Desmopressin interactions

With this approach, it mrned out that between 25 and 45 °C both fi and y factors hold similar values, indicating that the physical restriction and the chemical interactions contributed almost equally to the decrease in the mobility of the peptide within the Hn mesophase, compared to the water solution. However, above 45 °C increased values of y-factor suggested considerable weakening of the GMO and desmopressin interactions and even repulsive interactions between the surfactant and the peptide at 55 °C. This might trigger the observed decreased thermal stability of the loaded mesophase. Thus, it was concluded that the peptide dictated the phase behavior of the hexagonal structure, exhibiting the onset of the critical behavior at 45 °C. 

It would be interesting to compare these results with the findings of Ericsson et al. who measured diffusion of this peptide in the aqueous channels of the cubic phase [53]. According to these investigators, the self-diffusion data indicated that desmopressin interacted significantly with the monoolein-water interface. For example, the desmopressin diffusion coefficients in the cubic phase at 40 °C was about a factor 9 smaller than in H20 solution, a difference that is larger than what... 

In this work we will focus on the use of the cubic phase as a delivery system for oligopeptides - Desmopressin, Lysine Vasopressin, Somatostatin and the Renin inhibitor H214/03. The amino acid sequences of these peptides are given in Table I. The work focuses on the cubic phase as a subcutaneous or intramuscular depot for extended release of peptide drugs, and as a vehicle for peptide uptake in the Gl-tract. Several examples of how the peptide drugs interact with this lipid-water system will be given in terms of phase behaviour, peptide self-diffusion, in vitro and in vivo release kinetics, and the ability of the cubic phase to protect peptides from enzymatic degradation in vitro. Part of this work has been described elsewhere (4-6). 

NMR Self-Diffusion of Desmopressin. The NMR-diffusion technique (3,10) offers a convenient way to measure the translational self-diffusion coefficient of molecules in solution and in isotropic liquid crystalline phases. The technique is nonperturbing, in that it does not require the addition of foreign probe molecules or the creation of a concentration-gradient in the sample it is direct in that it does not involve any model dependent assumptions. Obstruction by objects much smaller than the molecular root-mean-square displacement during A (approx 1 pm), lead to a reduced apparent diffusion coefficient in equation (1) (10). Thus, the NMR-diffusion technique offers a fruitful way to study molecular interactions in liquids (11) and the phase structure of liquid crystalline phases (11,12). 

The Desmopressin diffusion coefficient in the cubic phase at 40 C (D=0.24 x 10-10 m2s-l) is about a factor 9 smaller than in 2H20-solution at 25 C (D=2.25 x 10-10 m s" ), a difference which is larger than what is expected from pure obstruction effects a reduction factor of three is expected from the inclusion of a solute in the water channels of the cubic phase (13). Thus, the results indicate an interaction between the peptide and the lipid matrix and/or membrane surface, especially since the peptide and lipid diffusion coefficients are very similar in the cubic phase (Table... 

The first was the physical restriction of the jjeptide motion, more specifically its diffusion within the water cylinders, owing to the geometric constrain of hexagonal architecture. The second factor is the chemical interactions of the peptide with the polar heads of monoolein. These two effects were separated and quantified by SD-NMR analysis (SD-NMR). Rankin s model [43] was used to calculate the theoretical diffusion coefficients of desmopressin within the channels of the Hu mesophase, assuming no interactions of the peptide with GMO and TAG. Using the theoretical diffusion coefficient of the drug and the measured diffusion values, the observed decrease in diffusion coefficients of the peptide in the Hn mesophase was clarified (Fig. 12.23), defining two obstruction factors. The obstruction factors enabled quantification of the effects of both physical restriction (p) and the chemical interactions (y). 

Fig. 12.23 a Desmopressin diHiision coefficients as a function of temperature in (A) 8 wt% in D2O solution (O) according to the Renkin model, ( ) 8 wt% in Hu mesophase as a funetion of temperature, b Obstruction factors calculated from the SD-NMR analysis as a function of temperature (O). The overall obstruction factor (A) ( ) fi is the obstruction factor responsible for the physical restriction of the peptide in the hexagonal structure (A) y is the obstruction factor associated with the chemical interactions between the peptide and GMO... 

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