The Parc – a fertile ground for innovation in pharma

The Parc responds to current challenges of pharmaceutical research related to the nature of low-molecular-weight active substances having poor solubility and low bioavailability. A number of outputs shows technological approaches leading to bioavailability increase. Recently created start-ups offer unique technologies applicable for such purposes.

Despite the increasing use of biologics, pharmaceutical companies still market most products containing active ingredient in the form of small molecules. In 2018, the FDA approved the largest number of biologics in history (18), but also 42 small molecules. The main advantages of using drug substances in the form of small molecules include their well-defined structure, which allows their unambiguous characterization, their stability, and the possibility to produce them by processes of chemical synthesis. The low molecular weight of drugs allows them to pass through cell walls and reach their target directly in the cell. Although pharmaceutical research on small molecule active ingredients is active and growing, the nature of small molecules is changing - they are often poorly soluble and highly potent. This poses many challenges for pharmaceutical companies, which must change their manufacturing trends and industrial backgrounds to formulate new active ingredients into drug products that become highly complex and require the use of innovative technologies. They therefore often contract smaller companies to develop these products. These are often specialized in a particular technology and can respond quickly and flexibly to the demand, becoming the driving force for the innovation of small molecules in pharmacy. 

Traditional formulation techniques cannot be used for the development of formulations of poorly soluble active ingredients. To improve the solubility, absorption and bioavailability of active ingredients, new technologies, that have already been successfully used for the production of originator dosage forms, need to be employed. To name a few of the most important approaches and technologies: (i) modification of the solid form of the active ingredient, (ii) particle size reduction (micronization, nanomilling); (iii) spray drying, (iv) hot-melt extrusion, (v) lipidic formulations (vi) inclusion complexes. These technologies can also be used to improve existing dosage forms to produce so-called "value-added medicine". The use of some of the above approaches/technologies allows, for example, to reduce the dose of the active substance while achieving the same therapeutic effect as the original drug product, to eliminate the "food effect", thus allowing the possibility of administering the product both with food or after fasting or to eliminate or reduce unwanted side effects. Knowledge of these technologies is thus essential not only for originator companies but also for generic companies, which can improve older and new dosage forms and launch more patient-friendly products. Where does the Czech pharmaceutical academic and industrial environment stand in terms of knowledge of these technologies? Could we bring a newly discovered poorly soluble active ingredient to the market? Are "value-added" products also of interest to our generic companies? We will try to find the answers in the next few paragraphs.

The patents of the Czech generic companies TEVA and Zentiva show a keen interest in the search for new solid forms of active substances. Those new forms are most often polymorphs, solvates, hydrates, salts and cocrystals. In the last three years, Teva filled more than 60 patents and Zentiva has around 20 patents on this topic. In 2018, Zentiva launched Zilbea on the market containing the active ingredient agomelatine in the form of a cocrystal with citric acid. In this case, the active substance itself was first registered as a cocrystal. Some patents also describe inclusion systems and simple formulations containing new solid forms of the active substances. In recent years, Czech patents for formulations based on spray drying and hot-melt extrusion have also appeared, but products made by using these technologies have not yet been marketed by Czech companies. This slow uptake is certainly caused by the financial cost of production facilities, but also by the lack of expertise in these innovative technologies.

The research cluster The Parc, which links academic and industrial research, appears to be a clear bearer of the development of formulation technologies for poorly soluble active ingredients in the Czech environment. The Parc is responding to the current demand for these technologies from the industry by defining specific Ph.D. projects. The students who tackle these projects are becoming experts in these innovative formulation technologies. The Parc has already achieved considerable success. It has published a number of high-quality publications describing not only the formulation technologies but also the in vitro and in vivo efficacy of the formulations prepared. In addition, several filed patents demonstrate the potential for industrial applications. Two start-ups have been established with the aim of offering their unique formulation technologies to pharmaceutical companies, either local or from abroad. The first company, MarbleMat, founded in 2020, formulates the active ingredient into a lipidic matrix in the form of so-called liquid marbles, which can be further filled into capsules/tubes. The second start-up, Levare, which was founded last year, uses glucan particles as a carrier in whose internal structure the active ingredient is incorporated. The glucan particles are prepared by spray drying technology. Both start-ups aim to take production to a larger scale (scale-up) and construct production devices that meet the requirements of good manufacturing practice (GMP). 

Hopefully, the knowledge of innovative formulation technologies will soon be applied to the formulation of newly discovered chemical entities in our country and value-added medicine will become an integral part of the development of medicines by Czech pharmaceutical companies. The Parc platform could facilitate the process of change in pharmaceutical research in the Czech Republic. The start-ups created and emerging from The Parc could be advantageously used by local and foreign companies to formulate poorly soluble active ingredients or value-added products for the patients.

March 28. 2022

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