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The scale up of production processes is a major challenge in pharmaceutical industry. Using a quality by design approach, upscaling can be based on the design space, which can be assessed on a small scale. In a previous study, the critical process parameters were identified by a definitive screening design on cetomacrogol ointment. In the current study, this lab scale (0.5 kg) study was scaled up to industrial scale (2000 kg, filling 100g tubes at 75 tubes/min). A similar trend for the influence of filling temperature on ointment yield stress was found for lab and industrial scale production. Furthermore, a process window for ointment filling viscosities was established. It was shown that between 26 and 170 Pa.s ointment could be filled into tubes with a low weight variation (< 0.5% RSD) resulting in a product with a yield stress that meets the pre-set criteria. This approach was subsequently verified using several creams and ointments and showed general applicability.

In order to study the influence of antigen composition, spatial organization of antigen and the route of administration, four cell culture-derived, inactivated, nonadjuvanted influenza vaccine formulations, i.e. whole inactivated virus (WIV), split, subunit and virosome vaccines were prepared from a single antigen batch. We directly compared the immunogenicity and efficacy of these vaccine formulations after intramuscular (i.m.) or intranasal (i.n.) administration in mice. Prime and boost vaccination were followed by a potentially lethal homologous aerosol challenge. For all vaccines, the i.m. route induced higher serum humoral immune responses as compared to the i.n. route and protected all mice against challenge at a dose of 5 μg. Upon i.n. immunization only WIV and split vaccines induced detectable IgG titers and partial protection against challenge but only very low HI titers were induced in almost all mice. WIV induced mainly IgG2a/c titers via both routes, whereas split vaccine induced exclusively IgG1 titers via both routes. Subunit and virosome vaccines induced exclusively IgG1 via the i.m. route. Mucosal sIgA levels were only detected after i.n. vaccination with WIV. Furthermore, vaccines containing all viral components (WIV and split vaccine) induced higher serum HI titers and serum antibody titers than subunit and virosome vaccines. The differences in magnitude and quality of immune responses of split and WIV, having the same composition, are likely related to their distinct spatial organization. In conclusion, the direct comparison between WIV, split, subunit and virosomes, shows that the differences in immune responses between these well known influenza vaccines can be explained by both the composition and particulate structure of these vaccine formulations.

Water content and granule size are recognized as critical process and product quality parameters during drying. The purpose of this study was to enlighten the granule behavior during fluid bed drying by monitoring the major events i.e. changes in water content and granule size. NIR spectra collected during drying and water content of sampled granules were correlated by principal component analysis (PCA) and partial least squares regression (PLSR). NIR spectra of dried granules were correlated to median granule size in a second PCA and PLSR. The NIR water model discriminates between various stages in fluid-bed drying. The water content can be continuously predicted with errors comparable to the reference method. The four PLS factors of the granule size model are related to primary particle size of lactose, median granule size exceeding primary particle size and amorphous content of granules. The small prediction errors enable size discrimination between fines and granules. For product quality reasons, discrimination between drying stages and end-point monitoring is highly important. Together with the possibilities to determine median granule size and to distinguish fines this approach provides a tool to design an optimal drying process.

Practical problems with the use of medicines, such as difficulties with breaking tablets, are an often overlooked cause for non-adherence. Tablets frequently break in uneven parts and loss of product can occur due to crumbling and powdering. Health characteristics, such as the presence of peripheral neuropathy, decreased grip strength and manual dexterity, can affect a patient's ability to break tablets. As these impairments are associated with aging and age-related diseases, such as Parkinson's disease and arthritis, difficulties with breaking tablets could be more prevalent among older adults. The objective of this study was to investigate the relationship between age and the ability to break scored tablets. A comparative study design was chosen. Thirty-six older adults and 36 young adults were systematically observed with breaking scored tablets. Twelve different tablets were included. All participants were asked to break each tablet by three techniques: in between the fingers with the use of nails, in between the fingers without the use of nails and pushing the tablet downward with one finger on a solid surface. It was established whether a tablet was broken or not, and if broken, whether the tablet was broken accurately or not. The older adults experienced more difficulties to break tablets compared to the young adults. On average, the older persons broke 38.1% of the tablets, of which 71.0% was broken accurately. The young adults broke 78.2% of the tablets, of which 77.4% was broken accurately. Further analysis by mixed effects logistic regression revealed that age was associated with the ability to break tablets, but not with the accuracy of breaking. Breaking scored tablets by hand is less successful in an elderly population compared to a group of young adults. Health care providers should be aware that tablet breaking is not appropriate for all patients and for all drugs. In case tablet breaking is unavoidable, a patient's ability to break tablets should be assessed by health care providers and instructions on the appropriate method of breaking should be provided.

