Ingunn Tho - Academia.edu (original) (raw)

Papers by Ingunn Tho

Tidsskrift for Den norske legeforening, 2012

Orally disintegrating tablets (ODT) or fast-melting tablets have gained appeal lately. ODT are ta... more Orally disintegrating tablets (ODT) or fast-melting tablets have gained appeal lately. ODT are tablets which disintegrate in the mouth within seconds without the need for additional liquid. This dosage form was originally developed to improve the compliance of patients who had difficulty in swallowing tablets, such as children, the elderly and bedridden patients. ODTs combine the advantages of solid dosage forms with those of liquid forms and appeal to broader groups of patients than originally expected. ODTs may prove to have higher bioavailability and an earlier pharmacological effect than conventional tablets. Technical challenges are related to taste masking, mechanical strength and stability to humidity.

Journal of Controlled Release

The influence of membrane composition on dissolution characteristics was determined for the osmot... more The influence of membrane composition on dissolution characteristics was determined for the osmotically controlled delayed release system described previously (Schultz and Kleinebudde, J. Control. Release (1997)). In a first step the influence of plasticizer lipophilicity on dissolution and swelling characteristics was determined. Furthermore the effect of varying amounts of TEC as plasticizer and micronized talc was investigated. The mechanical properties of dry and swollen film samples and plasticizer elution from free films during swelling were determined and compared to dissolution results. Increasing plasticizer lipophilicity led to an increase in swelling time of the pellets. Drug release started after maximum swelling of the pellets. The dissolution rate was decreased by the use of more lipophilic plasticizers. The plasticizers leached from the free films according to their solubilities. The mechanical properties of film samples changed immensely within the first minute of ex...

This study examines the contribution of a 3-D model in an early development of pectin tablets. Th... more This study examines the contribution of a 3-D model in an early development of pectin tablets. The aim of this work was to extract as much information of the compression behavior from as few tablets as possible. Pectins with various degrees of methoxylation (DM) were studied (4%-72%). The compressibility was evaluated using classic "in-die" Heckel and Kawakita analyses in addition to the 3-D modeling. For validation purposes well-known reference materials were included. 3-D modeling applied to data of single tablets yielded some information on their compressibility. When several tablets with different maximum relative densities (ρrel, max) were included, no additional information was obtained through classic evaluation. However, the 3-D model provided additional information through the shape of the 3-D parameter plot. Pectins with a DM ≥ 25% consolidated predominantly by elastic deformation similarly to the 3-D parameter plot of pregelatinized starch (PGS). The 3-D analysi...

Principal Component Analysis - Multidisciplinary Applications, 2012

PDA journal of pharmaceutical science and technology / PDA

This study investigates the validity, reliability, and detection limit of a visual examination me... more This study investigates the validity, reliability, and detection limit of a visual examination method utilizing the Tyndall effect to enhance visible detection of particles. The suitability of the method for compatibility testing of intravenous fluids in a hospital pharmacy context is discussed. A panel of 20 inspectors examined 20 samples, with and without particles, using two light sources (halogen lightbulb in a focused desk lamp and a red pocket laser pointer). The samples contained particles of different origin (precipitate, polystyrene standards), varying size, and concentrations. Light obscuration and turbidimetric measurements were used to obtain numeric references. The samples were divided into rejection probability zones, and the validity (sensitivity, specificity, and likelihood ratios) and reliability (inter-rater agreement coefficients Fleiss' kappa and Gwet's AC1) were estimated. The sensitivity of the laser pointer for detecting microprecipitates was quite hig...

European Journal of Hospital Pharmacy: Science and Practice, 2014

Pharmaceutics, 2013

Mucoadhesive liposomes offer a potential for improved residence time of liposomal systems targeti... more Mucoadhesive liposomes offer a potential for improved residence time of liposomal systems targeting contact with mucosal tissues, such as in buccal, oral, colon, and vaginal drug delivery. Most of the currently available methods rely on the coating of preformed liposomes by various mucoadhesive polymers. The aim of this study was to develop novel mucoadhesive system by the one-pot preparation method. The pectin- and chitosan-containing liposomes, namely pectosomes and chitosomes, were prepared by the modified solvent injection method. In order to optimize this novel delivery system, we used pectins and chitosans of both high and low degree of esterification/deacetylation (DE/DD), respectively. Sonication was applied to reduce the original vesicle size. All vesicles were characterized for their size, zeta potential, metronidazole entrapment, and stability. Both pectosomes and chitosomes were found to entrap more metronidazole than conventional plain liposomes. Preliminary data indica...

