Cyclodextrins Allow the Combination of Incompatible Vancomycin and Ceftazidime into an Ophthalmic Formulation for the Treatment of Bacterial Keratitis

Ceftazidime (CZ) and vancomycin (VA) are two antibiotics used to treat bacterial keratitis. Due to their physical incompatibility (formation of a precipitate), it is not currently possible to associate both molecules in a single container for ophthalmic administration. We firstly characterized the incompatibility then investigated if 2-hydroxypropyl-beta (HPβCD) and 2-hydroxypropyl-gamma cyclodextrins (HPγCD) could prevent this incompatibility. The impact of pH on the precipitation phenomena was investigated by analysing the supernatant solution of the mixture using high performance liquid chromatography. A characterization of the inclusion of CZ with HPγCD using 1H nuclear magnetic resonance (NMR), and VA with HPβCD using 1H-NMR and a solubility diagram was performed. A design of experiment was built to determine the optimal conditions to obtain a formulation that had the lowest turbidity and particle count. Our results showed that VA and CZ form an equimolar precipitate below pH 7.3. The best formulation obtained underwent an in-vitro evaluation of its antibacterial activity. The impact of HPCDs on incompatibility has been demonstrated through the inclusion of antibiotics and especially VA. The formulation has been shown to be able to inhibit the incompatibility for pH higher than 7.3 and to possess unaltered antibacterial activity.

Використання полімерних композиційних матеріалів для підвищення біодоступності гесперидина

Purpose. Investigation of the influence of the composition of polymeric solubilizers on the phase solubilization in water of the model active pharmaceutical ingredient of flavonoid nature hesperidin.Methods. Hesperidin was chosen as a model substance of characteristic chemical structure. Pharmaceutically acceptable high molecular weight polymers based on polyvinylpyrrolidone (PVP) with a molecular weight of from 2500 to 58000 D were used for research; cetylpyridinium chloride; β-cyclodextrin. Phase solubilization of hesperidin was investigated by the method of Higuchi and Connors. The concentration of hesperidin was determined spectrophotometrically by absorption at 284 nm. The phase solubility diagram was constructed as the dependence of the concentration of hesperidin in solution on the concentration of the polymer. The obtained phase solubility profiles of hesperidin were compared with standard curves. For different compositions at the experiment temperature of 37 ± 0.5 °C, the stability constant and the dissociation constant of intermolecular complexes were calculated.Scientific novelty. The influence of the composition of polymer solubilizers on the phase solubilization in water of the model API of flavonoid nature of hesperidin was established. Practical significance. The optimal composition of the polymer composite material with hesperidin in the form of a solid dispersed system to maximize the solubility of flavonoids in water is substantiated. Results. The influence of the composition of polymer solubilizers on the phase solubilization in water of the model API of flavonoid nature of hesperidin was investigated. Based on the results of graphical analysis of the obtained data, it was concluded that the solubility of hesperidin increases with increasing number of polymers with different molecular weights and surfactants. The increase in solubility depends on the composition. When adding several polymers or a combination of a polymer with a surfactant, the solubility increases significantly more than when adding one compound. It is shown that the maximum value of solubility increase is observed in the system with polymer C and K surfactant - 42.7 times. It was found that the stability constants of polymeric composite materials of hesperidin based on polyvinylpyrrolidones are in the range from 161.87 to 219.88 M-1, which indicates favorable conditions for the formation of complexes.

INTERACTION OF SOIL ORDERS AND LEVELS OF APPLIED PHOSPHORUS ON P-STATUS OF SOIL CALTIVATED WITH WHEAT AT ELONGATION STAGE

A pot experiment was carried out during autumn growing season of 2016-2017 at the Gerdarasha field of College of Agriculture Engineering Sciences, to study the effect of three dominant soil orders (Mollisols (M), Vertisols (V) and Aridisols (A)), five levelsof applied triple super phosphate (TSP) fertilizer (0, 80, 160, 240 and 320 kg TSP ha-1) and combination between them on chemical availability of phosphorus (P) using solubility diagram at elongation stage and wheat yield. The factorial experiment was depended using a completely randomized design (CRD) with three replicates. The results indicated that the soil orders were affected on phosphorus status, it has appeared that the studied soil order was located between TCP and HA for both Aridisols and Vertisols it means the solubility of phosphorus is low. but in Mollisols is slightly more than Vertisols and Aridisols. It is the P-status and availability was very low since shifting towards TCP, it means precipitation of P in a non-available form then decrease in its availability. The application of phosphorus fertilizers caused shifting the points towards a more soluble form of phosphorus. The results indicated that the application of TSP fertilizer increased the solubility of P in the studied dominate soil orders. Then, the treatment combination (M, V, A) TSP0 were the nearest point to TCP falling between TCP and OCP which were the lowest soluble of phosphorus there less available, phosphorus application of phosphorus caused to shifting towards DCP In contrast, for treatment combination (M,V and A) TSP320 kg ha-1 were located between OCP and DCP the nearest point treatment combination for DCP

