Most people prefer to take their medicine in the form of a tablet rather than by injection. However, the increasing complexity of novel drugs over the past century means that they have become less soluble and therefore more difficult to administer in the form of a tablet. Now researchers have discovered a way to embed drugs in tiny medicine sponges so that they potentially can be taken orally and remain stable during shelf life.
Equipped with ever more powerful computers and greater knowledge about human pathology, chemists can develop drugs that can treat diseases more precisely and effectively and with fewer side-effects. Nevertheless, most of these drugs will never be available to patients simply because they cannot be given orally in the form of a tablet. Instead, the drugs need to either be injected or be replaced with less effective drugs. However, researchers have now developed a type of formulation that can deliver these new and more effective drugs.
“Until the 1990s, most drugs were soluble in water. Today, up to 90% are poorly soluble and therefore difficult to administer orally. The apparent solubility can be increased significantly by using the high-energy amorphous form of the drug in nanosized pores of mesoporous silica particles. Further, coating these particles with an additional polymer layer, for example, ensures that the drug does not precipitate immediately,” explains a main driver behind the discovery, Matthias Manne Knopp, researcher at the contract research organization Bioneer:FARMA at the Department of Pharmacy, University of Copenhagen.
Like dissolving sand in water
The challenge is that the drug needs to be dissolved in the gastrointestinal fluid to pass through the intestinal wall and into the bloodstream: that is, to exert its effect. In recent years, chemists have used advanced computational chemistry to design drugs that directly affect specific receptors or chemical processes in the body. However, this has changed the physicochemical properties of the newly designed drugs significantly.
“To treat diseases and symptoms more effectively and with fewer side-effects, chemists are now designing drugs that target specific receptors or processes. Most of the body’s receptors are hydrophobic and can often only be affected by hydrophobic drugs, and the majority of novel drug candidates are therefore poorly soluble in the gastrointestinal fluid.”
This challenge is comparable to dissolving sand in water. Nevertheless, there are various ways to increase the solubility of these poorly soluble drugs. One way is to use the high-energy amorphous form of the drug.
“The amorphous form of a drug has no crystal structure or molecular order, and it therefore has high internal energy, which results in increased apparent solubility. However, the amorphous form is also very unstable and tends to crystallize into the stable but poorly soluble crystalline form. By embedding the amorphous drug in the nanosized pores of mesoporous silica particles, we can protect the drug from crystallizing during storage on the shelf.
Spring and parachute effect
Like a sponge that can soak up water, the nanosized pores in the mesoporous silica particles can adsorb, store and stabilize these otherwise unstable amorphous drugs. This is because getting the drug out of the sponge requires energy or water.
The surface of the medicine sponge has higher affinity to water than the drug, so contact with the gastrointestinal fluid forces the drug out of the pores and into solution. Unfortunately, the drug may also crystallize during storage.
However, the researchers have solved this issue. Coating the pores of the sponge with an ultra-thin layer of the drug, only one molecule deep, creates a physical barrier that ensures that the drug remains amorphous inside the pores. Simultaneously coating the particles with a polymer layer, for example, ensures that the drug does not crystallize immediately upon dissolving in the gut.
“We have exploited what is known as the spring-and-parachute effect in the pharmaceutical industry. The high-energy amorphous form of the drug is the spring that makes the drug dissolve rapidly, and the polymer is the parachute that ensures that the drug does not precipitate immediately but is retained in the supersaturated solution over a longer period.”
Cracking the code
In their most recent study, the Copenhagen researchers have developed a method for determining the precise quantity of a drug that can be adsorbed in these tiny medicine sponges.
In our recent study, we developed and tested a new thermoanalytical method on the already marketed drugs carvedilol, which lowers blood pressure, and indomethacin, which relieves pain. This method enables us to precisely determine how much drug the sponges can contain without risking crystallization during storage.
The concept still needs to be refined to be able to achieve the optimal therapeutic effect. Nevertheless, the main value is to ensure that new and effective drugs can be developed in tablet form to benefit patients.
Today, many promising and effective drug candidates are discarded early in the development phase simply because they would have no effect when given in a conventional tablet formulation. This probably constitutes the greatest challenge for the pharmaceutical industry at the moment. With our new contribution, we may have cracked the code for how these effective drugs can be administered orally to benefit patients.
“A fast and reliable DSC-based method to determine the monomolecular loading capacity of drugs with good glass-forming ability in mesoporous silica” has been published in International Journal of Pharmaceutics. In 2014, the Novo Nordisk Foundation awarded a grant to the principal investigator of this project, Korbinian Löbmann, Associate Professor, Department of Pharmacy, University of Copenhagen, for the project Break on Through to the Other Side: Making Anti-cancer Treatment Orally Available.