Patient Centricity Driving Formulation Innovation: Improvements in Patient Care Facilitated by Novel Therapeutics and Drug Delivery Technologies.

Innovative formulation technologies can play a crucial role in transforming a novel molecule to a medicine that significantly enhances patients' lives. Improved mechanistic understanding of diseases has inspired researchers to expand the druggable space using new therapeutic modalities such as interfering RNA, protein degraders, and novel formats of monoclonal antibodies. Sophisticated formulation strategies are needed to deliver the drugs to their sites of action and to achieve patient centricity, exemplified by messenger RNA vaccines and oral peptides. Moreover, access to medical information via digital platforms has resulted in better-informed patient groups that are requesting consideration of their needs during drug development. This request is consistent with health authority efforts to upgrade their regulations to advance age-appropriate product development for patients. This review describes formulation innovations contributingto improvements in patient care: convenience of administration, preferred route of administration, reducing dosing burden, and achieving targeted delivery of new modalities.

Early pediatric formulation development with new chemical entities: Opportunities of e-tongue besides human taste assessment.

The palatability of a pediatric drug formulation is one of the key prerequisites for therapeutic success. Liquid formulations are often chosen for pediatric drug products, and they require special attention regarding their taste, as they have direct contact to the taste buds and a relatively long residence time in the oral cavity. For ethical reasons, the role of electronic tongues in the development of oral drug formulations with new chemical entities (NCEs) for pediatric use is growing, however, little is known about the strategies how this instrumental taste assessment can be performed. The present study illustrates two possibilities to combine in-vitro and in-vivo data for the characterization of the palatability of the new drug candidates CSE3104 and CSE3165. As a first step, the implementation and suitability of electronic tongue measurements has been demonstrated by comparison of in-vivo and in-vitro data. In alignment with the taste assessment results during a single-center, double-blinded, randomized, placebo-controlled, single ascending dose (SAD) study in healthy subjects, the bitter taste perception of CSE3104 was assessed with e-tongue measurements. Moreover, the sensor response pattern showed comparable results of the e-tongue measurements to the human taste study of CSE3165: With increasing concentration, the bitterness values were increased. In addition, the human taste pattern showed increasing values for sourness due to higher volumes of the citric acid buffer. Results of the hedonic descriptor "unpleasant" within the human taste assessments could be related to bitterness in the instrumental taste assessment. For the second step in electronic tongue guided formulation development two possibilities are depicted in the article focusing on the effect of different excipients on the formulation on the one hand and on the assessment and comparison of two drug formulations on the other hand. Based on these results, the low number of healthy volunteers for the taste assessment in a Phase 1 study led to a meaningful interpretation, by applying in addition the electronic tongue. Using this instrumental approach led to reproducible data versus the human taste assessment, without ethical concerns, and with a reduction in time and costs.

Pediatric Dispersible Tablets: a Modular Approach for Rapid Prototyping.

PURPOSE: The design of pediatric formulations is challenging. Solid dosage forms for children have to meet the needs of different ages, e.g. high number of dosing increments and strengths. A modular formulation strategy offering the possibility of rapid prototyping was applied. Different tablet compositions and the resulting tablet characteristics were investigated for dispersible tablets using customized analytical methods. METHODS: Fluid bed granules were blended with extragranular components, and compressed to tablets. Disintegration behavior was studied with a Texture Analyzer and a Tensiometer. RESULTS: Methods for determination of disintegration time and water uptake of tablets were developed with a Texture Analyzer, and a Tensiometer, respectively. Twenty-two different tablet formulations were prepared and analyzed with respect to disintegration time, hardness, friability, and viscosity. Multivariate data analysis revealed a high impact of type and amount of viscosity enhancer on the disintegration behavior of tablets. An optimized formulation was selected with a disintegration time of 24 s. CONCLUSION: Methods providing additional information on the disintegration behavior of dispersible tablets compared to standard pharmacopoeia methods were established. Selecting the right type and level of viscosity enhancer and superdisintegrant was critical for developing pediatric tablets with a disintegration time of less than 30 s but still pleasant mouth feel.

State estimation for large-scale wastewater treatment plants.