Short-Stability Study of Rifaximin-Based Samples

Background Rifaximin is an oral antimicrobial with a daily dose ranging from 600 to 800 mg. It is classified as Class IV in the Biopharmaceutic Classification System. Thus, rifaximin-based samples were developed by complexation to β-cyclodextrin using a phase solubility diagram, and malaxation and decreasing particle size using wet milling. Objective Concomitant to the pharmaceutical technology, a stability studywas undertaken with the objective of verifying the integrity of the drug. Methods The stability of the new samples were studied for 6 months, without interruption, under controlled conditions of temperature and humidity in a climatic chamber. They were analyzed simultaneously by HPLC and microbiological turbidimetry at zero, 3, and 6 months. Results Two of the samples follow second reaction order and one follows zero reaction order. Microbiological analysis proved to be important in assessing the potency of rifaximin in one of the samples, and its results were more consistent than the results by HPLC. Conclusions The rifaximin-based samples were stable under controlled temperature and humidity conditions and the physical-chemical and microbiological methods were able to evaluate their behavior during the 6-month study. Highlights It is worth considering the development of these products, since the design process of formulation and pharmaceutical technology is financially more attractive than the development of new drugs that require high levels of investment in research and development, innovation of public policies, and regulatory actions.

Oral Bioavailability Enhancement of Amisulpride: Complexation and its Pharmacokinetics and Pharmacodynamics Evaluations

Background: Many CNS drugs have low bioavailability due to their poor water solubility of extensive first-pass metabolism and hence have less effectiveness. Objective: The present study aims to enhance the solubility and oral bioavailability of poorly watersoluble antipsychotic drug Amisulpride (AMS) through complexation with 2-hydroxypropyl β- cyclodextrin (HPβCD). It has slow and erratic absorption after oral administration. Methods: This report describes the study of the phase solubility diagram, preparation of the inclusion complex and tablet of prepared inclusion complex, characterization of the physico-chemical properties of the inclusion complex and tablet. Results: In-vitro study (100 % drug release in 15 minutes), and in-vivo study of an AL-type (linear type) phase solubility diagram indicated a complex of AMS-HP-β-CD with the constant complex formation of 13245 M−1 at 37°C. The complex formation was confirmed by DSC, IR, and X-ray diffraction. The extent of absorption of the complex was determined in rats and was compared with that of pure drug and the market product. The peak plasma concentration of pure drug was 30.05 ± 1.3 ng/ml (Cmax) at 60 ± 3 min, whereas with the market product the value was 54.85 ± 1.2 ng/ml at 40 ± 1 min and with AMS-HPβCD inclusion complex the value was 79.01 ± 1.5 ng/ml. The AUCtot of the pure drug was 2980.34±3.6, the market product was 7238.73±2.9 and of the inclusion complex was 11871.1±2.8. Conclusion: Pharmacodynamic studies in mice showed improved effectiveness of drug compared to pure drug. The oral bioavailability of AMS was improved from 48% to 78%.

On the mechanism of instability in a two-layer system with limited solubility of components

A two-layer system of miscible liquids is a common model system in studies of both fundamental and applied problems in hydrodynamics that associated with stratified media. Rayleigh-Taylor instabilities or double diffusive one can lead to a disturbance in mechanical equilibrium if both or at least one of the components dissolved in each of the layers are initially unstable stratified. The situation when both components have a stable initial density distribution is believed that absolutely stable and, usually, is not considered by researchers. This paper experimentally demonstrates the possibility of developing instability in such systems and proposes a physical mechanism based on the dependence of the solubility of one of the components on the concentration of the second component. It is shown that the evolution of the density profile, the possibility of the development of instability, and the properties of the arising convective motion are determined by the initial position of the system on the parameters plane of the solubility diagram.

