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Orally administered medications are susceptible to different conditions, which can change the pharmacokinetics (PK), and directly influence the bioavailability of a drug. Because older adults are susceptible to drug adverse effects, changes in drug PK may be harmful to them, therefore, it is favourable to know how they take their medications in real life. The presented thesis combines theoretical and practical aspects of dosing conditions. First, by means of a questionnaire study, the real-life dosing conditions in older adults were investigated to identify the possible problems that can affect the safety and efficiency of orally administered medications from a biopharmaceutical perspective. The developed questionnaire was applied in Germany and Poland. Both study populations were similar regarding drug intake. Typical dosing conditions reported by older populations in Germany and Poland that were the most important for drug absorption were as follows: I. Drug intake was on average, with ~100 mL of fluid (in Germany, most often ~200 mL, in Poland ~50 mL). II. Non-carbonated water, tea, coffee, and carbonated water were commonly used for drug administration. III. Medications were mostly taken directly after meals; in Germany, also 30 minutes before breakfast. IV. Bread-based meals dominated breakfast and dinner. V. Solid dosage forms were preferred for their ease of use and swallowing.
Second, the data about the most common fluids co-administered with medications by older adults were used to investigate the influence of real-life fluids on the disintegration of gelatine and HPMC capsules in vitro and in vivo. For in vitro studies, the USP 2 apparatus and the biorelevant GastroDuo model were used. In a clinical study with 12 young, healthy volunteers and 6 study arms, the salivary tracer technique was used. In the clinical study, the gastric emptying of administered fluids was also investigated.
In vitro data demonstrated that co-administered fluids strongly affected capsules' behaviour. For gelatine capsules, temperature had the greatest influence. HPMC capsules were more consistent, however, black tea delayed their opening time and drug release in the USP 2 apparatus. In vivo, gelatine capsules were also highly affected by the temperature, with the fastest opening in warm water and significantly slower in cold water. However, warm black tea significantly delayed the opening time of gelatine capsules in comparison to warm water. HPMC capsules behaved consistently in all fluids, showing no effect of temperature or black tea ingredients. Overall, HPMC capsules were more robust under fasting conditions. Results also highlighted differences between in vitro models. USP 2 apparatus captured mainly temperature effects, while GastroDuo better reflected in vivo conditions by simulating gastric emptying, pH, volumes of media, secretion and pressure events and predicted well the behaviour of HPMC capsules in vivo.
No significant differences in gastric emptying of tested fluids were observed, which demonstrates that the indirectly detected capsule behaviour is the result of their properties and the influence of the co-administered fluid, not a matter of differences in gastric emptying.
Older adults in Poland and Germany interviewed within the presented thesis mostly administered their medications with non-carbonated water. However, the usage of black tea was also worth noting, since it was especially prevalent among the Polish population and in further studies it was demonstrated that it significantly delayed the opening time of gelatine capsules in vivo. The collected data gave an overview of capsules' behaviour in real-life fluids and demonstrated that dosing conditions are important. Investigating how patients take their medications is a way to ensure a more patient-centric approach in drug development.
