Performance Evaluation of a Novel Biosourced Co-Processed Excipient in Direct Compression and Drug Release

This study exposes the potential usefulness of a new co-processed excipient, composed of alginic acid and microcrystalline cellulose (Cop AA-MCC), for the preparation of immediate drug release tablets by direct compression. Evaluation of the physical and mechanical properties as well as the disintegration behavior of Cop AA-MCC in comparison to commercial co-processed excipients (Cellactose®, Ludipress®, Prosolv® SMCC HD90 and Prosolv® ODT) and to the physical mixture of the native excipients (MCC and AA), was carried out. The obtained results illustrate the good performance of Cop AA-MCC in terms of powder flowability, tablet tensile strength, compressibility, and disintegration time. Although, this new co-processed excipient showed a slightly high lubricant sensitivity, which was explained by its more plastic than fragmentary deformation behavior, it presented a low lubricant requirement due to the remarkably low ejection force observed during compression. Compression speed and dwell time seemed not to affect significantly the tabletability of Cop AA-MCC. The study exposed evenly the performance of Cop AA-MCC compared to Prosolv® ODT, in terms of tabletability and dissolution rate of Melatonin. Cop AA-MCC presented comparable hardness, lower dilution potential, higher lubricant sensitivity, lower ejection force, and faster Melatonin’s release time than Prosolv® ODT. In summary, Cop AA-MCC exhibited interesting physical, mechanical, and biopharmaceutical properties, which demonstrate its concurrence to commercially available co-processed excipients. Furthermore, the simplicity of its composition and the scalability of its elaboration makes this multifunctional excipient highly recommended for direct compression.

Evaluation of Acid-Modified Ethiopian Potato (Plectranthus edulis) Starch as Directly Compressible Tablet Excipient

Ethiopian potato is one of the tuber-bearing members of the family Lamiaceae. It is an indigenous crop in Ethiopia and important source of starch. Unprocessed native starches are structurally weak and functionally restricted for application in pharmaceutical technologies. Consequently, starch is usually modified either chemically or physically to make it convenient for industrial use. The aim of the study was to prepare and characterize acid-modified Ethiopian potato starch (AMEPS) and evaluate its functionality as a direct compressible excipient in tablet formulations. The extracted starch from Ethiopian potato tuber was modified using 6% HCl concentration for 8 days, then dried using oven and spray drying techniques, and subsequently evaluated and compared with the native Ethiopian potato starch (NEPS) and S1500® as a direct compressible excipient. Acid modification of the NEPS decreased the moisture content and swelling power while increased the percent solubility. The X-ray diffraction revealed that both the NEPS and AMEPS have B-type crystal patterns. The AMEPS showed improved flowability compared to the NEPS. This improvement was further enhanced by the spray drying process. The compactability study revealed that the tensile strength of spray-dried AMEPS (16.76 kg/cm2) was significantly higher than that of the spray-dried NEPS (7.07 kg/cm2) and S1500® (11.66 kg/cm2). The AMEPS was less sensitive to lubricants compared to the NEPS and Starch 1500®. Similarly, the dilution potential of the AMEPS was superior to the NEPS and S1500®. The AMEPS accommodated up to 50% of paracetamol while the NEPS and S1500® were able to hold only up to 30%. Pharmacopoeial specifications for disintegration and dissolution were met by the paracetamol tablets prepared by AMEPS. Thus, considering all the results obtained, spray-dried AMEPS could be a potential alternative directly compressible tablet excipient.

Claudin-19 mediates the effects of NO on the paracellular pathway in thick ascending limbs

Claudins are a family of tight junction proteins that provide size and charge selectivity to solutes traversing the paracellular space. Thick ascending limbs (TALs) express numerous claudins, including claudin-19. Nitric oxide (NO), via cGMP, reduces dilution potentials in perfused TALs, a measure of paracellular permeability, but the role of claudin-19 is unknown. We hypothesized that claudin-19 mediates the effects of NO/cGMP on the paracellular pathway in TALs via increases in plasma membrane expression of this protein. We measured the effect of the NO donor spermine NONOate (SPM) on dilution potentials with and without blocking antibodies and plasma membrane expression of claudin-19. During the control period, the dilution potential was −18.2 ± 1.8 mV. After treatment with 200 μmol/l SPM, it was −14.7 ± 2.0 mV ( P < 0.04). In the presence of claudin-19 antibody, the dilution potential was −12.7 ± 2.1 mV. After SPM, it was −12.9 ± 2.4 mV, not significantly different. Claudin-19 antibody alone had no effect on dilution potentials. In the presence of Tamm-Horsfall protein antibody, SPM reduced the dilution potential from −9.7 ± 1.0 to −6.3 ± 1.1 mV ( P < 0.006). Dibutyryl-cGMP (500 µmol/l) reduced the dilution potential from −19.6 ± 2.6 to −17.2 ± 2.3 mV ( P < 0.002). Dibutyryl-cGMP increased expression of claudin-19 in the plasma membrane from 29.9 ± 3.8% to 65.9 ± 10.1% of total ( P < 0.011) but did not change total expression. We conclude that claudin-19 mediates the effects of the NO/cGMP signaling cascade on the paracellular pathway.

