| 1. |
- Borde, Annika, 1979, et al.
(författare)
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Preparation and evaluation of a freeze-dried oral killed cholera vaccine formulation
- 2011
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 79:3, s. 508-518
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Tidskriftsartikel (refereegranskat)abstract
- Different oral liquid cholera vaccines have proved to be safe and effective, but their formulations present problems for use in low-income countries, since large package volumes have to be transported and cold chain maintenance is required. A solid state formulation would here be more advantageous, and consequently, the possibility to develop a dry cholera vaccine formulation by freeze-drying was investigated. The ability of sucrose, trehalose and mannitol to provide process stabilization during freeze-drying was tested on a formalin-killed whole-cell Vibrio cholerae model vaccine. A matrix of sucrose or trehalose prevented bacterial aggregation, preserved cell morphology and maintained practically completely the protective lipopolysaccharide (LPS) antigen on the cell surface and its reactivity with specific antibody in vitro. After reconstitution, this formulation also retained the capacity to elicit a strong serum and gut mucosal anti-LPS antibody response in orally immunized mice, as compared to the corresponding liquid vaccine formulation. The full preservation of the in vivo immunogenicity was also maintained when the internationally widely licensed oral cholera vaccine Dukoral (TM), which comprises a cocktail of inactivated V. cholerae together with cholera toxin B-subunit (CTB), was freeze-dried using sucrose for stabilization. Thus, we present a process generating a dry oral inactivated whole-cell cholera vaccine formulation with attractive features for public health use in cholera-afflicted settings.
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| 2. |
- Borde, A. S., et al.
(författare)
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Assessment of enzymatic prodrug stability in human, dog and simulated intestinal fluids
- 2012
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 80:3, s. 630-637
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to determine the stability of three ester prodrugs, chloramphenicol succinate, enalapril and candesartan cilexetil, in human proximal small intestinal fluid (HIF), dog proximal small intestinal fluids (DIF) and simulated intestinal fluid (FaSSIF), with the addition of pancreatin. The total protein content in the proximal jejuna] fluids was determined in HIF and DIF, respectively. Candesartan cilexetil was significantly degraded in HIF (initial t(1/2(0-5min)) 5.4 +/- 0.5 min) and in DIF (initial t(1/2(0-5min))) = 5.7 +/- 0.1 min), while chloramphenicol succinate and enalapril were stable in both media. The degradation of candesartan cilexetil was shown to be mediated by enzymes following Michaelis-Menten enzyme kinetics and was inhibited by addition of esterase inhibitors. The enzymatic capacity reflected by V-max was 4-fold higher in DIF than in HIF and correlated to its 2-fold higher protein concentration. The degradation of candesartan cilexetil in the FaSSIF-pancreatin solution was slower (t(1/2) = 207 +/- 34 min) than the degradation in both HIF and DIF. Changing the pH to the enzyme optima or increasing the amount of pancreatin, increased the degradation rate of candesartan cilexetil, but not in the magnitude as in HIF. As a result, two in vitro models, based on in vivo intestinal fluids, were developed using candesartan cilexetil as a model drug. The DIF seems to be a reasonably good model for HIF, although the degradation capacity seems to be somewhat higher, possibly due to the higher enzyme concentration in DIF. Future investigations will develop novel enzymatic based in vitro models for rapid assessment and biopharmaceutical screening tools for prodrugs.
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| 3. |
- Dahlberg, Carina, et al.
(författare)
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Relationships between solid dispersion preparation process, particle size and drug release : an NMR and NMR microimaging study
- 2010
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 76:2, s. 311-319
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Tidskriftsartikel (refereegranskat)abstract
- Solid dispersion tablets prepared by either spray drying or rotoevaporation and exhibiting different grain and pore sizes were investigated under the process of hydration-swelling-gelation. H-2 and H-1 NMR microimaging experiments were used to selectively follow water penetration and polymer mobilization kinetics, respectively, while the drug release kinetics was followed by H-1 NMR spectroscopy. The obtained data, in combination with morphological information by scanning electron microscopy (SEM), reveal a complex process that ultimately leads to release of the drug into the aqueous phase. We find that the rate of water ingress has no direct influence on release kinetics, which also renders air in the tablets a secondary factor. On the other hand, drug release is directly correlated with the polymer mobilization kinetics. Water diffusion into the originally dry polymer grains determines the rate of grain swelling and the hydration within the grains varies strongly with grain size. We propose that this sets the stage for creating homogeneous gels for small grain sizes and heterogeneous gels for large grain sizes. Fast diffusion through water-rich sections of the inhomogeneous gels that exhibit a large mesh size is the factor which yields a faster drug release from tablets prepared by rotoevaporation.