Skeletal muscle is a dynamic tissue with high plasticity which maintains its functionality by regulating the balance between protein degradation and protein synthesis. In response to injury and other pathological conditions like inflammation and sepsis, a loss in muscle mass (muscle atrophy) and function (metabolic homeostasis, contractility) occurs. Critically ill septic patients often develop intensive care unit-acquired weakness (ICUAW), characterized by muscle weakness and atrophy as well as insulin resistance. Sepsis and inflammation are major risk factors for ICUAW. However, the pathogenesis of this syndrome is poorly understood but a disturbed glucose homeostasis and an enhanced inflammation are implicated. Previous RNA sequencing and quantitative real-time polymerase chain reaction (qRT-PCR) analyses of RNAs isolated from human M. vastus lateralis of critically ill patients and muscles from septic mice revealed an increased expression of the protein tyrosine phosphatases protein tyrosine phosphatase 1 B (PTP1B/PTPN1) and t-cell protein tyrosine phosphatase (TCPTP/PTPN2). In parallel a decreased expression of insulin receptor substrate (IRS) 1 and reduced insulin receptor (INSR) phosphorylation indicative for insulin resistance was observed. Because PTP1B and TCPTP are nodal enzymes in insulin and cytokine signaling in skeletal muscle and immune cells these data suggested their involvement in inflammation-mediated insulin resistance and skeletal muscle atrophy. I hypothesized that PTP1B and TCPTP are major regulators of insulin signaling and inflammation via dephosphorylation of cytokine receptor associated proteins in skeletal muscle. To investigate the mechanism responsible for Ptpn1 and Ptpn2 upregulation during inflammation I treated C2C12 myocytes with the inflammatory cytokine interleukin 6 (IL-6). IL-6 increased the expression of Ptpn1 and Ptpn2. Using small interfering RNA (siRNA) and chemical inhibitors, I found that this effect was mediated by the transmembrane IL-6 receptor glycoprotein 130 (Gp130) and the downstream kinases Janus kinase 2 (JAK2) and Signal transducer and activator of transcription 3 (STAT3). IL-6 facilitates its pro- and anti-inflammatory effects through the transcription factor STAT3, which gets tyrosine phosphorylated, translocates into the nucleus and modulates the expression of IL-6 responsive genes, such as suppressor of cytokine signaling 3 (Socs3). Overexpression of PTP1B and TCPTP attenuated IL-6 mediated STAT3 tyrosine phosphorylation and Socs3 gene expression. Overexpression of PTP1B but not TCPTP inhibited insulin mediated phosphorylation of the insulin receptor beta chain and its downstream targets IRS1, Akt (protein kinase B), and Akt substrate of 160 kDa (AS160) in C2C12 myocytes. To investigate the role of PTP1B and TCPTP in skeletal muscle in vivo, I generated male and female mice devoid of Ptpn1 (Ptpn1 cKO), Ptpn2 (Ptpn2 cKO) and Ptpn1+Ptpn2 (DKO) in myocytes. I subjected these mice to polymicrobial sepsis for 24 hours or 96 hours employing cecal ligation and puncture surgery (CLP). Sham treated male and female KO and wildtype (WT) mice served as controls. Septic DKO mice showed a higher mortality compared to their sham operated littermates and septic WT mice. Morphological and histological analyses showed a higher muscle mass loss and more muscle atrophy, tissue leucocyte infiltration and leucocyte marker gene expression in muscle of septic DKO mice. This was accompanied by an increased pro-inflammatory cytokine signature with increased amounts of interleukin 1 beta (IL-1β/Il1b), tumor necrosis factor alpha (TNFα/Tnfa), interferon gamma (IFNγ/Ifng) and IL-6/Il6 in skeletal muscle and serum of septic DKO mice. Chemokines that are chemo attractants for immune cells, like C-C-motif ligand 2 and 5 (Ccl2, Ccl5) and C-X-C motif ligands 9 and 10 (Cxcl9, Cxcl10) were upregulated on gene expression level in muscle tissue as well as in serum of septic DKO mice compared to septic WT mice. Additionally, I observed an increased NLR family pyrin domain containing 3 (NLRP3) -inflammasome activation in muscle of septic DKO mice. Inflammasomes are multiprotein complexes which facilitate innate immune responses after infection by activation of caspases which cleave and mediate the release pro-inflammatory cytokines like IL-1β and interleukin 18 (IL-18). In addition, using global proteomics analyses I observed a significantly dysregulated interferon γ (IFNγ) response in TA muscle of septic DKO mice shown by increased IFN stimulated gene (ISG) expression, increased abundancy of interferon regulatory factor 1 (IRF1) transcription factor as well as increased IFN-dependent chemokine expression. Utilizing murine myocytes in vitro and treating them with IFNγ, I reproduced the phenotype seen in mice. These data are indicative for a myocyte specific phenotype. I could also activate the NLRP3 inflammasome in primary myocytes from mice that were differentiated into myotubes. In these cells I show that the release of IL-1β and GSDMD is dependent on PTP1B and TCPTP; further validating the results seen in TA muscle of septic mice. In summary, deficiency of PTP1B and TCPTP caused a hyperinflammatory systemic and skeletal muscle phenotype which was caused by a dysregulated IFNγ and NLRP3 inflammasome response to infection. Furthermore, it pronounces the role of skeletal muscle as a highly immunomodulatory organ, which is crucial in maintaining whole body proteo- and homeostasis. Therefore, inhibition of PTPs should be carefully evaluated in a clinical setting.