International journal of pharmaceutics, Jan 3, 2006

This study has investigated the potential of immersion coating calcium containing pellet cores fi... more This study has investigated the potential of immersion coating calcium containing pellet cores first with pectin, and then with two different cross-linkers, calcium or chitosan. The interaction between pectin and calcium, and between pectin and chitosan, are believed to slow down the drug release, and thereby, the coated pellets might possibly be used for colon specific drug delivery. Both the calcium coated pellets and the chitosan coated pellets had a reduced drug release compared to uncoated pellets in 0.1M HCl (1 h) and phosphate buffer pH 6.8 (4 h). The most successful combination had a drug release of only 17% during the entire test period in comparison to the uncoated pellets that had a drug release of 80%. When chitosan was used as a cross-linker, a higher reduction in drug release was obtained than by using calcium as the cross-linker. For the pellets coated with pectin in combination with chitosan, the type of pectin with a degree of methoxylation (DM) of 35 was superior t...

Marine Drugs, 2015

Mucoadhesive drug therapy destined for localized drug treatment is gaining increasing importance ... more Mucoadhesive drug therapy destined for localized drug treatment is gaining increasing importance in today's drug development. Chitosan, due to its known biodegradability, bioadhesiveness and excellent safety profile offers means to improve mucosal drug therapy. We have used chitosan as mucoadhesive polymer to develop liposomes able to ensure prolonged residence time at vaginal site. Two types of mucoadhesive liposomes, namely the chitosan-coated liposomes and chitosan-containing liposomes, where chitosan is both embedded and surface-available, were made of soy phosphatidylcholine with entrapped fluorescence markers of two molecular weights, FITC-dextran 4000 and 20,000, respectively. Both liposomal types were characterized for their size distribution, zeta potential, entrapment efficiency and the in vitro release profile, and compared to plain liposomes. The proof of chitosan being both surface-available as well as embedded into the liposomes in the chitosan-containing liposomes was found. The capability of the surface-available chitosan to interact with the model porcine mucin was confirmed for both chitosan-containing and chitosan-coated liposomes implying potential mucoadhesive behavior. Chitosan-containing liposomes were shown to be superior in respect to the simplicity of preparation, FITC-dextran load, mucoadhesiveness and in vitro OPEN ACCESS Mar. Drugs 2015, 13 223 release and are expected to ensure prolonged residence time on the vaginal mucosa providing localized sustained release of entrapped model substances.

Camptothecin Multivariate analysis Surfactants Brain capillary endothelial cells (BCEC) Brain del... more Camptothecin Multivariate analysis Surfactants Brain capillary endothelial cells (BCEC) Brain delivery a

International journal of pharmaceutics, Jan 30, 2013

Photodynamic therapy has a great potential in the treatment of cervical cancer. The aim of this s... more Photodynamic therapy has a great potential in the treatment of cervical cancer. The aim of this study was to develop bioadhesive pellets containing hexylaminolevulinate (HAL), a precursor of the photoactive substance PpIX, with a fast release for vaginal drug delivery. Pellets were produced by extrusion/spheronization, and Carbopol(®) 934 was used to obtain bioadhesive properties. A 2(2)-factorial design with center point investigating the HAL content (1 and 10%, w/w) and Carbopol(®) 934 content (1 and 8%, w/w) was set up. The most suitable formulations were mechanically stable and showed bioadhesive properties toward vaginal tissue. The drug load was released within 20 min in phosphate buffer pH 4 and 6.8 in the in vitro dissolution test. The stability of HAL in the pellet formulations varied, but the most stable formulation showed 96-97% HAL remaining in the formulation after 6-7 weeks of storage at accelerated temperature conditions (40 °C). The investigated formulations seem pro...

