| 1. |
- Andersson, Helene, 1983, et al.
(författare)
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Effects of molecular weight on permeability and microstructure of mixed ethyl-hydroxypropyl-cellulose films
- 2013
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 48:1-2, s. 240-248
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Tidskriftsartikel (refereegranskat)abstract
- Films of ethyl cellulose (EC) and water-soluble hydroxypropyl cellulose (HPC) can be used for extended release coatings in oral formulations. The permeability and microstructure of free EC/HPC films with 30% w/w HPC were studied to investigate effects of EC molecular weight. Phase separation during film spraying and subsequent HPC leaching after immersion in aqueous media cause pore formation in such films. It was found that sprayed films were porous throughout the bulk of the films after water immersion. The molecular weight affected HPC leaching, pore morphology and film permeability; increasing the molecular weight resulted in decreasing permeability. A model to distinguish the major factors contributing to diffusion retardation in porous films showed that the trend in permeability was determined predominantly by factors associated with the geometry and arrangement of pores, independent of the diffusing species. The film with the highest molecular weight did, however, show an additional contribution from pore wall/permeant interactions. In addition, rapid drying and increasing molecular weight resulted in smaller pores, which suggest that phase separation kinetics affects the final microstructure of EC/HPC films. Thus, the molecular weight influences the microstructural features of pores, which are crucial for mass transport in EC/HPC films.
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| 2. |
- Andersson, Helene, et al.
(författare)
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Effects of Molecular Weight on Phase Separated Coatings for Controlled Release of Drugs
- 2013
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Ingår i: Annual Transactions of the Nordic Rheology Society. ; , s. 249-
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Tidskriftsartikel (refereegranskat)abstract
- Phase separated films with controlled porosity were made from ethyl cellulose (EC) and 30% w/w hydroxypropyl cellulose (HPC). The molecular weight of EC can be used to modify the mass transfer rate through coatings by effects on microstructure of the film. Processing conditions are, however, affected by the solution rheology, which could influence the film quality when using different molecular weights.
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| 3. |
- Andersson, Helene, 1983, et al.
(författare)
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The influence of the molecular weight of the water-soluble polymer on phase-separated films for controlled release
- 2016
-
Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 511:1, s. 223-235
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Tidskriftsartikel (refereegranskat)abstract
- Hydroxypropyl cellulose (HPC) and ethyl cellulose (EC) can be used for extended release coatings, where the water-soluble HPC may act as a pore former. The aim was to investigate the effect of the molecular weight of HPC on the microstructure and mass transport in phase-separated freestanding EC/HPC films with 30% w/w HPC. Four different HPC grades were used, with weight averaged molecular weights (Mw) of 30.0 (SSL), 55.0 (SL), 83.5 (L) and 365 (M) kg/mol. Results showed that the phase-separated structure changed from HPC-discontinuous to bicontinuous with increasing Mw of HPC. The film with the lowest Mw HPC (SSL) had unconnected oval-shaped HPC-rich domains, leaked almost no HPC and had the lowest water permeability. The remaining higher Mw films had connected complex-shaped pores, which resulted in higher permeabilities. The highest Mw film (M) had the smallest pores and very slow HPC leakage, which led to a slow increase in permeability. Films with grade L and SL released most of their HPC, yet the permeability of the L film was three times higher due to greater pore connectivity. It was concluded that the phase-separated microstructure, the level of pore percolation and the leakage rate of HPC will be affected by the choice of HPC Mw grade used in the film and this will in turn have strong impact on the film permeability.
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| 4. |
- Carlert, Sara, et al.
