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There is very often a great gap between the performance of oral drug delivery systems in vitro and in vivo. During the last decade modern high resolution and/or real time imaging techniques like Magnetic Marker Monitoring (MMM)  or Magnetic Resonance Imaging (MRI) [2, 3] have provided new insights into the in vivo performance of drug delivery systems and their interaction with the physiology of the gastrointestinal tract. The physiological conditions for drug absorption along the gastrointestinal tract are far from being constant. This applies to the expression of transport proteins and metabolizing enzymes as well as for the luminal conditions [3, 4]. Accordingly, gastrointestinal passage of a drug delivery system plays a crucial role for drug absorption. Gastrointestinal transit is also not a constant process. It is strongly controlled by feedback mechanisms that involve neuronal and hormonal signal pathways. In contrast to widespread assumption, transit times through all gastrointestinal organs, i. e. stomach, small intestine and colon, are highly variable. Gastric residence times are in general dependent on the energy content of the gastric filling. The rate of gastric emptying under fed conditions is controlled by the energy content of the meal, the energy requirement of the body and feedback mechanisms like the ileal brake mechanism. Furthermore, the rate of gastric emptying under fed conditions is also influenced by particle size. As a consequence, the emptying of drug substances from the digesting stomach is dependent on three main factors, the gastric emptying rate of the meal, the intragastric distribution of the drug and the particle size of the formulation. Examples for the in vivo behavior of different oral controlled release systems and resulting drug plasma concentration profiles will be shown and discussed.
Several inter-related issues relevant for the development of novel drug delivery systems are covered in the talk. They encompass:
Almost alone among the process industries, the pharmaceutical industry has tended to rely on batch operations. This is now changing, driven by a need for better utilisation of resources, particularly clean space, and a demand for more closely controlled processes. Process Analytical Technology (PAT) demands that processes be controlled; this is much more easily engineered into continuous processes.
Wet granulation presents a particular problem, in that it has traditionally been carried out in a high-shear mixer-granulator and is not particularly well understood. What is known is that the mechanisms of nucleation, consolidation, growth and breakage occur more-or-less simultaneously in a high shear environment, and in a relatively uncontrolled way. In principle, it would be highly attractive to separate these basic mechanisms so that they occur within a continuous process in a controlled way.
This paper proposes the practical development of an overall process for continuous pharmaceutical manufacture, with consideration of process control, instrumentation, validation and real-time product release.
Most currently produced pharmaceutical formulations are based on a single molecular entity – the active pharmaceutical ingredient (API) – that is synthesised in a dedicated (bio)chemical plant and then has to be stable throughout the supply chain all the way to the patient. However, many pathogens that the API is supposed to fight use a different strategy: they produce toxins locally within the host and the timing, quantity and even composition of the toxins can vary from host to host and depending on local conditions.
The aim of our work is to design and synthesise structured microparticles called chemical robots that are inspired by the structure and function of single-cell organisms. A chemical robot consists of an outer semi-permeable shell and several internal separate compartments able to store and release chemical reagents on demand. A predefined set of chemical or enzymatic reactions take place within the body of the chemical robot and the reaction product is released to the outside environment at a predefined rate. The chemical robot can therefore be thought of as a miniature chemical reactor with internal supply of reactants and a mechanism for triggering their release.
The synthesis of chemical robots follows a bottom-up strategy. In the first step, the internal compartments (either based on liposomes or on hollow mesoporous silica particles) are synthesised and pre-filled with the required reagents. Compartments containing different reagents are then mixed in a colloidal suspension called “roboplasma” (like cytoplasma), which is then encapsulated into the external membrane by means of either inkjet printing technology  or interfacial polymerisation . Finally, the outer surface of the chemical robots can be functionalised by attaching the desired functional groups e. g. for specific ligand-receptor binding. In this presentation the current status of chemical robot synthesis and functionality will be reviewed and some challenges for further research in this area will be outlined.
This work is supported by the European Research Council through grant number 200580-Chobotix.
Inflammatory bowel diseases, such as Morbus Crohn or Colitis Ulcerosa, are painful for the patient and moreover difficult to treat due to the increased mucus production and the occurrence of diarrhea. We could demonstrate that the anti-inflammatory drug rolipram, when delivered by nanoparticles made of biodegradable PLGA, led to a prolonged alleviation of colitis syndromes in rats and a reduction of central nervous side effects, compared to the same dose of the drug administered as an aqueous solution [1, 2].
