The antennal scape organ of Scutigera coleoptrata (Myriapoda) and a new type of arthropod tip-pore sensilla integrating scolopidial components.

BACKGROUND: Centipedes are terrestrial, predatory arthropods with specialized sensory organs. However, many aspects of their sensory biology are still unknown. This also concerns hygroreception, which is especially important for centipedes, as their epicuticle is thin and they lose water rapidly at low humidity. Thus, the detection of humid places is vital but to date no definite hygroreceptor was found in centipedes. House centipedes (Scutigeromorpha) possess a peculiar opening at the base of their antenna, termed 'scape organ', that houses up to 15 cone-shaped sensilla in a cavity. Lacking wall and tip-pores, these socket-less sensilla may be hypothesized to function as hygroreceptors similar to those found in hexapods. RESULTS: The cone-shaped sensilla in the scape organ as well as nearby peg-shaped sensilla are composed of three biciliated receptor cells and three sheath cells. A tip-pore is present but plugged by a highly electron-dense secretion, which also overlays the entire inner surface of the cavity. Several solitary recto-canal epidermal glands produce the secretion. Receptor cell type 1 (two cells in cone-shaped sensilla, one cell in peg-shaped sensilla) possesses two long dendritic outer segments that project to the terminal pore. Receptor cell type 2 (one cell in both sensilla) possesses two shorter dendritic outer segments connected to the first (proximal) sheath cell that establishes a scolopale-like structure, documented for the first time in detail in a myriapod sensillum. CONCLUSIONS: The nearly identical configuration of receptor cells 1 with their long dendritic outer segments in both sensilla is similar to hexapod hygroreceptors. In Scutigera coleoptrata, however, the mechanism of stimulus transduction is different. Water vapor may lead to swelling and subsequent elongation of the plug pin that enters the terminal pore, thus causing stimulation of the elongated dendritic outer segments. The interconnection of receptor cell 2 with short outer dendritic segments to a scolopale-like structure potentially suits both sensilla for vibration or strain detection. Thus, both sensilla located at the antennal base of scutigeromorph centipedes fulfill a dual function.

Extraordinary Long-Term-Stability in Kinetically Stabilized Amorphous Solid Dispersions of Fenofibrate.

Inhibition of recrystallization of the drug substance in kinetically stabilized amorphous solid dispersions (ASDs) within and beyond shelf life is still a matter of debate. Generally, these ASD systems are considered to be prone to recrystallization, but examples of their long-term stability are emerging in the literature. Since, in some cases, the formation of crystals may impact bioavailability, recrystallization may present a relevant risk for patients as it potentially lowers the effective dose of the formulation. This study shows that such metastable formulations may indeed remain amorphous even after 15 years of storage under ambient conditions. A formulation of fenofibrate stored for 15 years was compared to a freshly prepared batch. A complete physicochemical characterization regarding content, purity, water content and glass transition was conducted. The emphasis of this physicochemical characterization was on crystallinity as a critical quality attribute: polarized light microscopy (PLM) was used as the standard qualitative method and X-ray powder diffraction (XRPD) as the standard quantitative method. An investigation of the crystal growth kinetics by transmission Raman spectroscopy (TRS) was conducted to build a predictive model. The model was applied successfully to predict the observed physical state of the 15-year-old samples. The observations presented here demonstrate that kinetic stabilization alone is able to prevent crystallization in ASDs over prolonged storage periods, suggesting the need for a reassessment of the risk perception for this kind of ASD formulations.

Frozen in Time: Kinetically Stabilized Amorphous Solid Dispersions of Nifedipine Stable after a Quarter Century of Storage.

Kinetically stabilized amorphous solid dispersions are inherently metastable systems. Therefore, such systems are generally considered prone to recrystallization. In some cases, the formation of crystals will impact the bioavailability of the active pharmaceutical ingredient in these formulations. Recrystallization therefore may present a significant risk for patients as it potentially lowers the effective dose of the pharmaceutical formulation. This study indicates that such metastable formulations may indeed remain fully amorphous even after more than two decades of storage under ambient conditions. Different formulations of nifedipine stored for 25 years were compared with freshly prepared samples. A thorough physicochemical characterization including polarized light microscopy, differential scanning calorimetry, X-ray powder diffraction, and transmission Raman spectroscopy was undertaken. This in-depth characterization indicates no signs of recrystallization in the stored samples. The observations presented here prove that long-term stability of amorphous solid dispersions much beyond the typical shelf life for pharmaceutical formulations is indeed possible by kinetic stabilization alone. These findings implicate a reevaluation of the propensity to recrystallize for kinetically stabilized amorphous solid dispersions.

