Surface Properties of Carrier Particles for Pulmonary Delivery of Biopharmaceuticals: Lactose Crystallised from Whey

Lactose is the main excipient used in pulmonary drug delivery. Pulmonary drug delivery is mainly used for drugs that target the lungs, and is increasingly used and explored for systemic drugs due to the lungs good vascularisation, thinness of the alveolar epithelium and large surface area. Pulmonary drug delivery is used for systemic drug delivery compounds such as small molecules, glucose polymers (Icodextrin), and proteins (Advate). Pulmonary drug delivery is especially promising for systemic delivery of proteins, for example insulin, in light of their digestion in the stomach and the development of new antibody therapies. One of the challenges in pulmonary drug delivery of proteins is the relatively low doses that reach the blood as compared to injections and the control and reproducibility of the dose size. The aim of the proposed research is to understand the effects of downstream processing on the surface properties of lactose particles. We will use knowledge of interfacial properties to improve downstream processing operations in such a way as to produce particles of the optimum size and shape for delivery of protein based therapeutics. The research work will be based on recent improvements in instrumentation for determination of lactose particle surface properties due to variations in downstream processing operations. Friesland Foods is the world leader in inhalation lactose with a global market share of around 65%. The production of pharmaceutical lactose as is done at Friesland Foods Domo is described here. Whey is the remaining part of milk, when producing cheese. It consists mainly of water with whey-protein and carbohydrates (lactose). The milk fat and casein (a type of milk protein) mainly goes into the cheese. During the processing of whey, the water and protein will be removed, leaving lactose behind. After the purification process, during which traces of protein and riboflavin are removed, pure, pharmaceutical quality lactose is the remaining product. Lactose production from whey is in principle done by concentration of the lactose solution through evaporation and crystallisation in crystallisation tanks. The wet pharmaceutical lactose is then dried in three different ways giving as result three different types of lactose: alpha-monohydrate (fluid bed drying) beta-anhydrous (roller bed drying) and amorphous (spray drying). The alpha-monohydrate lactose is further processed in our dedicated Pharma Plant so that the lactose crystals have the required particle size distribution (PSD). The desired size distribution is reached by sieving, air-classification, milling, micronizing and then blending. While lactose crystals are rather smooth while in the 'wet pharmaceutical lactose' state, drying, transportation through the tubes, sieving, milling and micronization, modify the lactose crystals surfaces. Some of the major challenges during the production of inhalation lactose are related to the characterisation and control of the surface modifications to which the crystals are subjected to during these changes. The possibility to grow lactose crystals of desired size would then be of great use to the excipient industry because it will get rid of the need for breaking the crystal to achieve a desired particle size. Our research plan has two directions: First, we determine the effect of milling, sieving, classification, micronization, and lactose fractions in the blends on the surface properties of the final product. Improvements to the manufacturing process will be done to improve the final excipient mixtures surface properties. In the second direction we will explore new ways of crystal growth. Controlling crystal growth will allow us to make large crystals and get a better understanding of different surface energies for different crystal faces, and to achieve controlled crystallization to desired crystal sizes so that comminution processes are not needed anymore in inhalation lactose production.