Polyoxyethylene-polyoxypropylene Block Copolymer Research Articles

Effect of composition in the development of carbamazepine hot-melt extruded solid dispersions by application of mixture experimental design

This study investigates the application of hot-melt extrusion for the formulation of carbamazepine (CBZ) solid dispersions, using polyethyleneglycol-polyvinyl caprolactam-polyvinyl acetate grafted copolymer (Soluplus, BASF, Germany) and polyoxyethylene-polyoxypropylene block copolymer (Poloxamer 407). In agreement with the current Quality by Design principle, formulations of solid dispersions were prepared according to a D-optimal mixture experimental design, and the influence of formulation composition on the properties of the dispersions (CBZ heat of fusion and release rate) was estimated. Prepared solid dispersions were characterized using differential scanning calorimetry, attenuated total reflectance infrared spectroscopy and hot stage microscopy, as well as by determination of the dissolution rate of CBZ from the hot-melt extrudates. Solid dispersions of CBZ can be successfully prepared using the novel copolymer Soluplus. Inclusion of Poloxamer 407 as a plasticizer facilitated the processing and decreased the hardness of hot-melt extrudates. Regardless of their composition, all hot-melt extrudates displayed an improvement in the release rate compared to the pure CBZ, with formulations having the ratio of CBZ : Poloxamer 407 = 1 : 1 showing the highest increase in CBZ release rate. Interactions between the mixture components (CBZ and polymers), or quadratic effects of the components, play a significant role in overall influence on the CBZ release rate.

Effect of Oxyethylene Numbers on the Pharmacokinetics of Menatetrenone Incorporated in Oil-in-Water Lipid Emulsions Prepared with Polyoxyethylene-Polyoxypropylene Block Copolymers and Soybean Oil in Rats

We have prepared lipid emulsions of approximately 200 nm in diameter with soybean oil (SO) and a series of Pluronics with various numbers of oxyethylene units and about 60 oxypropylene units (SO/Pluronics), and studied the pharmacokinetics of menatetrenone incorporated into SO/Pluronics in rats. Emulsions of approximately 200 nm in diameter were obtained when SO contents were 2.5% and 20% (w/w) for 2.4% (w/w) PL101 and Pluronics that more than 30% was made up by oxyethylene units, respectively. The half-life of menatetrenone in plasma when oxyethylene units made up less than 30% of the Pluronic (SO/PL101 and SO/PP103) was similar to that for SO/egg yolk phosphatides (SO/EYP), but longer than that when oxyethylene units composed more than 40% of the Pluronic (SO/PP104 and SO/PF108, by 3- and 10-fold, respectively). Pretreatment with dextran sulfate 500000, an inhibitor of emulsion uptake by the reticuloendothelial system (RES), resulted in a higher plasma concentration and a lower liver uptake of menatetrenone as SO/PL101 at 10 min and SO/PP103 at 60 min, indicating that both SO/PL101 and SO/PP103 were taken up by the RES, although SO/PP103 required some time to be recognized by the RES. These findings suggested that larger numbers of oxyethylene units of Pluronics with 60 oxypropylene units were required for the longer plasma circulation of SO/Pluronics due to evasion of the RES.

Supercritical Antisolvent Versus Coevaporation— Preparation and Characterization of Solid Dispersions

The objective of this work was to improve the dissolution rate and aqueous solubility of oxeglitazar. Solid dispersions of oxeglitazar in PVP K17 (polyvinilpyrrolidone) and poloxamer 407 (polyoxyethylene-polyoxypropylene block copolymer) were prepared by supercritical antisolvent (SAS) and coevaporation (CoE) methods. Drug-carrier formulations were characterized by powder X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, gas chromatography, UV/VIS spectroscopy and in vitro dissolution tests. The highest dissolution rate (nearly 3-fold higher than raw drug) was achieved by preparation of drug/PVP K17 coevaporate. Oxeglitazar/PVP K17 solid dispersions were stabilized by hydrogen bonding but contained higher amount of residual dichloromethane (DCM) than poloxamer 407 formulations regardless of the method of preparation. SAS prepared oxeglitazar/poloxamer 407 dissolved more than two times faster than raw drug. However, unlike PVP K17, poloxamer 407 did not form a single phase amorphous solid solution with oxeglitazar which has been manifested in higher degrees of crystallinity, too. Among the two techniques, evaluated in this work, conventional coevaporation resulted in higher amorphous content but SAS reduced residual solvent content more efficiently.