The tracheal system of scutigeromorph centipedes and the evolution of respiratory systems of myriapods.

The tracheal system of scutigeromorph centipedes (Chilopoda) is special, as it consists of dorsally arranged unpaired spiracles. In this study, we investigate the tracheal systems of five different scutigeromorph species. They are strikingly similar to each other but depict unique characters compared to the tracheal systems of pleurostigmophoran centipedes, which has engendered an ongoing debate over a single versus independent origin of tracheal systems in Chilopoda. Up to now, only the respiratory system of Scutigera coleoptrata was investigated intensively using LM-, TEM-, and SEM-techniques. We supplement this with data for species from all three families of Scutigeromorpha. These reveal interspecific differences in atrial width and the shape and branching pattern of the tracheal tubules. Further, we investigated the tracheal system of Scutigera coleoptrata with three additional techniques: light sheet microscopy, microCT and synchrotron radiation based microCT analysis. This set of techniques allows a comparison between fresh versus fixed and dried material. The question of a unique vs. multiple origin of tracheal systems in centipedes and in Myriapoda as a whole is discussed with regard to their structural similarities and differences and the presence of hemocyanin as an oxygen carrier. We used morphological and molecular data and the fossil record to evaluate the alternative hypotheses.

A Rational Design of a Biphasic DissolutionSetup-Modelling of Biorelevant Kinetics for a Ritonavir Hot-Melt Extruded Amorphous Solid Dispersion.

Biphasic dissolution systems achieved good predictability for the in vivo performance of several formulations of poorly water-soluble drugs by characterizing dissolution, precipitation, re-dissolution, and absorption. To achieve a high degree of predictive performance, acceptor media, aqueous phase composition, and the apparatus type have to be carefully selected. Hence, a combination of 1-decanol and an optimized buffer system are proposed as a new, one-vessel biphasic dissolution method (BiPHa+). The BiPHa+ was developed to combine the advantages of the well-described biorelevance of the United States Pharmacopeia (USP) apparatus II coupled with USP apparatus IV and a small-scale, one-vessel method. The BiPHa+ was designed for automated medium addition and pH control of the aqueous phase. In combination with the diode array UV-spectrophotometer, the system was able to determine the aqueous and the organic medium simultaneously, even if scattering or overlapping of spectra occurred. At controlled hydrodynamic conditions, the relative absorption area, the ratio between the organic and aqueous phase, and the selected drug concentrations were identified to be the discriminating factors. The performance of a hot-melt extruded ritonavir-containing amorphous solid dispersion (ritonavir-ASD) was compared in fasted-state dissolution media leading to different dissolution-partitioning profiles depending on the content of bile salts. An advanced kinetic model for ASD-based well described all phenomena from dispersing of the ASD to the partitioning of the dissolved ritonavir into the organic phase.

The influence of liquid intake on the performance of an amorphous solid dispersion in rats.

The aim of this rat study was to investigate the effect of liquid intake on the oral bioavailability of an amorphous solid dispersion (ASD) containing the poorly water-soluble compound ABT-869. To this end, an ASD was prepared by hot-melt extrusion and administered in form of powder in an open gelatin capsule. The study consisted of three arms: (1) administration of the ASD without any liquid, (2) administration of the ASD with 1.5 mL of water, and (3) administration of a suspension of crystalline drug in water. Administration of the ASD without water resulted in a 4-fold higher exposure as compared to the suspension of crystalline drug. When administered together with water, the in vivo performance of the ASD was dramatically affected and not superior to that of the suspension of crystalline drug. The observed phenomena could not be explained mechanistically, but may be related to the following effects: (I) a faster dissolution in a larger volume of fluid and subsequent precipitation, (II) a change in gastrointestinal transit time that caused a mismatch between dissolution rate and absorption rate, and/or (III) a difference in the mucosal adherence/distribution pattern caused by the gelatin capsule. It remains to be investigated whether the phenomena observed in this study are exceptionally pronounced or even unique for this particular formulation. Yet, our findings emphasize that the amount of liquid co-administered with oral enabling formulations can have an impact on the bioavailability. The administration regime used in animal studies should therefore be considered carefully.

