Commercial challenges of protein drug delivery

Brown, L. R.

doi:10.1517/17425247.2.1.29

Cited by 190 publications

(122 citation statements)

References 41 publications

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“…In another study comparing different routes of GH administration without site rotation in thirteen children, two developed mild lipoatrophy on the arms (13). Finally, similar AEs have been observed in a cohort of children treated with a long-acting GH formulation with a progressive release of GH for up to 4 weeks (17). Injection site reactions occurred in nearly all patients and in 13% lipoatrophy was observed.…”

Section: Discussionmentioning

confidence: 54%

Lipoatrophy in GH deficient patients treated with a long-acting pegylated GH

Touraine

D'Souza

Kourides

et al. 2009

European Journal of Endocrinology

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Objective: Changes observed during adult GH deficiency (GHD) are most often reversed with the administration of recombinant human GH (rhGH). To avoid daily injections, a long-acting GH molecule has been obtained by covalent binding of polyethylene glycol (PEG) with rhGH (PEG-GH), allowing weekly s.c. injections. This study was designed to assess its efficacy and safety, in adult GHD subjects. Design and methods: This was a randomized, double-blind, placebo-controlled, multiple-dose, parallel group study. Subjects were recruited from 34 centers. A total of 105 subjects with GHD were assigned a treatment. They received 6 weekly injections of either PEG-GH or placebo. Subjects were randomized into one out of four treatment groups (Groups A-D) or placebo (Group E). Groups A, B, and C received 1, 3, and 4 mg PEG-GH respectively, for the first 3 weeks followed by 2, 6, and 8 mg PEG-GH respectively, for the remaining 3 weeks. Group D received 4 mg PEG-GH for 6 weeks. Group E received placebo. The study was suspended because of the development of lipoatrophy in certain subjects and restarted with an injection rotation plan, before being terminated due to further subjects developing lipoatrophy. Results: A total of 13 cases of injection-site lipoatrophy were reported, of which ten were in females and three occurred after the first injection; all cases were independent of PEG-GH dose or IGF1 levels, either basal or under treatment. Conclusion: The unpredictable occurrence of injection-site lipoatrophy with weekly long-acting pegylated GH molecules may be a limiting factor for their development.

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Section: Discussionmentioning

confidence: 54%

Lipoatrophy in GH deficient patients treated with a long-acting pegylated GH

Touraine

D'Souza

Kourides

et al. 2009

European Journal of Endocrinology

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“…Desmopressin (DDAVP®, Sanofi-Aventis, France) is a potent vasopressin analogue that is delivered orally, despite its very low F (0.1%) [28]. Successful approaches to overcoming poor intestinal permeability have also focused on prodrugs, inactive drug precursors with greater permeability across the intestinal epithelium than the active [7,[29][30][31]. Once absorbed across the intestinal epithelium the prodrug is hydrolytically or enzymatically converted to active drug.…”