(författare)
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Predicting intestinal precipitation : a case example for a basic BCS class II drug
- 2010
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Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 27:10, s. 2119-2130
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To investigate the prediction accuracy of in vitro and in vitro/in silico methods for in vivo intestinal precipitation of basic BCS class II drugs in humans. METHODS: Precipitation rate of a model drug substance, AZD0865 (pKa = 6.1; log K(D) = 4.2), was investigated in vitro using simulated intestinal media, and calculations of the crystallization rates were made with a theoretical model. Human intestinal precipitation was estimated by analysis of pharmacokinetic data from clinical studies at different doses. RESULTS: All in vitro models predicted rapid drug precipitation, where the intestinal concentration of dissolved AZD0865 at the highest dose tested was expected to decrease to half after less than 20 min. However, there was no indication of precipitation in vivo in humans as there was a dose proportional increase in drug plasma exposure. The theoretical model predicted no significant precipitation within the range of expected in vivo intestinal concentrations. CONCLUSIONS: This study indicated that simple in vitro methods of in vivo precipitation of orally administered bases overpredict the intestinal crystalline precipitation in vivo in humans. Hydrodynamic conditions were identified as one important factor that needs to be better addressed in future in vivo predictive methods.
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| 5. |
- Carmona, Pierre, 1995, et al.
(författare)
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Cross-sectional structure evolution of phase-separated spin-coated ethylcellulose/hydroxypropylcellulose films during solvent quenching
- 2022
-
Ingår i: RSC Advances. - : Royal Society of Chemistry. - 2046-2069. ; 12:40, s. 26078-26089
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Tidskriftsartikel (refereegranskat)abstract
- Porous phase-separated ethylcellulose/hydroxypropylcellulose (EC/HPC) films are used to control drug transport out of pharmaceutical pellets. The films are applied on the pellets using fluidized bed spraying. The drug transport rate is determined by the structure of the porous films that are formed as the water-soluble HPC leaches out. However, a detailed understanding of the evolution of the phase-separated structure during production is lacking. Here, we have investigated EC/HPC films produced by spin-coating, which mimics the industrial manufacturing process. This work aimed to understand the structure formation and film shrinkage during solvent evaporation. The cross-sectional structure evolution was characterized using confocal laser scanning microscopy (CLSM), profilometry and image analysis. The effect of the EC/HPC ratio on the cross-sectional structure evolution was investigated. During shrinkage of the film, the phase-separated structure undergoes a transition from 3D to nearly 2D structure evolution along the surface. This transition appears when the typical length scale of the phase-separated structure is on the order of the thickness of the film. This was particularly pronounced for the bicontinuous systems. The shrinkage rate was found to be independent of the EC/HPC ratio, while the initial and final film thickness increased with increasing HPC fraction. A new method to estimate part of the binodal curve in the ternary phase diagram for EC/HPC in ethanol has been developed. The findings of this work provide a good understanding of the mechanisms responsible for the morphology development and allow tailoring of thin EC/HPC films structure for controlled drug release.
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| 6. |
- Carmona, Pierre, 1995, et al.
(författare)
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Structure evolution during phase separation in spin-coated ethylcellulose/hydroxypropylcellulose films
- 2021
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Ingår i: Soft Matter. - : Royal Society of Chemistry. - 1744-683X .- 1744-6848. ; 17:14, s. 3913-3922
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Tidskriftsartikel (refereegranskat)abstract
- Porous phase-separated films made of ethylcellulose (EC) and hydroxypropylcellulose (HPC) are commonly used for controlled drug release. The structure of these thin films is controlling the drug transport from the core to the surrounding liquids in the stomach or intestine. However, detailed understanding of the time evolution of these porous structures as they are formed remains elusive. In this work, spin-coating, a widely applied technique for making thin uniform polymer films, was used to mimic the industrial manufacturing process. The focus of this work was on understanding the structure evolution of phase-separated spin-coated EC/HPC films. The structure evolution was determined using confocal laser scanning microscopy (CLSM) and image analysis. In particular, we determined the influence of spin-coating parameters and EC : HPC ratio on the final phase-separated structure and the film thickness. The film thickness was determined by profilometry and it influences the ethanol solvent evaporation rate and thereby the phase separation kinetics. The spin speed was varied between 1000 and 10 000 rpm and the ratio of EC : HPC in the polymer blend was varied between 78 : 22 wt% and 40 : 60 wt%. The obtained CLSM micrographs showed phase separated structures, typical for the spinodal decomposition phase separation mechanism. By using confocal laser scanning microscopy combined with Fourier image analysis, we could extract the characteristic length scale of the phase-separated final structure. Varying spin speed and EC : HPC ratio gave us precise control over the characteristic length scale and the thickness of the film. The results showed that the characteristic length scale increases with decreasing spin speed and with increasing HPC ratio. The thickness of the spin-coated film decreases with increasing spin speed. It was found that the relation between film thickness and spin speed followed the Meyerhofer equation with an exponent close to 0.5. Furthermore, good correlations between thickness and spin speed were found for the compositions 22 wt% HPC, 30 wt% HPC and 45 wt% HPC. These findings give a good basis for understanding the mechanisms responsible for the morphology development and increase the possibilities to tailor thin EC/HPC film structures.
