Oral Protein Drug Delivery and Hemophilia A

It is a bit of an understatement to suggest that there is considerable interest in the oral delivery of protein drugs.  There are two primary issues in the oral adsorption of proteins.  The first is stability to the

relatively harsh conditions in the stomach and intestine.  The second is the problem of size.  The first can be addressed by encapsulating the protein drug for release in the colon (1,2).  The second is a more

significant challenge (3,4). Hemophilia A is an attractive target for the development of an oral protein therapeutic.   The largest advantage is that there is a well-defined clinical endpoint and an accepted

surrogate assay.  As such, there has been an interest in the development of an oral therapeutic for hemophilia for some time.  A group at Harvard Medical School published a study in 1936 (5)

demonstrating  the therapeutic effectiveness of orally administered extract of human placenta (presumably crude human tissue factor) in children with hemophilia.  A study on the oral administration of

bovine serum was somewhat less successful (6).  In 1980, Hemker and colleagues (7) showed an effect of the administration of liposomal factor VIII (7).   Some concern was expressed about the potential

immunogenicity of the liposomal appoache (8) but there was additional work on the use of liposomal factor VIII for oral delivery in 1984 (9).  It was not possible to find additional work on development of

oral therapeutics for hemophilia A.  It is noted the pegylated liposomes are being developed for the treatment of hemophilia A (10). It is noted that the oral administration of glandular kallikrein has a

systemic effect on blood pressure (11). The above suggest that there is the oral absorption of biologically active proteins and in some cases special formulation is not an absolute requirement.


1.  Del Curto, M.D, Maroni, A., Foppoli, A., et al., Preparation and evaluation of an oral delivery system for time-dependent colon release of insulin and selected protease inhibitor and absorption enhancer compounds, J.Pharm.Sci. 98, 4661-4669, 2009.

2. Kumar, P. and Mishra, B., Colon targeted drug delivery systems - - an overview, Curr.Drug Deliv. 5, 186-198, 2008.

3.  Yuan, F., Krol, A., and Tong, S., Available space and extracellular transport of macromolecules, Ann.Biomed.Engineer. 29, 1150-1115, 2001.

4.  Venturoli, D. and Rippe, B., Ficoll and dextran vs. globular proteins as probes for testing glomerular permselectivity: effects of molecular size, shape, charge, and deformability, Am.J.Physiol.Renal Physiol. 288, F605-F613, 2005.

5. Eley, R.C., Green, A.A., and McKhann, C.F., The use of a blood coagulant extract from the human placenta in the treatment of hemophilia, J.Pediatr. 8, 135-147, 1936.

6. Bendien, W.M. and van Crevald, S., Investigations on hemophilia, J.Dis.Children  54, 713-725, 1937.

7.  Hemker, H.C., Muller, A.D., Th. Hermens, W., and Zwaal, R.F.A., Oral treatment of haemophilia by gastrointestinal absorption of factor VIII entrapped in liposomes, Lancet  315, 70-71, 1980.

8.  Morgenthaler, J.-J., Oral therapy for haemophilia, Lancet  315, 546, 1980.

9.  Kirby, C.J. and Gregoriadis, G., Preparation of liposomes containing factor VIII for oral treatment of haemophilia, J.Microencapsulation 1, 33-45, 1984.

10.  Powell, J.S., Nugent, D.J., Harrison, J.A., et al., Safety and pharmacokinetics of a recombinant factor VIII with pegylated liposomes in sever hemophilia A, J.Thromb.Haemost. 6, 277-283, 2008.

11. Overlack, A., Stumpe, K.O., Kolloch, R., et al., Antihypertensive effect of orally administered glandular kallikrein in essential hypertension. Results of a double blind study, Hypertension 3, I18-I21, 1981.