Evaluation of a Sulfobutyl Ether β-Cyclodextrin as a Solubilizing/Stabilizing Agent for Several Drugs

Abstract

To evaluate the potential use of β-cyclodextrin sulfobutyl ether, 7 sodium salt (SBE7-β-CD) as a drug solubilizing and stabilizing agent, the solubilizing effects of SBE7-β-CD on 22 different poorly water-soluble drugs were compared with those of intact β-CD and heptakis-(2,6-di-O-melhyl)-β-CD (DMCD). SBE7-β-CD was generally a more effective solubilizer for poorly water-soluble drugs than was intact β-CD, but SBE7-β-CD was not as effective as DMCD. The effects of SBE7-β-CD on the acid hydrolysis rate of prostaglandin I₂, the alkaline hydrolysis rate of indomethacin, the dehydration of prostaglandin E₁, and the isomerization of prostaglandin A₁ were also investigated and compared to those for intact β-CD, DMCD, and 2,3,6 partially methylated-β-CD (PMCD). The stabilizing effects of SBE7-β-CD on chemically unstable drugs were generally higher than those of other CDs.     

Preparation of 188Re-Labetalol as a β1-Adrenoceptor for Use in Nuclear Medicine

Radiochemistry - Labetalol was labeled with 188Re. The reaction conditions (amounts of stannous chloride and substrate, pH, time) were optimized, and the radiochemical yield as high as 95 ±...     

The Use of Microtracers ® in a Medicated Premix to Determine the Presence of Tiamulin in Final Feed

Abstract

Microtracers® consisting of iron particles coloured with codified food dyes (Micro-Tracers, Inc., San Francisco) were incorporated into a tiamulin (2%) premix. On dilution, to give drug concentrations of 100, 30 and 10 ppm, feed was assayed for both drug and microtracer. Good correlation was found between drug and microtracer recoveries. Thus the use of microctracers gives an easy and rapid method for semi quantitative detection of tiamulin in a non laboratory i.e. field environment.     

Bead Manufacture by Extrusion/spheronization – a Statistical Design for Process Optimization

Abstract

Our recent experience in developing bead formulations for a hydrophilic drug using an extrusion/spheronization technique highlighted several critical processing factors. It was observed that the yield of beads of desired size fraction was significantly affected by water level, water temperature, extrusion speed, spheronization speed, and spheronization time. To further elucidate the roles of these factors, a split-plot factorial design was used to evaluate their effects on the yield of desired size beads, and to determine the optimal levels to maximize the yield. Several 18 kg batches of beads were manufactured using a predetermined level of each factor. The finished beads were sieved using #14 and #20 mesh screens and the yields of beads between #14–20 mesh screen were determined. It was observed that the temperature of water used at the granulation stage significantly affected the bead formation. Using room temperature water for granulation, the significant factors were water level, extruder speed, spheronization speed, spheronization dwell time, and the interactions of water level with extruder speed and spheronization speed with dwell time. Whereas using 50 °C water, significant factors were water level, extruder speed, spheronization speed, and the interaction of water level with spheronization speed. The best fitting regression model describing the relationship between the found yields and the factors was used to find the levels of each factor that would optimize the yield. Two scale-up batches at 100 kg each were manufactured using the optimal process conditions to verify the room temperature model. The yields from the two scale-up batches were within 0.4% of the predicted yield using the regression model.     

Integral as a Function of the Upper Limit to Solve Axial Symmetrical Rod Drawing and Extrusion

A kinematically admissible velocity field which is different from Avitzur's has been proposed for axialsymmetrical rod drawing and extrusion.An upper-bound analytical solution in cylindrical coordinates hasbeen obtained without any mathematical simplification in this paper.     

Measurement and Correlation of Electrical Conductivity of β-Cyclodextrin in Water Solution

The electrical conductivity of 4% β-cyclodextrin in water solution had been measured by electrode method from（323.65~353.65） K at atmospheric pressure. The expe...     

