کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5550882 | 1557302 | 2016 | 12 صفحه PDF | دانلود رایگان |
The intrinsic osmolality of aqueous solutions of sodium salt antisense oligonucleotides (ASOs) has been studied to inform formulation practices, understand the molecular basis underlying the difference between theoretical and empirical results, and determine suitable measurement methods. It was found that regardless of nucleotide sequence, ASO concentration of â¼140Â mg/mL has isotonic osmolality of â¼290Â mOsm/kg water (SI unit: mmol osmotically-active particles/kg water), such that lower concentration formulations require excipients for tonicity adjustment. The range of osmolality values at a given active ingredient concentration can be ascribed to drug substance lot-to-lot purity differences impacting total oligonucleotide content (i.e., including oligonucleotide-related impurities). Empirical osmolality measurements were found to be â¼70% of theoretical values, which corresponds to an osmotic coefficient value of â¼0.7, thus inferring incomplete counterion dissociation. When comparing theoretical (ideal) osmolality of multiple sequences with various nucleotide compositions and chemistries at the same w/v concentration, the “average osmolar mass” (molar mass of the oligonucleotide, including the sodium counterions, divided by the ideal Van't Hoff factor, iid) appears to be the strongest factor governing theoretical osmolality values. Other factors examined were the sequence length, backbone chemistry, 2â² sugar chemistry, and nucleotide composition. A head-to-head comparison between two osmolality techniques showed that vapor pressure osmometry is generally more suitable than freezing point osmometry for oligonucleotide solutions greater than â¼150Â mg/mL due to viscosity effects, but the two techniques are comparable otherwise.
108
Journal: International Journal of Pharmaceutics - Volume 515, Issues 1â2, 30 December 2016, Pages 788-799