With respect to skin drug delivery, there is an interesting new hypothesis that nanoparticles may penetrate along hair shafts and to thus accumulate in hair follicles . However, applying PLGA nanoparticles loaded with flufenamic acid, were mostly seen in the intercellular clefts between the keratinocytes . The observed enhancement of epidermal penetration may instead be explained by an acidic microclimate around the hydrolyzing polymer particles, leading to a reduced dissociation and higher lipophilicity/better penetration of flufenamic acid . This data points out that, besides of their small size, the chemical composition of such nanomaterials remains evenly important.
Due to their large surface area and excellent blood supply, the lungs are an attractive alternative route for drug delivery, both for local as well as for systemic action. By escaping mucociliary or macrophage clearance, inhaled nanopharmaceuticals could perhaps be used as platform for pulmonary sustained release delivery systems. Finally, nanoplexes formed between biodegradable polymeric carriers and DNA/RNA-based drugs can be used to facilitate cellular transfection . We are currently using this approach for the delivery of telomerase inhibiting antisense oligonucleotides to lung cancer cells [7, 8].
Nanoparticles represent useful drug delivery systems for the specific transport of drugs to target cells and tissues. Over the last 30 years a multitude of different nanoparticle systems based on several starting materials were described. Recently, albumin based nanoparticles were approved by the FDA and EMEA as drug delivery device for tumor therapy. Most often nanoparticles are developed with the aim of selectively transporting a drug to a diseased tissue or organ. To reach this goal, such drug carrier systems may be combined with targeting ligands, which enable a cell-specific accumulation of the nanoparticles.
Within the presentation the development of targeted nanoparticles for tumor therapy will be described. The preparation and characterisation of antibody-modified protein-based nanoparticles will be focused . The ability of the particle systems to specifically accumulate in different tumor cell models by receptor-mediated endocytosis will be presented .
The results indicate that protein-based nanoparticles conjugated to an antibody against a specific cellular epitope hold promise as selective drug delivery systems for the treatment of cells and tissues expressing a specific cellular antigen.
Nanoparticles (NP) are increasingly used in a wide range of applications in science, technology and medicine. Since they are produced for specific purposes which cannot be met by larger particles and bulk material they are likely to be highly reactive, in particular, with biological systems. Direct routes of intake into the organism are (1) inhalation and deposition of NP in the respiratory tract and (2) oral intake of NP and ingestion. Recently there is evidence that nanoparticles can cross body membranes – such as the air-blood-barrier in lungs and the intestinal epithelium – reaching blood circulation and accumulating in secondary target organs. Therefore, direct intravenous administration of NP into circulation provides a powerful tool to shed light on the various interactions of crossing body membranes.
To quantitatively determine accumulated NP fractions in such organs the ultimate aim is to balance the NP fractions in all interesting organs and tissues including the remaining body and total excretion. Since these gross determinations of NP contents in organs and tissues do not provide microscopic information on the anatomical and cellular location of nanoparticles such studies are to be complemented by electron microscopy analysis as demonstrated for inhaled titanium dioxide nanoparticles.
Based on quantitative biokinetics after all three routes of administration in a rat model (lungs, blood, gastro-intestinal tract) we found small NP fractions (iridium, carbon, titanium dioxide, gold,) in all secondary organs studied including brain, heart and even in foetuses. Fractions per secondary organ were usually below 0.1% of the administered dose but depended strongly on particle size, material and surface modifications as well as on the route of intake.
The current knowledge on systemic translocation of NP and their accumulation in secondary target organs and tissues of man and animal models does not suggest to cause acute effects of translocated NP but chronic exposure may lead to elevated NP accumulations resulting eventually in adverse health effects.
In fact, there is growing evidence that ambient ultrafine particles and some of the engineered NP can induce acute adverse health effects in humans and in animal models not only in the respiratory tract but also in the cardio-vascular-system. Since NP translocation is so low these effects are likely to be triggered by mediators released in the organ of intake.
Understanding the intracellular localisation of biomedical nanoparticles (NPs), such as their co-localisation within cellular organells, e. g. endosomes, lysosomes, mitochondria or nuclei, or, alternatively free in the cytosol, can provide essential information in regard to the potential toxicity of NPs.
Polymer coated iron-platinum and gold NPs with a fluorescent dye embedded in the polymer shell were used to investigate their intracellular localization in lung cells, i. e. epithelial cells, macrophages as well as dendritic cells , and their potential to induce a pro-inflammatory response dependent on concentration and incubation time . In addition, a quantitivate method  was used to evaluate the intracellular gold NP distribution by transmission electron microsopy within time (1h, 4h and 24h).