Many relevant process states in wastewater treatment are not measurable, or their measurements are subject to considerable uncertainty. This poses a serious problem for process monitoring and control. Model-based state estimation can provide estimates of the unknown states and increase the reliability of measurements. In this paper, an integrated approach is presented for the optimization-based sensor network design and the estimation problem. Using the ASM1 model in the reference scenario BSM1, a cost-optimal sensor network is designed and the prominent estimators EKF and MHE are evaluated. Very good estimation results for the system comprising 78 states are found requiring sensor networks of only moderate complexity.

Protease-catalysed coupling of N-protected amino acids and peptides with 4-aminoantipyrine.

The enzymatic synthesis of N-protected L-aminoacyl- and L-peptidyl-antipyrine amides was accomplished by proteases from different classes. Serine and cysteine proteases proved to be suitable tools for the production of amino acids and peptides conjugated to 4-aminoantipyrine, whereas metalloproteases do not seem to be very qualified for accepting this nucleophile. The product yields were optimised by applying ample opportunities of medium engineering, e.g. aqueous-organic, biphasic, suspension and solid-to-solid reaction systems. Thus, yields up to 100% could be obtained. The products were purified and characterised by polarimetry and NMR spectroscopy. These results broaden the common knowledge of the catalytic potential of proteases, in particular with regard to the suitability of a special heterocyclic 1,2-amino ketone as a nucleophile for the biocatalytic amidation of amino acids and peptides.

The kinetics of transcriptomic changes induced by cigarette smoke in rat lungs reveals a specific program of defense, inflammation, and circadian clock gene expression.

Gene expression profiling in animal models exposed to cigarette mainstream smoke (CS) shapes up as a promising tool for investigating the molecular mechanisms involved in the onset and development of CS-related disease and may aid in the identification of disease candidate genes. Here we report on differential gene expression in lungs of rats exposed for 2, 7, and 13 weeks to 300 and 600 microg total particulate matter/l CS with sacrifice 2, 6, or 20 h after the last exposure. Regarding antioxidant and xenobiotic-metabolizing (phase I/II) enzymes, a stereotypic, mostly transient, expression pattern of differentially expressed genes was observed after each exposure period. The expression patterns were generally dose dependent for antioxidant and phase II genes and not dose dependent for phase I genes at the CS concentrations tested. However, with increasing length of exposure, there was a distinct, mostly sustained and dose-sensitive, expression of genes implicated in innate and adaptive immune responses, clearly pointing to an emerging inflammatory response. Notably, this inflammatory response included the expression of lung disease-related genes not yet linked to CS exposure, such as galectin-3, arginase 1, and chitinase, as well as genes encoding proteolytic enzymes. Finally, our experiments also revealed a CS exposure-dependent shift in the cyclical expression of genes involved in controlling the circadian rhythm. Altogether, these results provide further insight into the molecular mechanisms of CS-dependent disease onset and development and thus may also be useful for defining CS-specific molecular biomarkers of disease.

Receptor-agonist interactions in service-theoretic perspective, effects of molecular timing on the shape of dose-response curves.

Service-theoretic concepts and methods, widely used in other fields (e.g., telecommunication and operations research), are useful also in a biochemical setting because the treatment of biocatalysts (enzymes, receptors) as servers and their ligands as customers, based on the established formal methods of service or queuing theory, may lead to insights and results unobtainable by conventional, mass-action-law-based theories. In this article, we apply the service-theoretic approach to receptor-agonist systems and show how by changing the stochastic time pattern of "operationally relevant" point events (e.g., instants of agonist arrival, instants of post-climax agonist departure) a great variety of dose-response curves may be generated, even in very simple reaction schemes, which, according to mass action kinetics, invariably lead to hyperbolic r(A) curves (r and A stand for response and agonist concentration, respectively). The molecular timing inherent to a hyperbolic response system is not optimal: for instance, at the agonist concentration A(50), half of the agonist molecules are rejected ("lost") because of unfortunate timing of the arrival events. The fraction of lost arrivers can be diminished considerably if the arrivals are better timed: "sub-Poisson" arrivals improve the timing and, thus, convert hyperbolic r(A) curves into "lifted" nonhyperbolic ones. Conversely, "super-Poisson" arrivals make the non-optimal timing in hyperbolic response systems even worse and, thus, convert hyperbolic r(A) curves into "depressed" nonhyperbolic ones. Furthermore, under special timing conditions, nonhyperbolic r(A) curves can be generated, which are partly lifted, partly depressed relative to the reference hyperbola, and which resemble in shape well-known nonhyperbolic forms of enzyme and receptor kinetics (negatively cooperative, positively cooperative, and sigmoidal kinetics). In addition unusual (undulatory and sawtooth-like) r(A) curves can be generated solely by changing the temporal pattern of arrival and service completion instants. Virtually any shape of dose-response curves may be obtained by allowing for probability distributions whose characteristic shape varies with their mean; we call such distributions "variomorphic" and apply them to the arrival process of agonist molecules.

