The widely used food ingredient inulin could be a more effective alternative to established excipients in stabilising protein-based medicines and improving their shelf life, according to researchers at the University of Groningen in the Netherlands.
And proteins stabilised using inulin may also be suitable for non-injectable routes of administration, including oral delivery, according to Dr Wouter Hinrichs, a UoG scientist who presented the research at the annual seminar of International Pharmaceutical Excipients Council (IPEC ) Europe seminar in Cannes, France, last week.
Protein drugs are produced as aqueous solutions, which are unstable and have a limited shelf life. For this reason, they are usually freeze- or spray-dried to create a powder, which improves their stability and allow them to be used in a broader range of dosage forms.
At present, disaccharide sugars such as trehalose are often used as a stabilising excipient during drying, as they substitute for the water in solution and help the protein maintain its structure and activity during the process. In effect, the sugar folds the protein in a glassy matrix, rather like a fly in amber, said Dr Hinrichs.
Inulin is a monosaccharide, which means that it can exist in different chain lengths that can alter its characteristics. Hinrichs et al hypothesised that its chain structure would make it more flexible and allow it to coat protein more effectively. In theory, this should provide an improvement in protein stability compared to the relatively inflexible disaccharide excipients.
To test the idea, the UoG team compared a freeze-dried powder of alkaline phosphatase made with inulin to others based trehalose and glucose, and tested the stability of the molecule after storage for six days at 60 degrees C and 8 per cent humidity.
There was no residual activity at the end of the study for the trehalose, glucose and low molecular weight inulin powders, but the one made using a high molecular weight inulin was still 80 per cent active. Subsequent experiments found that trehalose could stabilise the preparation, but only in amounts far greater than would be needed with inulin.
The team then made a tablet out of the powders to examine the shelf life in this form. The trehalose tablets lost activity after a few days as the sugar crystallised, but the inulin tablets stayed in an amorphous state and retained their activity.
The researchers decided to test oral dosing of an enteric-coated tablet containing inulin and alkaline phosphatase in rats, and discovered that while there was no release of the protein into the stomach (where it would have been quickly denatured by the acid environment), it was delivered successfully into the intestines, giving a preliminary indication that such a formulation could be used for the oral delivery of some protein-based drugs.
Hinrichs told the meeting that inulin has also been used to stabilise delta-9-tetrahydrocannabinol (THC), the active principle in marijuana, into both a rapid-dissolve sublingual formulation and an inhaled version.
As of last March, marijuana is licensed as a medicine in the Netherlands for various uses, including pain relief in cancer, HIV and multiple sclerosis patients. Because THC is unstable and has poor bioavailability, the only option available to patients is to smoke the herb, which has health implications and may not appeal to all patients.
Inulin could provide a way for new formulations to be developed that get around this problem suggested Hinrichs.