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| 7. |
- Carmona, Pierre, 1995, et al.
(författare)
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Structure formation and coarsening kinetics of phase-separated spin-coated ethylcellulose/hydroxypropylcellulose films
- 2022
-
Ingår i: Soft Matter. - : Royal Society of Chemistry. - 1744-683X .- 1744-6848. ; 18:16, s. 3206-3217
-
Tidskriftsartikel (refereegranskat)abstract
- Porous phase-separated ethylcellulose/hydroxypropylcellulose (EC/HPC) films are used to control drug transport from pharmaceutical pellets. The drug transport rate is determined by the structure of the porous films that are formed as water-soluble HPC leaches out. However, a detailed understanding of the evolution of the phase-separated structure in the films is lacking. In this work, we have investigated EC/HPC films produced by spin-coating, mimicking the industrial fluidized bed spraying. The aim was to investigate film structure evolution and coarsening kinetics during solvent evaporation. The structure evolution was characterized using confocal laser scanning microscopy and image analysis. The effect of the EC:HPC ratio (15 to 85 wt% HPC) on the structure evolution was determined. Bicontinuous structures were found for 30 to 40 wt% HPC. The growth of the characteristic length scale followed a power law, L(t) ∼ t(n), with n ∼ 1 for bicontinuous structures, and n ∼ 0.45-0.75 for discontinuous structures. The characteristic length scale after kinetic trapping ranged between 3.0 and 6.0 μm for bicontinuous and between 0.6 and 1.6 μm for discontinuous structures. Two main coarsening mechanisms could be identified: interfacial tension-driven hydrodynamic growth for bicontinuous structures and diffusion-driven coalescence for discontinuous structures. The 2D in-plane interface curvature analysis showed that the mean curvature decreased as a function of time for bicontinuous structures, confirming that interfacial tension is driving the growth. The findings of this work provide a good understanding of the mechanisms responsible for morphology development and open for further tailoring of thin EC/HPC film structures for controlled drug release. © 2022 The Royal Society of Chemistry
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| 8. |
- Eriksson Barman, Sandra, 1985, et al.
(författare)
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New characterization measures of pore shape and connectivity applied to coatings used for controlled drug release
- 2021
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Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 1520-6017 .- 0022-3549. ; 110:7, s. 2753-2764
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Tidskriftsartikel (refereegranskat)abstract
- Pore geometry characterization-methods are important tools for understanding how pore structure influences properties such as transport through a porous material. Bottlenecks can have a large influence on transport and related properties. However, existing methods only catch certain types of bottleneck effects caused by variations in pore size. We here introduce a new measure, geodesic channel strength, which captures a different type of bottleneck effect caused by many paths coinciding in the same pore. We further develop new variants of pore size measures and propose a new way of visualizing 3-D characterization results using layered images. The new measures together with existing measures were used to characterize and visualize properties of 3-D FIB-SEM images of three leached ethyl-cellulose/hydroxypropyl-cellulose films. All films were shown to be anisotropic, and the strongest anisotropy was found in the film with lowest porosity. This film had very tortuous paths and strong geodesic channel-bottlenecks, while the paths through the other two films were relatively straight with well-connected pore networks. The geodesic channel strength was shown to give important new visual and quantitative insights about connectivity, and the new pore size measures provided useful information about anisotropies and inhomogeneities in the pore structures. The methods have been implemented in the freely available software MIST.