International Journal of Pharmaceutics, 2012

For the purpose of brain delivery upon intravenous injection, formulations of camptothecin-loaded... more For the purpose of brain delivery upon intravenous injection, formulations of camptothecin-loaded solid lipid nanoparticles (SLN), prepared by hot high pressure homogenisation, were designed. Incorporation of camptothecin in the hydrophobic and acidic environment of SLN matrix was chosen to stabilise the lactone ring, which is essential for its antitumour activity, and for avoiding premature loss of drug on the way to target camptothecin to the brain. A multivariate approach was used to assess the influence of the qualitative and quantitative composition on the physicochemical properties of camptothecin-loaded SLN in comparison to plain SLN. Mean particle sizes of ≤200 nm, homogenous size distributions and high encapsulation efficiencies (>90%) were achieved for the most suitable formulations. In vitro release studies in plasma, showed a prolonged release profile of camptothecin from SLN, confirming the physical stability of the particles under physiological pH. A higher affinity of the SLN to the porcine brain capillary endothelial cells (BCEC) was shown in comparison to macrophages. MTT studies in BCEC revealed a moderate decrease in the cell viability of camptothecin, when incorporated in SLN compared to free camptothecin in solution. In vivo studies in rats showed that fluorescently labelled SLN were detected in the brain after i.v. administration. This study indicates that the camptothecin-loaded SLN are a promising drug brain delivery system worth to explore further for brain tumour therapy.

International Journal of Pharmaceutics, 2014

The choice of drug therapy in pregnant patients suffering from vaginal infections is limited by t... more The choice of drug therapy in pregnant patients suffering from vaginal infections is limited by the safety profile of the drug. Assuring the efficient topical therapy to avoid systemic absorption is considered the best therapy option. Chitosan-coated liposomes have been developed and optimized to assure localized therapy of clotrimazole. Chitosan was selected as mucoadhesive polymer both to prolong system's retention at the vaginal site and act on biofilms responsible for high recurrence of infections. Sonicated liposomes were coated with chitosan in three different concentrations, namely 0.1, 0.3 and 0.6% (w/v). Clotrimazole-containing (22 μg/mg lipid) chitosan-coated liposomes were in the size range of 100-200 nm. The in vitro release studies confirmed prolonged release of clotrimazole from both non-coated and chitosan-coated liposomes as compared to control. The ex vivo penetration experiments performed on the pregnant sheep vaginal tissue showed that coated liposomes assured increased clotrimazole tissue retention and reduced its penetration as compared to the control. Mucin studies revealed that the coating with lower chitosan concentration increased the system's mucoadhesive potential, as compared to coating with higher concentrations. These results provide a good platform for further in vivo animal studies on mucoadhesive liposomes destined to localized vaginal therapy.

Pharmaceutics, 2014

Different non-ionic cellulose ethers (methyl cellulose, MC; hydroxyethyl cellulose, HEC; hydroxyp... more Different non-ionic cellulose ethers (methyl cellulose, MC; hydroxyethyl cellulose, HEC; hydroxypropyl cellulose, HPC; hydroxypropylmethyl cellulose, HPMC) and microcrystalline cellulose (MCC) were investigated as matrix formers for preparation of mini-tablets targeting vaginal drug delivery. Hexyl aminolevulinat hydrochloridum (HAL) was used as a model drug. The mini-tablets were characterized with respect to their mechanical strength, bioadhesion towards cow vaginal tissue in two independent tests (rotating cylinder test, detachment test using texture analyzer), and dissolution rate in two media mimicking the pH levels of fertile, healthy and post-menopausal women (vaginal fluid simulant pH 4.5, phosphate buffer pH 6.8). Mini-tablets with a matrix of either HPMC or HPC were found to possess adequate mechanical strength, superior bioadhesive behavior towards vaginal tissue, and pH independent controlled release of the model drug, suggesting that both systems would be suited for the treatment of women regardless of age, i.e., respective of their vaginal pH levels. Bioadhesive mini-tablets offer a potential for improved residence time in the vaginal cavity targeting contact with mucosal tissue and prolonged release of the drug.