By laser scanning microscopy it was shown that the iron-platinum NP were taken up by all three cell types but macrophages and dendritic cells to a higher extent than epithelial cells. In both cell types of the defence system but not in epithelial cells, a particle dose-dependent increase of tumor necrosis factor-α is found. By comparing the iron-platinum- and the gold NPs as well as the shell only it was shown that the cores combined with the shells are responsible for the induction of inflammatory effects and not the shells alone. The quantitative analysis revealed a significant, non-random intracellular gold NP distribution. No particles were observed in the nucleus, mitochondria, endoplasmatic reticulum or golgi, and the cytosol was not the preferred NP compartment. A significant increased gold NP localization in large vesicles (lysosomes) was found with prolonged post-incubation times, indicating intracellular particle trafficking.
In conclusion, by using sophisticated cell culture and microscopic methods, it is possible to determine if NPs exposed to cultured lung cells can penetrate into these cells, inducing an effect and furthermore, in which intracellular compartments they are subsequently localized (trafficking).
This work was supported by the German Research Foundation (DFG SPP 1313), the Swiss National Foundation (Nr. 3100A0_118420), the Doerenkamp Zbinden Foundation and the AnimalFreeResearch.
Continuous processing offers many advantages in pharmaceutical manufacturing. Low capital investment from a small factory foot print, removal of scale-up issues during process development and support of agile /lean supply chain being key economic benefits.
Process analytical technology is a key enabler of continuous processing of pharmaceuticals. The ability of rapid on-line measurement technologies reduces the risk of continuous mixing systems, and can support a QbD approach to control and lead to adoption of Real Time Release strategies for the product.
This paper will describe the on-line PAT systems developed for, and installed in Pfizer’s first commercial scale continuous drug product manufacturing facility. The focus will be on design of sample interfaces and the measure capability related to the product specifications. The paper will also include a discussion on method validation philosophies for on-line real time technologies applied to pharmaceutical processes.
Different solid state characterization techniques have been widely used to gain a better understanding of the physical solid state characteristics of drug substances and drug formulations. In the past, physical characterization in the pharmaceutical industry mainly relied on x-ray powder diffraction, thermal analysis and microscopy. More recently, vibrational spectroscopic techniques such as infrared (IR), near-infrared (NIR), Raman and solid state nuclear magnetic resonance spectroscopy (SS-NMR) have attracted growing attention in both academia and industry. Even more recently, terahertz pulsed spectroscopy (TPS) has also been utilized to investigate pharmaceutical materials.
Spectroscopic techniques possess many advantages over other traditional analytical techniques, for instance the fact that they allow rapid, non-destructive measurements, suitable for use in the process analytical technology (PAT) setting. In this presentation recent examples of the use of spectroscopic techniques especially Raman spectroscopy, NIR and TPS on characterizing pharmaceutical compounds and formulations will be presented. Specific examples from our own work will be presented in this talk.
Using the example of the important anticonvulsant drug carbamazepine (CBZ), we will demonstrate that Raman spectroscopy combined with partial least squares (PLS) analyses can be used to quantify the conversion of CBZ polymorphs to the CBZ dihydrate in aqueous suspension. It was found that crystal morphology and polymorphic form have a large effect on the conversion, but that the conversion is not quantitative. An increased understanding of the influence of factors of this conversion such as defects, crystalline face differences, which are important to the physical stability of CBZ, can be obtained using a combination of spectroscopic and imaging techniques.
Coating of tablets is an important way to design properties of the final dosage form. The purposes for coating are manifold, e. g. taste masking, humidity protection, gastric resistance, modified release, active coating. In some cases the coating uniformity is critical for the intended use. Therefore, it is important to know coating uniformity of tablets can be achieved and analysed. Several aspects have to be taken into account, namely the intra-tablet coating uniformity, the inter-tablet coating uniformity, and the batch-to-batch coating uniformity.
The intra-tablet coating uniformity can be determined by different methods. One modern approach is the determination of coating thickness by Terahertz pulsed imaging. Several thousands measurements can be done to scan the total surface of a coated tablet. It turns out that the coating thickness is higher on the upper and lower surface compared with the central band. This has consequences for the modified drug release. From simulations the film distribution on the tablet surface can be estimated.
The inter-tablet coating uniformity can also be estimated from simulations. These simulations are the basis for machine and process optimization in order to minimize the tablet-to-tablet coating variability. In case of active coating the content uniformity is limiting the variability. While the inter-tablet coating uniformity is typically determined offline first attempts are made for inline measurements.
Not only the amount and distribution of coated material on the surface of a tablet can influence the product properties, but also the quality of the film. Tablets coated with the same amount of polymer can show different release profiles, because the film thickness differs due to different densities of the film. Thus, not only the film thickness is of importance but also the film structure.
