Development of advanced nanoparticulate drug delivery systems for protective functions of the teeth

For many decades there has been a large focus on having a good dental health. This has led to low amount of caries. However, it seems that the decrease in the occurrence of caries has stagnated and that caries is increasing among the youngest part of the population. Also tooth wear is an increasing problem. This may be caused by the increased intake of acidic drinks such as juice and Coca Cola. According to WHO, dental caries and periodontal diseases are still huge problems, even though the overall world's dental health has been improved. It has been shown that continuous presence of fluoride, even in low concentrations, is favorable in the inhibition of caries. In order to protect the teeth, fluoride has to be attached to the teeth. The use of toothpastes with fluoride has so far proven to be the most effective self-care products. The drawback with such products, however, is the short exposure time due to the fast clearance of fluoride from the mouth due to the secretion of saliva. However, saliva is an important component in the mouth for maintaining both the oral and the dental health. In the current project we have worked with the development of a new administration system based on nanoparticles for their potential protective functions of the teeth. Nanoparticles are small spherical entities with a size in the area of nanometer (10^-9 m). The particles have a large relative surface area and can be given special properties for instance bioadhesive properties. Bioadhesive particles can attach to surfaces f. ex the teeth or the oral cavity. When the particles are attached, they will not be swallowed together with the secretion of saliva. This will be an advantage compared to other administration systems for protective functions of the teeth already present on the marked. In the project we are solving the challenges related to developing particles protecting the teeth in two different ways, a direct approach trying to prepare particles with fluoride preventing demineralization of the teeth and an indirect approach focusing on saliva?s properties of rehydrating the oral cavity. Regarding the direct approach, we have prepared and characterized biopolymer-based nanoparticles. Biopolymers are long chained entities derived from different natural sources such as algae, crab- citrus- and apple peels. The particles have been tested for their ability to interact with artificial saliva and also their cytotoxicity has been investigated. The results showed that the particles least cytotoxic were also the particles most reactive towards the electrolytes of saliva. Still, the particles seem promising but the particles must be optimised. Fluoride has also been loaded into the particles, but in a very small amount. However, it has previous been shown that just a small increase in the amount of fluoride in the oral cavity can significantly decrease the amount of dental caries. In order to verify the effect of the particles new studies must be conducted. The release of fluoride from the particles was slow. This could be an advantage to keep the level of fluoride in the oral cavity increased over an extended period of time. In addition the release was dependent of the pH of the release medium. More fluoride was released when the pH was lowered. This could also be an advantage since the pH in the mouth is lowered during an acid attack. When it comes to the indirect approach liposomes were chosen as the vehicle. Liposomes are based on lipids forming a double bilayer with a hollow core. The core can be loaded with a drug or a liquid. Liposomes were chosen due to their similarities with saliva. A new method was developed in order to determine the amount of moisture in the liposomes. The method determined the particles ability to adsorb and desorb water. In order to have effect, the particles should be able to adsorb high amounts of water and when placed in a dry oral cavity the particles should slowly desorb the water and hence rehydrate the oral cavity. First; two different administration systems were tested; naked liposomes and a solution of the hydrophilic biopolymer pectin as a reference since products existing on the marked are based on hydrophilic polymers. The study showed that liposomes seem to have a high potential when it comes to a slowly delivering of moisture. Second: the liposomes were covered with a hydrophilic biopolymer. This even increased their suitability of taking up and releasing a high amount of water. Based on all the conducted studies, it can be concluded that nanoparticles have a huge potential for protecting the teeth.

According to WHO dental caries and periodontal diseases have historically been considered the most important global oral health burdens. In the current project drug loaded bioadhesive nanoparticles will be developed and evaluated for their potential prote ctive functions of the teeth focusing on dental caries and dental erosion. In order to protect the teeth from these complications, a moderate to high saliva production is important to lubricate the teeth, but also a supply of fluoride is important. In t his project we will investigate the possibility of protecting the teeth by both a direct approach and an indirect approach. Concerning the direct approach, the drug delivery system should be bioadhesive and adhere directly to the dental enamel, the oral b iofilm or the oral mucosa and deliver fluoride in a controlled and sustained manner. Concerning the indirect approach the drug delivery system should be able to rehydrate the oral mucosa and by such reduce the tendency for dry mouth. If bioadhesive nanopa rticles are successfully produced and meet both the criterion outlined, there will be a dual action and greater possibility to reach the ultimate goal of protecting the teeth. The project strategy is to combine our knowledge of designing drug delivery sy stems (pharmaceutics and biopharmaceutics) with physics (bioimpedance) and develop new advanced drug delivery systems with protective functions of the teeth (dentistry). This will be realized with three scientifically work packages. WP1: Production, enca psulation of the active drug and characterization of the nanoparticles, followed by an investigation of the drug release from the particles and in vitro stability. WP2: Investigate the bioadhesive properties of the nanoparticles and their potential in de creasing caries and erosion of the teeth i.e. the direct approach. WP3: Investigate the mucoadhesive and the rehydrating properties of the nanoparticles towards the oral mucosa i.e. the indirect approach.