Gender-based differences in children with sepsis and ARDS: the ESPNIC ARDS Database Group.

Male gender predisposes to severe sepsis and septic shock. This effect has been ascribed to higher levels of testosterone. The ESPNIC ARDS database was searched, to determine if there was evidence of a similar male preponderance in severe sepsis in prepubertal patients in spite of low levels of male sex hormones at this age. A total of 72 patients beyond neonatal age up to 8 years of age with sepsis were identified. The male/female (M/F) ratio was 1.7 (1.0;2.7) and differed significantly from non-septic ARDS patients in this age group [n = 209; M/F = 1.0 (0.8;1.3)]. The highest M/F-ratio was observed in the first year of life. The gender-ratio was the same as reported in adult patients with sepsis. In infants between 1 month and 12 months of age, the ratio was 2.8 (1.2;6.1) (Chi2= 5.6; P< 0.01), in children from 1 year to 8 years of age it was 1.2 (0.7;2.2) (n.s.). In a subgroup of patients with severe sepsis or septic shock, caused by other bacteria than Neisseria meningitidis, the M/F-ratio was 2.1 (1.2;3.6) (Chi2= 4.9; P<0.05), while in patients with meningococcal sepsis (n=20) the M/F-ratio was 1.0 (0.4;2.3). In prepubertal ARDS patients with sepsis an increased frequency of male patients is found, comparable to adults. No male preponderance exists in patients with ARDS due to meningococcal septic shock. Since levels of testosterone and other sex hormones are extremely low at this age, we conclude that factors others than testosterone are involved in the male preponderance in severe sepsis.

Tabletting of pellet-matrix systems: ability of parameters from dynamic and kinetic models to elucidate the densification of matrix formers and of pellets.

Two different types of pellets, i.e. drug-free sugar spheres, and pellets, spray-layered with crystalline theophylline and coated with Eudragit RS/RL, were tabletted each in combination with matrix-forming powder mixtures of Avicel PH200 and PEG 4000. The die fills from pellets and powder mixtures were regarded as two-compartment systems with a volume fraction of the pellets being limited to 0.52 corresponding to a cubic lattice, and the maximum degrees of densifications were adjusted related to the matrix. To data measured during single compression cycles on an instrumented eccentric tabletting machine and transformed appropriately, the Kawakita equation, the Heckel function, and a modified Weibull function were fitted, and the total work of compression was calculated. The Kawakita model fitted well systems with both types of pellets. Its parameters reflected the additional densification of the theophylline pellets separately from that of the matrix formers. The Heckel function could only be applied to systems containing non-porous sugar spheres, since the theophylline pellets underwent considerable densification and deformation. Only, when the Heckel porosity function was related to the volume fraction of the matrix, excluding the sugar spheres, the approximately linear regions for mixtures with increasing volume proportions of sugar spheres occured in comparable regions of densification. Parameters of the modified Weibull function demonstrated an increasing resistance against densification with increasing amounts of pellets. The total work of compression increased steeply with increasing volume fractions for pellets from 0.42 to 0.46 indicating, that the resistance against densification already rose when the pellets were still isolated. In conclusion, the combination of dynamic and kinetic models provides a comprehensible insight into the process of tabletting powder mixtures with pellets. Particularly, the Kawakita model was a suitable tool to differentiate the actual changes in porosity during compression from the compressibility of such complex systems.