The majority of active agents used in medicinal therapy belong to category BCS II, which means that they have poor dissolution and good absorption properties, thus their absorption can be controlled and promoted first of all with various formulation technologies. Melt granulation, which is a thermomechanical technology, is used more and more frequently for the formulation of these poorly soluble active agents.
It can be considered as a possible technological operation only if the active agent(s) and excipients to be used are not heat-sensitive, and if the binding material has a solid state at room temperature but can be melted between about 30–90 °C. During the operation the active agent is either melted or is aggregated with the melt of the excipient.
Our aim was to create an excipient system with melt granulation the thermoanalytical and physical properties of which correspond to the values required for further processing (tabletting, encapsulation), and in which active agents belonging to category BCS II can also be processed well.
Melt granulation was performed with the hydrophilic Gelucire 44/14 (Gattefossé) lipid system, Mg-Al-silicate (Neusilin US2, Fuji Chem. Ind.) was used as a vehicle. Granulates were made with ProCepT high sheer granulator. The particle size distribution and the sphericity of the granulates was examined with Camsizer (Retsch Technology), their flowability with Erweka GT, the physical parameters of the tablets (breaking hardness, friability, disintegration) with Pharmatest equipment, while the dissolution studies were made with a Hanson apparatus. The changes in the thermoanalytical properties of the granulates were followed with DSC and TG (Perkin Elmer). A drug reducing appetite was used as an active agent.
During our work we were successful in formulating melt granulates which contained a sufficient quantity of adsorbed lipids to enhance the solubility of BCS II active agents and also had appropriate physical properties necessary for tabletting.
It was found that the yield of the granulate increases with the increase in the concentration of Gelucire, in addition to which its density also increases and its thermal stability improves.
Variability among individuals that affects clinical outcome is still one of the major challenges in drug development and in the practice of medicine. No single drug is 100% efficacious in all patients. While some individuals obtain the desired effects, there can be no or little therapeutic response in others. Additionally, some patients might experience adverse effects. This interindividual variability is a consequence of myriad of factors, such as disease states, genetic factors, patient age, concomitant medications, and life style factors such as smoking. Most drugs undergo biotransformation and their disposition in the body may involve multiple transport proteins. In addition, they interact with diverse protein targets. This concerted action results in the multigenic nature of a majority of drug responses. Pharmacogenomics, in the future, may provide a complex and more precise set of tools for clinicians to use for diagnosis and treatment. Extensive pharmacometric expertise and model building enables personalization of therapies, which is far from trivial if one considers the complexities of designing the most effective dosage regimen of one or more drugs in conjunction with novel biomarkers. Population pharmacokinetic/pharmacodynamic methods, such as nonlinear mixed effects modeling are able to obtain relevant information in patients who are representative of the target population. They recognize sources of variability such as inter- and intraindividual as important drug characteristics, and seek to explain variability by identifying various covariates, including genetic factors. Additionally, they aim to quantitatively estimate the magnitude of the unexplained part of the variability, which is important because the efficacy and safety of a drug may decrease as unexplained variability increases. This presentation will demonstrate how pharmacogenetics and population pharmacokinetics can personalize treatment with warfarin, leflunomide , and risperidone .
The dramatic changes in the demographics will increase the number of elderly people from today’s 10 % to 20% of the population in 2050, which is considered of one of the biggest challenge for our society. Geriatric therapeutic care is a multidisciplinary task that starts early on in the therapy of older adults and involves all stakeholders, including the patient, clinicians, physician, pharmacist, nurse, pharmaceutical industry and sciences and health care providers and policy makers . When chronic diseases develop along with the increasing age and people start to take regularly medicines. With other diseases or symptoms occuring additional medications are given in the best intend of curing. Various physiological, biological, physical and social functions are changing with age too, leading to an increasingly heterogeneous patient group of the people 65 years and older. With 30–50% of all prescription drugs elderly patients represent the majority of drug users; however, their needs are poorly recognized in drug products development as well as their perception on medicines and their individual goals in drug prescription and therapy. Changes in the physiological and functional capacities, declining cognitive functions, impaired vision , increasing motoric limitations , an increasing difficulty of swallowing  and an increasing number of chronic diseases occurs with age. Within our drug product development programs the needs of special patient populations like elderly have to be taken into consideration. Age related changes need to be better understood and integrated into an overall therapeutic care plan that reflects the patient expectations and goals in the therapy as well as the patient life style to be executable.
The author would like to thank all members of the ‘Geriatric Medicines Society’ for the contributions to this paper.