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| 4. |
- Gavini, Elisabetta, et al.
(författare)
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Influence of polymeric microcarriers on the in-vivo intranasal uptake of an anti-migraine drug for brain targeting
- 2013
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 83:2, s. 174-183
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to investigate the effect of polymeric microcarriers on the in-vivo intranasal uptake of an anti-migraine drug for brain targeting. Mucoadhesive powder formulations consisted of antimigraine drug, zolmitriptan, and chitosans (various molecular weights and types) or hydroxypropyl methylcellulose (HPMC). Their suitability for nasal administration was evaluated by in-vitro and ex-vivo mucoadhesion and permeation tests. The formulations based on chitosan glutamate (CG) or HPMC were tested in-vivo because they showed good mucoadhesive properties and altered the permeation rate of the drug. The in-vivo results from intravenous infusion and nasal aqueous suspension of the drug or nasal particulate powders were compared. The plasmatic AUC values obtained within 8 h following intravenous administration appeared about three times higher than those obtained by nasal administration, independent of the formulations. Zolmitriptan concentrations in the cerebrospinal fluid obtained from nasal and intravenous administrations were respectively 30 and 90 times lower than the concentrations of the drug in the blood. Thus, nasal administration potentiated the central zolmitriptan activity allowing a reduction of the drug peripheral levels, with respect to the intravenous administration. Among nasally administered formulations, CG microparticles showed the highest efficacy in promoting the central uptake of zolmitriptan within 1 h.
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| 5. |
- Klevan, Ingvild, et al.
(författare)
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A statistical approach to evaluate the potential use of compression parameters for classification of pharmaceutical powder materials
- 2010
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 75:3, s. 425-435
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Tidskriftsartikel (refereegranskat)abstract
- The current work aims to investigate whether a multivariate statistical approach could reveal latent structures in compression data and group powders with respect to their compression behavior in a way that is consistent with an earlier proposed classification system. Seventeen pharmaceutically relevant materials, exhibiting a wide range of mechanical properties, were used as supplied, compressed, and parameters from three commonly used powder compression models (Kawakita parameters a and b(-1), the rearrangement index ab, the Shapiro f parameter and Heckel P(y)) were retrieved. Multivariate analysis of the compression parameters was done with a Principal Component Analysis (PCA). It was found that the latent structures could be divided into three main parts; the most variation was found in the direction associated with particle rearrangement, second largest variation was found in the direction described by the particle fragmentation propensity, and the least variation was found in the direction associated with the plasticity of the particles. This work demonstrates that a combination of the selected compression parameters could be utilized to find relevant differences in compression behavior for a wide range of materials, and that this information can be presented in an efficient way by applying multivariate data analysis techniques.
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| 6. |
- Larsson, Mikael, 1982, et al.
(författare)
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Effect of ethanol on the water permeability of controlled release films composed of ethyl cellulose and hydroxypropyl cellulose
- 2010
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Ingår i: European Journal of Pharmaceutics and Biopharmaceutics. - : Elsevier BV. - 1873-3441 .- 0939-6411. ; 76:3, s. 428-432
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Tidskriftsartikel (refereegranskat)abstract
- The robustness of controlled release formulations when co-ingested with alcohol is a current concern expressed by regulatory authorities, especially with regard to dose dumping. One such controlled release formulation commonly used is film coating composed of ethyl cellulose (EC) and hydroxypropyl cellulose (HPC). The aim of this study was to investigate how the presence of ethanol in the dissolution medium affects the water permeability of such films. Film samples were prepared in various EC–HPC compositions, and the effect of different ethanol concentrations in the dissolution medium on the permeability was studied using a modified Ussing chamber and tritiated water. It was found that the effect of ethanol on the film permeability varied depending on the composition of the films. The results were interpreted in terms of swelling of the EC in the films, where the swelling increased with increasing ethanol concentration. Thus, for films with low HPC content (non-interconnected pores), the water permeability of the films increased with increasing ethanol concentration as the diffusion through the ethyl cellulose increased due to swelling. However, for films with higher HPC content (having interconnected pores through the films), the permeability decreased, likely due to the swelling of the ethyl cellulose blocking the pores. The interpretation of the results was supported by dynamic mechanic analysis and SEM analysis.
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| 7. |
- Mak, Wing Cheung, 1977-, et al.