Powder Technology, 2010

The present work evaluates the usefulness of “in die” elastic recovery descriptors as an indicato... more The present work evaluates the usefulness of “in die” elastic recovery descriptors as an indicator of tabletability. Tablet elastic recovery (“in die” and “out-of-die”) with respect to applied compression speed and dwell time were evaluated by applying 22-full factorial ...

Pharmaceutical Development and Technology, 2012

This study examines the effect of the degree of methoxylation (DM) and particle size on compressi... more This study examines the effect of the degree of methoxylation (DM) and particle size on compression properties and compactibility of pectin powders. A powder classification system based on sequential handling of compression parameters was applied. A single size fraction (90-125 μm) of pectin powders with DM values ranging from 5-72% was studied. For DM 25%, the effect of different particle size fractions (180-250, 125-180, 90-125, 63-90, 45-63, <45 μm) were investigated. Compression parameters were derived based on time-resolved force-displacement data using Heckel, Kawakita and Shapiro equations. Volume-specific surface area was estimated for powders and tablets. Tablet tensile strength was determined. It was found that all pectin powders displayed low degrees of particle rearrangement and relatively low degrees of fragmentation (class IIA materials). Pectin particles were found to be relatively soft, with a tendency towards softer particles for pectins of higher DM. The overall variation in fragmentation and deformation behavior was limited. Both DM and initial particle size affected the tensile strength of pectin tablets. The difference in surface hydrophobicity caused by the DM was suggested as being responsible for the variation in the mechanical strengths. The study shows that pectin grades with DM ≤ 40% are potential direct compression excipients.

Pharmaceutical Development and Technology, 2009

The present work challenges a newly developed approach to tablet formulation development by using... more The present work challenges a newly developed approach to tablet formulation development by using chemically identical materials (grades and brands of microcrystalline cellulose). Tablet properties with respect to process and formulation parameters (e.g. compression speed, added lubricant and Emcompress fractions) were evaluated by 2(3)-factorial designs. Tablets of constant true volume were prepared on a compaction simulator at constant pressure (approx. 100 MPa). The highly repeatable and accurate force-displacement data obtained was evaluated by simple 'in-die' Heckel method and work descriptors. Relationships and interactions between formulation, process and tablet parameters were identified and quantified by multivariate analysis techniques; principal component analysis (PCA) and partial least square regressions (PLS). The method proved to be able to distinguish between different grades of MCC and even between two different brands of the same grade (Avicel PH 101 and Vivapur 101). One example of interaction was studied in more detail by mixed level design: The interaction effect of lubricant and Emcompress on elastic recovery of Avicel PH 102 was demonstrated to be complex and non-linear using the development tool under investigation.

Journal of Pharmacy and Pharmacology, 2010

The phospholipid vesicle-based barrier has recently been introduced as an in-vitro permeation mod... more The phospholipid vesicle-based barrier has recently been introduced as an in-vitro permeation model mimicking gastro-epithelial barriers in terms of passive diffusion of drugs. The aim of this study was to investigate whether the phospholipid vesicle-based barrier was suitable for permeability screening of complex formulations such as solid dispersions. Methods Solid dispersions containing the poorly water-soluble drugs HIV-PI 1 (log P = 6.2, molar mass = 628.80 g/mol) and HIV-PI 2 (log P = 5.3, molar mass = 720.95 g/ mol), a hydrophilic polymer and different surfactants were tested with respect to their influence on integrity of the barrier in terms of electrical resistance and permeability for calcein. Furthermore, utilisation of a more biologically relevant medium, Hank's balanced salt solution supplemented with Mg 2+ -and Ca 2+ -ions (HBSS (Mg 2+ , Ca 2+ )), has been tested. Key findings Except for the polyoxyl 40 hydrogenated castor oil-containing solid dispersion, no influence on the phospholipid vesicle-based barrier could be observed from the tested samples. Presence of active pharmaceutical ingredients (APIs) in the solid dispersions led to the same results as the corresponding placebo results. First experiments analysing the passive diffusion of both APIs in HBSS (Mg 2+ , Ca 2+ ), evaluated as suitable transport medium, have shown promising results regarding the suitability of the phospholipid vesiclebased barrier for investigation of solid dispersions. Conclusions The study indicated that the phospholipid vesicle-based barrier was compatible with selected melt extrudate formulations. The model seemed capable to reveal different transport routes in comparison with Caco-2 cell permeability tests.