(Sub)micron particles forming in aqueous dispersions of amorphous solid dispersions of the poorly soluble drug ABT-199: A combined particle optical counting and field-flow fractionation study.

The dispersive behavior of three different amorphous solid dispersion (ASD) formulations of the poorly soluble ABT-199 (Venetoclax) were studied in aqueous and biomimetic media and spontaneously forming supramolecular associates and particles analysed. To this end, the aqueous dispersions were fractionated into a submicron (colloidal) and micrometer-sized particle-fraction by bench-top centrifugation. The submicron fraction was characterized by Asymmetric Flow Field-Flow Fractionation in conjunction with Multi-angle Laser Light Scattering (AF4-MALLS), Dynamic Light Scattering (DLS) and zeta potential analysis. The micron particle fraction was characterized by Single Particle Optical Sensing (SPOS) and light microscopy. Furthermore, drug contents were monitored in terms of total dispersed drug and apparently dissolved drug in the submicron fraction. Despite the fact, that all three formulations showed decent dispersive behavior with almost the complete drug content rapidly dispersed, substantial differences were identified between two of the formulations and the third one: ABT-199/12 and ABT-199/20 showed pronounced precipitation of the drug in form of micrometer particles, a phenomenon described as glass liquid phase separation (GLPS) and only a marginal fraction of the drug was found in the submicron-fraction, i.e. associated with 3 to 4 different supramolecular assemblies (micelles), irrespective whether buffer or fasted state simulated intestinal fluid (FaSSIF) were used as dispersion media. In contrast, ABT-199/40 showed pronounced formation of a wide variety of supramolecular assemblies (micelles) along with substantial association of the drug with all of these, but reduced glass liquid phase separation.

The hydrogenosomes of Psalteriomonas lanterna.

BACKGROUND: Hydrogenosomes are organelles that produce molecular hydrogen and ATP. The broad phylogenetic distribution of their hosts suggests that the hydrogenosomes of these organisms evolved several times independently from the mitochondria of aerobic progenitors. Morphology and 18S rRNA phylogeny suggest that the microaerophilic amoeboflagellate Psalteriomonas lanterna, which possesses hydrogenosomes and elusive "modified mitochondria", belongs to the Heterolobosea, a taxon that consists predominantly of aerobic, mitochondriate organisms. This taxon is rather unrelated to taxa with hitherto studied hydrogenosomes. RESULTS: Electron microscopy of P. lanterna flagellates reveals a large globule in the centre of the cell that is build up from stacks of some 20 individual hydrogenosomes. The individual hydrogenosomes are surrounded by a double membrane that encloses a homogeneous, dark staining matrix lacking cristae. The "modified mitochondria" are found in the cytoplasm of the cell and are surrounded by 1-2 cisterns of rough endoplasmatic reticulum, just as the mitochondria of certain related aerobic Heterolobosea. The ultrastructure of the "modified mitochondria" and hydrogenosomes is very similar, and they have the same size distribution as the hydrogenosomes that form the central stack.The phylogenetic analysis of selected EST sequences (Hsp60, Propionyl-CoA carboxylase) supports the phylogenetic position of P. lanterna close to aerobic Heterolobosea (Naegleria gruberi). Moreover, this analysis also confirms the identity of several mitochondrial or hydrogenosomal key-genes encoding proteins such as a Hsp60, a pyruvate:ferredoxin oxidoreductase, a putative ADP/ATP carrier, a mitochondrial complex I subunit (51 KDa), and a [FeFe] hydrogenase. CONCLUSION: Comparison of the ultrastructure of the "modified mitochondria" and hydrogenosomes strongly suggests that both organelles are just two morphs of the same organelle. The EST studies suggest that the hydrogenosomes of P. lanterna are physiologically similar to the hydrogenosomes of Trichomonas vaginalis and Trimastix pyriformis. Phylogenetic analysis of the ESTs confirms the relationship of P. lanterna with its aerobic relative, the heterolobosean amoeboflagellate Naegleria gruberi, corroborating the evolution of hydrogenosomes from a common, mitochondriate ancestor.

PermeaLoop™, a novel in vitro tool for small-scale drug-dissolution/permeation studies.

