Design of solid dosage forms for mucosal vaccination - Investigations on the influence of excipients on product performance
Doktorsavhandling, 2012

Most vaccines today are liquid formulations for parental administration. However, there are several drawbacks connected to these vaccines. Since injectable vaccines only induce systemic antibody responses, they are not effective against the various pathogens that affect mucosal surfaces with poor permeability for serum-derived antibodies, e.g. the small intestine. Further disadvantages of liquid injectable vaccines are the need for medical personnel for the administration, cold chain requirements and large packaging sizes, which all are especially negative factors in developing countries. Solid and preferably mucoadhesive vaccine formulations that are administered via mucosal surfaces would offer a good alternative to many of these problems. The aim of this thesis was therefore to study the influence of excipients in the design of such formulations regarding i) formulation-related properties (mucoadhesion and antigen release) and ii) antigen-functionality preservation during freeze-dying. Mechanistic and immunological investigations using mucoadhesive hydrophilic matrix tablets as potential formulations for sublingual immunization were performed. The effect of osmotic pressure differences on the adhesiveness of hydrophilic swelling matrix tablets was investigated and it was found that a decrease in the osmotic pressure difference resulted in a decrease in the adhesive force, i.e. the force required to detach the tablet from a wet surface. Release of the model antigen ovalbumin from hydrophilic matrix tablets and a fast releasing formulation was characterized. The Bradford Assay used for the protein quantification was found to be disturbed by the hydrophilic polymer Carbopol and a correction method was set up. Sublingual immunizations in BALB/c mice indicated a poor potential of all ER tablets to evoke intestinal immune responses, whereas an immediate release resulted in high antibody titres. Thus it was concluded that the latter formulation type should be preferred in sublingual immunization. In the second part of the thesis the stabilizing potential of different excipients during freeze-drying was tested on killed whole-cell Vibrio cholerae bacteria as a model vaccine for pathogens causing mucosal infections. Sucrose showed great potential to avoid bacterial aggregation, preserve important antigen structures and to maintain the immunogenicity of the bacteria. Hopefully, the presented findings are a help and inspiration for formulators and immunologists to develop mucosal vaccine formulations so that diseases for which today no vaccines exist can be prevented in all parts of the world.

hydrophilic matrix tablets

osmotic pressure

protein release


Vibrio cholerae


Bradford Assay

sublingual vaccine tablet

mucosal vaccination

KB-salen, Kemigården 4, Chalmers University of Technology, Sweden
Opponent: Dr Erik Björk, Institutionen för farmaci, Uppsala University, Sweden


Annika Borde

Chalmers, Kemi- och bioteknik, Farmaceutisk teknologi

SuMo Biomaterials

Effect of protein release rates from tablet formulations on the immune response after sublingual immunization

European Journal of Pharmaceutical Sciences,; Vol. 47(2012)p. 695-700

Artikel i vetenskaplig tidskrift

Quantification of protein concentration by the Bradford method in the presence of pharmaceutical polymers

Analytical Biochemistry,; Vol. 411(2011)p. 116-121

Artikel i vetenskaplig tidskrift

Preparation and evaluation of a freeze-dried oral killed cholera vaccine formulation

European Journal of Pharmaceutics and Biopharmaceutics,; Vol. 79(2011)p. 508-518

Artikel i vetenskaplig tidskrift

Osmotic-driven mass transport of water: Impact on the adhesiveness of hydrophilic polymers

Journal of Colloid and Interface Science,; Vol. 341(2009)p. 255-260

Artikel i vetenskaplig tidskrift

Vaccination är idag det viktigaste och mest effektiva sättet för att skydda oss mot sjukdomar. Det finns idag ett 40-tal vacciner på marknaden som nästan alla är injicerbara flytande beredningar. Dessa vacciner ger dock ett dåligt skydd mot infektioner som drabbar slemhinnor där det krävs en lokal vaccination för att uppnå immunitet i slemhinnorna. Injektionsvacciner ställer också till med problem i utvecklingsländerna där stora förpackningsvolymer och krav på en kylkedja utgör problem under transport och lagring och det krävs personal för administreringen. Torra formuleringar för mukosal vaccination, dvs. för en administration via slemhinnor, skulle kunna lösa många av dessa problem. Avhandlingen lyfter fram några viktiga frågeställningar i utvecklingen av sådana formuleringar där vidhäftningsförmågan och frisättning från tabletter samt torkning av antigen, dvs. den komponenten i ett vaccin som stimulerar immunsystemet, har studerats närmare. Avhandlingen har visat att valet av hjälpämnen utgör en viktig del i designen av torra vaccinformuleringar för mukosal administration och presenterar slutsatser kring hur hjälpämnen kan användas för att tillverka effektiva formuleringar.

Vaccination is today the most important and most effective way of treating and protecting the body against diseases. Today there are about 40 vaccines on the market and almost all of them are liquid injectable vaccines. However, these vaccines provide only poor protection against infections at mucosal surfaces. Here, a local vaccination is required instead. Furthermore, the large package sizes and cold chain requirements of injectable vaccines limit their use in developing countries. Solid state formulations for mucosal vaccination, i.e. for an administration via mucosal surfaces, could solve many of these problems. This thesis highlights some important issues in the design of such formulations. Mucoadhesion and release from tablets as well as drying of antigenic material, i.e. the component in a vaccine that is able to stimulate the immune system, have been studied in a closer examination. The results of this work show that the use of excipients is a key issue in the design of solid mucosal vaccine formulations and conclusions on how excipients can be used to improve product performance were made.


Farmaceutisk synteskemi


Biomedicinsk laboratorievetenskap/teknologi




Livsvetenskaper och teknik (2010-2018)



Doktorsavhandlingar vid Chalmers tekniska högskola. Ny serie: 3436

KB-salen, Kemigården 4, Chalmers University of Technology, Sweden

Opponent: Dr Erik Björk, Institutionen för farmaci, Uppsala University, Sweden

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