Low-grade inflammation and barrier disruption are increasingly acknowledged for their association with non-communicable diseases (NCDs). Short chain fatty acids (SCFAs), especially butyrate, could be a potential treatment because of their combined anti-inflammatory and barrier- protective capacities, but more insight into their mechanism of action is needed. In the present study, non-activated, lipopolysaccharide-activated and αCD3/CD28-activated peripheral blood mononuclear cells (PBMCs) with and without intestinal epithelial cells (IEC) Caco-2 were used to study the effect of butyrate on barrier function, cytokine release and immune cell phenotype. A Caco-2 model was used to compare the capacities of butyrate, propionate and acetate and study their mechanism of action, while investigating the contribution of lipoxygenase (LOX), cyclooxygenase (COX) and histone deacetylase (HDAC) inhibition. Butyrate protected against inflammatory-induced barrier disruption while modulating inflammatory cytokine release by activated PBMCs (interleukin-1 beta↑, tumor necrosis factor alpha↓, interleukin-17a↓, interferon gamma↓, interleukin-10↓) and immune cell phenotype (regulatory T-cells↓, T helper 17 cells↓, T helper 1 cells↓) in the PBMC/Caco-2 co-culture model. Similar suppression of immune activation was shown in absence of IEC. Butyrate, propionate and acetate reduced inflammatory cytokine-induced IEC activation and, in particular, butyrate was capable of fully protecting against cytokine-induced epithelial permeability for a prolonged period. Different HDAC inhibitors could mimic this barrier-protective effect, showing HDAC might be involved in the mechanism of action of butyrate, whereas LOX and COX did not show involvement. These results show the importance of sufficient butyrate levels to maintain intestinal homeostasis.

The purpose of this work was to study the relevant physicochemical properties for the absorption of steroids. Various physicochemical properties of steroids were calculated (molecular weight, ClogP, static polar surface area [PSA], etc.). Within this series of steroids, different pharmacological groups were defined. Based on the outcome of this survey, steroids were selected for the Caco-2 permeability study. The apparent permeability coefficients (Papp) were related to the calculated and measured physicochemical properties. Between the defined groups of steroids, ClogP was the most discriminative descriptor. The steroids were well transported over the cell monolayers and the Papp was independent of the concentration and the transport direction. No relationship was found with the PSA; however, the Papp showed a weak inverse correlation with ClogP. The molecular descriptors and Papp values showed that all steroids are well transported. The small differences in the Papp values showed a weak inverse correlation with ClogP: the hydrophilic steroids (ClogP approximately 0-2) tend to diffuse faster over the cell monolayers compared with the more hydrophobic steroids (ClogP approximately 5). The relationship with ClogP suggests that partitioning of steroids between the biologic membrane and the surrounding aqueous phase is one of the main mechanisms for absorption.

Non-communicable diseases are increasing and have an underlying low-grade inflammation in common, which may affect gut health. To maintain intestinal homeostasis, unwanted epithelial activation needs to be avoided. This study compared the efficacy of butyrate, propionate and acetate to suppress IFN-γ+/−TNF-α induced intestinal epithelial activation in association with their HDAC inhibitory capacity, while studying the canonical and non-canonical STAT1 pathway. HT-29 were activated with IFN-γ+/−TNF-α and treated with short chain fatty acids (SCFAs) or histone deacetylase (HDAC) inhibitors. CXCL10 release and protein and mRNA expression of proteins involved in the STAT1 pathway were determined. All SCFAs dose-dependently inhibited CXCL10 release of the cells after activation with IFN-γ or IFN-γ+TNF-α. Butyrate was the most effective, completely preventing CXCL10 induction. Butyrate did not affect phosphorylated STAT1, nor phosphorylated NFκB p65, but inhibited IRF9 and phosphorylated JAK2 protein expression in activated cells. Additionally, butyrate inhibited CXCL10, SOCS1, JAK2 and IRF9 mRNA in activated cells. The effect of butyrate was mimicked by class I HDAC inhibitors and a general HDAC inhibitor Trichostatin A. Butyrate is the most potent inhibitor of CXCL10 release compared to other SCFAs and acts via HDAC inhibition. This causes downregulation of CXCL10, JAK2 and IRF9 genes, resulting in a decreased IRF9 protein expression which inhibits the non-canonical pathway and CXCL10 transcription.

