WHITEPAPER - Drug Delivery – Recent Trends, Enabling Technologies, In-Vitro-In-Vivo Predictions & Personalized Medicine

By: Dr. Jens Morgenthaler, General Manager and Dr. Matthias Rischer, Head of Innovation, Losan Pharma GmbH

 Introduction

The successful formulation of small molecules is still one of the important challenges of today, especially if these drugs belong to the BioClassificationSystem II and IV (1). The small molecule drug discovery landscape has been estimated to around 32.15 billion USD in 2025 and is expected to increase to more than 50 billion USD in 2026 rising at a CAGR of 8.16% (2). The CDER has approved 50 novel drugs either as new molecular entities (NMEs) under New Drug Applications (NDAs), or as new therapeutic biologics under Biologics License Applications (BLAs) in the year 2024 (3). Among these, the small molecules drug products still represent the majority of approvals, 18 approvals for biosimilars and 26 (52%) for rare disease applications. In 2024, EMA recommended 114 medicines for marketing authorisation. Of these, 46 had a new active substance which had never been authorised in the European Union before, including 28 recommendations for new biosimilar products and 15 for Orphan medicines (4). The trend of filing of new active substances especially as Orphan Medicines persists beside the increasing number of biological drug applications. However, bifunctional molecules like proteolysis-targeting chimera (PROTAC) lead to a target protein degradation offering a completely new area of interest after the first clinical proof-of-concept against two well-established cancer targets provided in 2020 (5).  Vepdegestrant has got fast track designation by the FDA for the treatment of advanced or metastatic breast cancer in 2024 (6). Especially the development of PROTACS for oral applications seems to be very challenging due to challenges with solubility, permeability, ternary complex formation and further physicochemical properties (7). But, the interest for the development of PROTACS in different clinical applications is still high (8):

Figure 1. Therapeutic applications of PROTACS.

Enabling technologies such as Nanotechnology, Amorphous Solid Dispersions, Self-emulsifying/nanoemulsifying drug delivery systems (SEDDS/SNEDDS) or Lipid Nano Particles (LNPs) for oral delivery are key elements for the development of complex and difficult to develop small molecules (9-15). Although these technologies have been well-established so far with a comprehensive understanding of the design, characterisation, stability and permeability, the in-vivo predictability of formulations is still quite limited, leading to sometimes negative results in in-vivo studies with animals in early pk testing.

Attempts have also been made to develop drug medication more personalized following a Point-of-Care (PoC) approach (16). However, this approach is still lacking regulatory confidence and willingness for fast-track designation by the authorities and, therefore, are still difficult to establish (17). Tailored 3D printing by using a high number of printing modules or specific printing applications for screening have recently overcome the low printing speed and producing a reasonable high number of tablets per hour/day (18, 19).

Enabling technologies for development of complex, low soluble and/or low permeable molecules Nanotechnology

Gao et. al. recently published an overview on drug nanosuspensions (9). He claimed that nanosuspensions are frequently used as a universal formulation approach for improved drug delivery of hydrophobic drugs and are one of the most promising approaches for increasing the biopharmaceutical performance of poorly water-soluble active substances (mainly BCS II). Nano-size formulations increase the bioavailability, which may directly reduce the applied dose and therefore improve patient compliance. In addition, the effect of food can often be minimized as successfuly shown with the nanosized formulation of Fenofibrate (Tricor) several years ago. Due to the characteristics of a small particle size and a large specific surface area, nanosuspensions have a relatively high adhesion towards the gastrointestinal mucosa, thus extending the retention time in the gastrointestinal tract. The drug is released at the adsorption site, the drug saturation solubility increases, as well as the concentration gradient in the intestinal wall and in the plasma, accelerating the absorption rate and increasing the absorption. In addition, lymphocytes of the gastrointestinal tract can cytophagy the nanosuspensions, and therefore the nanocrystals exhibit a targeting effect and can avoid the first-pass-effect. For stabilisation of nanosuspensions formulations only small amounts of surfactants and polymers are added and, therefore adverse reactions caused by organic solvents or excipients used for solubilisation are fully avoided. The top-down process with wet media milling is nowadays well-established, widely used and safe, also due to the superior performance of the used Zirconia beads which do not show any significant defects, even after the wet milling process. Thereof, virtually no residues are obtained in the final product of this less toxic Zirconium and Yttrium (used for further hardness of the Zirconia beads):

Figure 2. Residues of Zirconium and Yttrium after wet ball milling.

