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Purpose To measure aggregate and particle formation in tumor necrosis factor-alpha (TNF-α) inhibitors etanercept, adalimumab and certolizumab pegol product samples after exposure to freezing temperature conditions similar to storage conditions previously observed in patients’ homes. Methods TNF-α inhibitors in their original primary and secondary packaging were exposed to 32 freeze-thaw cycles (−10°C for 120min/5°C for 60 min) or continuous low storage temperature (−20°C for 96 h) before thawing at 2–8°C. Non-stressed products were used as controls. The products were analyzed by high pressure size exclusion chromatography (HP-SEC), dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), micro-flow imaging (MFI) and second derivative ultraviolet (UV) spectroscopy. Results Ten out of twenty-one stressed product samples (47.6%) showed increased particle numbers in the submicron and micron size range when compared to controls. For each product, DLS,MFI and NTA detected an increase in particle level in at least one stressed syringe (both continuous freezing and freeze-thaw), whereas HP-SEC and UV spectroscopy showed no differences between stressed and non-stressed products. Conclusion TNF-α inhibitors are relatively resistant to freezing temperatures similar to storage conditions previously observed in patients’ homes.However, almost half of the stressed product samples showed formation of particles in the submicron and micron size range. [ABSTRACT FROM AUTHOR]

The effect of the polypeptide salmon calcitonin (sCT) on serum calcium concentrations following intranasal and intravenous administration was studied in young rabbits. A small, hypocalcemic effect was observed after nasal administration of sCT without additives, indicating that the nasal sCT absorption was low. The absorption could be improved by addition of an absorption-enhancing adjuvant to the nasal preparation. The absorption, however, was still far from complete as was apparent from the much stronger effect of intravenously injected sCT. When a number of sCT doses were given during a 10-week period, the hypocalcemic effect per sCT dose in the young rabbits decreased after intravenous and, although less pronounced, after nasal administration. The decreased response to sCT is probably not related to the induction of neutralizing antibodies or desensitization of sCT receptors, but is more likely associated with the age-dependent level of bone activity. [ABSTRACT FROM AUTHOR]

The absorption enhancing effect of methylated beta-cyclodextrins on the nasal absorption of salmon calcitonin (sCT) was studied in rats and rabbits. The nasal absorption of sCT following administration without additives was low in both species. The absorption in rats could be largely improved by coadministration of cyclodextrins as apparent from the effect on serum calcium concentrations. Trimethyl-beta-cyclodextrin (TM beta CD), at a concentration of 5% (w/v), was the least potent enhancer. Randomly methylated-beta-cyclodextrin (RM beta CD) and dimethyl-beta-cyclodextrin (DM beta CD), all at a concentration of 5% (w/v), were almost equally effective in decreasing serum calcium levels, and the hypocalcemic responses were similar to those of i.v. and s.c. injected sCT. Absorption enhancement was already achieved with 1% DM beta CD added to the nasal formulations. In rabbits, only the effect of DM beta CD on the nasal sCT absorption was investigated. A total serum calcium decrement in 4 hours of 9.4 +/- 3.9% (mean +/- SD) was observed following nasal administration of 12.6 IU/kg sCT with 5% DM beta CD, comparable to that of i.v.-injected sCT. In conclusion, the methylated cyclodextrins DM beta CD and RM beta CD are suitable absorption enhancers for nasal sCT administration, which is expected to have a clinical impact on the therapy with calcitonin. [ABSTRACT FROM AUTHOR]

The absorption enhancing effect of methylated β-cyclodextrins on the nasal absorption of salmon calcitonin (sCT) was studied in rats and rabbits. The nasal absorption of sCT following administration without additives was low in both species. The absorption in rats could be largely improved by coadministration of cyclodextrins as apparent from the effect on serum calcium concentrations. Trimethyl-β-cyclodextrin (TMβCD), at a concentration of 5% (w/v), was the least potent enhancer. Randomly methylated-β-cyclodextrin (RMβCD) and dimethyl-β-cyclodextrin (DMβCD), all at a concentration of 5% (w/v), were almost equally effective in decreasing serum calcium levels, and the hypocalcemic responses were similar to those of i.v. and s.c. injected sCT. Absorption enhancement was already achieved with 1% DMβCD added to the nasal formulations. In rabbits, only the effect of DMβCD on the nasal sCT absorption was investigated. A total serum calcium decrement in 4 hours of 9.4±3.9% (mean±SD) was observed following nasal administration of 12.6 IU/kg sCT with 5% DMβCD, comparable to that of i.v.-injected sCT. In conclusion, the methylated cyclodextrins DMβCD and RMβCD are suitable absorption enhancers for nasal sCT administration, which is expected to have a clinical impact on the therapy with calcitonin. [ABSTRACT FROM AUTHOR]