The Variation of “Surface” Pressure in a Nanocrystal as a Function of Temperature

The Mie-Lennard-Jones potential of interatomic interaction is used to derive an expression for “surface” pressure in a nanocrystal with free surface. The nanocrystal has the form of a parallelepiped with a square base. The number of atoms N may vary from eight to ∞. It is found that a certain “inversion temperature” T _i exists for any substance, where the temperature dependences of surface pressure for different sizes of nanocrystal intersect. When the crystal disperses in the T < T _i region, the “surface” pressure increases, and in the T > T _i region decreases, with decreasing size of nanocrystal: P _sf(N) ～ N ^?1/3. The greater the deviation of the nanocrystal shape from cubic, the stronger the dependence P _sf(N). It is demonstrated that, at some temperatures (T < T ₀), the “surface” pressure compresses the nanocrystal, and at other temperatures-stretches this nanocrystal, as its size decreases. The more clearly the quantum effects are defined in the crystal, the lower the value of the “temperature of zero surface pressure” T ₀, which depends on the nanocrystal size and shape.     

Complexation Study of the Anticancer Agent EO-9 with 2-hydroxypropyl-β-Cyclodextrin

For the development of a bladder instillation of the indoloquinone agent EO-9, use of the complexing agent 2-hydroxypropyl-β-cyclodextrin (HPβCD) was considered. Therefore, a complexation study of EO-9 with HPβCD was performed. Complexation was studied in aqueous solution and in solid freeze-dried products. A phase solubility study, UV-visible spectroscopy (UV/VIS), and analysis of the effect of HPβD on the stability of EO-9 were performed. With the phase solubility study, a complexation constant (K1:1) of 32.9, a complexation efficiency (CE) of 0.0457, and a utility number (UCD) of 38.3 were calculated. These K1:1 and CE values indicate a weak complex, but the UCD shows that HPβCD can be very useful as solubilizer in the desired formulation. Furthermore, a positive effect of HPβCD on the chemical stability of EO-9 in solution was seen. Subsequently, complexation in the freeze-dried products was studied more thoroughly using Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and scanning electron microscopy (SEM) analyses. HPβCD was found to be an excellent pharmaceutical complexing agent for application in formulations for EO-9 bladder instillations. Reconstitution before use of the developed freeze-dried products can be simply accomplished with water for injection.     

Influence of Hydroxypropyl- β-Cyclodextrin on the Transdermal Permeation and Skin Accumulation of Oxybenzone

ABSTRACT

The objective of the present study was to determine the effects of hydroxypropyl-β-cyclodextrin (HPCD) concentration on the transdermal permeation and skin accumulation of a model ultraviolet (UV) absorber, oxybenzone. The concentration of oxybenzone was held constant at 2.67 mg/mL for all formulations, while the HPCD concentrations varied from 0 to 20% (w/w). Complexation of oxybenzone by HPCD was demonstrated by differential scanning calorimetry. A modified Franz cell apparatus was used in the transdermal experiments, with aliquots of the receptor fluid assayed for oxybenzone by high-performance liquid chromatography. From the permeation data, flux of the drug was calculated. Skins were removed from the diffusion cells at specified time points over a 24-hr period and the oxybenzone content in the skin determined. The aqueous solubility of oxybenzone increased linearly with increasing HPCD concentration, following a Higuchi A_L-type complexation. The stability constant of the reaction was calculated from the phase-solubility diagram and found to be 2047 M^?1. As the concentration of HPCD was increased from 0 to 10%, transdermal permeation and skin accumulation of oxybenzone increased. Maximum flux occurred at 10% HPCD, where sufficient cyclodextrin was added to completely solubilize all oxybenzone. When the concentration of HPCD was increased to 20%, both transdermal permeation and skin accumulation decreased. These data suggest the formation of a drug reservoir on the surface of the skin.     

