| 1. |
- Bergström, Christel, 1973-, et al.
(författare)
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Biorelevant intrinsic dissolution profiling in early drug development : Fundamental, methodological, and industrial aspects
- 2019
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier. - 0939-6411 .- 1873-3441. ; 139, s. 101-114
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Forskningsöversikt (refereegranskat)abstract
- Intrinsic dissolution rate (IDR) is the surface specific dissolution rate of a drug. In early drug development, this property (among other parameters) is measured in order to compare different polymorphs and salt forms, guide formulation decisions, and to provide a quality marker of the active pharmaceutical ingredient (API) during production. In this review, an update on different methods and small-scale techniques that have recently evolved for determination of IDR is provided. The importance of biorelevant media and the hydrodynamic conditions of dissolution are also discussed. Different preparation techniques for samples are presented with a focus on disc, particle- and crystal-based methods. A number of small-scale techniques are then described in detail, and their applicability domains are identified. Finally, an updated industrial perspective is provided about IDR's place in the early drug development process.
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| 2. |
- Boge, Lukas, 1987, et al.
(författare)
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Cubosomes for topical delivery of the antimicrobial peptide LL-37
- 2019
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Ingår i: European Journal of Pharmaceutics and Biopharmaceutics. - : Elsevier BV. - 1873-3441 .- 0939-6411. ; 134, s. 60-67
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Tidskriftsartikel (refereegranskat)abstract
- In this study, the use of cubosomes for topical delivery of the antimicrobial peptide (AMP) LL-37 was investigated. Topical delivery of AMPs is of great interest for treatment of skin infections caused by bacteria, such as Staphylococcus aureus. AMP containing cubosomes were produced by three different preparation protocols and compared: (i) pre-loading, where LL-37 was incorporated into a liquid crystalline gel, which thereafter was dispersed into nanoparticles, (ii) post-loading, where LL-37 was let to adsorb onto pre-formed cubosomes, and (iii) hydrotrope-loading, where LL-37 was incorporated during the spontaneously formed cubosomes in an ethanol/glycerol monooleate mixture. Particle size and size distribution were analyzed using dynamic light scattering (DLS), liquid crystalline structure by small angle x-ray scattering (SAXS) and release of LL-37 by a fluorescamine assay. Proteolytic protection of LL-37 as well as bactericidal effect after enzyme exposure was investigated. The skin irritation potential of cubosomes was examined by an in vitro epidermis model. Finally, the bacterial killing property of the cubosomes was examined by an ex vivo pig skin wound infection model with Staphylococcus aureus. Data showed that a high loading of LL-37 induced formation of vesicles in case of cubosomes prepared by sonication (pre-loading). No release of LL-37 was observed from the cubosomes, indicating strong association of the peptide to the particles. Proteolysis studies showed that LL-37 was fully protected against enzymatic attacks while associated with the cubosomes, also denoting strong association of the peptide to the particles. As a consequence, bactericidal effect after enzyme exposure remained, compared to pure LL-37 which was subjected to proteolysis. No skin irritation potential of the cubosomes was found, thus enabling for topical administration. The ex vivo wound infection model showed that LL-37 in pre-loaded cubosomes killed bacteria most efficient.
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| 3. |
- Boge, Lukas, et al.
