Spray-dried amorphous isomalt and melibiose, two potential protein-stabilizing excipients

Co-amorphous drug-amino acid mixtures have shown potential for improving the solid-state stability and dissolution behavior of amorphous drugs. In previous studies, however these mixtures have been produced mainly with small-scale preparation methods, or with methods that have required the use of organic solvents or other dissolution enhancers. In the present study, co-amorphous ibuprofen-arginine and indomethacin-arginine mixtures were spray dried from water. The mixtures were prepared at two drug-arginine molar ratios (1:1 and 1:2). The properties of the prepared mixtures were investigated with differential scanning calorimetry, X-ray powder diffractometry, Fourier-transform infrared spectroscopy and a 24h, non-sink, dissolution study. All mixtures exhibited a single glass transition temperature (T), evidence of the formation of homogenous single-phase systems. Fourier transform infrared spectroscopy revealed strong interactions (mainly salt formation) that account for the positive deviation between measured and estimated T values. No crystallization was observed during a 1-year stability study in either 1:1 or 1:2 mixtures, but in the presence of moisture, handling difficulties were encountered. The formation of co-amorphous salts led to improved dissolution characteristics when compared to the corresponding physical mixtures or to pure crystalline drugs.

Section: Spray Dryingmentioning

confidence: 99%

Spray drying of poorly soluble drugs from aqueous arginine solution

Ojarinta

Lerminiaux

Laitinen

2017

“…The different isomalt samples remained physically stable during the storage period, which is likely to be one of the reasons why isomalt mixtures were able to stabilize the protein activity during storage. Also, in previous studies, amorphous isomalt has exhibited high physicochemical stability at different humidities and temperatures, which supports its potential as a freeze-drying excipient in protein formulations (Koskinen, et al 2016;Lipiäinen, et al 2016).…”

Section: Physical Propertiesmentioning

confidence: 53%

Isomalt and its diastereomer mixtures as stabilizing excipients with freeze-dried lactate dehydrogenase

Tuderman

Strachan

Juppo

2018

The purpose of this research was to study isomalt as a protein-stabilizing excipient with lactate dehydrogenase (LDH) during freeze-drying and subsequent storage and compare it to sucrose, a standard freeze-drying excipient. Four different diastereomer mixtures of isomalt were studied. The stability of the protein was studied with a spectrophotometric enzyme activity test and circular dichroism after freeze-drying and after 21 days of storage at 16% RH. Physical stability was analyzed with differential scanning calorimetry and Karl Fischer titration. Statistical analysis was utilized in result analysis. LDH activity was almost completely retained after freeze-drying with sucrose; whereas samples stabilized with isomalt diastereomer mixtures had a considerably lower protein activity. During storage the sucrose-containing samples lost most of their enzymatic activity, while the isomalt mixtures retained the protein activity better. In all cases changes to protein secondary structure were observed. Isomalt diastereomer mixtures have some potential as protein-stabilizing excipients during freeze-drying and subsequent storage. Isomalt stabilized LDH moderately during freeze-drying; however it performed better during storage. Future studies with other proteins are required to evaluate more generally whether isomalt would be a suitable excipient for pharmaceutical freeze-dried protein formulations.

“…Powder yields were in the range of 39-74%, and similar for the two formulations. For melibiose, the powder recoveries were clearly higher compared to drying the sugar without protein, where lower yields (18-29%) have been observed when drying at similar temperatures (Lipiäinen et al, 2016). The small protein addition (1:250 w/w) resulted in increased melibiose yields, but such an effect was not observed for trehalose.…”

Section: Powder Yieldmentioning

confidence: 90%

“…Melibiose also has a high T g for a sugar, and it has advantages in spray drying compared to other carbohydrates, including sucrose and isomalt (Lipiäinen et al, 2016). Melibiose has shown potential in lyophilised protein formulations, and even though it is a reducing sugar, no evidence of Maillard reaction-based protein degradation was observed during a three-month study with monoclonal antibodies (Heljo et al, 2013;Heljo et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Comparison of melibiose and trehalose as stabilising excipients for spray-dried β-galactosidase formulations

Lipiäinen

Räikkönen

Kolu

et al. 2018

Self Cite

Spray-dried protein formulations commonly require stabilising excipients to prevent protein degradation during processing and storage, and trehalose has been commonly used. The purpose of this work was to evaluate melibiose in spray-dried protein formulations in comparison to trehalose. The protein-activity-preserving efficacy, process behaviour and storage stability were studied. Spray drying of β-galactosidase was carried out using different process temperature, drying air flow and feed liquid atomisation settings. Both melibiose and trehalose reduced protein activity loss during drying. A decrease in activities was observed when the process temperature exceeded a threshold temperature. During storage (30 days at 18% RH and 20 or 40 °C), the formulations dried below this threshold temperature showed no further activity loss, and the stabilising efficacy of the two disaccharides was equal. With higher process temperatures, the remaining protein activities after storage trended higher with melibiose formulations. All formulations remained amorphous. The powder yields of melibiose formulations were similar to trehalose. There was a difference in residual moisture contents, with melibiose formulations giving drier products. In conclusion, protein formulations with melibiose could be spray dried into amorphous powders that were physically stable, contained lower moisture contents and protected protein activity at least as well as trehalose formulations.