Here we report first experiences with the novel in vitro dissolution/permeation setup PermeaLoop™. It was designed to overcome current limitations of in vivo predictive dissolution testing of enabling formulations, such as lack of relevant absorptive drag to allow for meaningful interplay between dissolution and permeation, as it is occurring in vivo. We propose a novel setup with a high area-to-volume ratio and report as a model case the dissolution/permeation behavior of an enabling formulation of the poorly soluble and poorly permeable drug ABT-869. Mini tablets consisting of an amorphous solid dispersion were tested at a downscaled clinically relevant dose. At room temperature, release was fast, and more than 35% of the employed dose permeated within 6 h. In consequence, the amount in the donor decreased significantly. By contrast, only 9% of the employed dose was released when performing the experiment at 35 °C. Still, most of the released drug permeated into the acceptor (>80%), and the permeation rate was release-dependent and vice versa, i.e. the scenario was highly dynamic. Hence, due to a sufficiently large permeation area the dissolution step became rate-limiting. Therefore, PermeaLoop™ is regarded a promising tool for evaluating enabling formulations.

Dynamic dissolution-/permeation-testing of nano- and microparticle formulations of fenofibrate.

The aim of the current study was to evaluate a dynamic dissolution-/permeation-system for prediction of gastrointestinal and absorption-behavior of two commercial fenofibrate formulations. To this end, both dissolution and barrier-flux were followed simultaneously for fenofibrate powder, a microparticle formulation (Lipidil® 200mg) and a nanoparticle formulation (LIPIDIL 145 ONE®) using a pair of side-by side diffusion cells separated by a cellulose hydrate membrane. Under such dynamic conditions, transient supersaturation arising from the nanoparticle formulation could be demonstrated for the first time. Furthermore, the dissolution-/permeation-system introduced here allowed for in-depth mechanistic insights: Biomimetic media, despite enhancing the apparent solubility of fenofibrate via micellar solubilization, did not increase permeation rate, irrespective whether the micro-/ or nanoparticle-formulation was tested. Nondissolved nano-/microparticles served as a reservoir helping to maintain high levels of molecularly dissolved drug, which in turn caused high and constant permeation rates. The micelle-bound drug may also serve as a drug-reservoir, yet of subordinate importance as long as there are nano-/microparticles present. Despite the limitations of the current experimental set-up, combined dissolution-/permeation-testing appears a valuable new tool to promote mechanistic understanding during formulation development. Last but not least, the in vitro dissolution and permeation behavior revealed here was in good qualitative agreement with human duodenal and plasma values reported in literature for the same formulations.

Evaluation of a dynamic dissolution/permeation model: Mutual influence of dissolution and barrier-flux under non-steady state conditions.

Combined dissolution/permeation testing is gaining increasing attention as an in vitro tool for predictive performance ranking of enabling oral formulations. The current aim was to study how in vitro drug permeation evolves under conditions, where the donor concentration is changing (non-steady state). To this end, a model case was construed: compacts of pure crystalline hydrocortisone methanolate (HC·MeOH) of slow release rates were prepared, and their dissolution and permeation determined simultaneously in a side-by-side setup, separated by a biomimetic barrier (Permeapad®). This was compared to a corresponding setup for a suspension of micronized hydrocortisone (HC). The HC suspension showed constant dissolved HC concentration and constant flux across the barrier, representing the permeation-limited situation. For the HC·MeOH compacts, various dynamic scenarios were observed, where dissolution rate and flux influenced each other. Interestingly, for all the dynamic scenarios, the incremental flux values obtained correlated nicely with the corresponding actual donor concentrations. Furthermore, donor depletion was tested using a HC solution. The dynamic interplay between decrease in donor concentration (down to less than 10% of the initial concentration) and flux was studied. The experiences gained are discussed in terms of further developing combined dissolution/permeation setups.

Ultrastructural investigation of a salivary gland in a centipede: structure and origin of the maxilla I-gland of Scutigera coleoptrata (Chilopoda, Notostigmophora).

The maxilla I-gland of Scutigera coleoptrata was investigated using light and electron microscopy methods. This is the first ultrastructural investigation of a salivary gland in Chilopoda. The paired gland opens via the hypopharynx into the foregut and extends up to the third trunk segment. The gland is of irregular shape and consists of numerous acini consisting of several gland units. The secretion is released into an arborescent duct system. Each acinus consists of multiple of glandular units. The units are composed of three cell types: secretory cells, a single intermediary cell, and canal cells. The pear-shaped secretory cell is invaginated distally, forming an extracellular reservoir lined with microvilli, into which the secretion is released. The intermediary cell forms a conducting canal and connects the secretory cell with the canal cell. Proximally, the intermediary cell bears microvilli, whereas the distal part is covered with a distinct cuticle. The cuticle is a continuation of the cuticle of the canal cells. This investigation shows that the structure of the glandular units of the salivary maxilla I-gland is comparable to that of the glandular units of epidermal glands. Thus, it is likely that in Chilopoda salivary glands and epidermal glands share the same ground pattern. It is likely that in compound acinar glands a multiplication of secretory and duct cells has taken place, whereas the number of intermediary cells remains constant. The increase in the number of salivary acini leads to a shifting of the secretory elements away from the epidermis, deep into the head. Comparative investigations of the different head glands provide important characters for the reconstruction of myriapod phylogeny and the relationships of Myriapoda and Hexapoda.

