Publications (13)46.22 Total impact
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Article: Characterization and skin permeation of ketoprofen loaded vesicular systems.
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ABSTRACT: PURPOSE: To determine the effect of elasticity on the skin permeation of ketoprofen from surfactant-based vesicular formulations and elastic liposomes. METHODS: Ketoprofen loaded surfactant-based vesicles and elastic liposomes were prepared by sonication. Citric buffer (at pH 3.0) was used as rehydration buffer. Characterization studies of the prepared liposomal formulations were performed by dynamic light scattering, extrusion, and (1)H and (31)P-nuclear magnetic resonance (NMR) spectroscopy. Ketoprofen transport studies across human skin were performed for all formulations. RESULTS: Stable ketoprofen loaded formulations were prepared. Addition of an edge activator, in the absence of the drug, increased the elasticity of the vesicles and liposomes. Ketoprofen loading reduced the elasticity of the liposomes and surfactant-based-vesicles. However, at saturation the elasticity was still higher than that in the absence of the edge activator and ketoprofen, except for ketoprofen loaded liposomes with Span 80. NMR studies revealed that the ketoprofen molecules were entrapped in a vesicle bilayer in all vesicular formulations, and that the ketoprofen molecules affected the phosphate mobility in the liposomal formulations. Ketoprofen transport studies across human skin clearly showed that the surfactant-based vesicular formulations were superior to the elastic liposomal formulations. CONCLUSION: Surfactant-based vesicles enhance ketoprofen transport across human skin, while no enhancement of ketoprofen was observed when loaded in elastic liposomes.European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 03/2013; · 3.15 Impact Factor -
Article: Fluorescent nanoparticle adhesion assay: a novel method for surface pKa determination of self-assembled monolayers on silicon surfaces.
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ABSTRACT: Since the computer industry enables us to generate smaller and smaller structures, silicon surface chemistry is becoming increasingly important for (bio-)analytical and biological applications. For controlling the binding of charged biomacromolecules such as DNA and proteins on modified silicon surfaces, the surface pK(a) is an important factor. Here we present a fluorescent nanoparticle adhesion assay as a novel method to determine the surface pK(a) of silicon surfaces modified with weak acids or bases. This method is based upon electrostatic interactions between the modified silicon surface and fluorescent nanoparticles with an opposite charge. Silicon slides were modified with 3-aminopropyltriethoxysilane (APTES) and were further derivatized with succinic anhydride. Layer thickness of these surfaces was determined by ellipsometry. After incubating the surfaces with an amine-reactive fluorescent dye, fluorescence microscopy revealed that the silicon surfaces were successfully modified with amine- and carboxyl-groups. Two surface pK(a) values were found for APTES surfaces by the fluorescent nanoparticle adhesion assay. The first surface pK(a) (6.55 ± 0.73) was comparable with the surface pK(a) obtained by contact angle titration (7.3 ± 0.8), and the second surface pK(a) (9.94 ± 0.19) was only found by using the fluorescent nanoparticle adhesion assay. The surface pK(a) of the carboxyl-modified surface by the fluorescent nanoparticle adhesion assay (4.37 ± 0.59) did not significantly differ from that found by contact angle titration (5.7 ± 1.4). In conclusion, we have developed a novel method to determine the surface pK(a) of modified silicon surfaces: the fluorescent nanoparticle adhesion assay. This method may provide a useful tool for designing pH-dependent electrostatic protein and particle binding/release and to design surfaces with a pH-dependent surface charge for (bio-)analytical lab-on-a-chip devices or drug delivery purposes.Langmuir 02/2012; 28(7):3403-11. · 4.19 Impact Factor -
Article: Microneedle technologies for (trans)dermal drug and vaccine delivery.