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| 9. |
- Fager, Cecilia, 1990, et al.
(författare)
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Correlating 3D porous structure in polymer films with mass transport properties using FIB-SEM tomography
- 2021
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Ingår i: Chemical Engineering Science: X. - : Elsevier BV. - 2590-1400. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Porous polymer coatings are used to control drug release from pharmaceutical products. The coating covers a drug core and depending on the porous structure, different drug release rates are obtained. This work presents mass transport simulations performed on porous ethyl cellulose films with different porosities. The simulations were performed on high spatial resolution 3D data obtained using a focused ion beam scanning electron microscope. The effective diffusion coefficient of water was determined using a diffusion chamber. Lattice Boltzmann simulations were used to simulate water diffusion in the 3D data. The simulated coefficient was in good agreement with the measured coefficient. From the results it was concluded that the tortuosity and constrictivity of the porous network increase with decreasing amount of added hydroxypropyl cellulose, resulting in a sharp decrease in effective diffusion. This work shows that high spatial resolution 3D data is necessary, and that 2D data is insufficient, in order to predict diffusion through the porous structure with high accuracy.
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| 10. |
- Kjaer Jepsen, Philip, 1995, et al.
(författare)
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Wurster fluidised-bed coating: Coarse-graining technique within CFD-DEM in conjunction with heat and mass transfer
- 2024
-
Ingår i: Powder Technology. - 1873-328X .- 0032-5910. ; 443
-
Tidskriftsartikel (refereegranskat)abstract
- In this study, we use a combined CFD-Discrete Element Method to assess predictive capabilities and numerical implications of a coarse-graining technique in Wurster fluidised-bed coaters. We investigated both hydrodynamics and heat and mass transfer and conducted simulations of a full three-phase system for the original and three coarse-grained systems, analysing velocity distributions, macroscopic solid stresses, moisture content and phase temperatures. We achieved a logarithmic simulation speed-up by aggregating up to 64 original particles into each coarse grain. This was accomplished while maintaining fidelity to the original CFD-DEM system in terms of reproducing with high accuracy macroscopic granular flow properties in different regions of a coater (drying, tube and bed regions). By integrating a liquid spray and humid air, we demonstrated that the phase temperatures were accurately predicted within the coarse-grained system, with a high capability of delivering liquid spray distributions with the same uniformity and drying. We also give arguments for choosing a certain degree of coarse-graining as a compromise between a desired reduction of computational costs and a trustworthy reproduction of granular-flow physics encountered in different regions of a Wurster bed. Our findings pave the way to using CFD-DEM to industrially-scaled Wurster-bed systems, which is currently unfeasible due to prohibitive computational costs.
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| 11. |
- Li, Liang, 1987, et al.
(författare)
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Effect of drag models on residence time distributions of particles in a wurster fluidized bed: A DEM-CFD study
- 2016
-
Ingår i: KONA Powder and Particle Journal. - : Hosokawa Powder Technology Foundation. - 0288-4534 .- 2187-5537. ; 2016:33, s. 264-277
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Tidskriftsartikel (refereegranskat)abstract
- Fluidized bed coating has been used to coat pellets or tablets with functional substances for a number of purposes. In this coating process, particle wetting, drying and film formation are coupled to particle motion. It is therefore of interest to study particle motion in such fluidized beds and to use the results to develop a model for predicting the quality of the final product. In this paper, we present results from DEM-CFD simulations, i.e. discrete element method and computational fluid dynamics simulations of particle motion in a laboratory-scale Wurster fluidized bed that was also employed in positron emission particle tracking (PEPT) experiments. As the drag force is the dominant interaction between the gas flow and the particle motion in this type of fluidized bed, the effect of drag models on the particle motion is investigated. More specifically, the particle velocity and residence time distributions of particles in different regions calculated from five different drag models are presented. It is found that the Gidaspow and Tang drag models predict both particle cycle and residence times well. The HKL and Beetstra drag models somewhat overestimate the particle velocity in the Wurster tube and therefore predict a reduced number of recirculations and a significantly shorter cycle time.