Ultrastructure of the maxillary organ of Scutigera coleoptrata (Chilopoda, Notostigmophora): description of a multifunctional head organ.

The maxillary organ of Scutigera coleoptrata was investigated using light microscopy, electron microscopy, and maceration techniques. Additionally, we compared the maxillary organ of S. coleoptrata with those of two other notostigmophoran centipedes, Parascutigera festiva and Allothereua maculata, using SEM. The maxillary organ is located inside the posterior coxal lobes of the first maxillae and extends posteriorly as sac-like pouches. The narrow epidermis of the maxillae is differentiated to form the epithelium of the maxillary organ. Two types of epithelia are distinguishable: a simple cuboidal epithelium of different height and differentiation (types I, II, IV) and a pseudostratified columnar epithelium (type III). These epithelia are covered by a highly specialized cuticle. The pseudostratified epithelium is the most prominent feature of the maxillary organ. It is covered with hundreds of setae, protruding deep into the maxillary organ. Two different types of setae can be distinguished, filiform and fusiform. The maxillary organ communicates with the oral cavity, the maxillary organ gland, the maxillary nephridium, and with a large number of epidermal glands that secrete into the maxillary organ. Epithelium III allows the extension of the maxillary organ when its pouches are filled with secretion. The maxillary organ is a complex multifunctional organ. The organ probably stores excretion from the maxillary nephridia and secretory fluid from the maxillary organ gland and other epidermal glands. The fluid is primarily required as preening fluid. The ammonia of the excretory fluid is thought to evaporate via the setae and the wide opening of the maxillary organ. It is likely that parts of the fluid can be reabsorbed by the animal via the oral cavity.

Ultrastructural organization of the anal organs in the anal capsule of Craterostigmus tasmanianus Pocock, 1902 (Chilopoda, Craterostigmomorpha).

We describe the ultrastructural organization of the anal organs of Craterostigmus tasmanianus, which are located on the ventral side of the bivalvular anal capsule. Each part of the capsule bears four pore fields with several anal pores. The pores lead into a pore canal, which is surrounded by the single-layered epithelium of the anal organs. Each anal organ is composed of four different cell types: transporting cells of the main epithelium, junctional cells, isolated epidermal glands, and the cells forming the pore canal. The transporting cells exhibit infoldings of the outer cell membranes, forming a basal labyrinth and a poorly developed apical complex. The cells are covered by a specialized cuticle with a widened subcuticular layer. Only the cuticle of the main epithelium is covered by a mucous layer, secreted by the epidermal glands. The ultrastructural organization of the anal organ is comparable to the coxal and anal organs of other pleurostigmophoran Chilopoda. It is likely that the coxal and anal organs of the Pleurostigmophora are homologous, due to their identical ultrastructural organization. Differences concerning the location on the trunk of Pleurostigmophora are not sufficient to reject a hypothesis of homology. Anal organs are found not only in Craterostigmomorpha, but also in most adult Geophilomorpha, and in larvae and most adults of Lithobiomorpha. The anal organs of C. tasmanianus are thought to play an important role in the uptake of atmospheric water. J. Morphol.

Ultrastructure of the epidermal maxilla II-gland of Scutigera coleoptrata (Chilopoda, Notostigmophora) and the ground pattern of epidermal gland organs in Myriapoda.

The epidermal maxilla II-gland of Scutigera coleoptrata was investigated using light and electron microscopy. The glandular epithelium surrounds a spacious integumental cavity at the base of the maxilla II. The gland is formed as a compound gland organ that is composed of thousands of epidermal gland units. Each of them consists of four different cell types: a secretory cell, an accessory or intermediary cell, and a proximal and distal canal cell. The intermediary and the two canal cells form a conducting canal. Only in the most distal part of the intermediary cell is the canal lined by a cuticle. In the area of the two canal cells, the conducting canal is completely covered by a cuticle. The canal passes through the cuticle and opens into the spacious integumental cavity, which serves as a secretion reservoir. The structural organization of the epidermal maxilla II-gland was compared to that of other compound epidermal gland organs in Chilopoda and Diplopoda. All these glandular organs in Myriapoda share the same ground pattern.

