Injectability as a function of viscosity and dosing materials for subcutaneous administration.

Injectability is a term related to the ease of parenteral administration of a dosing solution, and includes dose preparation, dose administration, ergonomics related to these procedures, pain of injection, and other adverse events at the injection site. This article focuses on force measurements related to injectability, namely: force to expel syringe contents (expulsion force - a mimic for in vivo injection force), needle-penetration force, and needle-bending force, and these results are supplemented by expulsion time measurements with 18 participants, as well as injections in a porcine model. Based on the expulsion time measurements, where 80 N injection force was found to be difficult for most people, we consider the maximum acceptable injection force to be 40 N, and recommend targeting no more than 20 N, especially if the configuration may be used in an autoinjector or similar device. The injectability of antisense oligonucleotide solutions was assessed to determine optimal dosing materials (among those evaluated) for a variety of solution viscosities. Dosing materials varied in syringe inner diameter, needle inner diameter, needle length, and needle wall thickness: standard-wall vs. thin-wall. In general, short (6-8 mm) thin-wall needles are recommended as a way to improve patient perception and comfort during subcutaneous dose administration.

Synthesis and antisense properties of 2'-O-(2S-methoxypropyl)-RNA-modified gapmer antisense oligonucleotides.

To ascertain whether increasing hydrophobicity can enhance the activity of second-generation antisense oligonucleotides (ASOs) in muscle, we investigated the antisense properties of 2'-O-(2S-methoxypropyl)-RNA (2S-MOP)-modified ASOs. Synthesis of the 2S-MOP 5-methyl uridine phosphoramidite was accomplished on a multi-gram scale by Lewis-acid-catalyzed ring opening of 5'-O-tert-butyldiphenylsilyl ether-protected 2,2'-anhydro-5-methyl uridine with 2S-methoxy-1-propanol. Synthesis of the 2S-MOP 5-methyl cytidine nucleoside from the corresponding 5-methyl uridine nucleoside was accomplished by formation and displacement of a 4-triazolide intermediate with aqueous ammonia. 2S-MOP-modified oligonucleotides were prepared on an automated DNA synthesizer and showed similar enhancements in duplex thermal stability as 2'-O-methoxyethyl RNA (MOE)-modified oligonucleotides. 2S-MOP-containing antisense oligonucleotides were evaluated in Balb-c mice and showed good activity for decreasing the expression levels of scavenger receptor B1 (Srb1) and phosphatase and tensin homologue (PTEN) mRNA in liver and muscle tissue.