| 1. |
- Fransén, Nelly, et al.
(författare)
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Changes in the mucoadhesion of powder formulations after drug application investigated with a simplified method
- 2008
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Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 97:9, s. 3855-3864
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Tidskriftsartikel (refereegranskat)abstract
- The residence time in the nasal cavity can be prolonged by dry particles that absorb water and subsequently increase the viscosity of the mucus layer. A novel nasal drug delivery system based on interactive mixtures has previously been developed, where fine particles of the active component are adhered to the surface of mucoadhesive carrier particles by dry mixing. The surface coverage may alter the original mucoadhesiveness of the carrier particles and to investigate this, a simplified tensile strength method was developed and evaluated. Reliable results were obtained with a plastic coated absorbent paper covered by a mucin solution as a substitution for porcine nasal mucosa and should also be applicable to other dry particle systems. The method showed that the swelling of sodium starch glycolate particles was slightly delayed, corresponding to the degree of hydrophobic surface coverage. Carrier particles of partly pregelatinized maize starch were not influenced by the addition of a hydrophobic substance, probably because of the rough particle shape that inhibited a complete surface coverage. It was concluded that the surface coverage of carrier particles in interactive mixtures only could cause a short delay in water absorption that should not affect their mucoadhesive characteristics in vivo.
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| 2. |
- Fransén, Nelly, et al.
(författare)
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Clinical study shows improved absorption of desmopressin with novel formulation
- 2009
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Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 26:7, s. 1618-1625
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Tidskriftsartikel (refereegranskat)abstract
- To create improved pharmaceutical formulations for nasal and sublingual administration of desmopressin and investigate their pharmacokinetic profiles in comparison with a commercial nasal liquid spray and finally to evaluate the volunteers' opinions on the different dosage forms. Both formulations were based on the characteristics of interactive mixtures. The nasal powder spray was produced by a rotary evaporator technique with sodium starch glycolate as carrier material and the sublingual tablet by direct compression after dry mixing with mannitol as carrier. The clinical study was an open-label, randomised cross-over pharmacokinetic study in healthy volunteers. The nasal powder formulation gave a threefold increase in the absorption, unaltered time to maximum plasma concentration and a tendency to lower variability in the amount absorbed compared with the liquid spray. The powder was reported to be more irritating than the liquid but was still well accepted by the volunteers. The tablet did not improve the uptake of desmopressin, likely because of a poor disintegration sublingually. The nasal powder formulation is a promising new dosage form for the delivery of desmopressin and other compounds. The sublingual tablet has a beneficial means of production and may be further developed by decreasing its disintegration time.
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| 3. |
- Fransén, Nelly, et al.
(författare)
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Development and characterisation of interactive mixtures with a fine-particulate mucoadhesive carrier for nasal drug delivery
- 2007
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 67:2, s. 370-376
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate whether mucoadhesive interactive mixtures can be created using carrier particles in a size range appropriate for nasal administration, i.e. 10–50 μm. We also used theoretical models to investigate if homogeneity measurements can be used to evaluate the formation of interactive mixtures containing carrier particles in this size range. Sodium starch glycolate (SSG) was used as carrier material and sodium salicylate (SS) as the model fine-particulate drug. The size ranges of SSG particles and amounts of SS were varied to find the smallest carrier particle size and highest amount of drug that still resulted in an interactive mixture. Visual inspection of the mixtures by scanning electron microscopy showed that interactive mixtures could be formed with carrier particles as small as 30 μm and containing up to 4% (w/w) of SS. Comparisons with theoretical models highlighted the difficulties of using homogeneity measurements to determine if interactive mixtures were formed. The measured coefficients of variation (CV) for the amount of drug in the samples were low and inferior mixtures were associated with only a slight increase. It was thus concluded that mucoadhesive interactive mixtures can be created in an appropriate size range for nasal administration, but that visual inspection of these mixtures is initially necessary to confirm the formation of an interactive mixture.
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| 4. |
- Fransén, Nelly, et al.
(författare)
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Physicochemical interactions between drugs and superdisintegrants
- 2008
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Ingår i: Journal of Pharmacy and Pharmacology (JPP). - 0022-3573 .- 2042-7158. ; 60:12, s. 1583-9
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Tidskriftsartikel (refereegranskat)abstract
- We have evaluated the interactions between superdisintegrants and drugs with different physicochemical characteristics, which may affect the in-vivo absorption e.g. after mucosal administration. The binding of sodium salicylate, naproxen, methyl hydroxybenzoate (methylparaben), ethyl hydroxybenzoate (ethylparaben), propyl hydroxybenzoate (propylparaben), atenolol, alprenolol, diphenhydramine, verapamil, amitriptyline and cetylpyridinium chloride monohydrate (CPC) to different superdisintegrants (sodium starch glycolate (SSG), croscarmellose sodium (CCS) and crospovidone) and one unsubstituted comparator (starch) was studied spectrophotometrically. An indication of the in-vivo effect was obtained by measuring the interactions at physiological salt concentrations. SSG was investigated more thoroughly to obtain release profiles and correlation between binding and ionic strength. The results showed that the main interactions with the anionic hydrogels formed by SSG and CCS were caused by ion exchange, whereas the neutral crospovidone exhibited lipophilic interactions with the non-ionic substances. The effect of increased ionic strength was most pronounced at low salt concentrations and the ion exchange interactions were almost completely eradicated at physiological conditions. The release profile of diphenhydramine was significantly affected by the addition of salt. It was thus concluded that the choice of buffer was of great importance for in-vitro experiments with ionic drugs. At physiological salt concentrations the interactions did not appear to be strong enough to influence the in-vivo bioavailability of any of the drug molecules.