Journal of Pharmaceutical Sciences, 2012

Curcumin is a well-established natural antioxidant and anti-inflammatory agent. Up till now its p... more Curcumin is a well-established natural antioxidant and anti-inflammatory agent. Up till now its potential in treatment of vaginal inflammation has not been evaluated. We are aiming at developing liposomal delivery system for curcumin targeting vaginal administration. Liposomes as nanosized phospholipid-based vesicles are expected to solubilize curcumin and enhance its activity, thus serving as an advanced topical formulation in the treatment of vaginal inflammation. Curcumin and curcuminoids were analyzed by the high-performance liquid chromatography method. Liposomes containing curcumin/curcuminoids of various sizes were prepared and characterized. Antioxidant activities of curcumin and liposomal curcumin were compared based on 1,1-diphenyl-2-picrylhydrazyl radical scavenging and superoxide dismutase activities. The anti-inflammatory activities were determined by measuring the inhibition of lipopolysaccharide -induced nitric oxide, interleukin-1$, and tumor necrosis factor-" production in macrophage RAW 264.7 cells. Curcumin/curcuminoids were encapsulated in phosphatidylcholine vesicles with high yields. Vesicles in the size range around 200 nm were selected for stability and cell experiments. Liposomal curcumin were found to be twofold to sixfold more potent than corresponding curcuminoids. Moreover, the mixture of curcuminoids was found to be more potent than pure curcumin in regard to the antioxidant and anti-inflammatory activities. Liposomal delivery systems for curcumin are promising formulations for the treatment of vaginal inflammation.

Journal of Pharmaceutical and Biomedical Analysis, 2010

Particle size 23 a b s t r a c t

Tidsskrift for Den norske legeforening, 2012

Orally disintegrating tablets (ODT) or fast-melting tablets have gained appeal lately. ODT are ta... more Orally disintegrating tablets (ODT) or fast-melting tablets have gained appeal lately. ODT are tablets which disintegrate in the mouth within seconds without the need for additional liquid. This dosage form was originally developed to improve the compliance of patients who had difficulty in swallowing tablets, such as children, the elderly and bedridden patients. ODTs combine the advantages of solid dosage forms with those of liquid forms and appeal to broader groups of patients than originally expected. ODTs may prove to have higher bioavailability and an earlier pharmacological effect than conventional tablets. Technical challenges are related to taste masking, mechanical strength and stability to humidity.

Journal of Controlled Release

The influence of membrane composition on dissolution characteristics was determined for the osmot... more The influence of membrane composition on dissolution characteristics was determined for the osmotically controlled delayed release system described previously (Schultz and Kleinebudde, J. Control. Release (1997)). In a first step the influence of plasticizer lipophilicity on dissolution and swelling characteristics was determined. Furthermore the effect of varying amounts of TEC as plasticizer and micronized talc was investigated. The mechanical properties of dry and swollen film samples and plasticizer elution from free films during swelling were determined and compared to dissolution results. Increasing plasticizer lipophilicity led to an increase in swelling time of the pellets. Drug release started after maximum swelling of the pellets. The dissolution rate was decreased by the use of more lipophilic plasticizers. The plasticizers leached from the free films according to their solubilities. The mechanical properties of film samples changed immensely within the first minute of ex...

This study examines the contribution of a 3-D model in an early development of pectin tablets. Th... more This study examines the contribution of a 3-D model in an early development of pectin tablets. The aim of this work was to extract as much information of the compression behavior from as few tablets as possible. Pectins with various degrees of methoxylation (DM) were studied (4%-72%). The compressibility was evaluated using classic "in-die" Heckel and Kawakita analyses in addition to the 3-D modeling. For validation purposes well-known reference materials were included. 3-D modeling applied to data of single tablets yielded some information on their compressibility. When several tablets with different maximum relative densities (ρrel, max) were included, no additional information was obtained through classic evaluation. However, the 3-D model provided additional information through the shape of the 3-D parameter plot. Pectins with a DM ≥ 25% consolidated predominantly by elastic deformation similarly to the 3-D parameter plot of pregelatinized starch (PGS). The 3-D analysi...

