Improving the outcomes of biopharmaceutical delivery via the subcutaneous route by understanding the chemical, physical and physiological properties of the subcutaneous injection site

Subcutaneous (SC) injection is currently the most common route of self-administering biopharmaceuticals such as proteins and peptides. While pharmaceutical scientists have acquired great skill in identifying formulations for these proteins and peptides with multi-year shelf life stability, the SC injection of these formulations can result in inconsistent or particularly low bioavailability outcomes. We hypothesise that upon injection, the chemical, physical and physiological properties of the subcutaneous tissue may play a crucial role in determining the therapeutic outcomes of SC injected biopharmaceuticals. We contend that physical and chemical stresses placed upon the injected protein or peptide as it transitions from the non-physiological environment of its formulation to the homeostatic conditions of the SC tissue can affect its fate following injection, and that by taking this environment into account when formulating, more precisely controlled release of SC injected biopharmaceuticals could be achieved. In this mini-review we describe how events that occur to an injected protein or peptide during this post-injection transition period could affect the diffusion of bioactive material to blood capillaries and lymphatic vessels. With this in mind, we have reviewed the chemical, physical and physiological attributes of the SC tissue and collated studies on how these properties are known to affect protein stability and diffusional properties. Finally, examples where the understanding of the properties of the SC tissue when formulating for SC injected biopharmaceuticals has improved the predictability of drug delivery via the SC route are discussed, with the need for novel tools for rational and informed formulation development highlighted

Photoelectron imaging of guinea pig, hamster, and human spermatozoa

12 pagesPhotoelectron images of mammalian spermatozoa were obtained by subjecting the specimens to u.v.-irradiation and focussing the emitted electrons by electron optics (photoelectron microscopy). Guinea-pig, hamster and human sperm atozoa were fixed in glutaraldehyde, deposited on conductive glass discs, and dehydrated. Sufficient quantities of photoelectrons were released from the surface of spermatozoa to produce images without staining, coating or metal shadowing. The large planar heads of guinea-pig spermatozoa were easily resolved with good delineation of acrosomal and postacrosomal regions. Residual vesicles could be visualized on the surface of the inner acrosomal membrane of spermatozoa that had undergone the acrosome reaction. Also detectable in these photoelectron images were finer membrane surface details, periodicities in the midpiece region of the tail which coincided with the distribution of mitochondria, and periodicities in the principal piece which appeared to be related to fibrous sheath components. Hamster spermatozoa were similarly well resolved but human spermatozoa were more difficult to image because of their increased surface curvature. The mechanism responsible for detection of these surface details is primarily topographical contrast rather than material contrast, since spermatozoa coated with a thin layer of gold or platinum exhibited similar features, althoughat reduced resolution, as the uncoated specimens