Interestingly, the milling beads are covered with polymers and surfactants after the wet ball milling process. After washing with aqueous media almost all polymer and surfactant residues disappear. The obtained cleaned beads show only very few minor cracks on the surface after the milling process underlining the safety of such process:

Figure 3. 0.3 mm Zirconium beads after milling process: uncleaned (left) and cleaned (right).

The stability of nanosuspensions however, are dependent on many different factors:

Figure 4. General stabilization of Nanoparticles.

In the absence of any well-established theoretical model to predict the performance and stability of nanosuspensions in the presence of different polymers and surfactants, we have established a fast screening system for nano-sized suspensions in collaboration with the University of Freiburg (Germany) and Netzsch several years ago. In this screening system, we have successfully established the efficient screening of 40 samples within a few hours with mg to a few grams API consumption. Even Design of Experiments (DoE) trials at this early development stage can easily be performed (9):

Figure 5. DoE generated contour plot of PSD (D90-values) from screening investigations of suspensions containing 10% Fenofibrate milled under constant milling conditions to investigate the samples leading to the smallest particle size.

Heat and wear stress can be well controlled and most of the investigated drug substances have not shown any degradation or polymorphic change, which is another advantage of the described nanomilling process.

However, many researchers simply forget that nanoparticles can easily be converted into agglomerated particles again during the drying on a carrier followed by encapsulation or compression into tablets. Special knowledge is needed to select the right stabilisers and process conditions as shown in figure 5 for Abiraterone nanosuspensions used in a fluid bed drying process followed by a compression step to oblong tablets:

Figure 6. PSD (Malvern Mastersizer 3000) of not successfully FBD dried Abiraterone granules on a carrier.

Figure 7. PSD (Malvern Mastersizer 3000) of FBD granules of Abiraterone before and after drying on a carrier.

Amorphous Solid Dispersions (ASDs)

The AbbVie colleges have recently given a comprehensive review of the principles (20), charac-terisations and formulation development of ASDs. Hot Melt Extrusion, as one of the well-established processes to produce ASDs, has been used for many commercial products so far:

Figure 8. Approved Drugs produced by Holt Melt Extrusion.

As seen for the Nanotechnology an efficient screening model for ASD formulations is a key aspect to generate important data with minimal amounts of the API in a short period of time. The melt prep system is a nice and time-efficient screening tool to generate small discs with the corresponding API embedded into different polymer matrices to be investigated on recrystallisation of the drug after storage under different humidity conditions:

Figure 9. Set-up of screening system for ASD formulations.

Beside the screening of suitable polymers and the stabilisation of the amorphous API, the solubilisation and the saturation respective over-saturation of the investigated API is important. Several methods are existing to investigate this parameter in relation to process conditions like FT-Raman mapping (22) or solubility curves derived from the Flory-Huggins lattice theory (12):

Figure 10. Efavirenz (w/w) solubility curves in polymers, derived from the Flory-Huggins lattice theory. The dashed lines represent the 95% prediction intervals.

Figure 11. Overview of the stability of ASD samples with either 20% (w/w) Efavirenz or an Efavirenz load of 20% above the solubility limit in the polymer (High) stored at three conditions.

Figure 12. Recrystallisation of Efavirenz in a Polyvinylalcohol (PVOH) matrix (20%) after storage at 37°C/75% rh after 1 day.

While bioavailability enhancement of ASDs is well documented, it has often been a challenge to establish a predictive model describing in vitro-in vivo relationship (IVIVR). We established an in-vitro dissolution-permeation (D/P)-setup that might aid in providing a more reliable evaluation of formulations of poorly water-soluble drugs before initiating animal studies (13).