Interaction of the tracheal tubules of Scutigeracoleoptrata (Chilopoda, Notostigmophora) with glandular structures of the pericardial septum.

Notostigmophora (Scutigeromorpha) exhibit a special tracheal system compared to other Chilopoda. The unpaired spiracles are localized medially on the long tergites and open into a wide atrium from which hundreds of tracheal tubules originate and extend into the pericardial sinus. Previous investigators reported that the tracheal tubules float freely in the hemolymph. However, here we show for the first time that the tracheal tubules are anchored to a part of the pericardial septum. Another novel finding is this part of the pericardial septum is structured as an aggregated gland on the basis of its specialized epithelium being formed by hundreds of oligocellular glands. It remains unclear whether the pericardial septum has a differently structure in areas that lack a connection with tracheal tubules. The tracheal tubules come into direct contact with the canal cells of the glands that presumably secrete mucous substances covering the entire luminal cuticle of the tracheal tubules. Connections between tracheae and glands have not been observed in any other arthropods.

Ultrastructural characterization of the accessory lobes of Lachi in the lumbosacral spinal cord of the pigeon with special reference to intrinsic mechanoreceptors.

The lumbosacral spinal cord of birds is unique among vertebrates in that segmentally organized accessory lobes protrude from the ventrolateral spinal cord into the vertebral canal. Recently, it has been suggested that these lobes may be part of an extralabyrinthine sense organ of equilibrium. For a better understanding of such a function, a complete analysis of the structural basis was performed by means of electron microscopy. The lobes consist of multipolar neurons, myelinated and unmyelinated axons, glia-derived glycogen cells, glial cells, and capillaries. The dorsal part of the lobe is covered by a loose mesh of pia mater. Ventrolaterally, an arachnoidal trabecle is in close contact with the lobe. Extracellular lacunae extend from the periphery deep into each lobe. The lacunae are separated from the subarachnoidal space by a loose mesh of processes of the glycogen cells with its basal lamina. The lacunae are filled by a network of processes of glycogen cells, glial cell, dendrites, and small axons. Both neuronal somata and dendrites are contacted by numerous axon terminals that form rather uniform synapses. Finger-like processes emerge from both the somata and the dendrites. The dendrites branch deeply into the extracellular lacunae and form lateral ramifications, which consist of narrow stalks with serially arranged bulbous portions, from which finger-like processes emerge. Finger-like processes are well-known elements in mechanotransduction. Glycogen cells and lacunae may contribute to transmission of hydrostatic pressure changes during movements of the body.

Ultrastructure, functional morphology and evolution of recto-canal epidermal glands in Myriapoda.

In Chilopoda, solitary epidermal glands are composed of a couple of cells only. These glands are highly abundant on the entire body surface and are distributed throughout the single-layered epidermis. Some authors provided more or less comprehensive observations on the structure of epidermal glands of specific chilopod taxa. However, no information is hitherto available on the ultrastructural diversity of these glands. Furthermore, potential homologies of these chilopod epidermal glands and of their characteristic cellular components remain unknown. Based on our results, we are now able to distinguish two types of epidermal glands in Chilopoda that can be clearly distinguished by their structure and the course of their conducting canal: recto-canal epidermal glands (rceg) and flexo-canal epidermal glands (fceg). In the present paper, we focus on the rceg. We examined the ultrastructural organization of these glands in the head region and on the anterior trunk segments of various representatives of the five extant chilopod orders by light- and electron-microscopy. According to our terminology, rceg consist of up to five different cell types including: a) distal canal cells, b) proximal canal cells, c) intermediary cells, and d) two different types of secretory cells. Intermediary and canal cells form a common conducting canal. The rceg may taxon-specifically differ in relative size and subcellular architecture, but all have the following features in common: 1) a wide distribution on various body regions among all five chilopod subtaxa, 2) the straight, broad and locally dilated conducting canal surrounded by closely packed microvilli or microvilliform infoldings around the apex of the canal cell(s), and 3) the tendency to aggregate to form compound glandular organs of massive size and complexity. Tricellular glandular units established by three different cell types are observed in Scutigeromorpha and Geophilomorpha, whereas four cell types constitute rceg in Lithobiomorpha and Craterostigmomorpha. Five different cell types per glandular unit are found only in Scolopendromorpha. The partial cuticularization of the lower part of the conducting canal formed by the intermediary cell, as found in Chilopoda, differs from the pattern described for equivalent euarthropod epidermal glands, as for instance in Hexapoda. Their wide distribution in Chilopoda and Progoneata makes it likely that tricellular rceg were at least present in the last common ancestor of the Myriapoda. Concerning Chilopoda, the evolution of highly diverse rceg is well explained on the basis of the Pleurostigmophora concept. Glands of the recto-canal type are also found in other arthropods. The paper discusses cases where homology of rceg and also fceg may be assumed beyond Myriapoda and briefly evaluates the potentials and the still-to-be-solved issues prior to use them as an additional character system to reconstruct the phylogeny of the Euarthropoda.