Der Ösophagus ist aufgrund seiner Physiologie und der dort herrschenden Bedingungen ein schwer zugänglicher Applikationsort für eine lokale Arzneimitteltherapie. Nichtsdestotrotz besteht für einige Krankheitsbilder wie beispielsweise eosinophile Ösophagitis (EoE) ein ansteigendes Bedürfnis für Möglichkeiten zur lokalen Pharmakotherapie. Im Rahmen dieser Arbeit wurde ein Übersichtsartikel verfasst, der die anatomischen und physiologischen Besonderheiten dieses Applikationsortes hervorhebt und diskutiert, wie diese überwunden werden können.
Die vorliegende Arbeit beschäftigt sich außerdem mit der Weiterentwicklung eines Modells zur Simulation der Speiseröhre unter dem Aspekt der Biorelevanz. In einer vorausgegangenen Arbeit wurde bereits der Einfluss von Peristaltik, Flussrate des Freisetzungsmediums und Neigungswinkel des Modells auf die Verweildauer eines Polymerfilms untersucht. Aufgrund der komplexen physiologischen Vorgänge im Ösophagus ist es schwierig den Einfluss dieser Parameter auf eine Arzneiform separat voneinander zu untersuchen. Auf Basis bereits durchgeführter Untersuchungen an dem etablierten EsoPeriDiss-Modell wurden zwei Testszenarien entwickelt. Der stimulierte und nicht stimulierte Modus simulieren physiologische Zustände in wachen Proband*innen tagsüber beziehungsweise entsprechend in schlafenden Proband*innen nachts. Die Untersuchungen mit einem mukoadhäsiven Polymerfilm und einer viskosen Lösung zeigen, dass die Verweilzeit beider Arzneiformen verlängert ist, im Vergleich zu einer Standardlösung. Erhöhte Stressbedingungen für die Arzneiform im stimulierten Modus, welche durch eine erhöhte Flussrate, hohen Neigungswinkel und häufige peristaltische Ereignisse gekennzeichnet sind, führen außerdem zu einer kürzeren Verweilzeit in dem EsoPeriDiss-Modell. Des Weiteren wurde eine Temperierung des gesamten Modells implementiert, wodurch nicht nur das Freisetzungsmedium, sondern auch der Applikationsort auf 37 °C beheizt werden konnte. Zur Steigerung der Biorelevanz wurden außerdem verschiedene künstliche Speichelmedien hergestellt und getestet. Es zeigte sich, dass vor allem der Zusatz eines Viskositätserhöhers zu einer Änderung der Verweilzeit eines applizierten Films beitrug. Insgesamt bildet das weiterentwickelte EsoPeriDiss-Modell die Komplexität des Ösophagus als Applikationsort gut ab und stellt eine gute Alternative zu kompendialen Testmethoden dar. Die Simulation von Peristaltik und verschiedenen Flussraten des Freisetzungsmediums bilden die physiologischen Bedingungen im Ösophagus genauer ab, als es mit Standardtestapparaturen der Arzneibücher möglich ist. Daraus ergibt sich ein Erkenntnisgewinn über ein mögliches Verhalten der Arzneiform in vivo. Zukünftige Untersuchungen mit diesem Ösophagus-Modell könnten einen Fokus auf die Abbildung von peristaltischen Dysfunktionen legen. Durch die Integration von In vivo-Daten könnte die Funktionalität von Arzneiformen wie der EsoCap in der Anwendung in erkrankten Patient*innen besser untersucht werden.