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| 12. |
- Li, Liang, 1987, et al.
(författare)
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PEPT Study of Particle Cycle and Residence Time Distributions in a Wurster Fluid Bed
- 2015
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Ingår i: AICHE Journal. - : Wiley. - 1547-5905 .- 0001-1541. ; 61:3, s. 756-768
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Tidskriftsartikel (refereegranskat)abstract
- Particle cycle and residence time distributions are critical factors in determining the coating quality in the Wurster process. Positron emission particle tracking experiments are performed to determine the cycle and residence times of particles in different regions of a Wurster fluid bed. The results show that particles tend to recirculate in and sneak out below from the Wurster tube. The experiments also show that a larger batch size leads to a shorter cycle time and a narrower cycle time distribution (CTD). It is possible to avoid recirculations and obtain a shorter cycle time and a narrower CTD by selecting the operating conditions appropriately or via equipment design. Experiments using binary mixtures of particles with a diameter ratio of 1.5 show that large particles have a longer cycle time than small particles and that the cycle time is shorter for mixtures with approximately equal amounts of small and large particles.
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| 13. |
- Li, Liang, 1987, et al.
(författare)
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Residence time distributions of different size particles in the spray zone of a Wurster fluid bed studied using DEM-CFD
- 2015
-
Ingår i: Powder Technology. - : Elsevier BV. - 1873-328X .- 0032-5910. ; 280, s. 124-134
-
Tidskriftsartikel (refereegranskat)abstract
- Particle cycle and residence time distributions in different regions, particularly in the spray zone, play an important role in fluid bed coating. In this study, a DEM-CFD (discrete element method, computational fluid dynamics) model is employed to determine particle cycle and residence time distributions in a laboratory-scale Wurster fluid bed coater. The calculations show good agreement with data obtained using the positron emission particle tracking (PEPT) technique. The DEM-CFD simulations of different size particles show that large particles spend a longer time in the spray zone and in the Wurster tube than small particles. In addition, large particles are found on average to move closer to the spray nozzle than small particles, which implies that the large particles could shield small particles from the spray droplets. Both of these effects suggest that large particles receive a greater amount of coating solution per unit area per cycle than small particles. However, the simulations in combination with the PEPT experiments show that this is partly compensated for by a longer cycle time for large particles. Large particles thus receive more coating per unit area per pass through the spray zone, but also travel through the spray zone less frequently than small particles.
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| 14. |
- Marucci, Mariagrazia, et al.
(författare)
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New insights on how to adjust the release profile from coated pellets by varying the molecular weight of ethyl cellulose in the coating film
- 2013
-
Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 458:1, s. 218-223
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Tidskriftsartikel (refereegranskat)abstract
- The major aims of this work were to study the effect of the molecular weight (Mw) of ethyl cellulose (EC) on the drug release profile from metoprolol succinate pellets coated with films comprising EC and hydroxypropyl cellulose (HPC) with a weight ratio of 70:30, and to understand the mechanisms behind the different release profiles. A broad range of Mws was used, and the kinetics of drug release and HPC leaching followed. The higher the Mw of EC, the slower the HPC leaching and the drug release processes. Drug release occurred by diffusion through the pores created in the coating by the HPC leaching. A novel method was used to explain the differences in the release profiles: the effective diffusion coefficient (De) of the drug in the coating film was determined using a mechanistic model and compared to the amount of HPC leached. A linear dependence was found between De and the amount of HPC leached and, importantly, the value of the proportionality constant decreased with increasing Mw of EC. This suggests that the Mw of EC affects the drug release profile by affecting the phase separated microstructure of the coating and the hindrance it imparts to drug diffusion.
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| 15. |
- Marucci, Mariagrazia, et al.
(författare)
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Polymer leaching from film coating: Effects on the coating transport properties.