Solid Dispersions of Oxeglitazar in PVP K17 and Poloxamer 407 by Supercritical Antisolvent and Coevaporation Methods

The objective of this work was to improve the dissolution rate and aqueous solubility of oxeglitazar. Solid dispersions of oxeglitazar in PVP K17 (polyvinilpyrrolidone) and Poloxamer 407 (polyoxyethylene-polyoxypropylene block copolymer) were prepared by supercritical antisolvent (SAS) and coevaporation (CoE) methods. Drug-carrier formulations were characterized by powder X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, gas chromatography, UV/VIS spectroscopy and in vitro dissolution tests. The highest dissolution rate (nearly 3-fold higher than raw drug) was achieved by preparation of drug/PVP K17 coevaporate. Oxeglitazar/PVP K17 solid dispersions were stabilized by hydrogen bonding but contained higher amount of residual DCM than Poloxamer 407 formulations regardless of the method of preparation. SAS prepared oxeglitazar/Poloxamer 407 dissolved more than two times faster than raw drug. However, unlike PVP K17, Poloxamer 407 did not form a single phase amorphous solid solution with oxeglitazar which has been manifested in higher degrees of crystallinity, too. Among the two techniques, evaluated in this work, conventional coevaporation resulted in higher amorphous content but SAS reduced residual solvent content more efficiently.

Bioavailability enhancement of an active substance by supercritical antisolvent precipitation

Oxeglitazar is a new orally administered poorly water soluble active substance used in the treatment of type II diabetes. Our research aimed to improve the bioavailability of this active substance using Supercritical Antisolvent (SAS) process. Oxeglitazar was coprecipitated with various solubilizing excipients: polyoxyethylene–polyoxypropylene block copolymers (Poloxamer 188 and 407), polyethylene glycol (PEG 8000) and polyvinilpyrrolidone (PVP K17) from six different solvents: ethanol (EtOH), tetrahydrofuran (THF), dichloromethane (DCM), chloroform (CHCl 3), N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO) and two binary solvent mixtures: EtOH/THF (50:50%, v/v) and EtOH/CHCl 3 (50:50%, v/v). Formulations were compared in terms of particle morphology, crystallinity, polymorphic purity, residual solvent content, precipitation yield and dissolution kinetics. SAS formulations of oxeglitazar–PEG 8000, Poloxamer 188 and 407 contained acicular drug crystals that were partly embedded in polymeric spheres while experiments with PVP K17 resulted in quasi amorphous solid dispersions with high density and good flowability. In spite of the greater particle size, SAS formulations exhibited significantly greater dissolution rate compared to raw drug and physical mixtures. More than twice as much active substance was dissolved at 5 min from Poloxamer 407 and PVP K17 formulations than from unprocessed drug. In addition, SAS prepared Poloxamer 407 formulation from DCM solution exhibited high polymorphic purity, good flow properties, acceptable precipitation yield and low residual solvent content.

Molar solubility of felodipine in different aqueous systems

The molar solubility of felodipine in water was calculated and experimentally determined. A polyoxyethylene-polyoxypropylene block copolymer (Synperonic T304) and sodium lauryl sulfate as surfactants and ethanol as cosolvent were used as solubilizing agents. Significantly different molar solubilities were determined for felodipine according to the approach used to achieve solubilization. Such differences are the result of the different mechanisms of solubilization of the additives.

Polyoxyethylene-polyoxypropylene block copolymer gels as sustained release vehicles for subcutaneous drug administration

Polyoxyethylene-polyoxypropylene surface-active block copolymers (Pluronic®) were evaluated as a vehicle for subcutaneous administration of drugs using a phenolsulfophthalein (PR) as a tracer. The type of Pluronic® copolymer (F108 or F127), and their concentrations, and the effect of solutes (NaOH, NaCl or PR) on gelation properties were studied. Sodium hydroxide and sodium chloride decreased the gel-sol transition temperature, whereas the opposite effect was observed with PR. The ‘in vitro’ release rates obtained for PR were inversely proportional to the concentration of Pluronic used and a zero-order release rate was observed in all preparations assayed. Pluronic® F127/PR preparations were administered subcutaneously (SC) to Wistar rats and PR plasma levels were compared with those reached after SC or intravenous (i.v.) administration of a PR aqueous solution. The gel formulation produced a sustained plateau level within 15 min that lasted 8–9 h. In vivo data analysis was performed with the JANA and PCNONLIN computer programs. The best fittings for experimental data from Pluronic gels were obtained using a zero-order input and first-order output two-compartment model. The results obtained suggest that PF127 aqueous gels may be of practical use as a vehicle for SC administration of drugs.

Interactions of a non-ionic surfactant with mixed phospholipid—oleic acid monolayers. Studies under dynamic conditions

Surface pressure studies of pure and mixed monolayers of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and oleic acid (OA) spread at the air—water interface were performed in the presence and in the absence of ABA polyoxyethylene-polyoxypropylene block copolymer (non-ionic surfactant, POL) in the aqueous subphase. The results reveal that PC—PE mixtures (PL) form homogeneous monolayers.It was found that while the mean surface areas of the mixed PL—OA monolayers followed the additivity rule, the surface pressures (π) corresponded to the phospholipid π values. It was concluded that the non-ideal behavior of OA—PL mixed films resulted from the molecular interactions occurring between the hydrophobic parts of the film-forming components, and that the double bond of oleic acid is involved in these interactions. The mixing energies and interaction parameters at intermediate and collapse pressures were calculated according to the Goodrich and Joos approaches. Negative values of these parameters indicated that OA—PL mixed films were thermodynamically more stable than the films of each component. The addition of POL into the aqueous subphase yielded films capable of supporting higher compressions, a fact attributed to the partial penetration of POL molecules into the lipid monolayers. From these data, models of PL—OA—POL arrangements in the interfacial region are proposed for the expanded and condensed states of monolayers.

