively, without Zn2+ and HisTags to ~100%, ~83%, and ~75% with Zn2+ and HisTags. These three proteins were continuously released in immunoreactive form over seven to ten weeks to 73%–100% complete release, and GM‐CSF showed bioactivity >95% relative to immunoreactive protein throughout the release interval. Increased encapsulation efficiencies were also found with other divalent transition metals ions (Co2+, Cu2+, Ni2+, and Zn2+), but not with Ca2+. Ethylenediaminetetraacetic acid was found to interfere with this process, reverting encapsulation efficiency back to Zn2+‐free levels. These results indicate that M2+‐immobilized self‐healing microspheres can be prepared for simple and efficient encapsulation by simple mixing in aqueous solutions. These formulations provide slow and continuous release of immunoreactive proteins of diverse types by using a amount of protein (e.g., <10 μg), which may be highly useful in the discovery and early preclinical development phase of new protein active pharmaceutical ingredients, allowing for improved translation to further development of potent proteins for local delivery.

The acidic microclimate in poly(D, L-lactide-co-glycolide) 50/50 microspheres has been previously demonstrated by our group as the primary instability source of encapsulated bovine serum albumin (BSA). The objectives of this study were to stabilize the encapsulated model protein, BSA, and to achieve continuous protein release by using a blend of: slowly degrading poly(D, L-lactide) (PLA), to reduce the production of acidic species during BSA release; and pore-forming poly(ethylene glycol) (PEG), to increase diffusion of BSA and polymer degradation products out of the polymer. Microspheres were formulated from blends of PLA (Mw 145,000) and PEG (Mw 10,000 or 35,000) by using an anhydrous oil-in-oil emulsion and solvent extraction (O/O) method. The polymer blend composition and phase miscibility were examined by FTIR and DSC, respectively. Microsphere surface morphology, water uptake, and BSA release kinetics were also investigated. The stability of BSA encapsulated in microspheres was examined by losses in protein solubility, SDS-PAGE, IEF, CD, and fluorescence spectroscopy, PEG was successfully incorporated in PLA microspheres and shown to possess partial miscibility with PLA. A protein loading level of 5% (w/w) was attained in PLA/PEG microspheres with a mean diameter of approximately 100 microm. When PEG content was less than 20% in the blend, incomplete release of BSA was observed with the formation of insoluble, and primarily non-covalent aggregates. When 20%-30% PEG was incorporated in the blend formulation, in vitro continuous protein release over 29 days was exhibited. Unreleased BSA in these formulations was water-soluble and structurally intact. Stabilization and controlled relaease of BSA from PLA/PEG microspheres was achieved due to low acid and high water content in the blend formulation.

Remote loading microencapsulation of peptides into polymer microspheres without organic solvent represents a promising alternative to develop long-acting release depots relative to conventional encapsulation methods. Here, we formulated drug-free microspheres from two kinds of uncapped poly(lactide-co-glycolides) (PLGAs), i.e., ring-opening polymerized Expansorb ® DLG 50-2A (50/50, 11.2 kDa) and Expansorb ® DLG 75-2A (75/25, 9.0 kDa), and evaluated their potential capacity to remote-load and control the release of two model peptides, leuprolide and octreotide. Degradation and erosion kinetics, release mechanism, and storage stability was also assessed. As control formulations, peptide was loaded in the same PLGA 75/25 polymer by the conventional double emulsion-solvent evaporation method (W/O/W) and remote loaded in polycondensation poly(lactic-co-glycolic acid) 75/25 (Wako 7515, 14.3 kDa). Loading content of 6.7%–8.9% w/w (~ 67%–89% encapsulation efficiency (EE)) was attained for octreotide, and that of 9.5% w/w loading (~ 95% EE) was observed for leuprolide, by the remote loading paradigm. Octreotide and leuprolide were both slowly and continuously released in vitro from the remote-loaded Expansorb ® DLG 75-2A MPs for over 56 days, which was highly similar to that observed from traditionally-loaded formulations by W/O/W (8.8% loading, 52.8% EE). The faster release kinetics was observed for the faster degrading PLGA 50/50 remote-loaded Expansorb ® DLG 50-2A MPs relative to microspheres from the PLGA 75/25 Expansorb ® DLG 75-2A. Despite slight differences in degradation kinetics, the release mechanism of octreotide from the Expansorb ® microspheres, whether remote loaded or by W/O/W, was identical as determined by release vs. mass loss curves. Octreotide acylation was also minimal (< ~ 10%) for this polymer. Finally, drug-free Expansorb ® DLG 75-2A MPs displayed excellent storage stability over 3 months. Overall, this work offers support for the use of ring-opening Expansorb ® PLGA-based microspheres to remote load peptides to create simple and effective long-acting release depots. Graphical Abstract

Copolymers of lactic (or lactide) and glycolic (or glycolide) acids (PLGAs) are among the most commonly used materials in biomedical applications, such as parenteral controlled drug delivery, due to their biocompatibility, predictable degradation rate, and ease of processing. Besides manufacturing variables of drug delivery vehicles, changes in PLGA raw material properties can affect product behavior. Accordingly, an in-depth understanding of polymer-related “critical quality attributes” can improve selection and predictability of PLGA performance. Here, we selected 19 different PLGAs from five manufacturers to form drug-free films, submillimeter implants, and microspheres and evaluated differences in their water uptake, degradation, and erosion during in vitro incubation as a function of L/G ratio, polymerization method, molecular weight, end-capping, and geometry. Uncapped PLGA 50/50 films from different manufacturers with similar molecular weights and higher glycolic unit blockiness and/or block length values showed faster initial degradation rates. Geometrically, larger implants of 75/25, uncapped PLGA showed higher water uptake and faster degradation rates in the first week compared to microspheres of the same polymers, likely due to enhanced effects of acid-catalyzed degradation from PLGA acidic byproducts unable to escape as efficiently from larger geometries. Manufacturer differences such as increased residual monomer appeared to increase water uptake and degradation in uncapped 50/50 PLGA films and poly(lactide) implants. This dataset of different polymer manufacturers could be useful in selecting desired PLGAs for controlled release applications or comparing differences in behavior during product development, and these techniques to further compare differences in less reported properties such as sequence distribution may be useful for future analyses of PLGA performance in drug delivery. Graphical abstract

Structural and functional differences between REMICADE and its two FDA-approved biosimilars appear to have clinical implications. We suggest a personalized biosimilar substitution approach based on prescribed indication, biosimilar afucosylation level, and a patient’s FCGR3A polymorphism. We also advocate for establishing glycosylation variation limits for biosimilar approvals.