- 2011
-
Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 1873-3476 .- 0378-5173. ; 411, s. 43-48
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Tidskriftsartikel (refereegranskat)abstract
- The release mechanism of metoprolol succinate pellets coated with a blend of a water-insoluble polymer, ethyl cellulose (EC), and a water-soluble polymer, hydroxypropyl cellulose (HPC) is mechanistically explained. The kinetics of drug release and HPC leaching were followed for drug doses. The coating was initially not permeable to the drug, and release started only after a critical amount of the HPC had been leached out. Drug release occurred mainly through pores created in the coating by the HPC dissolution. Single-pellet release experiments were also performed. The coating thickness and size of each pellet were measured. In order to quantitatively characterize the transport properties of the coating of the individual pellets, and to determine the effective diffusion coefficient (D(e)) of the drug in the coating, a mechanistic model was used to fit the single-pellet release data. It was found that D(e) increased with time due to an increase in the amount of HPC leached. It was also found that D(e) was dependent on the coating thickness, and increased more slowly with a thicker coating. This agreed well with the finding that the HPC leaching rate decreased with increasing film thickness.
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| 16. |
- Moore, Helene A., et al.
(författare)
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New insights on the influence of manufacturing conditions and molecular weight on phase-separated films intended for controlled release
- 2018
-
Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 536:1, s. 261-271
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of this work was to investigate how manufacturing conditions influence phase-separated films of ethyl cellulose (EC) and hydroxypropyl cellulose (HPC) with different molecular weights of HPC. Two HPC grades, SSL and M, with weight average molecular weights (Mw) of 30 × 103 g/mol and 365 × 103 g/mol, respectively, were combined with EC 10 cps (70:30 w/w EC/HPC) and spray-coated from ethanol solutions onto a rotating drum under well-controlled process conditions. Generally, a low spray rate resulted in a more rapid film drying process and, consequently, in smaller HPC-rich domains in the phase-separated film structure. For EC/HPC films with the low Mw HPC (SSL) the most rapid drying process resulted in a shift from a HPC-discontinuous to a partly bicontinuous structure and an increase in the permeability for water. In contrast, films containing the high Mw HPC (M) all showed bicontinuous structures, which resulted in overall higher water permeabilities and polymer release compared to the low Mw films. Interestingly, a maximum in permeability was observed for the high Mw films at intermediate spray rates. Below this spray rate the permeability decreased due to a lower amount of polymer released and at higher spray rates, the permeability decreased due to a loss of pore connectivity (or increased tortuosity). To conclude, this study shows that different Mw systems of EC/HPC can respond differently to variations in manufacturing conditions.
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| 17. |
- Nyström, Lina, et al.
(författare)
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In Vitro and In Vivo Performance of Pickering Emulsion-Based Powders of Omega-3 Polyunsaturated Fatty Acids
- 2024
-
Ingår i: Molecular Pharmaceutics. - : American Chemical Society. - 1543-8384 .- 1543-8392. ; 21:2, s. 677-
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Tidskriftsartikel (refereegranskat)abstract
- Omega-3 polyunsaturated fatty acids (n-3 PUFA) are essential nutrients for human health and have been linked to a variety of health benefits, including reducing the risk of cardiovascular diseases. In this paper, a spray-dried powder formulation based on Pickering emulsions stabilized with cellulose nanocrystals (CNC) and hydroxypropyl methylcellulose (HPMC) has been developed. The formulation was compared in vitro and in vivo to reference emulsions (conventional Self-Emulsifying Drug Delivery System, SEDDS) to formulate n-3 PUFA pharmaceutical products, specifically in free fatty acid form. The results of in vivo studies performed in fasted dogs showed that Pickering emulsions reconstituted from powders are freely available (fast absorption) with a similar level of bioavailability as reference emulsions. In the studies performed with dogs in the fed state, the higher bioavailability combined with slower absorption observed for the Pickering emulsion, compared to the reference, was proposed to be the result of the protection of the n-3 PUFAs (in free fatty acid form) against oxidation in the stomach by the solid particles stabilizing the emulsion. This observation was supported by promising results from short-term studies of chemical stability of powders with n-3 PUFA loads as high as 0.8 g oil/g powder that easily regain the original emulsion drop sizes upon reconstitution. The present work has shown that Pickering emulsions may offer a promising strategy for improving the bioavailability and stability as well as providing an opportunity to produce environmentally friendly (surfactant free) and patient-acceptable solid oral dosage forms of n-3 PUFA in the free fatty acid form.