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| 5. |
- Fransén, Nelly, 1978-
(författare)
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Studies on a Novel Powder Formulation for Nasal Drug Delivery
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Nasal administration has potential for the treatment of indications requiring a fast onset of effect or for drugs with low oral bioavailability. Liquid nasal sprays are relatively common, but can be associated with suboptimal absorption from the nasal cavity; this thesis shows that nasal absorption can be significantly enhanced with a dry powder formulation. It was shown that interactive mixtures, consisting of fine drug particles adhered to the surface of mucoadhesive carrier particles, could be created in a particle size suitable for nasal administration. Sodium starch glycolate (SSG), a common tablet excipient, was used as carrier material. In vitro evaluation of the formulation indicated that the mucoadhesion of the carrier was unlikely to be affected by the addition of a drug. The powder formulation did not improve the in vitro transfer of dihydroergotamine across porcine nasal mucosa compared with a liquid formulation; however, the results were associated with methodological shortcomings. The binding of model substances to SSG and three other excipients was evaluated. Ion exchange interactions were for example detected between SSG and cationic drugs, but these interactions were most extensive at low salt concentrations and should unlikely affect in vivo bioavailability at physiological salt concentrations. Absorption of the peptide drug desmopressin from the SSG nasal formulation, from a novel sublingual tablet formulation and from a commercial nasal liquid spray was evaluated in a clinical trial. While no improvement over the liquid spray was seen with the sublingual tablet, plasma concentrations after the nasal powder formulation were three times higher than those after the liquid spray. All formulations were well accepted by the volunteers. The use of currently available mucoadhesive carrier particles in interactive mixtures offers potential for a new method of producing nasal powder formulations that should also be applicable to large scale production.
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| 6. |
- Fransén, Nelly, et al.
(författare)
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The in vitro transport of dihydroergotamine across porcine nasal respiratory and olfactory mucosa and the effect of a novel powder formulation
- 2007
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Ingår i: Journal of Drug Delivery Science and Technology. - 1773-2247. ; 17:4, s. 267-271
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Tidskriftsartikel (refereegranskat)abstract
- The objective was to investigate the transport of dihydroergotamine (DHE) across porcine nasal respiratory and olfactory mucosa and to evaluate the absorption enhancing effect of a novel dry powder formulation compared with a reference solution with the horizontal Ussing chamber method. The powder formulation was obtained by mixing micronized DHE particles and mucoadhesive carrier particles (sodium starch glycolate) to create an interactive mixture. The horizontal Ussing chamber method was chosen as the in vitro model since it provides the opportunity to apply a dry powder formulation and compare the transport across the two types of nasal mucosa. A histological evaluation confirmed that the mucosa had been correctly isolated. The results showed no significant difference in the absorption from the powder formulation compared with the reference solution, but the transport of DHE was significantly higher across olfactory mucosa than across respiratory mucosa. This may be explained by facilitated transport through paracellular transfer along the olfactory nerve cells.
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| 7. |
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| 8. |
- Mihranyan, Albert, et al.
(författare)
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Order and disorder in powder mixtures : Spatial distribution functions as tools to assess powder homogeneity
- 2009
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Ingår i: Particle & particle systems characterization. - : Wiley. - 0934-0866 .- 1521-4117. ; 25:5-6, s. 397-405
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Tidskriftsartikel (refereegranskat)abstract
- In interactive mixtures with small carrier particles, the content variability is often higher than predicted by available models despite the significant degree of interaction visualized with Scanning Electron Microscopy (SEM). The present work details how pair-correlation functions can be used to reveal information about the spatial distribution of mixture constituents and their interactions. SEM pictures of a 2 % w/w oxazepam/sodium starch glycolate (SSG) mixture were recorded (n = 14). The constituent coordinates were extracted and pair-correlation functions as well as the cross-correlation function were calculated. A significant degree of interaction was observed between the constituents in the experimental mixture, compared to a randomized control system. In particular, the probability of finding an oxazepam particle was especially high inside the perimeter of the carrier particle and along its edges. The observed cross-correlation between oxazepam and SSG particles was periodic and repeated at distances corresponding to 1-1.5 carrier diameters. It was concluded that interactive mixtures of powders can be compared to disordered/amorphous solids since both exhibit short-range order, whilst lacking long-range translational periodicity.
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