During development of ASD formulations the obtained in-vitro dissolution data are generally focussing on the full release of the API and the respective release profile over time.  However, in biorelevant media, for example, a sustained parachute effect by the polymers used is very often overestimated and in many cases a spring effect is achieved instead with precipitation of the active ingredient after a short retention time in vivo. To achieve a better predictability, we have investigated in the last years together with Prof. Thomas Rades and Prof. Anette Muellertz from the University of Copenhagen, Denmark, a model to ensure a better ivivc for certain drugs. After some evaluation a model by using the µFlux system has been implemented:

Figure 13. µFlux system from PION.

It could be demonstrated that for the BCS II drug substance Efavirenz the use of a double membrane system was superior compared to a single membrane system in comparison to the obtained in-vivo data, with regard to a successful in-vitro-in-vivo (IVIVC) correlation (12):

Figure 14. µFlux data for Efavirenz with a different method set-up.

Figure 15. in-vivo data (Male Sprague–Dawley rats) for ASD from Efavirenz after oral application.

After the short screeening phase suitable, well-designed equipment for lab scale trials is needed to ensure no surprise by the further process development on the one hand and to avoid use of larger amounts of API on the other hand. Process conditions (e.g., speed, design of screwing elements, temperature) can be well-designed in a lab extruder like the Pharma 11 from Thermo Fisher, but also the control of the final particle size distribution of the milled extrudate is another important parameter to be considered. A new hammer-type mill has been recently installed to ensure a proper milling of extrudates from early lab scale trials.

Figure 16. EasyMill-Lab HM-1 from Frewitt

SMEDDS

The use of solid SMEDDS (S-SMEDDS) is a new and suitable approach for reducing production costs, by providing stability improvements, for better patient compliance, and improvements in dosing accuracy. Safety can also be improved, since solid systems are less irritating to the gastrointestinal mucosa. Adsorption on carriers via Fluid Bed Drying or Hot Melt Extrusion are valid approaches to achieve solid SMEDDS (22). We have started a project recently investing a Fluid Bed Layering/Drying Process for small molecules with low water solubility (BCS II) to evaluate the performance of these dosage forms in comparison to the e.g., Nanotechnology platform.

 The personalized medicines problem

As pointed out in the introduction the PoC approach is still lacking regulatory strategy and approval. Therefore, we have evaluated the use of 3D printing in the spotlight for use of small batches intended for Orphan Drug Indications and the flexibility of dosing and production. In contrast to many applications and publications we have been focussing on Immediate Release (IR) formulations. The printing time has been in the range of 2-8 min per tablet depending of the dose and mass applied.

Figure 17. Concept for 3D printing batches with easy dose variation and production on demand by using spooled filaments produced via HME

It has been further demonstrated that the dissolution of the IR formulations needs a careful evaluation of the dissolution system which is applied to analyse the 3D-printed tablet containing different excipients as compared to normal tablets, leading easily to sticking of the tablets to the surface of dissolution vessels in a standard set-up and causing a delay in the release profile.

Figure 18. Dissolution profiles of Domperidone 10mg 3D printed tablets with different dissolution equipment (and Ultra Turrax treatment at the end of the process to provoke complete dissolution)

Future

These described aspects for the Nanotechnology and the fact that no relevant bead residues in drug products have been detected have led to the application of the Nanotechnology also for s.c., i.m. and even i.v. applications of nanosuspensions in the last years (23). Even the use in intranasal applications especially for nose to brain delivery is getting more and more interest (24). For oral treatments this technology is already a key one to be applied in early development and clinical phase. Certainly, new drug products will appear on the commercial market using this Nanotechnology in the next years.

The ASD landscape is further elaborating as well. Compared to the Nanotechnology more drugs have reached the market so far and new polymers like the HPMC-AS have led to a real push of this technology also for this polymer in comparison to the widely used polymer Copovidone. With the further use of other polymers or polymer mixtures this could even accelerate the application of this technology for further drug substances, presumably also for high melting ones like the Tyrosine Kinase Inhibitors.

 References

(1) ICH HARMONISED GUIDELINE BIOPHARMACEUTICS CLASSIFICATION SYSTEM-BASED BIOWAIVERS, M9, Final version, Adopted on 20 November 2019.