Ein weiterer Teil der Arbeit befasst sich mit der Herstellung von patientenindividuellen Filmen mit innovativen Verfahren wie dem 2D-Druck. Die Herstellung von ösophageal applizierten Polymerfilmen kann neben bewährten Methoden wie dem Solvent-Casting-Verfahren auch mittels neuerer Technologien geschehen. Der 2D-Druck von Arzneiformen ist neben dem 3D-Druck eine bereits viel untersuchte Herstellungstechnik. Sie bringt vor allem in der Zubereitung von individualisierter Arzneimitteltherapie einige Vorteile mit sich. In den durchgeführten Versuchen wurde allerdings deutlich, dass die Verwendung eines herkömmlichen Tintenstrahldruckers zwar eine gute Auflösung von gedruckten Formen auf Placebo-Filmen hervorbringt, eine Gehalteinstellung mittels der genutzten Software allerdings nicht ohne weiteres möglich ist. Untersuchungen mit hochkonzentrierten Koffeinlösungen zeigten, dass es durch ein Verdunsten der leicht flüchtigen Bestandteile der wirkstoffhaltigen Tinte zu einer Verstopfung der Druckkopfdüsen kommt. Durch diese Problematik wird im Vergleich zur offizinellen Herstellung von Kapseln eine geringere Präzision und Richtigkeit des Gehalts erreicht. Die durchgeführten Versuche zeigen die zum aktuellen Zeitpunkt bestehenden Limitationen dieser Technologie. Es bedarf weiterer Forschung im Bereich der Entwicklung von wirkstoffhaltigen Tinten, Implementierung von Überwachungssystemen zur Qualitätskontrolle und Nutzung der Systeme unter GMP-Bedingungen. Insbesondere für die Herstellung von Arzneiformen mit empfindlichen aktiven Substanzen wie beispielsweise Proteine oder Nukleinsäuren, könnte der 2D-Druck in der Zukunft eine vielversprechende Herstellungstechnologie sein.
SC administration is used for delivering drugs which cannot be administered via the oral route. Yet, the absorption profile after SC administration is difficult to predict from preclinical studies. One of the main reasons for this poor prediction may be the differences in the physiology that preclinical species and humans have, but there is a lack of information about the SC tissue composition and, particularly, about the fluid that perfuses this area, the ISF. Better knowledge on the composition and physicochemical properties of the ISF may provide better insights into in vivo drug performance and even allow for developing simulated ISF to be used in in vitro models, to further investigate in vivo drug performance. To date, a comparison of ISF from different preclinical species and humans has not been published. Furthermore, few simulated ISF media have been proposed. Yet, those are literature-based and most of them cannot be regarded as biorelevant since non-physiological components are part of the composition. In this context, this study aimed to investigate the composition and physicochemical properties of the ISF from preclinical species and humans, to discern interspecies differences and, ultimately, to develop SISFs for in vitro predictive assays.
As a first step, ISF was isolated from the SC tissue of preclinical species and humans using the centrifugation method. This technique results in undisturbed ISF, a critical factor to consider given the invasiveness of the isolation process. Secondly, the isolated ISF samples were characterized using the same techniques across all samples, to enable data comparison. The characterization studies constituted a considerable contribution towards the understanding of the ISF composition across species. Similar values for pH, electrolyte content and osmolality were found for the ISF samples from the different species, while significant differences were observed for some parameters, particularly for albumin content. For instance, non-human primates ISF samples showed significantly higher albumin content than rodents ISF samples, while being in the same range than human ISF samples.
After the isolation and characterization of ISF samples, the resulting data were utilized to develop simulated ISF media. These SISFs aimed to replicate as closely as possible, the experimental characterization data, while keeping overall composition and preparation of the media simple to ensure easy implementation in the laboratory. pH, osmolality, and electrolyte and albumin content were set as target parameters. Meanwhile, buffer capacity, colloid osmotic pressure and surface tension were defined as reference parameters, i.e., were only assessed after preparation. Initially, a buffer was prepared, considering the target pH, electrolyte content, and osmolality, as these parameters were consistent across all species. The physicochemical properties of this buffer were measured, and the buffer was designated as Blank SISF. Different albumin concentrations were incorporated into the Blank SISF for representing ISF of mice and rats (17.5 g/L) and non-human primates and humans (30.0 g/L), developing in this way two media: the SMR-ISF and the SHM-ISF. After preparation, the SISFs were screened in the same manner as the ISF samples, and the resulting data were compared. At this step, slight adjustments were made in the electrolyte composition to better approximate the desired physicochemical properties.