Measurement of ultrasonic absorption in a gel by light diffraction and resonator methods

Abstract A new sample cell construction for a light diffraction method permits absolute measurements of the ultrasonic absorption coefficient for a strongly absorbing transparent gel. By means of this cell the absorption coefficient at 6.2 MHz has been measured as a function of the temperature in the gelling temperature range for a 25% (w/w) aqueous solution of the ABA polyoxyethylene-polyoxypropylene block copolymer PLURONIC R F 127. The resonator method has been used under the same experimental conditions. The strongly absorbing gel causes overlapping of the resonance signals. A calibration based on resonance experiments compared with the absolute measurements yields a solution to that problem and thus makes the resonator method applicable to a strongly absorbing gel.

Glomerular filtration in the isolated perfused kidney. I. Sieving of macromolecules.

The permeability of the glomerular capillary wall to neutral macromolecules was studied in isolated perfused rat kidneys. Pluronic F108 (BASF, Wyandotte, MI, USA), a polyoxyethylene-polyoxypropylene block copolymer of mol weight approximately 14,000, was used as plasma expander. Pore theory was applied to the fractional clearances of Pluronic F108 and dextran (mol weight 19,400) molecules measured both as a function of glomerular filtration rate. Using the pore model of Verniory et al. [30] the effective pore radius (60.9 A) and the ratio of total pore area and pore length (4.0 cm/nephron) were estimated, and a hydraulic permeability coefficient KF (0.036 nl/s . mm Hg) was calculated. There was no significant difference between the fractional clearance of Pluronic F108 obtained with different Pluronic F108 concentrations over the range 15-35 g/l, hence with largely differing osmotic pressures. It was concluded that the sieving properties of the glomerular membrane of the isolated perfused rat kidney are not detectably different from those in the intact rat, at least in the case of uncharged macromolecules.

Preparation of Hydrophilic Albumin Microspheres Using Polymeric Dispersing Agents

A new method for preparing glutaraldehyde cross-linked human serum albumin microspheres has been developed. Important aspects of this method include addition of glutaraldehyde in the organic phase and use of concentrated solutions of hydrophobic polymers (polymethylmethacrylate) or hydrophilic polymers (polyoxyethylene-polyoxypropylene block copolymer) as dispersion media. Uniform, round, solid, 3-150-μm hydrophilic microspheres were readily prepared by this process. The average size of microspheres was a function of dispersion time and energy input. Surface properties were altered by chemical modification using either 2-aminoethanol or aminoacetic acid to quench residual aldehyde groups. Optical and scanning electron microscopy and electronic particle size characterization indicate that the process is versatile in producing solid microspheres in a wide size range. Albumin microspheres of this type are readily dispersed in aqueous media for injection, without the need for surfactants.

Ultrasonic velocity and light-scattering studies on the polyoxyethylene—polyoxypropylene copolymer Pluronic F127 in aqueous solution

Ultrasonic velocity and light-scattering measurements on aqueous solutions of the ABA polyoxyethylene-polyoxypropylene block copolymer, Pluronic F127, have clearly indicated a micellar mode of association over the temperature range 10–40°C. The extent of association was limited below 25°C but increased markedly at higher temperatures giving micelles with a mean weight-average aggregation number of 44 at 40°C. A pronounced decrease in the critical micelle concentration accompanied the micellar enlargement. Aggregates were asymmetric at low temperatures but increased in symmetry with temperature increase becoming spheroidal above 25°C. A theoretical treatment of the concentration-dependent changes in ultrasonic velocity is proposed from which information concerning the volume change on micellization may be obtained. Micellization of F127 over the temperature range 20–30°C has been shown to be associated with a very small change in the molar volume of the monomers and this volume change decreased with increases in temperature to the extent of 2%/°C. The temperature-dependent changes in micellar properties have been related to the reversible thermal gelation of this block copolymer.

Adsorption characteristics of certain polyoxyethylene-polyoxypropylene block co-polymers on polystyrene latex

The adsorption of a series of commerical polyoxyethylenepolyoxypropylene block copolymers onto polystyrene latex has been studied. Adsorption was Langmuirian in all cases with maximum adsorption occuring after the apparent critical micelle concentration had been reached. Examination of molecular areas at the interface indicate that for high ethylene oxide content surfactants, the hydrophilic chains adsorb as loops. This was confirmed by measurements of the adsorbed layer thickness determined by intensity fluctuation spectroscopy and microelectrophoresis.