Study of Omeprazole-γ-Cyclodextrin Complexation in the Solid State

The possibility of obtaining inclusion complexes between omeprazole (OME) and γ-cyclodextrin (γ-CD) by kneading, spray-drying, coprecipitation, and freeze-drying was evaluated. All these methods lead to the isolation of a true inclusion compound, as evidenced by differential scanning calorimetry (DSC), infrared spectroscopy, and X-ray diffractometry on powder (PXRD). Moreover, PXRD and scanning electron microscopy (SEM) afforded data concerning crystallinity and surface characteristics of the solid phases obtained. In all cases, a significant increase of the release rate with respect to the drug alone was found, and it was attributed to the formation of an inclusion compound. Among the solid phases obtained, the coprecipitated product presented the highest dissolution rate.     

The growth of stem cells within β-TCP scaffolds in a fluid-dynamic environment

A three-dimensional dynamic perfusion system was developed to provide mass transport and nutrient supply to permit the cell proliferation during the long-term culture inside a β-tricalcium phosphate (β-TCP) scaffold. Also the flow field throughout the scaffold was studied. The porous cylindrical scaffold with a central channel was seeded with the sheep mesenchymal stem cells (MSCs). Then the cell-seeded scaffolds were continuously perfused with the complete α-MEM medium by a peristaltic pump for 7, 14 and 28 days, respectively. Histological study showed that the cell proliferation rates were different throughout the whole scaffolds and the different cell coverage was shown in different positions of the scaffold. Unoccupied spaces were found in many macropores. A computational fluid dynamics (CFD) modeling was used to simulate the flow conditions within perfused cell-seeded scaffolds to give an insight into the mechanisms of these cell growth phenomena. Relating the simulation results to perfusion experiments, the even fluid velocity (approximately 0.52 mm/s) and shear stress (approximately 0.0055 Pa) were found to correspond to increased cell proliferation within the cell–scaffold constructs. Flow speeds were between 0.25 and 0.75 mm/s and shear stresses were between 0.003 and 0.008 Pa in approximately 75% of the regions. This method exhibits novel capabilities to compare the results obtained for different perfusion rates or different scaffold microarchitectures. It may allow specific fluid velocities and shear stresses to be determined to optimize the perfusion flow rate, porous scaffold architecture and distribution of in vitro tissue growth.     

Inclusion Complexation of 4-Biphenylacetic Acid with β-Cyclodextrin

Abstract

The preparation of an inclusion complex of 4-biphenylacetic acid (BPAA), a non-steroidal antiinflammatory drug, with β-cyclo-dextrin is described. The presumible structure of the inclusion system, the molar ratio, which was found 1:1, and the formation constant were calculated by the analysis of IR, UV, DSC, X-ray diffraction, and ¹H-NMR. Dissolution rate and solubility were also studied. BPAA solubility in water resulted significantly (4,2-fold) increased by complexation, such as its dissolution rate which appears, in the first 12 min, 18 times greater for the complex than the drug alone.     

Comparison of the cytotoxicity of molybdenum as powder and as alloying element in a niobium–molybdenum alloy

Commercially pure metal niobium (c.p. Nb) as well as niobium–molybdenum (Nb–Mo) alloys were produced following several powder metallurgical routes. In brief, niobium and molybdenum powders were blended and milled in order to form Nb–Mo alloys. The alloy powders and the c.p. Nb were then either pressed and sintered, or cold isostatically pressed followed by hot isostatically pressing. In order to assess the cytotoxicity of the c.p. Nb and c.p. Mo powders, a 72 h minimal essential medium-extraction test was performed according to ISO/EN 10993–5. The cytotoxicity of the c.p. Nb metal and the Nb–Mo alloys was tested in a 72 h direct contact test. Compared to a negative control (UHMWPE), c.p. Nb was non-toxic, but c.p. Mo was moderately toxic. None of the powder metallurgically produced materials were toxic. Neither differences in molybdenum concentration, nor in porosity of the samples, due to different production routes, had any influence on the toxicity of the materials. Rat bone marrow cultures showed that only on c.p. Nb was a mineralized extracellular matrix formed, while on the more porous Nb–Mo alloys, cell growth was observed, but no mineralization. In conclusion, c.p. Mo powder is moderately toxic, however, as an alloying element it is non-toxic. Material porosity seems to influence differentiation of bone tissue in vitro. © 1998 Kluwer Academic Publishers     