Finally, in vitro experiments with the SISFs were conducted to analyze the influence of their composition, particularly their albumin content, on drug diffusion from the interstitial to the intravascular space. Liraglutide was selected as the model drug due to its high affinity for albumin. For these experiments, the Artificial Subcutaneous Tissue assay was utilized. The latter consists of a transwell plate with a gel-like artificial matrix mimicking key components of the extracellular matrix, such as collagen and hyaluronic acid. For these studies, SISF was added on the matrix prior to the incorporation of the formulation to be tested and PBS was used as receiver medium. Since PBS does not contain albumin, it was defined as Blank SPlasma. In a second step, Blank SPlasma was spiked with albumin to mimic the composition of the plasma samples determined in the characterization studies (25 g/L for the SMR-Plasma and 60 g/L for the SHM-Plasma). In this way, the SMR-ISF was used in conjunction with the SMR-Plasma in one setup, and the SHM-ISF was used together with the SHM-Plasma in a second setup. Higher diffusion rates were observed when the respective SISF at the apical side was combined with Blank SPlasma at the basolateral side, i.e., in absence of albumin in the receiver media. The samples analysis revealed the diffusion of both liraglutide and albumin through the membrane until equilibrium was achieved. Therefore, the results obtained with Blank SPlasma may be more representative of the physiological diffusion of liraglutide than those obtained with SPlasma containing albumin. Overall, these new media are promising tools in the context of developing new biorelevant models aiming to explain the differences in the in vivo performance of SC injectables in preclinical species and humans. This is because biorelevant components such as albumin significantly impact the physicochemical properties of the media. However, other aspects, such as the fat content difference in the SC tissue or even the exact injection point, may also influence in vivo performance and could be considered for future investigations.
In conclusion, this study has provided essential insights into the composition and properties of the SC ISF, clarifying previously limited data. The findings suggest that, among the studied preclinical species, the ISF of non-human primates is the most similar to human ISF. Yet, further research is needed to understand which differences between non-human primates and humans influence the bioavailability profile disparities. The ISF characterization data were utilized to develop SISFs. The addition of albumin at targeted concentrations resulted in physicochemical properties closer to those of the reference ISF data. The results presented here indicate that these media offer several advantages over those previously described in literature. Principally, the SISFs provide a better representation of the ISF composition and physicochemical properties, while also accounting for the differences among species. Although the in vitro model used for the first in vitro experiments still requires refinement, the SISFs will undoubtedly help to better understand the in vivo performance of subcutaneously injected formulations. Furthermore, the SISFs can provide insights into how results obtained in preclinical species can be extrapolated to humans and, more importantly, avoid unnecessary animal testing. Overall, the work presented in this research therefore marks a significant step forward in developing in vitro tools to investigate the behavior of SC injectables and should inspire further investigation and refinement for future applications.
The aim of the present study was to investigate the gastroretentive capacity of different formulation principles. This was indirectly determined by the absorption behavior of caffeine from the dosage forms. A slow and continuous appearance of caffeine in the saliva of healthy volunteers was used as a parameter for a prolonged gastric retention time. For this purpose, a four-way study was conducted with twelve healthy volunteers using the following test procedures: (1) Effervescent granules with 240 mL of still water administered in fed state, (2) effervescent granules with 20 mL of still water in fed state, (3) extended release (ER) tablet with 240 mL of still water in fed state, and (4) effervescent granules with 240 mL of still water in fasted state. The initial rise of the caffeine concentrations was more pronounced after the intake of the effervescent granules in the fed state compared to that of the ER tablets. However, tmax tended to be shorter in the fed study arms following administration of the ER tablet compared to the granules. Overall, the application of active pharmaceutical ingredients formulated as effervescent granules seems to be a promising approach to increase their gastric residence time after intake in fed state.