Principal Component Analysis - Multidisciplinary Applications, 2012

PDA journal of pharmaceutical science and technology / PDA

This study investigates the validity, reliability, and detection limit of a visual examination me... more This study investigates the validity, reliability, and detection limit of a visual examination method utilizing the Tyndall effect to enhance visible detection of particles. The suitability of the method for compatibility testing of intravenous fluids in a hospital pharmacy context is discussed. A panel of 20 inspectors examined 20 samples, with and without particles, using two light sources (halogen lightbulb in a focused desk lamp and a red pocket laser pointer). The samples contained particles of different origin (precipitate, polystyrene standards), varying size, and concentrations. Light obscuration and turbidimetric measurements were used to obtain numeric references. The samples were divided into rejection probability zones, and the validity (sensitivity, specificity, and likelihood ratios) and reliability (inter-rater agreement coefficients Fleiss' kappa and Gwet's AC1) were estimated. The sensitivity of the laser pointer for detecting microprecipitates was quite hig...

European Journal of Hospital Pharmacy: Science and Practice, 2014

Pharmaceutics, 2013

Mucoadhesive liposomes offer a potential for improved residence time of liposomal systems targeti... more Mucoadhesive liposomes offer a potential for improved residence time of liposomal systems targeting contact with mucosal tissues, such as in buccal, oral, colon, and vaginal drug delivery. Most of the currently available methods rely on the coating of preformed liposomes by various mucoadhesive polymers. The aim of this study was to develop novel mucoadhesive system by the one-pot preparation method. The pectin- and chitosan-containing liposomes, namely pectosomes and chitosomes, were prepared by the modified solvent injection method. In order to optimize this novel delivery system, we used pectins and chitosans of both high and low degree of esterification/deacetylation (DE/DD), respectively. Sonication was applied to reduce the original vesicle size. All vesicles were characterized for their size, zeta potential, metronidazole entrapment, and stability. Both pectosomes and chitosomes were found to entrap more metronidazole than conventional plain liposomes. Preliminary data indica...

International journal of pharmaceutics, Jan 3, 2006

This study has investigated the potential of immersion coating calcium containing pellet cores fi... more This study has investigated the potential of immersion coating calcium containing pellet cores first with pectin, and then with two different cross-linkers, calcium or chitosan. The interaction between pectin and calcium, and between pectin and chitosan, are believed to slow down the drug release, and thereby, the coated pellets might possibly be used for colon specific drug delivery. Both the calcium coated pellets and the chitosan coated pellets had a reduced drug release compared to uncoated pellets in 0.1M HCl (1 h) and phosphate buffer pH 6.8 (4 h). The most successful combination had a drug release of only 17% during the entire test period in comparison to the uncoated pellets that had a drug release of 80%. When chitosan was used as a cross-linker, a higher reduction in drug release was obtained than by using calcium as the cross-linker. For the pellets coated with pectin in combination with chitosan, the type of pectin with a degree of methoxylation (DM) of 35 was superior t...

Marine Drugs, 2015

Mucoadhesive drug therapy destined for localized drug treatment is gaining increasing importance ... more Mucoadhesive drug therapy destined for localized drug treatment is gaining increasing importance in today's drug development. Chitosan, due to its known biodegradability, bioadhesiveness and excellent safety profile offers means to improve mucosal drug therapy. We have used chitosan as mucoadhesive polymer to develop liposomes able to ensure prolonged residence time at vaginal site. Two types of mucoadhesive liposomes, namely the chitosan-coated liposomes and chitosan-containing liposomes, where chitosan is both embedded and surface-available, were made of soy phosphatidylcholine with entrapped fluorescence markers of two molecular weights, FITC-dextran 4000 and 20,000, respectively. Both liposomal types were characterized for their size distribution, zeta potential, entrapment efficiency and the in vitro release profile, and compared to plain liposomes. The proof of chitosan being both surface-available as well as embedded into the liposomes in the chitosan-containing liposomes was found. The capability of the surface-available chitosan to interact with the model porcine mucin was confirmed for both chitosan-containing and chitosan-coated liposomes implying potential mucoadhesive behavior. Chitosan-containing liposomes were shown to be superior in respect to the simplicity of preparation, FITC-dextran load, mucoadhesiveness and in vitro OPEN ACCESS Mar. Drugs 2015, 13 223 release and are expected to ensure prolonged residence time on the vaginal mucosa providing localized sustained release of entrapped model substances.

