A review of existing strategies for designing long-acting parenteral formulations: Focus on underlying mechanisms, and future perspectives

Abstract

The need for long-term treatments of chronic diseases has motivated the widespread development of long-acting parenteral formulations (LAPFs) with the aim of improving drug pharmacokinetics and therapeutic efficacy. LAPFs have been proven to extend the half-life of therapeutics, as well as to improve patient adherence; consequently, this enhances the outcome of therapy positively. Over past decades, considerable progress has been made in designing effective LAPFs in both preclinical and clinical settings. Here we review the latest advances of LAPFs in preclinical and clinical stages, focusing on the strategies and underlying mechanisms for achieving long acting. Existing strategies are classified into manipulation of in vivo clearance and manipulation of drug release from delivery systems, respectively. And the current challenges and prospects of each strategy are discussed. In addition, we also briefly discuss the design principles of LAPFs and provide future perspectives of the rational design of more effective LAPFs for their further clinical translation.

Keywords: 2′-F, 2′-fluoro; 2′-O-MOE, 2′-O-(2-methoxyethyl); 2′-OMe, 2′-O-methyl; 3D, three-dimensional; ART, antiretroviral therapy; ASO, antisense oligonucleotide; Biomimetic strategies; Chemical modification; DDS, drug delivery systems; ECM, extracellular matrix; ENA, ethylene-bridged nucleic acid; ESC, enhanced stabilization chemistry; EVA, ethylene vinyl acetate; Fc/HSA fusion; FcRn, Fc receptor; GLP-1, glucagon like peptide-1; GS, glycine–serine; HA, hyaluronic acid; HES, hydroxy-ethyl-starch; HP, hypoparathyroidism; HSA, human serum albumin; Hydrogels; ISFI, in situ forming implants; IgG, immunoglobulin G; Implantable systems; LAFs, long-acting formulations; LAPFs, long-acting parenteral formulations; LNA, locked nucleic acid; Long-acting; MNs, microneedles; Microneedles; NDS, nanochannel delivery system; NPs, nanoparticles; Nanocrystal suspensions; OA, osteoarthritis; PCPP-SA, poly(1,3-bis(carboxyphenoxy)propane-co-sebacic-acid); PEG, polyethylene glycol; PM, platelet membrane; PMPC, poly(2-methyacryloyloxyethyl phosphorylcholine); PNAs, peptide nucleic acids; PS, phase separation; PSA, polysialic acid; PTH, parathyroid hormone; PVA, polyvinyl alcohol; RBCs, red blood cells; RES, reticuloendothelial system; RNAi, RNA interference; SAR, structure‒activity relationship; SCID, severe combined immunodeficiency; SE, solvent extraction; STC, standard template chemistry; TNFR2, tumor necrosis factor receptor 2; hGH, human growth hormone; im, intramuscular; iv, intravenous; mPEG, methoxypolyethylene glycol; sc, subcutaneous.

Graphical abstract

Figure 1

Strategies for long-acting parenteral formulations. (A) Chemical modification. (B) Fc/HSA fusion. (C) Cell-mediated biomimetic strategies. (D) Micro-encapsulation. (E) DepoFoamTM technology. (F) Oil-based formulation. (G) NanoCrystal technology. (H) Biomineralization. (I) Long-acting hydrogels. (J) Long-acting microneedles. (K) Long-acting implantable systems.

Figure 2

TransConTM technology platform. (A) TransCon molecules consist of three components: a therapeutic drug, a protective carrier and a cleavable linker, which is used to temporarily bind the above two parts. The protective carrier has the ability to inactivate and shield the therapeutic drug and the cleavable linker is designed to achieve the predictable release of active parent drug under a specific physiological environment. (B) The structure of TransCon PTH and the mechanism of drug release. Reproduced with the permission from Ref. 33. Copyright © 2017 Oxford University Press.

Figure 3

Structures of common chemical modifications of nucleic acid. (A) The structure of natural nucleic acid. (B) The structures of phosphate backbone modifications. (C) The structures of sugar modifications.

Figure 4

The structures of a series of Fc fusion proteins. (A) The structure of (drug-Fc)₂. (B) The structure of drug-Fc₂. (C) The structure of drug-sc(Fc)₂. Reproduced with the permission from Ref. 64. Copyright © 2017 Elsevier.

Figure 5

The strategies of RBC-hitchhiking and membrane engineering. (A) The strategy of RBC-hitchhiking. Reproduced with the permission from Ref. 82. Copyright © 2013 American Chemical Society. (B) The membrane of RBCs is used to form camouflaged NPs. Reproduced with the permission from Ref. 84. Copyright © 2011 National Academy of Sciences. (C) The platelet membrane (PM) is extracted from the blood and then used to form PM-modified NPs. Reproduced with the permission from Ref. 88. Copyright © 2015 John Wiley and Sons.

Figure 6

The structures of a series of liposomes. (A) The structure of monolayer and multilayer liposome. (B) The structure of multivesicular liposome. Reproduced with the permission from Ref. 101. Copyright © 2002 Elsevier.

Figure 7

The preparation process and the mechanism of long-acting nanocrystals. This strategy is suitable for drugs/prodrugs with a low solubility in water. The manufacturing of nanocrystals can be achieved by milling or high-pressure homogenization. The long-term effect of the suspension of nanocrystalline is mainly achieved by the following two ways: (A) after im/sc administration, a primary depot of insoluble drugs/prodrugs can be formed in the site of injection, and then the drugs/prodrugs are slowly drained into the thoracic lymphatic vessels to form secondary depot. Subsequently, the active substance is gradually released from the lymphatic system into systemic circulation for long-acting effect; (B) after iv administration, macrophages phagocytize nanocrystals to act as a drug reservoir resulting in sustained drug release in systemic circulation. Reproduced with the permission from Ref. 116. Copyright © 2020 Elsevier.

Figure 8

The common designs of microneedles. (A) The needles separate from the backing layer triggered by degradation-based mechanism. (B) The needles separate from the backing layer triggered by bubble-aided mechanism. (C) Bioinspired needles to achieve firm skin adhesion. Reproduced with the permission from Ref. 141. Copyright © 2020 Elsevier.

Figure 9

The design of long-acting implantable systems. (A) Polymer-based implants. (B) Osmotic pumps are composed of a drug reservoir, an osmotic engine and a movable piston. A semipermeable membrane is used to separate the osmotic from the outside, and micro-holes are designed to connect the drug reservoir and the outside. The increased hydrostatic pressure in the osmotic engine is the motive force of pumps for drug release. (C) Positive displacement is the motive force of peristaltic pump for transporting the fluid inside the tube. (D) Implantable infusion pumps are divided into three parts including a propellant, a collapsible bellow and drug reservoir. The propellant changes bigger in the volume under body temperature leading to compression of collapsible bellow, following the drug release. (E) The mechanism of implantable chip is that the single reservoir can be opened by applying an electrical potential to the gold membrane resulting in the complete dissolution of the membrane, which subsequently results in the release of the drug. (F) A drug reservoir can be conveniently covered by the nanochannel delivery system (nDS) membrane to achieve zero-order kinetic drug release from the reservoir. Reproduced with the permission from Ref. 153. Copyright © 2019 Springer Nature.