Media that mimic physiological fluids at the site of administration have proven to be valuable in vitro tools for predicting in vivo drug release, particularly for routes of administration where animal studies cannot accurately predict human performance. The objective of the present study was to develop simulated interstitial fluids (SISFs) that mimic the major components and physicochemical properties of subcutaneous interstitial fluids (ISFs) from preclinical species and humans, but that can be easily prepared in the laboratory and used in in vitro experiments to estimate in vivo drug release and absorption of subcutaneously administered formulations. Based on data from a previous characterization study of ISFs from different species, two media were developed: a simulated mouse-rat ISF and a simulated human-monkey ISF. The novel SISFs were used in initial in vitro diffusion studies with a commercial injectable preparation of liraglutide. Although the in vitro model used for this purpose still requires significant refinement, these two new media will undoubtedly contribute to a better understanding of the in vivo performance of subcutaneous injectables in different species and will help to reduce the number of unnecessary in vivo experiments in preclinical species by implementation in predictive in vitro models.
Physiologically based pharmacokinetic (PBPK) models can help to understand the effects of gastric emptying on pharmacokinetics and in particular also provide a platform for understanding mechanisms of food effects, as well as extrapolation between different postprandial conditions, whether standardized clinical or patient-oriented, non-clinical conditions. By integrating biorelevant dissolution data from the GastroDuo dissolution model into a previously described mechanistic model of fed-state gastric emptying, we simulated the effects of a high-calorie high-fat meal on the pharmacokinetics of sildenafil, febuxostat, acetylsalicylic acid, theobromine and caffeine. The model was able to simulate the variability in Cmax and tmax caused by the presence of the stomach road. The main influences investigated to affect the gastric emptying process were drug solubility (theobromine and caffeine), tablet dissolution rate (acetylsalicylic acid) and sensitivity to gastric motility (sildenafil and febuxostat). Finally, we showed how PBPK models can be used to extrapolate pharmacokinetics between different prandial states using theobromine as an example with results from a clinical study being presented.
Nowadays, life expectancy is consistently rising, and the population of older people is growing exponentially worldwide. Even though older people are the main end users of drug products, yet they are significantly underrepresented in clinical trials focused on new drug entities. Currently, clinical trials predominantly involve younger adults, overlooking the physiological changes relevant to oral drug absorption in older individuals. This exclusion is concerning given the incidence of changes in the physiology of the aging gastrointestinal tract that may impact gastric emptying and motility and therefore oral drug absorption. In particular, gastric emptying of water is an important parameter for oral biopharmaceutics since clinical bioavailability and bioequivalence studies typically include the ingestion of oral formulations with a glass of water under fasted and fed state conditions.
Even though plentiful of studies have investigated gastric water emptying in younger volunteers, this is not the case in older people. Data from gastric emptying studies in older people is limited and contradictory, whereas the occurrence of the Magenstrasse in the fed state in older individuals has been up to date not investigated. A patient-centred approach to drug development is crucial, ensuring that medications are appropriately tested and optimized for the physiological needs of older patients, particularly under varying prandial conditions. To close these knowledge gaps, in this work the gastric emptying rate of water was assessed using the indirect method of salivary caffeine kinetics. This non-invasive method was further advanced by the development of a novel formulation containing the salivary marker caffeine to increase its suitability for use in older people, and therefore patient acceptability and compliance with the study procedure.
Summarized, the results of this thesis can be outlined as follows:
First, an extensive literature review was conducted to gather all relevant information regarding previous clinical studies investigating age-dependent changes in the physiological characteristics of the gastrointestinal tract relevant to oral drug absorption. Results from gastric emptying studies in older individuals are controversial, mainly because of different methods, study designs, and measurement parameters used.
