Improved formulations of recombinant human bile salt-stimulated lipase
A bile-salt-stimulated lipase and preparation technology, which is applied in the field of improved recombinant human bile-salt-stimulated lipase preparations, and can solve problems such as unreported rhBSSL preparations
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Embodiment 1
[0196] Example 1: Experiment AH7507
[0197] Experimental setup: The effect of crystalline bulking agent and optional amorphous stabilizer on the properties of lyophilized formulations of rhBSSL was investigated using a full factorial 2-level design with 2 center points (22). Excipients in various combinations and amounts were used to prepare 7 Table 1 A lyophilized formulation of the composition shown in . Temperature was added as a third factor in the factorial design for samples to be stored for 18 months (18 months at +5°C and +25°C), and samples were also stored at +40°C for 9 months short period. Various lyophilized formulations were periodically sampled during storage and studied using size exclusion high performance liquid chromatography (SE-HPLC), powder X-ray diffraction (PXRD) and other techniques.
[0198] Table 1 Amounts of rhBSSL and excipients in the lyophilized powder of the lyophilized formulation of AH7507.
[0199]
[0200] *The amount of sodium ph...
Embodiment 2
[0225] Example 2: Experiments AH7513 and AH7517
[0226] Experimental setup: The effect of glycine as an amorphous stabilizer on the properties of lyophilized formulations of rhBSSL was also investigated in two further experiments, AH7513 and AH7517. Excipients in various combinations and amounts were used to prepare table 3 Four additional lyophilized formulations of the compositions shown in . The samples were stored for different times at +5°C, +25°C and +40°C. Samples were taken from various lyophilized formulations periodically during storage and investigated using size exclusion high performance liquid chromatography (SE-HPLC), powder X-ray diffraction (PXRD) and other techniques.
[0227] table 3 Amounts of rhBSSL and excipients in lyophilized powders of lyophilized formulations of AH7513 and AH7517.
[0228]
[0229] *The amount of sodium phosphate calculated from the weighted average molecular weight of the two sodium phosphate components and the mass of the ...
Embodiment 3
[0242] Example 3: Comparison with liquid formulations of rhBSSL
[0243]By way of additional evidence of the superiority of the lyophilized formulations of the present invention, liquid formulations of rhBSSL (prepared drug substance (DS) as described in Example 4 below) were subjected to similar conditions by storage at +25°C up to 3 months. stability studies. After 3 months of storage at +25°C, SE-HPLC of DS showed 93.3% of the main peak (rhBSSL monomer) and 3.6% of total integrated HMW peaks (indicating rhBSSL aggregates). Surprisingly, this was less stable than any of the lyophilized formulations of the invention. For example, even formulation N1 of experimental AH7505 (without glycine but with "low" amounts of mannitol) did not lose as much of the %Main peak or produce as much of the %HMW peak, even after 18 months of storage at the same temperature (see respectively figure 2 and Figure 5 ). Furthermore, the optimized lyophilized formulations G2 and G3, despite sto...
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