کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5550882 1557302 2016 12 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Osmolality of antisense oligonucleotide parenteral formulations: Implications on counterion dissociation and recommended osmometry techniques
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی علوم دارویی
پیش نمایش صفحه اول مقاله
Osmolality of antisense oligonucleotide parenteral formulations: Implications on counterion dissociation and recommended osmometry techniques
چکیده انگلیسی

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 ∼140 mg/mL has isotonic osmolality of ∼290 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 ∼70% of theoretical values, which corresponds to an osmotic coefficient value of ∼0.7, 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, 2′ 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 ∼150 mg/mL due to viscosity effects, but the two techniques are comparable otherwise.

108

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: International Journal of Pharmaceutics - Volume 515, Issues 1–2, 30 December 2016, Pages 788-799
نویسندگان
, ,