(författare)
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Drug delivery into the skin by degradable particles
- 2011
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier. - 0939-6411 .- 1873-3441. ; 79:1, s. 23-27
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Tidskriftsartikel (refereegranskat)abstract
- Recently, it was demonstrated that particles could be utilized as carrier systems for drugs into the hair follicles. In the present study, a two-component drug delivery system is presented consisting of degradable particles loaded with fluorescein isothiocyanate and a separate protease formulation for degradation. The particles were applied alone, 30 min previous to the protease application and simultaneously with the protease onto porcine skin. Subsequently, biopsies were removed, and the penetration depths of the particles were analyzed using laser scanning microscopy.The obtained results demonstrate that the particles alone achieved a penetration depth of around 900 μm. Similar results were obtained for the successive application of particles and protease, whereas a release of the fluorescent dye was only observed in the upper 250 μm corresponding to the penetration depth of the protease. In the case of the simultaneous application, the particles were partly dissolved before application, leading to a reduced particle size and diminished penetration depth.The results revealed that degradable particles are a promising tool for drug delivery into the skin.
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| 8. |
- Morales, Javier O., et al.
(författare)
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Manufacture and characterization of mucoadhesive buccal films
- 2011
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 77:2, s. 187-199
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Tidskriftsartikel (refereegranskat)abstract
- The buccal route of administration has a number of advantages including bypassing the gastrointestinal tract and the hepatic first pass effect. Mucoadhesive films are retentive dosage forms and release drug directly into a biological substrate. Furthermore, films have improved patient compliance due to their small size and reduced thickness, compared for example to lozenges and tablets. The development of mucoadhesive buccal films has increased dramatically over the past decade because it is a promising delivery alternative to various therapeutic classes including peptides, vaccines, and nanoparticles. The "film casting process" involves casting of aqueous solutions and/or organic solvents to yield films suitable for this administration route. Over the last decade, hot-melt extrusion has been explored as an alternative manufacturing process and has yielded promising results. Characterization of critical properties such as the mucoadhesive strength, drug content uniformity, and permeation rate represent the major research areas in the design of buccal films. This review will consider the literature that describes the manufacture and characterization of mucoadhesive buccal films.
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| 9. |
- Nordstrom, Josefina, et al.
(författare)
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A protocol for the classification of powder compression characteristics
- 2012
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 80:1, s. 209-216
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Tidskriftsartikel (refereegranskat)abstract
- In this paper, a structured protocol for powder compression analysis as a test to assess the mechanical properties of particles in a formulation development programme is presented. First, the sequence of classification steps of the protocol is described, and secondly, the protocol is illustrated using compression data of six powders of two model substances, sodium chloride and mannitol. From powder compression data, a set of compression variables are derived, and by using critical values of these variables, the stages expressed during the compression of the powders are identified and the powders are classified into groups with respect to the expression of particle rearrangement, particle fragmentation and particle plastic deformation during compression. It is concluded that the proposed protocol could, in a satisfactorily way, describe and distinguish between the powders regarding their compression behaviour. Hence, the protocol could be a valuable tool for the formulation scientist to comprehensively assess important functionality-related characteristics of drugs and excipients.
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| 10. |
- Viridén, Anna, 1977, et al.
(författare)
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The consequence of the chemical composition of HPMC in matrix tablets on the release behaviour of model drug substances having different solubility
- 2011
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Ingår i: European Journal of Pharmaceutics and Biopharmaceutics. - : Elsevier BV. - 1873-3441 .- 0939-6411. ; 77:1, s. 99-110
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Tidskriftsartikel (refereegranskat)abstract
- This study investigates the effect of the chemical heterogeneity of hydroxypropyl methylcellulose (HPMC) on the release of model drug substances from hydrophilic matrix tablets. The hypothesis was that the release of drug substances could be influenced by possible interactions with HPMC batches having different chemical heterogeneity. The cloud point of the most heterogeneous batch was more affected by the model drug substances, methylparaben and butylparaben, and most by butylparaben with the lowest solubility. The different clouding behaviour was explained by the heterogeneously substituted batches being more associative and the more lipophilic butylparaben being able to interact more efficiently with the hydrophobic HPMC transient crosslinks that formed. Interestingly, tablet compositions of the heterogeneously substituted HPMC batches released the more soluble methylparaben at lower rates than butylparaben. The explanation is that the hydrophobic HPMC interactions with butylparaben made the gel of the tablet less hydrated and more fragile and therefore more affected by erosional stresses. In contrast, drug release from compositions consisting of the more homogeneously substituted batches was affected to a minor extent by the drugs and was very robust within the experimental variations. The present study thus reveals that there can be variability in drug release depending on the lipophilicity of the drug and the substituent heterogeneity of the HPMC used.
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