(författare)
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Cubosomes for topical delivery of the antimicrobial peptide LL-37
- 2019
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 134, s. 60-67
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Tidskriftsartikel (refereegranskat)abstract
- In this study, the use of cubosomes for topical delivery of the antimicrobial peptide (AMP) LL-37 was investigated. Topical delivery of AMPs is of great interest for treatment of skin infections caused by bacteria, such as Staphylococcus aureus. AMP containing cubosomes were produced by three different preparation protocols and compared: (i) pre-loading, where LL-37 was incorporated into a liquid crystalline gel, which thereafter was dispersed into nanoparticles, (ii) post-loading, where LL-37 was let to adsorb onto pre-formed cubosomes, and (iii) hydrotrope-loading, where LL-37 was incorporated during the spontaneously formed cubosomes in an ethanol/glycerol monooleate mixture. Particle size and size distribution were analyzed using dynamic light scattering (DLS), liquid crystalline structure by small angle x-ray scattering (SAXS) and release of LL-37 by a fluorescamine assay. Proteolytic protection of LL-37 as well as bactericidal effect after enzyme exposure was investigated. The skin irritation potential of cubosomes was examined by an in vitro epidermis model. Finally, the bacterial killing property of the cubosomes was examined by an ex vivo pig skin wound infection model with Staphylococcus aureus. Data showed that a high loading of LL-37 induced formation of vesicles in case of cubosomes prepared by sonication (pre-loading). No release of LL-37 was observed from the cubosomes, indicating strong association of the peptide to the particles. Proteolysis studies showed that LL-37 was fully protected against enzymatic attacks while associated with the cubosomes, also denoting strong association of the peptide to the particles. As a consequence, bactericidal effect after enzyme exposure remained, compared to pure LL-37 which was subjected to proteolysis. No skin irritation potential of the cubosomes was found, thus enabling for topical administration. The ex vivo wound infection model showed that LL-37 in pre-loaded cubosomes killed bacteria most efficient.
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| 4. |
- Borde, Annika, 1979, et al.
(författare)
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Preparation and preclinical evaluation of a freeze-dried formulation of a novel combined multivalent whole-cell/B-subunit oral vaccine against enterotoxigenic Escherichia coli diarrhea
- 2016
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Ingår i: European Journal of Pharmaceutics and Biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 108, s. 18-24
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Tidskriftsartikel (refereegranskat)abstract
- A promising liquid killed multivalent whole-cell plus enterotoxin B-subunit oral vaccine against enterotoxigenic Escherichia coli (ETEC), the primary cause of diarrhea among children in low-income countries and travelers to these areas, has recently been developed and tested in preclinical and phase-I and phase-II clinical studies. The vaccine contains killed E. coli bacteria over-expressing the main ETEC colonization factors (CFs) CFA/I, CS3, C5 and C6, and a recombinant enterotoxin B subunit protein (LCTBA) given together with a recently developed enterotoxin-derived adjuvant, dmLT. A dry-powder vaccine formulation should be advantageous especially for use in low-income countries. Here we describe a method to produce a dry-powder formulation by freeze-drying of the vaccine using inulin as stabilizer. Although not completely preventing aggregation of bacteria during freeze-drying, the stabilizer provided both improved overall bacterial morphology and almost complete recovery of the CF and B subunit antigens. Most importantly, oral-intragastric immunization of mice with the freeze-dried vaccine together with dmLT adjuvant elicited strong intestinal mucosal and serum antibody responses against all vaccine antigens, which were comparable to those achieved with the liquid vaccine. Our results indicate the feasibility to use freeze-drying with inulin as stabilizer for preparing a dry-powder formulation of the novel ETEC vaccine with retained oral-mucosal immunogenicity compared to the liquid formulation. © 2016 Elsevier B.V.
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| 5. |
- Cai, Bing, et al.
(författare)
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Bioceramic microneedles with flexible and self-swelling substrate
- 2015
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 94, s. 404-410
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Tidskriftsartikel (refereegranskat)abstract
- To reduce the effort required to penetrate the skin and optimize drug release profiles, bioceramic microneedle arrays with higher-aspect-ratio needles and a flexible and self-swelling substrate have been developed. Swelling of the substrate can assist in separating it from the needles and leave them in the skin as a drug depot. The preparation procedures for this bioceramic microneedle are described in the paper. Clonidine hydrochloride, the model drug, was released in a controlled manner by the microneedle device in vitro. Results showed that the microneedle array with a flexible and self-swelling substrate released the drug content faster than the array with a rigid substrate. Disintegration of the needle material and diffusion of the drug molecules are believed as the main control mechanisms of the drug release from these microneedle arrays. Ex vivo skin penetration showed that they can effectively penetrate the stratum corneum without an extra device. This work represents a progression in the improvement of bioceramic microneedles for transdermal drug delivery.
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| 6. |
- Dahlgren, David, et al.