(2) Small Molecule Drug Discovery Market- Growth Trends, COVID-19 Impact, and Forecast (2022-2027). Mordor Intelligence. 2022. Available at: https://www. mordorintelligence.com/industry-reports/small-molecule-drug-discovery market.

(3) FDA New drug therapy approvals 2024 (new-drug-therapy-2025-annual-report).

(4) New Medicines Report 2024 EMA.

(5) PROTAC targeted protein degraders: the past is prologue, Nature reviews drug discovery, 18.01.2022.

(6) https://www.pfizer.com/news/announcements/arvinas-and-pfizers-vepdegestrant-arv-471-receives-fda-fast-track-designation.

(7) The Quest for Oral PROTAC drugs: Evaluating the Weaknesses of the Screening Pipeline, Caron et. al., ACS Med. Chem. Lett. 2023, 14, 879−883.

(8) A comprehensive primer and review of PROTACs and their In Silico design, Computer Methods and Programs in Biomedicine 264 (2025) 108687.

(9) Nanosuspensions technology as a master key for nature products drug delivery and In vivo fate, Gao et. al., European Journal of Pharmaceutical Sciences 185 (2023) 106425,

(10) Dual centrifugation – A new technique for nanomilling of poorly soluble drugs and formulation screening by an DoE-approach, M. Hagedorn et. al., International Journal of Pharmaceutics 530 (2017) 79–88.

(11) Rapid development of API nano-formulations from screening to production combining dual centrifugation and wet agitator bead milling, M. Hagedorn et. al., International Journal of Pharmaceutics 565 (2019) 187 – 198.

(12) Stability and intrinsic dissolution of vacuum compression molded amorphous solid dispersions of efavirenz, A. Muellertz et. al., International Journal of Pharmaceutics 632 (2023) 122564.

(13) In vitro-in vivo relationship for amorphous solid dispersions using a double membrane dissolution-permeation setup, T. Rades et. al., European Journal of Pharmaceutics and Biopharmaceutics 188 (2023) 26–32.

(14) Preparation of a solid self-microemulsifying drug delivery system by hot melt extrusion, R.M. Maretto et. al., International Journal of Pharmaceutics 541 (2018) 1-10.

(15) Oral Lipid Nanoparticles for Improving the Efficiency of Drug Delivery Systems in Ulcerative Colitis: Recent Advances and Future Prospects, Long and Dai et. al., Pharmaceutics 2025, 17, 547

(16) A framework for conducting clinical trials involving 3D printing of medicines at the point-of-care, A. Goyanes et. al., Drug Delivery and Translational Research, April 2025.

(17) The Human Medicines (Amendment) (Modular Manufacture and Point of Care) Regulations 2025.

(18) Zheng Y, Deng F, Wang B, Wu Y, Luo Q, Zuo X, et al. Melt extrusion deposition (MED™) 3D printing technology – A paradigm shift in design and development of modified release drug products. Int. J. Pharm. 2021.

(19) https://www.laxxonmedical.com/technology

(20) Solid solutions for insoluble drug substances, AbbVie, Pharmakon 6/2023

(21) Shu Li, Yiwei Tian, David S. Jones, and Gavin P. Andrews, Optimising Drug Solubilisation in Amorphous Polymer Dispersions: Rational Selection of Hot-melt Extrusion Processing Parameters, AAPS PharmSciTech, Vol. 17, No. 1, February 2016

(22) Preparation of a solid self-microemulsifying drug delivery system by hot melt extrusion, Ricardo N. Marreto et. al., International Journal of Pharmaceutics 541 (2018) 1–10

(23) Parenteral nanosuspensions: a brief review from solubility enhancement to more novel and specific applications, M.Misra et. al., Acta Pharmaceutica Sinica B 2018; 8(5):733–755.

(24) Nose to brain delivery of tailored clozapine nanosuspension stabilized using (+)-alpha-tocopherol polyethylene glycol 1000 succinate: Optimization and in vivo pharmacokinetic studies, H.P. Patel et al., International Journal of Pharmaceutics, Volume 600, 1 May 2021, 120474.