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ABSTRACT: Microneedles have been used for the dermal and transdermal delivery of a broad range of drugs, such as small molecular weight drugs, oligonucleotides, DNA, peptides, proteins and inactivated viruses. However, until now there are no microneedle-based (trans)dermal drug delivery systems on the market. In the past decade various types of microneedles have been developed by a number of production processes. Numerous geometries of microneedles have been designed from various materials. These microneedles have been used for different approaches of microneedle-based (trans)dermal drug delivery. Following a brief introduction about dermal and transdermal drug delivery, this review describes different production methods for solid and hollow microneedles as well as conditions that influence skin penetration. Besides, the four microneedle-based (trans)dermal drug delivery approaches are discussed: "poke and flow", "poke and patch", "poke and release", and "coat and poke". A separate section of this review is devoted to the use of microneedles for the delivery of therapeutic proteins and vaccines. Finally, we give our view on research and development that is needed to render microneedle-based (trans)dermal drug delivery technologies clinically useful in the near future.Journal of Controlled Release 02/2012; 161(2):645-55. · 5.73 Impact Factor -
Article: Physicochemical characterization of drug-loaded rigid and elastic vesicles.
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ABSTRACT: Ketorolac loaded rigid and elastic vesicles were prepared by sonication and the physicochemical properties of the drug loaded-vesicle formulations were examined. Rigid and elastic vesicles were prepared from the double chain surfactant sucrose-ester laurate (L-595) and the single chain surfactant octaoxyethylene-laurate ester (PEG-8-L). Sulfosuccinate (TR-70) was used as a negative charge inducer. Evaluation of the prepared vesicle was performed by dynamic light scattering, extrusion and by (1)H NMR (T(2) relaxation studies). The vesicles mean size varied between 90 and 150 nm. The elasticity of the vesicles was enhanced with increasing PEG-8-L/L-595 ratio, while an increase in loading of ketorolac resulted in a reduction in vesicle elasticity. (1)H NMR measurements showed that the molecular mobility of ketorolac was restricted, which indicates that ketorolac molecules were entrapped within the vesicle bilayers. The T(2) values of the aromatic protons of ketorolac increased gradually at higher PEG-8-L levels, indicating that ketorolac mobility increased in the vesicle bilayer. The chemical stability of ketorolac was dramatically improved in the vesicle formulation compared to a buffer solution. The strong interactions of ketorolac with the bilayers of the vesicles might be the explanation for this increased stability of ketorolac.International journal of pharmaceutics 06/2011; 412(1-2):142-7. · 2.96 Impact Factor -
Article: Effect of the ω-acylceramides on the lipid organization of stratum corneum model membranes evaluated by X-ray diffraction and FTIR studies (Part I).
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ABSTRACT: The lipid organization in the outermost layer of the skin, the stratum corneum, is important for the skin barrier function. The stratum corneum lipids are composed of ceramides (CER), free fatty acids (FFA) and cholesterol (CHOL). In the present study Fourier transform infrared (FTIR) and small-angle X-ray scattering (SAXS) techniques were utilized to evaluate the effect of three C18 fatty acid esterified ω-acylceramides (CER EOS) on the lipid organization of stratum corneum model membranes. FTIR spectra (scissoring and rocking bands) showed as a function of temperature significant line-shape changes for both components assigned to the orthorhombic phase. Second-derivative analyzes revealed a significant decrease in the interchain coupling strength (Δν values) for the samples formed by CER EOS with the linoleate (CER EOS-L) and oleate (CER EOS-O) moiety around 28.5°C. However, only a gradual decrease in the Δν values was noticed for the mixture formed with CER EOS with the stearate moiety (CER EOS-S) over the whole temperature range. In the absence of CER EOS the decrease started already at 25.5°C, demonstrating that CER EOS stabilized the orthorhombic lattice. This stabilization was most pronounced for the CER EOS-S. Spectral fittings allowed to evaluate the orientation changes of the skeletal plane within the orthorhombic unit cell (θ values) for a given temperature range. From the best-fit parameters (peak area values), a decrease in the orthorhombic phase contribution to the scissoring band was also monitored as a function of the temperature. SAXS studies showed the coexistence of two lamellar phases with a periodicity of ∼5.5 nm (short periodicity phase, SPP) and ∼12 nm (LPP) in the presence of the CER EOS-L and CER EOS-O. However, no diffraction peaks associated to the LPP were detected for CER EOS-S. While CER EOS-S most efficiently stabilized the orthorhombic phase, CER EOS-L and CER EOS-O promoted the presence of the LPP. Therefore, the presence of all three CER EOS as observed in human stratum corneum may contribute to a proper skin barrier function.Chemistry and physics of lipids 01/2011; 164(3):184-95. · 2.15 Impact Factor -
Article: Antigen-adjuvant nanoconjugates for nasal vaccination: an improvement over the use of nanoparticles?