Shannon's entropy as a measure of the “life” of the literature of a discipline

The paper is divided in two parts. Part I deals with the novel use of the concept ofentropy H (measured in nepers) of the ageT of references cited in the literature of a specialty, and the derived parameterS=exp(H) (measured in years). We have proposed to useS (orH) as a measure of the obsolescence of the literature. The concept of entropy comes from the Theory of Information (Shannon) where its mathematical properties have been widely studied and are thus available.H andS have been calculated for the log-normal probability density functions (which model the empirical distributions ofT) of some IEEE journals and for the 58-year collection of an electronics journal, and then they have been compared to the total utility function, this latter defined in the literature. Part II recalls and discusses the mean residual life,M(T), and the expected lifeE(T), of a reference of ageT (concepts borrowed from lifetime data analysis). Besides their intrinsic applications, another possible application of these concepts may be in defining quantitatively the age of historical papers. Examples taken from the literatures of the XX and XIX centuries have been reported.Paper presented at the Fourth International Conference on Bibliometrics, Informetrics and Scientometrics in Berlin (Germany), September 11–15, 1993.     

Production of Carbopol® 974P and Carbopol® 971P Pellets by Extrusion‐Spheronization: Optimization of the Processing Parameters and Water Content

Pellets obtained by extrusion‐spheronization represent multiparticulate dosage forms whose interest in intestinal drug delivery can be potentiated and targeted through bioadhesive properties. However, adhesion itself makes the process difficult or even impossible. The problem of tackiness encountered with bioadhesive wet masses was previously eliminated by the use of electrolytes such as CaCl₂. This approach is known to reduce the viscosity of polyacrylic acids by disturbing the interactions between carboxylate groups on adjacent polymer molecules, thereby decreasing their bioadhesive properties. The present study aimed at producing pellets containing carbomers without addition of electrolytes in order to maintain their bioadhesive potentiality at its maximum. Carbopol® 974P (10%, 15% and 20%) and Carbopol® 971P (10%) were used in combination with Avicel® PH101. The extrusion speed (30, 45, 60, 90, and 150 rpm), spheronizer speed (350, 700, 960, 1000, and 1300 rpm), spheronization time (5, 10, 15, and 20 minutes) and amount of water (45%, 50%, 54%, and 58%) were optimized in order to obtain the highest yield of spherical pellets ranging 710–1000 µm in diameter. For pellets containing 10%, 15% Carbopol® 974P or 10% Carbopol® 971P and 45% water content, 30 rpm extrusion speed, 960 rpm, and 10 minutes spheronization speed and time led to the highest yields and sphericities, respectively, 72% and 0.91, 67% and 0.78, and 76% and 0.80. Production of pellets with 20% Carbopol® 974P could be achieved through the increase of the water content up to 58% and implementation of 30 rpm extrusion speed, 1300 rpm, and 10 minutes spheronization speed and time. The yield and sphericity were 42% and 0.78 respectively.     

Influence of Hydroxypropyl β-Cyclodextrin on Solubility and Dissolution Profile of Ketoprofen in Its Solid Dispersions

Abstract

Solid dispersions of hydroxypropyl β-cyclodextrins (HPB), a highly water soluble derivative of β-cyclodextrin and ketoprofen (KPF), were prepared by kneading, coevaporation, and freeze-drying. X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy were used to investigate characteristics of the solid dispersions and to study the possibility of complexation of the drug with HPB. A marked difference in characteristics of dispersions was observed due to their methods of preparation. The solubility of KPF in the solid dispersions was studied by the dispersed powder technique and was found to have improved considerably over that of the drug pure alone. The dispersions had good compressibiliry. Tablets so compressed displayed good dissolution profiles.