Section: [11] Alternative Approaches To Delivery Of Poorly Permeablementioning

confidence: 99%

Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

Maher

Leonard²,

Jacobsen

et al. 2009

Advanced Drug Delivery Reviews

197

176

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A major challenge in oral drug delivery is the development of novel dosage forms to promote absorption of poorly permeable Class III drugs across the intestinal epithelium.To date, no absorption promoter has been approved in a formulation specifically designed for oral delivery of Class III molecules. Promoters that are designated safe for human consumption have been licensed for use in a recently approved buccal insulin spray delivery system and also for many years as part of an ampicillin rectal suppository.Unlike buccal and rectal delivery, oral formulations containing absorption promoters have the additional technical hurdle whereby the promoter and payload must be coreleased in high concentrations at the small intestinal epithelium in order to generate significant but rapidly reversible increases in permeability. The most advanced promoter in the clinic is the medium chain fatty acid (MCFA), sodium caprate (C 10 ) , a compound already approved as a direct food additive. We discuss how it has evolved to a matrix tablet format suitable for administration to humans under the headings of mechanism of action at the cellular and tissue level and in vitro and in vivo efficacy and safety studies.In specific clinical examples, we review how C 10 -based formulations are being tested for oral delivery of bisphosphonates using Gastro Intestinal Permeation Enhancement Technology, GIPET® (Merrion Pharmaceuticals, Ireland) and in a related solid dose format for anti-sense oligonucleotides (ISIS Pharmaceuticals, USA).Keywords: Oral drug delivery, Sodium caprate (C 10 ), absorption promoter, drug delivery platforms, clinical trials, oral formulation, drug delivery systems.3 TJs form a barrier to the uncontrolled absorption of noxious luminal antigens (gate function), and maintain epithelial polarity (fence function) [8,9]. In general, the TJ consists of a restrictive pathway (shunt) with a sharp molecular size cut off, and a second unrestrictive pathway (small pore) that permits paracellular permeation of molecules of radii <4.0 Å [10,11]. Depending on the intestinal region, TJ pore sizes range from 6-22Å, sufficient to permit mannitol (6.7 Å) and EDTA (10.8 Å) to permeate to an extent, whereas the passage of inulin (30-40 Å) and fluorescent-dextran 4kDa (FD-4, 26 Å) is essentially impeded [12][13][14][15][16].A number of approaches have been used to promote oral delivery of Class III drugs ( Alternatively, the use of nanoparticles comprising biocompatible polymers (e.g. chitosan,polylactide-co-glycolide, starch and glucans) can protect cargoes from GI proteases, increase GI retention and promote absorption across gut associated lymphoid tissue (GALT) and to a lesser extent, enterocytes [45][46][47]. Most data on nanoparticle absorption from rodent models suggest that M cells in the follicle-associated epithelium of Peyer's patches (PP) are the favored site of uptake for particles of diameter 500nm-1000nm [45].Given the paucity of M cells in the GI tract of adults, the relevance of PP uptake remains controversial ...

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“…10 Many strategies, including the addition of stabilizing excipients, the optimization of process conditions, chemical modifications such as glycosylation and pegylation have been developed to overcome antigen instability during encapsulation and release process. 11 Moreover, application of protein adsorption instead of encapsulation not only dissolves many of problems regarding protein instability during particle preparation, but also facilities PLGA particle sterilization by gamma irradiation before protein loading. 1 This review will focus on the application of PLGA particles as delivery system for peptide/protein based vaccine, and will touch on different methods for the preparation of protein/peptide PLGA particles.…”

Section: Introductionmentioning

confidence: 99%

Peptide/protein vaccine delivery system based on PLGA particles

Allahyari

Mohit

2015

Human Vaccines & Immunotherapeutics

180

118

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Due to the excellent safety profile of poly (D,L-lactide-co-glycolide) (PLGA) particles in human, and their biodegradability, many studies have focused on the application of PLGA particles as a controlled-release vaccine delivery system. Antigenic proteins/peptides can be encapsulated into or adsorbed to the surface of PLGA particles. The gradual release of loaded antigens from PLGA particles is necessary for the induction of efficient immunity. Various factors can influence protein release rates from PLGA particles, which can be defined intrinsic features of the polymer, particle characteristics as well as protein and environmental related factors. The use of PLGA particles encapsulating antigens of different diseases such as hepatitis B, tuberculosis, chlamydia, malaria, leishmania, toxoplasma and allergy antigens will be described herein. The co-delivery of antigens and immunostimulants (IS) with PLGA particles can prevent the systemic adverse effects of immunopotentiators and activate both dendritic cells (DCs) and natural killer (NKs) cells, consequently enhancing the therapeutic efficacy of antigen-loaded PLGA particles. We will review co-delivery of different TLR ligands with antigens in various models, highlighting the specific strengths and weaknesses of the system. Strategies to enhance the immunotherapeutic effect of DCbased vaccine using PLGA particles can be designed to target DCs by functionalized PLGA particle encapsulating siRNAs of suppressive gene, and disease specific antigens. Finally, specific examples of cellular targeting where decorating the surface of PLGA particles target orally administrated vaccine to Mcells will be highlighted.

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Commercial challenges of protein drug delivery

Cited by 190 publications

References 41 publications

Lipoatrophy in GH deficient patients treated with a long-acting pegylated GH

Lipoatrophy in GH deficient patients treated with a long-acting pegylated GH

Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

Peptide/protein vaccine delivery system based on PLGA particles

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