Oral Delivery of Antisense Oligonucleotides in Man

Tillman, Lloyd; Geary, Richard S.; Hardee, Gregory E.

doi:10.1002/jps.21084

Cited by 110 publications

(79 citation statements)

References 15 publications

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“…The rapid absorption kinetics of C 10 stimulated design of a pulsatile formulation, characterized by an immediate release of high concentrations of the promoter with the oligonucleotide cargo, followed by pulsed replenishment of C 10 to sustain the enhancement window. In human patients, the bioavailability of these formulations ranged from 7-12% [30].…”

Section: Resultsmentioning

confidence: 99%

Restoration of Rat Colonic Epithelium After In Situ Intestinal Instillation of the Absorption promoter, Sodium Caprate

Wang

Maher

Brayden

2010

Therapeutic Delivery

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Section: Resultsmentioning

confidence: 99%

Restoration of Rat Colonic Epithelium After In Situ Intestinal Instillation of the Absorption promoter, Sodium Caprate

Wang

Maher

Brayden

2010

Therapeutic Delivery

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“…It is currently in clinical trials as a key component of several proprietary oral formulations [24][25][26]. The nature of its mechanism of action, efficacy, and the possibility of inducing toxicity are of primary interest in commercialization of formulations based on this technology.…”

Section: ] Conclusion [1] Introductionmentioning

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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“…Tissue histology of the small intestine and large intestine indicated no changes after once daily dosing of tablets containing approximately 1 g of sodium caprate for seven consecutive days. Oral ISIS 104838 was also evaluated in humans using solid formulations designed to combine immediate release and delayed release sodium caprate (660 mg total) in an enteric-coated capsule (27). The formulation providing the greatest average oral bioavailability resulted in 12.0% average bioavailability relative to subcutaneous injection and ranging from approximately 2% to 27.5% in ten fasted subjects.…”

Section: Products In Developmentmentioning

confidence: 99%

Absorption Enhancers: Applications and Advances

Aungst¹

2011

AAPS J

254

119

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Abstract. Absorption enhancers are functional excipients included in formulations to improve the absorption of a pharmacologically active drug. The term absorption enhancer usually refers to an agent whose function is to increase absorption by enhancing membrane permeation, rather than increasing solubility, so such agents are sometimes more specifically termed permeation enhancers. Absorption enhancers have been investigated for at least two decades, particularly in efforts to develop non-injection formulations for peptides, proteins, and other pharmacologically active compounds that have poor membrane permeability. While at least one product utilizing an absorption enhancer for transdermal use has reached the market, quite a few more appear to be at the threshold of becoming products, and these include oral and transmucosal applications. This paper will review some of the most advanced absorption enhancers currently in development and the formulation technologies employed that have led to their success. In addition, a more basic review of the barriers to absorption and the mechanisms by which those barriers can be surmounted is presented. Factors influencing the success of absorption-enhancing formulations are discussed. If ultimately successful, the products now in development should offer noninjection alternatives for several peptide or protein drugs currently only administered by injection. The introduction of new absorption enhancers as accepted pharmaceutical excipients, and the development of formulation technologies that afford the greatest benefit/risk ratio for their use, may create opportunities to apply these enabling technologies more broadly to existing drugs with non-optimal delivery properties.

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Oral Delivery of Antisense Oligonucleotides in Man

Cited by 110 publications

References 15 publications

Restoration of Rat Colonic Epithelium After In Situ Intestinal Instillation of the Absorption promoter, Sodium Caprate

Restoration of Rat Colonic Epithelium After In Situ Intestinal Instillation of the Absorption promoter, Sodium Caprate

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

Absorption Enhancers: Applications and Advances

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