(författare)
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Evaluation of drug permeability calculation based on luminal disappearance and plasma appearance in the rat single-pass intestinal perfusion model
- 2019
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 142, s. 31-37
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Tidskriftsartikel (refereegranskat)abstract
- The rat single-pass intestinal perfusion (SPIP) model is commonly used to investigate gastrointestinal physiology and membrane drug transport. The SPIP model can be used with the intestinal segment inside or outside the abdomen. The rats can also be treated with parecoxib, a selective cycloxygenase-2 inhibitor that has been shown to affect some intestinal functions following abdominal surgery, such as motility, epithelial permeability, fluid flux and ion transport. However, the impact of extra-abdominal placement of the intestinal segment in combination with parecoxib on intestinal drug transport has not been investigated. There is also uncertainty how well intestinal permeability determinations based on luminal drug disappearance and plasma appearance correlate in the rat SPIP model. The main objective of this rat in vivo study was to investigate the effect of intra- vs. extra abdominal SPIP, with and without, pretreatment with parecoxib. The effect was evaluated by determining the difference in blood-to-lumen Cr-51-EDTA clearance, lumen-to-blood permeability of a cassette-dose of four model compounds (atenolol, enalaprilat, ketoprofen, and metoprolol), and water flux. The second objective was to compare the jejunal permeability values of the model drugs when determined based on luminal disappearance or plasma appearance. The study showed that the placement of the perfused jejunal segment, or the treatment with parecoxib, had minimal effects on membrane permeability and water flux. It was also shown that intestinal permeability of low permeability compounds should be determined on the basis of data from plasma appearance rather than lumina] disappearance. If permeability is calculated on the basis of luminal disappearance, it should preferably include negative values to increase the accuracy in the determinations.
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| 7. |
- Dahlgren, David, et al.
(författare)
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Intestinal absorption-modifying excipients : A current update on preclinical in vivo evaluations
- 2019
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 142, s. 411-420
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Tidskriftsartikel (refereegranskat)abstract
- Pharmaceutical excipients in drug products are defined as pharmacologically inactive and are integral constituents of all types of oral dosage forms. However, some excipients may increase drug absorption by interacting with the mucosal membrane. If the strategy is to use an excipient with a potential to affect the processes determining the rate and/or extent of the intestinal drug absorption, it is defined as an absorption-modifying excipients (AME). These pharmaceutical excipients may act as AMEs, depending on the amounts applied, and accordingly influence bioequivalence assessment of innovative and generic drug products, as well as enable oral delivery of peptides and oligonucleotides. This review discusses the mechanisms by which AMEs increase drug absorption, and especially permeation step. The focus is on the most recent data regarding how AMEs can be evaluated in preclinical models, with an emphasis on in situ and in vivo intestinal absorption models. The in vivo predictive value of these models is reviewed for five factors of clinical relevance for the intestinal absorption performance: (a) effect and response rate of AMEs, (b) mucosal exposure time and intestinal transit of AMEs, (c) intraluminal AME dilution and prandial state, (d) mucosa] recovery and safety, and (e) variability in the effects of the AMEs. We argue that any preclinical investigations of AMEs that fail to consider these processes will ultimately be of limited clinical value and add little to our understanding of how excipients affect intestinal drug absorption.
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| 8. |
- Dahlgren, David, et al.
(författare)
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Time-dependent effects on small intestinal transport by absorption-modifying excipients
- 2018
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 132, s. 19-28
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Tidskriftsartikel (refereegranskat)abstract
- The relevance of the rat single-pass intestinal perfusion model for investigating in vivo time-dependent effects of absorption-modifying excipients (AMEs) is not fully established. Therefore, the dynamic effect and recovery of the intestinal mucosa was evaluated based on the lumen-to-blood flux (Jabs) of six model compounds, and the blood-to-lumen clearance of 51Cr-EDTA (CLCr), during and after 15- and 60-min mucosal exposure of the AMEs, sodium dodecyl sulfate (SDS) and chitosan, in separate experiments. The contribution of enteric neurons on the effect of SDS and chitosan was also evaluated by luminal coadministration of the nicotinic receptor antagonist, mecamylamine. The increases in Jabs and CLCr (maximum and total) during the perfusion experiments were dependent on exposure time (15 and 60 min), and the concentration of SDS, but not chitosan. The increases in Jabs and CLCr following the 15-min intestinal exposure of both SDS and chitosan were greater than those reported from an in vivo rat intraintestinal bolus model. However, the effect in the bolus model could be predicted from the increase of Jabs at the end of the 15-min exposure period, where a six-fold increase in Jabs was required for a corresponding effect in the in vivo bolus model. This illustrates that a rapid and robust effect of the AME is crucial to increase the in vivo intestinal absorption rate before the yet unabsorbed drug in lumen has been transported distally in the intestine. Further, the recovery of the intestinal mucosa was complete following 15-min exposures of SDS and chitosan, but it only recovered 50% after the 60-min intestinal exposures. Our study also showed that the luminal exposure of AMEs affected the absorptive model drug transport more than the excretion of 51Cr-EDTA, as Jabs for the drugs was more sensitive than CLCr at detecting dynamic mucosal AME effects, such as response rate and recovery. Finally, there appears to be no nicotinergic neural contribution to the absorption-enhancing effect of SDS and chitosan, as luminal administration of 0.1 mM mecamylamine had no effect.