Second, a novel rapid-disintegrating and dissolving tablet formulation containing caffeine was developed to advance the salivary caffeine method to be applied in the study including older individuals. According to this method, gastric water emptying is indirectly assessed by evaluating the pharmacokinetic profile of salivary caffeine concentrations. The new tablet formulation was successfully validated against the previous formulation (i.e. the ice capsule) in healthy young adults in a clinical study under fasted and fed state conditions.
Third, the impact of advanced age in gastric water emptying was investigated with the aforementioned method. Healthy older and healthy younger volunteers were recruited in a clinical study in fasted (after overnight fasting) and fed state (after the intake of a low-fat breakfast). Differences between gastric emptying of the two population groups was evaluated indirectly by evaluating the AUC ratios (%) of salivary caffeine concentrations in specific time segments. No significant difference could be proven (p > 0.05), which indicates that gastric water emptying remains unchanged in relation to healthy aging.
These results provide a better understanding in oral drug absorption in older individuals and facilitate the drug development of oral drug products specified to the needs of the aging population. However, taking into consideration the high proportion of older people affected by multimorbidity, polypharmacy and frailty, we could surely say that these outcomes are not representative of the whole cohort of older individuals. As the aging population is very heterogeneous, a useful approach would be to investigate the impact of these factors by creating subgroups of this population and studying specific parameters separately (e.g. older individuals with multimorbidity versus healthy older individuals). Given these factors, future studies are needed to better understand how they may affect gastric emptying rates and motility. This will lead to a better understanding of the underlying mechanism of any changes observed in oral drug absorption and disposition in older adults, and therefore improve oral drug development.
Dosing conditions (type and amount of accompanying fluid, the type of food, the time of administration, and dosage form modifications such as crushing tablets) are critical and affect the performance of oral dosage forms in the gastrointestinal tract and thus bioavailability. Because older adults are the primary users of medications and are more susceptible to adverse effects, it is important to understand how they take their medications in order to reduce risks and increase benefits of the pharmacotherapy. The aim of the study was to investigate the real-life drug intake behaviour in geriatric patients and older adults and discuss their influence on drug absorption after oral administration. The data from two settings home vs. hospital and genders women vs. men were presented. A questionnaire study was performed among people aged at least 65 years from two settings (hospital vs. home), recruited mostly from community pharmacies and a regional hospital in Mecklenburg – Western Pomerania. The obtained data demonstrates that older adults and geriatric patients take their medications in the same way regardless of the setting and gender. There were no significant differences. Interviewed participants were mostly adherent to the doctor's recommendations and mostly took their medications in the same way every day. Medications are most commonly taken with a small (100 mL) or large (200 mL) glass of noncarbonated water, after food (during or after breakfast 64 % of intakes in the morning and during or after dinner 81 % of intakes in the evening). Meal usually consisted of bread, either with jam or honey (breakfast), or ham and cheese (dinner). All reported dosage form modifications were made to tablets. In almost all cases it was splitting the tablet, which was performed due to doctor's indication.
Impact of advanced age on the gastric emptying of water under fasted and fed state conditions
(2024)
Although older people are the main users of oral medications, few studies are reported on the influence of advanced age on gastric emptying rate of non-caloric liquids. This study aimed at evaluating the gastric emptying of 240 ml water in healthy older and young adults in fasted and fed state conditions using the established method of salivary caffeine kinetics. The gastric emptying of water was evaluated in 12 healthy older volunteers (mean age: 73 ± 6 years) and 12 healthy younger volunteers (mean age: 25 ± 2 years) with the ingestion of a rapid disintegrating tablet containing 20 mg of 13C3-caffeine. The gastric emptying of water was assessed indirectly by calculating the AUC ratios of salivary caffeine concentrations in specific time segments. Comparison of the AUC ratios showed no statistically significant difference between young and older volunteers in both fasted and fed state conditions (p > 0.05). Advanced age itself seems to have no relevant effect on gastric emptying of water in either fasted or fed state conditions and the phenomenon of Magenstrasse appears to follow a similar pattern in healthy older adults as in healthy younger adults.