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ABSTRACT: Entrapment of antigens in mucoadhesive nanoparticles prepared from N-trimethyl chitosan (TMC) has been shown to increase their immunogenicity. However, because of their large size compared to soluble antigens, particles poorly diffuse through the nasal epithelium. The aim of this work was to study whether nasal vaccination with a much smaller TMC-antigen nanoconjugate would result in higher antibody responses as compared to TMC nanoparticles. TMC was covalently linked to a model antigen, ovalbumin (OVA), using thiol chemistry. For comparison, TMC/OVA nanoparticles and solutions of OVA and a physical mixture of TMC and OVA were made. As shown previously for TMC/OVA nanoparticles, TMC-OVA conjugate prolonged the nasal residence time of the antigen. TMC-OVA conjugate diffused significantly better through a monolayer of lung carcinoma (Calu-3) cells than TMC/OVA nanoparticles did. Moreover, nasal immunization of mice with the conjugate resulted in significantly more OVA positive DCs in the cervical lymph nodes as compared to TMC/OVA nanoparticles. Mice nasally immunized with TMC-OVA conjugate produced high levels of secretory IgA in nasal washes and higher titers of OVA-specific IgG than mice immunized with TMC/OVA nanoparticles after a priming dose. Moreover, as compared to TMC/OVA nanoparticles, TMC-OVA conjugate induced a more balanced IgG1/IgG2a response. In conclusion, the TMC-antigen nanoconjugate improves nasal delivery and immunogenicity of the antigen. This suggests that efficient codelivery of antigen and adjuvant to DCs, rather than a particulate form of the antigen/adjuvant combination, is decisive for the immunogenicity of the antigen.Molecular Pharmaceutics 11/2010; 7(6):2207-15. · 4.78 Impact Factor -
Article: Nasal vaccination with N-trimethyl chitosan and PLGA based nanoparticles: nanoparticle characteristics determine quality and strength of the antibody response in mice against the encapsulated antigen.
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ABSTRACT: Nasal vaccination is a promising, needle-free alternative to classical vaccination. Nanoparticulate delivery systems have been reported to overcome the poor immunogenicity of nasally administered soluble antigens, but the characteristics of the ideal particle are unknown. This study correlates differences in physicochemical characteristics of nanoparticles to their adjuvant effect, using ovalbumin (OVA)-loaded poly(lactic-co-glycolic acid) nanoparticles (PLGA NP), N-trimethyl chitosan (TMC) based NP (TMC NP) and TMC-coated PLGA NP (PLGA/TMC NP). PLGA NP and PLGA/TMC NP were prepared by emulsification/solvent extraction and TMC NP by ionic complexation. The NP were characterized physicochemically. Their toxicity and interaction with and stimulation of monocyte derived dendritic cells (DC) were tested in vitro. Furthermore, the residence time and the immunogenicity (serum IgG titers and secretory IgA levels in nasal washes) of the nasally applied OVA formulations were assessed in Balb/c mice. All NP were similar in size, whereas only PLGA NP carried a negative zeta potential. The NP were non-toxic to isolated nasal epithelium. Only TMC NP increased the nasal residence time of OVA compared to OVA administered in PBS and induced DC maturation. After i.m. administration all NP systems induced higher IgG titers than OVA alone, PLGA NP and TMC NP being superior to PLGA/TMC NP. Nasal immunization with the slow antigen releasing particles, PLGA NP and PLGA/TMC NP, did not induce detectable antibody titers. In contrast, nasal immunization with the positively charged, fast antigen releasing TMC NP led to high serum antibody titers and sIgA levels. In conclusion, particle charge and antigen release pattern of OVA-loaded NP has to be adapted to the intended route of administration. For nasal vaccination, TMC NP, releasing their content within several hours, being mucoadhesive and stimulating the maturation of DC, were superior to PLGA NP and PLGA/TMC NP which lacked some or all of these characteristics.Vaccine 08/2010; 28(38):6282-91. · 3.77 Impact Factor -
Article: Skin barrier disruption by acetone: observations in a hairless mouse skin model.