Degenerative joint disease osteoarthritis (OA) is characterized by the degeneration of cartilage, synovial inflammation and low-grade systemic inflammation in association with microbial dysbiosis and intestinal barrier defects. Butyrate is known for its anti-inflammatory and barrier protective effects and might benefit OA patients. In a double-blind placebo-controlled randomized trial, the effects of four to five weeks of oral treatment with sustained-release (SR) butyrate tablets (600 mg/day) on systemic inflammation and immune function were studied in hand OA patients. Serum markers for systemic inflammation and lipopolysaccharide (LPS) leakage were measured and ex vivo stimulation of whole blood or peripheral blood mononuclear cells (PBMCs) was performed at baseline and after treatment. Butyrate treatment did not affect the serum markers nor the cytokine release of ex vivo LPS-stimulated whole blood or PBMCs nor the phenotype of restimulated monocytes. By contrast, butyrate treatment reduced the percentage of activated T helper (Th) cells and the Th17/Treg ratio in αCD3/CD28-activated PBMCs, though cytokine release upon stimulation remained unaffected. Nevertheless, the percentage of CD4+IL9+ cells was reduced by butyrate as compared to the placebo. In both groups, the frequency of Th1, Treg, Th17, activated Th17, CD4+IFNγ+ and CD4+TNFα+ cells was reduced. This study shows a proof of principle of some immunomodulatory effects using a SR butyrate treatment in hand OA patients. The inflammatory phenotype of Th cells was reduced, as indicated by a reduced percentage of Th9 cells, activated Th cells and improved Th17/Treg balance in ex vivo αCD3/CD28-activated PBMCs. Future studies are warranted to further optimize the butyrate dose regime to ameliorate inflammation in OA patients.

SummaryLately, the usefulness of liposomal drug delivery systems has been debated. To better understand the underlying pharmacokinetics of the targeted drug delivery by liposomes, individual encapsulated and non-encapsulated drug concentrations in blood, tumor, liver, spleen and kidneys were quantified after i.v. administration of liposomal prednisolone phosphate in mice. Kinetic analysis shows that the tumor influx of encapsulated drug is not dominant compared to the uptake by the other tissues. Further, from a quantitative point of view, the availability of non-encapsulated drug in the tumor tissue after liposomal delivery is not pronounced as compared to the other tissues studied. However, drug release in the tumor seems more extended than in the other tissues and the non-encapsulated drug concentration decreases more slowly in the tumor than in the liver and spleen. The spleen shows a high affinity for the uptake of encapsulated drug as well as the release of drug from the liposomes. Subsequently, released drug in the spleen, and possibly also in other tissues, is probably quickly redistributed towards the blood and other tissues. This also impairs the drug delivery effect of the liposomes. In contrast to the released drug in the central circulation, liver and spleen, the released drug concentration in the tumor remains at a fairly constant level likely due to the extended release kinetics from the liposomes. These extended release characteristics in the tumor most probably contribute to the beneficial effect. Nevertheless, it should be noted that larger released drug concentrations are formed in healthy tissues.

Purpose By pharmaceutical processes and in the presence of solid excipients physical–chemical changes are known to occur, leading to increased rate of chemical degradation. The purpose of this work was to determine the critical aspects in the stability of a steroid in the presence of a commonly used excipient, lactose. Methods A steroid was either mixed or wet granulated with lactose with different particle size. Results Small lactose particles lead to a higher degree of degradation. Degradation was enhanced under warm humid conditions although the presence of water alone could not account for this effect. Lactose-phosphate, a known intrinsic contaminant in lactose is demonstrated to enhance the degradation of the steroid. Stability was improved in high purity lactose and deteriorated upon extra addition of phosphates. Since the exposure to the contaminant is a function of the surface area of the lactose, particle size differences of the excipient have a clear consequence. High shear granulated lactose granules exhibit a heterogeneous composition; large granules consist of small primary particles and vice versa. It is shown that the large granules, composed of the small primary lactose particles reveal the highest degree of degradation. Granule composition dictates the stability profile of the granules. Conclusion The lactose contaminant and grandule composition dictates the stability profile of the granules and mixtures.