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| 9. |
- Dubbelboer, Ilse R, et al.
(författare)
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Rat intestinal drug permeability : A status report and summary of repeated determinations
- 2019
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 142, s. 364-376
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Tidskriftsartikel (refereegranskat)abstract
- Intestinal permeability is a key biopharmaceutical variable in pharmaceutical research and development, and regulatory assessment. In situ rat models are often used to predict the corresponding human intestinal permeability data. The rat single-pass intestinal perfusion (SPIP) and intestinal closed loop (ICL) models are commonly applied. The primary objective of this study was to collect, summarize, and evaluate all the available intestinal permeability data for drugs that have been obtained using these two in-situ rat models. The permeability data were also investigated for variability between the experimental designs. The literature survey found 635 permeability determinations for 90 drugs. The studies were performed on the jejunum (n = 284), whole small intestine (n = 111), colon (n = 108), ileum (n = 101), and duodenum (n = 30). All the SPIP (n = 484) and ICL (n = 147) permeability values were summarized in an easily accessible database. There was wide variability in the intestinal permeability to each drug between studies, which was unrelated to the permeability class of the drug. There was no relationship between rat intestinal permeability and luminal pH, luminal drug concentration, rat strain, experimental method, or intestinal region. There was, however, a correlation between permeability values determined in the same laboratory. This report showed that the SPIP and ICL methods are important in situ models for understanding and predicting intestinal drug absorption. However, conclusions based on permeability values sourced from different laboratories may not be reliable. Because each permeability study is unique and because between- and even within-laboratory variability can be substantial, data from individual studies should preferably be interpreted separately.
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| 10. |
- Eriksson, Johanna, et al.
(författare)
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Pulmonary absorption - estimation of effective pulmonary permeability and tissue retention of ten drugs using an ex vivo rat model and computational analysis
- 2018
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : ELSEVIER SCIENCE BV. - 0939-6411 .- 1873-3441. ; 124, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Permeation of inhaled drugs across the pulmonary epithelium can regulate the rate and extent of local drug absorption and hence the pulmonary tissue concentration. Therefore, understanding pulmonary epithelial transport could be important for successful design of novel inhaled medicines. To enhance understanding of pulmonary epithelial transport, drug transport data were generated for a set of inhaled compounds (n = 10) in the single-pass, isolated perfused rat lung model. A compartmental in silica model was used to estimate pulmonary permeability and tissue retention. The theoretical model was also used to re-analyze previously obtained historical drug transport data from the isolated perfused lung (n = 10) with re-circulating buffer. This was performed to evaluate the re-circulating model for assessing tissue retention measurements and to increase the number of data points. The tissue retention was an important parameter to estimate to be able to describe the drug transport profiles accurately of most of the investigated compounds. A relationship between the pulmonary permeability and the intrinsic (carrier-mediated transport inhibited) permeability of Caco-2 cell monolayers (n = 1-6) was also established. This correlation (R-2 = 0.76, p < .0001) suggests that intrinsic Caco-2 permeability measurements could offer early predictions of the passive transcellular permeability of lung epithelium to candidate drugs. Although, for some compounds a deviation from the correlation suggests that other transport mechanisms may coexist. The compartmental in silica model was successful in describing the pulmonary drug transport profiles of the investigated compounds and has potential for further development to investigate the effects of formulations with different features on the pulmonary overall absorption rate.
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