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ABSTRACT: To disrupt the barrier function of the skin, different in vivo methods have been established, e.g., by acetone wiping or tape-stripping. In this study, the acetone-induced barrier disruption of hairless mice was investigated in order to establish a reliable model to study beneficial, long-term effects on barrier recovery after topical application. For both treatments (i.e., acetone treatment and tape-stripping) the transepidermal water loss directly after disruption and the subsequent barrier recovery profile were similar. Histological assessment showed significant lower number of corneocyte layers in acetone-treated and tape-stripped skin compared to untreated skin, while there was no statistical difference between the two treatments. Lipid analysis of acetone-treated skin revealed that only small fraction of lipids were extracted consisting of predominantly nonpolar lipids. Importantly, the ratio of the barrier lipids, i.e., cholesterol, free fatty acids and ceramides, remained similar between control and acetone-treated skin. This reflects the undisrupted lipid organization, as determined by small-angle X-ray diffraction measurements: the long-periodicity lamellar phase was still present after acetone treatment. Our results contradict earlier studies which reported no mechanical stratum corneum removal, a substantial extraction of lipids and disruption in lipid organization. In conclusion, our studies demonstrate that barrier disruption due to acetone treatment is mainly due to removal of corneocytes.Archives for Dermatological Research 05/2009; 301(8):609-13. · 2.28 Impact Factor -
Article: Long periodicity phase in extracted lipids of vernix caseosa obtained with equilibration at physiological temperature.
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ABSTRACT: The outermost layer of the skin, the stratum corneum (SC), comprises the main barrier function between body and environment. The SC features a highly structured lipid organization: a short periodicity phase and a long periodicity phase (LPP) with a repeat distance of 6 and 13 nm, respectively. Like SC, vernix caseosa (VC), the creamy white skin-surface biofilm of the newborn, also contains barrier lipids, i.e. ceramides, cholesterol and free fatty acids. Aim of this study was to investigate whether isolated VC lipids also form the characteristic LPP. Several preparation methods were examined and only when the solution of the lipid mixture, isolated either from VC or SC, was dried under nitrogen at 37 degrees C and subsequently spread onto a support, the LPP was formed. When VC barrier lipids were first exposed to elevated temperatures and subsequently cooled down, the LPP was formed at around 34 degrees C, which is at a much lower temperature than observed with the lipids in SC. In conclusion, we showed for the first time that depending on the preparation method, (i) VC lipids also form the LPP and (ii) the LPP in VC lipids and SC lipids was obtained at a low equilibration temperature, mimicking the physiological condition.Chemistry and physics of lipids 11/2008; 158(1):32-8. · 2.15 Impact Factor -
Article: A novel in vitro percutaneous penetration model: evaluation of barrier properties with p-aminobenzoic acid and two of its derivatives.
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ABSTRACT: The objective of this study was to evaluate the utility of a stratum corneum substitute (SCS) as a novel in vitro percutaneous penetration model. The SCS consists of synthetic stratum corneum (SC) lipids (cholesterol, free fatty acids, and specific ceramides) applied onto a porous substrate. The composition, organization, and orientation of lipids in the SCS bear high resemblance to that of the intercellular barrier lipids in SC. The barrier integrity of the SCS was evaluated by means of passive diffusion studies, using three model compounds with different lipophilicities. The effects of lipid layer thickness, permeant lipophilicity, and altered lipid composition on the barrier properties were investigated, using isolated human SC as a control sample. For all three model compounds, the permeability characteristics of the SCS with a 12-mum-thick lipid layer closely resemble those of human SC. Modification of the lipid composition, generating an SCS that lacks the characteristic long periodicity phase as present in SC, was accompanied by a 2-fold increased permeability. The SCS offers an attractive tool to predict solute permeation through human skin. Moreover, as its lipid composition can be modified, they may also serve as a suitable screening model for diseased skin.Pharmaceutical Research 06/2006; 23(5):951-60. · 4.09 Impact Factor -
Article: Preparation and characterization of a stratum corneum substitute for in vitro percutaneous penetration studies.