INTESTINAL ABSORPTION OF EPROSARTAN MESYLATE FROM SELF EMULSIFYING SYSTEM AND CYCLODEXTRIN COMPLEX

<p class="MsoNormal" style="margin-top: 6.0pt; margin-right: 0in; margin-bottom: 6.0pt; margin-left: 0in; text-align: justify; line-height: 97%;"><strong><span style="font-size: 8.0pt; line-height: 97%; font-family: 'Cambria','serif';">Objective: </span></strong><span style="font-size: 8.0pt; line-height: 97%; font-family: 'Cambria','serif';">The aim of this work was to determine the intestinal membrane transport parameters of eprosartan mesylate (EM) and to investigate self-nano emulsifying drug delivery systems (SNEDDS) and inclusion complexation with hydroxypropyl </span><span style="font-size: 8.0pt; line-height: 97%; font-family: Symbol;">b </span><span style="font-size: 8.0pt; line-height: 97%; font-family: 'Cambria','serif';">cyclodextrin (HP</span><span style="font-size: 8.0pt; line-height: 97%; font-family: Symbol;">b</span><span style="font-size: 8.0pt; line-height: 97%; font-family: 'Cambria','serif';">CD) for enhanced intestinal absorption of eprosartan mesylate. </span></p><p class="MsoNormal" style="margin-top: 6.0pt; margin-right: 0in; margin-bottom: 6.0pt; margin-left: 0in; text-align: justify; line-height: 97%;"><strong><span style="font-size: 8.0pt; line-height: 97%; font-family: 'Cambria','serif';">Methods: </span></strong><span style="font-size: 8.0pt; line-height: 97%; font-family: 'Cambria','serif';">The intestinal absorption was monitored using the in situ rabbit intestinal perfusion technique. SNEDDS was developed using labrafil, Lauroglycol with a tween in the presence of ethanol. Inclusion complexation was achieved by construction of phase solubility diagram in the presence of HP</span><span style="font-size: 8.0pt; line-height: 97%; font-family: Symbol;">b</span><span style="font-size: 8.0pt; line-height: 97%; font-family: 'Cambria','serif';">CD. The prepared complex was evaluated using Fourier Transform Infrared Spectroscopy (FTIR) and differential scanning calorimetry (DSC). </span></p><p class="MsoNormal" style="margin-top: 6.0pt; margin-right: 0in; margin-bottom: 6.0pt; margin-left: 0in; text-align: justify; line-height: 97%;"><strong><span style="font-size: 8.0pt; line-height: 97%; font-family: 'Cambria','serif';">Results: </span></strong><span style="font-size: 8.0pt; line-height: 97%; font-family: 'Cambria','serif';">The drug was found to be poorly absorbed from the jejuno-ileum and the colon with the absorption being mainly through paracellular pathway. An inclusion complex was developed between the drug and HPβCD. Perfusion of the drug in the nanoemulsion formulation or as an inclusion complex resulted in a significant increase in the intestinal absorption of the drug compared with the control<strong>.</strong></span></p><p class="MsoNormal" style="margin-top: 6.0pt; margin-right: 0in; margin-bottom: 6.0pt; margin-left: 0in; text-align: justify; line-height: 97%;"><strong><span style="font-size: 8.0pt; line-height: 97%; font-family: 'Cambria','serif';">Conclusion: </span></strong><span style="font-size: 8.0pt; line-height: 97%; font-family: 'Cambria','serif';">SNEDDS and inclusion complexation are promising strategies for enhanced intestinal absorption of eprosartan mesylate.</span></p><p><!--[if gte vml 1]><v:shapetype id="_x0000_t32" coordsize="21600,21600" o:spt="32" o:oned="t" path="m,l21600,21600e" filled="f"> <v:path arrowok="t" fillok="f" o:connecttype="none"/> <o:lock v:ext="edit" shapetype="t"/> </v:shapetype><v:shape id="_x0000_s1026" type="#_x0000_t32" style='position:absolute; margin-left:.55pt;margin-top:12.95pt;width:7in;height:0;z-index:251664384' o:connectortype="straight" strokeweight="2.5pt"> <v:shadow color="#868686"/> </v:shape><![endif]--><!--[if !vml]--><span style="mso-ignore: vglayout; position: absolute; z-index: 251664384; margin-left: -1px; margin-top: 15px; width: 676px; height: 4px;"><br /></span></p>