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| 18. |
- Thoren, Per, 1972, et al.
(författare)
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Interactions of novel, nonhemolytic surfactants with phospholipid vesicles.
- 2007
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Ingår i: Langmuir. - : American Chemical Society (ACS). - 1751-6668 .- 0743-7463 .- 1520-5827. ; 23:13, s. 6956-6965
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Tidskriftsartikel (refereegranskat)abstract
- PEG-12-acyloxystearates constitute a novel class of pharmaceutical solubilizers and are synthesized from polyethylene glycol and 12-hydroxystearic acid, which has been esterified with a second acyl chain. The hemolytic activity of these surfactants decreases drastically with increasing pendant acyloxy chain length, and surfactants with an acyloxy chain of 14 carbon atoms or more are essentially nonhemolytic. In this paper, the interactions of PEG-12-acyloxystearates (acyloxy chain lengths ranging from 8 to 16 carbon atoms) with phosphatidylcholine vesicles, used as a model system for erythrocyte membranes, were studied in search of an explanation for the large variations in hemolytic activity. Surfactant-induced alterations of membrane permeability were investigated by studying the leakage of vesicle-entrapped calcein. It was found that all of the surfactants within the series interact with the vesicle membranes and cause slow leakage at elevated surfactant concentrations, but with large variations in leakage kinetics. The initial leakage rate decreases rapidly with increasing pendant acyloxy chain length. After prolonged incubation, on the other hand, the leakage is not a simple function of acyloxy chain length. The effect of the surfactants on membrane integrity was also investigated by turbidity measurements and cryo-transmission electron microscopy. At a surfactant/lipid molar ratio of 0.4, the vesicle membranes are saturated with surfactant. When the surfactant/lipid molar ratio is further increased, the vesicle membranes are progressively solubilized into mixed micelles. The rate of this process decreases strongly with increasing acyloxy chain length. When comparing the results of the different experiments, it can be concluded that there is no membrane permeabilization below saturation of the vesicle membranes. The large variations in the kinetics suggest that several steps are involved in the mechanism of leakage induced by PEG-12-acyloxystearates and that their relative rates vary with acyloxy chain length. The slow kinetics may in part be explained by the low critical micelle concentrations (CMCs) exhibited by the surfactants. The CMCs were found to be in the range of 0.003-0.025 microM.
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| 19. |
- Thoren, Per, 1972, et al.
(författare)
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Solubilization of sparingly soluble active compounds in lecithin-based microemulsions: Influence on phase behavior and microstructure
- 1999
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Ingår i: Langmuir. - 1520-5827 .- 0743-7463. ; 15:11, s. 3710-3717
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Tidskriftsartikel (refereegranskat)abstract
- Starting from the pharmaceutically interesting Winsor III system of water, l-propanol, soybean phosphatidylcholine, and medium-chain triglycerides (MCT), the influence of two active drug compounds, felodipine and (R)-N-2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]argininamide (BIBP3226), on the phase behavior and microstructure was studied by means of phase studies, NMR self-diffusion measurements, and measurements of drug solubility in the aqueous phase and the oil phase. Felodipine, being practically insoluble in water and slightly soluble in MCT, was found to act as a nonpenetrating oil. With increasing concentration of felodipine in the oil phase, the polarity of the oil phase increases, which in turn curves the surfactant film toward water. Thus, water is expelled from the microemulsion phase, and oil is incorporated as felodipine is added. With the composition used here, the microstructure remains bicontinuous, however, even at high felodipine concentrations. The increase in the polarity of the oil phase also has the effect of increasing the partitioning of 1-propanol in the oil phase, which increases the solubility of felodipine, The maximum solubility of felodipine in the system was 9 wt %, defined as the weight percent of felodipine/(felodipine + MCT). This value should be compared to 3 wt %, which is the solubility in pure MCT. BIBP3226 on the other hand, is a charged molecule and practically insoluble in MCT but slightly soluble in water. Furthermore, it has an affinity far the lecithin monolayer and is therefore partitioned between the water phase and the surfactant film. Mainly because of solubilization of BIBP3226 in the surfactant film and the entropy of the accompanying counterions, the excess water is incorporated in the microemulsion at a very low concentration of BIBP3226. At the drug concentration at which the water phase as well as the surfactant film is saturated with drug, the microstructure has changed from a bicontinuous structure to oil-swollen micelles (oil-in-water microemulsion). At this point, approximately 60% of the drug molecules are located in the surfactant film.