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ABSTRACT: The intercellular stratum corneum (SC) lipids form the main barrier for diffusion of substances through the skin. A porous substrate covered with synthetic SC lipids would be an attractive model to study percutaneous penetration, hereby replacing native human SC. Prerequisite is that this stratum corneum substitute (SCS) is prepared with a uniform lipid composition and layer thickness. Furthermore, the lipid organization and orientation should resemble that in SC. The objective of this study was to investigate the utility of an airbrush spraying device to prepare a SCS composed of cholesterol, ceramides and free fatty acids on a polycarbonate filter. The results demonstrate that a proper choice of solvent mixture and lipid concentration is crucial to achieve a uniform distribution of the applied lipids over the filter surface. A smooth and tightly packed lipid layer is only obtained when the equilibration conditions are appropriately chosen. The SCS possesses two crystalline lamellar phases with periodicities similar to those present in native SC. The orientation of these lamellae is mainly parallel to the surface of the polycarbonate filter, which resembles the orientation of the intercellular SC lipids. In conclusion, the airbrush technique enables generation of a homogeneous SCS, which ultimately may function as a predictive in vitro percutaneous penetration model.Biochimica et Biophysica Acta 06/2006; 1758(5):636-44. · 4.66 Impact Factor -
Article: Acylceramide head group architecture affects lipid organization in synthetic ceramide mixtures.
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ABSTRACT: The lipid organization in the upper layer of the skin, the stratum corneum (SC), is important for the skin barrier function. This lipid organization, including the characteristic 13 nm lamellar phase, can be reproduced in vitro with mixtures based on cholesterol, free fatty acids and natural as well as synthetic ceramides (CER). In human SC, nine CER classes have been identified (CER1-CER9). Detailed studies on the effect of molecular structure of individual ceramides on the SC lipid organization are only possible with synthetic lipid mixtures, as their composition can be accurately chosen and systematically modified. In the present study, small-angle X-ray diffraction was used to examine the organization in synthetic lipid mixtures of which the synthetic ceramide fraction was prepared with sphingosine-based CER1 or phytosphingosine-based CER9. The latter acylceramide contains an additional hydroxyl group at the sphingoid backbone. The results show that a gradual increase in CER1 level consistently promotes the formation of the 13 nm lamellar phase and that partial replacement of CER1 by CER9 does not affect the phase behavior. Interestingly, complete substitution of CER1 with CER9 reduces the formation of the long periodicity phase and results in phase separation of CER9.Journal of Investigative Dermatology 12/2004; 123(5):911-6. · 6.31 Impact Factor -
Article: Effect of electrolyte on the phase behavior and emulsion stability in the system didodecyldimethylammonium bromide (DDAB)/dodecane/water
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ABSTRACT: The DDAB/dodecane/water system has been studied with respect to phase behavior and emulsion stability, and the effects from added electrolytes have been investigated. The repeat distance in the lamellar liquid crystalline phase has been measured by X-ray scattering. Electron microscopy pictures of the lamellar phase reveal that thermodynamically unstable vesicles are formed in the pure phase, introducing a reduction in repeat distance. At low salinity and surfactant concentrations, a three-phase region L1 + L2 + D is found. Emulsions prepared in this three-phase region are extremely stable against coalescence. Upon addition of electrolytes, this three-phase equilibrium disappears and is replaced by a new three-phase region L1 + L2 + F and a reduction in emulsion stability is obtained. This reduction has been discussed with respect to several factors, including the change in curvature obtained for the surfactant film when electrolytes are added. At constant salinities, however, the existence of a hexagonal phase does not influence the stability of the emulsions.Journal of Colloid and Interface Science.
Top co-authors
Top Journals
Institutions
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2004–2012
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Universiteit Leiden
- Leiden Amsterdam Center for Drug Research
Leiden, South Holland, Netherlands
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2011
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Universidade de São Paulo
Ribeirão Preto, Estado de Sao Paulo, Brazil -
The University of Tokyo
- Department of Pharmacy
Tokyo, Tokyo-to, Japan
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