Paracellular transport of phosphate along the intestine

Inorganic phosphate (Pi) is crucial for many biological functions, such as energy metabolism, signal transduction, and pH buffering. Efficient systems must exist to ensure sufficient supply for the body of Pi from diet. Previous experiments in humans and rodents suggest that two pathways for the absorption of Pi exist, an active transcellular Pi transport and a second paracellular pathway. Whereas the identity, role, and regulation of active Pi transport have been extensively studied, much less is known about the properties of the paracellular pathway. In Ussing chamber experiments, we characterized paracellular intestinal Pi permeabilities and fluxes. Dilution potential measurements in intestinal cell culture models demonstrated that the tight junction is permeable to Pi, with monovalent Pi having a higher permeability than divalent Pi. These findings were confirmed in rat and mouse intestinal segments by use of Ussing chambers and a combination of dilution potential measurements and fluxes of radiolabeled 32Pi. Both techniques yielded very similar results, showing that paracellular Pi fluxes were bidirectional and that Pi permeability was ~50% of the permeability for Na+ or Cl−. Pi fluxes were a function of the concentration gradient and Pi species (mono- vs. divalent Pi). In mice lacking the active transcellular Pi transport component sodium-dependent Pi transporter NaPi-IIb, the paracellular pathway was not upregulated. In summary, the small and large intestines have a very high paracellular Pi permeability, which may favor monovalent Pi fluxes and allow efficient uptake of Pi even in the absence of active transcellular Pi uptake. NEW & NOTEWORTHY The paracellular permeability for phosphate is high along the entire axis of the small and large intestine. There is a slight preference for monovalent phosphate. Paracellular phosphate fluxes do not increase when transcellular phosphate transport is genetically abolished. Paracellular phosphate transport may be an important target for therapies aiming to reduce intestinal phosphate absorption.

PROTOTYPE SELF EMULSIFYING SYSTEM OF ETRAVIRINE: DESIGN, FORMULATION AND IN VITRO EVALUATION

Objective: Lipid-based formulations have gained much attention, particularly on self-emulsifying drug delivery systems (SEDDS), to improve the oral bioavailability of lipophilic drugs. In the present study, an attempt was made to develop and evaluate prototype SEDDS of poorly soluble antiviral BCS class IV drug etravirine.Methods: Various oils, surfactants and co-surfactants were screened for their suitability in the formulation of SEDDS. Based on the screening, gelucire 44/14, as the oil, labrasol as a surfactant and transcutol HP as the co-surfactant were selected. SEDDS with drug etravirine was formulated and evaluated for emulsifying ability, dilution potential and microscopic properties. The emulsion area for each of the combination of oil and surfactant co-surfactant mixture (Smix) was determined by the construction of pseudo-ternary phase diagrams.Results: The optimized formulation with oil (gelucire 44/14) and Smix (labrasol: transcutol HP, 6:1) in a ratio of 2:8 exhibited a rapid emulsification rate and a good polydispersibility index of 0.103±0.012 indicating uniformity of the formed droplets. The size of the droplets was determined by zetasizer and was found to be in 200 nm range. The drug release from the final formulation after 2hr was found to be 41.15%±0.5 compared to 19.3%±3.8 of pure drug indicating enhanced dissolution profile of the drug.Conclusion: In vitro study illustrated enhanced dissolution rate of formulated prototype SEDDS of BCS class IV drug etravirine for oral delivery.

Abstract P607: Nitric Oxide (NO) Regulates Paracellular Permselectivity in Isolated, Perfused Rat Thick Ascending Limbs through Claudin-19

About 50% of the Na reabsorbed in thick ascending limbs (TALs) traverses the paracellular pathway. The ionic selectivity of this route is regulated by claudins in the tight junctions. TALs express claudin-19 which has been reported to regulate TAL Na permeability. We showed that nitric oxide (NO) decreases Na/Cl permeability ratio (PNa/PCl) in TALs by increasing the absolute permeabilities of both ions though PCl increased more. However, whether NO affects paracellular permeability via claudin-19 is unknown. We hypothesize that NO regulates the paracellular permselectivity in TALs through this claudin. To test this we perfused TALs from Sprague Dawley rats and measured dilution potentials (a measure of permselectivity) with and without exogenously-added or endogenously-produced NO in the presence or absence of an antibody against an extracellular domain of claudin-19 or Tamm-Horsfall protein (control). Dilution potentials were generated by reducing bath NaCl from 141 to 32 mM. For the NO donor spermine NONOate (SPM): during the control period, the dilution potential was -9.3 ± 1.8 mV. After SPM (200 μM), it was -6.7 ± 1.6 mV (n = 6; p < 0.003). In the presence of the claudin-19 antibody, SPM had no significant effect on dilution potentials (claudin-19 antibody alone: -12.7 ± 2.1 mV vs claudin-19 antibody + SPM: -12.9 ± 2.4 mV; n = 6). The claudin-19 antibody alone had no effect on dilution potentials. In the presence of the Tamm-Horsfall protein, the effect of SPM was still present (Tamm-Horsfall protein antibody alone: -9.7 ± 1.0 mV; Tamm-Horsfall protein antibody + SPM: -6.3 ± 1.1 mV, p<0.006, n = 6). For experiments with endogenously-produced NO, L-arginine the substrate for NO synthase was added. During the control period, the dilution potential was -11.0 ± 1.1 mV. After L-arginine (500 μM) treatment, they were -9.0 ± 1.2 mV (n = 9; p < 0.05). In the presence of the claudin-19 antibody, L-arginine had no significant effect on dilution potentials (claudin-19 antibody alone: -10.1 ± 0.9 mV vs claudin-19 antibody + L-arginine: -10.1 ± 1.0 mV; n = 9). In the presence of the Tamm-Horsfall protein, the effect of L-arginine was still present. We conclude that the actions of NO on the paracellular permselectivity in thick ascending limbs are at least in part mediated by claudin-19.