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| 20. |
- Vaccaro, Mauro, et al.
(författare)
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Investigation of the adsorption of PEG1500-12-acyloxystearate surfactants onto phospholipid bilayers: An ellipsometry and Cryo-TEM study
- 2007
-
Ingår i: Biophysical Journal. - : Elsevier BV. - 1542-0086 .- 0006-3495. ; 93:12, s. 4300-4306
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Tidskriftsartikel (refereegranskat)abstract
- In this article we present a study of a new class of surfactants denoted as PEG1500-12-acyloxystearates, which have potential use as pharmaceutical solubilizers. These amphiphilic molecules present interesting properties with regard to cell damage effects. PEG1500-12-acyloxystearates with C-14 to C-16 acyloxy chains cause little or no damage to red blood and intestinal cells, whereas the surfactants with shorter chains, from C-8 to C-12, induce measurable damage. To start unraveling the reason why there is this rather marked dependence of the cell damage effect on surfactant chain length, we have carried out systematic studies of adsorption properties of the surfactants onto phospholipid bilayers by means of ellipsometry. The rate of incorporation of the surfactants in the lipid membrane decreases with increasing length of the acyloxy chain. Cryo-TEM images strengthen the ellipsometry results by showing that the dissolution of the phospholipid bilayer is slower for the surfactants of the series having longer chains.
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| 21. |
- von Corswant, Christian
(författare)
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Lecithin-Based Microemulsions for Pharmaceutical use - Phase behavior and Solution Structure
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Microemulsions are thermodynamically stable, transparent solutions of water, oil and amphiphile(s). It is possible to incorporate large amounts of oil in microemulsions, which makes them interesting for use as a drug delivery vehicle for water insoluble drugs. A prerequisite for pharmaceutical use, however, is a low toxicity of the composition. The aim of this thesis has thus been to characterize microemulsion systems based on the pharmaceutically acceptable components lecithin (soybean phosphatidylcholine), medium-chain and long-chain triglycerides and isopropyl myristate (IPM). An analysis was made of the microstructure of these systems and their phase behavior determined. The effect of the addition of hydrophilic amphiphiles (the IPM system) and of two drug compounds, felodipine and BIBP3226 was also analyzed. Felodipine, being practically insoluble in water and slightly soluble in MCT, was found to act as a non-penetrating oil with only a slight influence (decrease) on the curvature of the amphiphilic film. BIBP3226, on the other hand, being practically insoluble in MCT but slightly soluble in the aqueous phase, had an affinity for the lecithin monolayer which significantly increased both the solubility and the spontaneous curvature of the film. At the point of saturation, approximately 60 percent of the drug molecules were located in the film. A microemulsion system suitable for intravenous administration is presented. It is composed of a medium-chain triglyceride as the oil, soybean phosphatidylcholine and polyethylene glycol(660)-12-hydroxystearate as amphiphiles, and polyethylene glycol 400 and ethanol as cosolvents. The microstructure of this microemulsion was found to be of a bicontinuous nature, even at high oil concentrations. When diluted with water, the microemulsion spontaneously formed an oil-in-water emulsion with a mean droplet diameter between 60 and 200 nm depending on the oil content of the microemulsion. It was possible to administer up to 1.5 ml/kg of the microemulsion intravenously to conscious rats without causing any permanent changes in the hemodynamic parameters studied.
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