What is the mechanism behind increased permeation rate of a poorly soluble drug from aqueous dispersions of an amorphous solid dispersion?

Our aim was to explore the influence of micelles and microparticles emerging in aqueous dispersions of amorphous solid dispersions (ASDs) on molecular/apparent solubility and Caco-2 permeation. The ASD, prepared by hot-melt extrusion, contained the poorly soluble model drug ABT-102, a hydrophilic polymer, and three surfactants. Aqueous dispersions of the ASD were investigated at two concentrations, one above and one close to the critical micelle concentration of the surfactants blend in the extrudate. Micelles were detected at the higher concentration and no micelles at the lower concentration. Apparent solubility of ABT-102 was 20-fold higher in concentrated than in diluted dispersions, because of micelles. In contrast, Caco-2 permeation of ABT-102 was independent of the ASD concentration, but three times faster than that of crystalline suspensions. Molecular solubility of ABT-102 (equilibrium dialysis) was also independent of the ASD concentration, but by a factor 2 higher than crystalline ABT-102. The total amount of ABT-102 accumulated in the acceptor during Caco-2 experiments exceeded the initial amount of molecularly dissolved drug in the donor. This may indicate that dissolution of amorphous microparticles present in aqueous dispersions induces lasting supersaturation maintaining enhanced permeation. The hypothesis is supported by a slower drug permeation when the microparticles were removed.

The amorphous solid dispersion of the poorly soluble ABT-102 forms nano/microparticulate structures in aqueous medium: impact on solubility.

Amorphous solid dispersions (ASDs) are a promising formulation approach for poorly soluble active pharmaceutical ingredients (APIs), because they ideally enhance both dissolution rate and solubility. However, the mechanism behind this is not understood in detail. In the present study, we investigated the supramolecular and the nano/microparticulate structures that emerge spontaneously upon dispersion of an ASD in aqueous medium and elucidated their influence on solubility. The ASD, prepared by hot melt extrusion, contained the poorly soluble ABT-102 (solubility in buffer, 0.05 µg/mL), a hydrophilic polymer, and three surfactants. The apparent solubility of ABT-102 from the ASD-formulation was enhanced up to 200 times in comparison to crystalline ABT-102. At the same time, the molecular solubility, as assessed by inverse equilibrium dialysis, was enhanced two times. Asymmetrical flow field-flow fractionation in combination with a multiangle light-scattering detector, an ultraviolet detector, and a refractometer enabled us to separate and identify the various supramolecular assemblies that were present in the aqueous dispersions of the API-free ASD (placebo) and of binary/ternary blends of the ingredients. Thus, the supramolecular assemblies with a molar mass between 20,000 and 90,000 could be assigned to the polyvinylpyrrolidone/vinyl acetate 64, while two other kinds of assemblies were assigned to different surfactant assemblies (micelles). The amount of ABT-102 remaining associated with each of the assemblies upon fractionation was quantified offline with high-performance liquid chromatography-ultraviolet-visible. The polymeric and the micellar fraction contributed to the substantial increase in apparent solubility of ABT-102. Furthermore, a microparticulate fraction was isolated by centrifugation and analyzed by scanning electron microscopy, X-ray scattering, and infrared spectroscopy. The microparticles were found to be amorphous and to contain two of the surfactants besides ABT-102 as the main component. The amorphous microparticles are assumed to be the origin of the observed increase in molecular solubility ("true" supersaturation).