Camptothecin Multivariate analysis Surfactants Brain capillary endothelial cells (BCEC) Brain del... more Camptothecin Multivariate analysis Surfactants Brain capillary endothelial cells (BCEC) Brain delivery a

International journal of pharmaceutics, Jan 30, 2013

Photodynamic therapy has a great potential in the treatment of cervical cancer. The aim of this s... more Photodynamic therapy has a great potential in the treatment of cervical cancer. The aim of this study was to develop bioadhesive pellets containing hexylaminolevulinate (HAL), a precursor of the photoactive substance PpIX, with a fast release for vaginal drug delivery. Pellets were produced by extrusion/spheronization, and Carbopol(®) 934 was used to obtain bioadhesive properties. A 2(2)-factorial design with center point investigating the HAL content (1 and 10%, w/w) and Carbopol(®) 934 content (1 and 8%, w/w) was set up. The most suitable formulations were mechanically stable and showed bioadhesive properties toward vaginal tissue. The drug load was released within 20 min in phosphate buffer pH 4 and 6.8 in the in vitro dissolution test. The stability of HAL in the pellet formulations varied, but the most stable formulation showed 96-97% HAL remaining in the formulation after 6-7 weeks of storage at accelerated temperature conditions (40 °C). The investigated formulations seem pro...

International Journal of Pharmaceutics, 2012

For the purpose of brain delivery upon intravenous injection, formulations of camptothecin-loaded... more For the purpose of brain delivery upon intravenous injection, formulations of camptothecin-loaded solid lipid nanoparticles (SLN), prepared by hot high pressure homogenisation, were designed. Incorporation of camptothecin in the hydrophobic and acidic environment of SLN matrix was chosen to stabilise the lactone ring, which is essential for its antitumour activity, and for avoiding premature loss of drug on the way to target camptothecin to the brain. A multivariate approach was used to assess the influence of the qualitative and quantitative composition on the physicochemical properties of camptothecin-loaded SLN in comparison to plain SLN. Mean particle sizes of ≤200 nm, homogenous size distributions and high encapsulation efficiencies (>90%) were achieved for the most suitable formulations. In vitro release studies in plasma, showed a prolonged release profile of camptothecin from SLN, confirming the physical stability of the particles under physiological pH. A higher affinity of the SLN to the porcine brain capillary endothelial cells (BCEC) was shown in comparison to macrophages. MTT studies in BCEC revealed a moderate decrease in the cell viability of camptothecin, when incorporated in SLN compared to free camptothecin in solution. In vivo studies in rats showed that fluorescently labelled SLN were detected in the brain after i.v. administration. This study indicates that the camptothecin-loaded SLN are a promising drug brain delivery system worth to explore further for brain tumour therapy.

International Journal of Pharmaceutics, 2014

The choice of drug therapy in pregnant patients suffering from vaginal infections is limited by t... more The choice of drug therapy in pregnant patients suffering from vaginal infections is limited by the safety profile of the drug. Assuring the efficient topical therapy to avoid systemic absorption is considered the best therapy option. Chitosan-coated liposomes have been developed and optimized to assure localized therapy of clotrimazole. Chitosan was selected as mucoadhesive polymer both to prolong system's retention at the vaginal site and act on biofilms responsible for high recurrence of infections. Sonicated liposomes were coated with chitosan in three different concentrations, namely 0.1, 0.3 and 0.6% (w/v). Clotrimazole-containing (22 μg/mg lipid) chitosan-coated liposomes were in the size range of 100-200 nm. The in vitro release studies confirmed prolonged release of clotrimazole from both non-coated and chitosan-coated liposomes as compared to control. The ex vivo penetration experiments performed on the pregnant sheep vaginal tissue showed that coated liposomes assured increased clotrimazole tissue retention and reduced its penetration as compared to the control. Mucin studies revealed that the coating with lower chitosan concentration increased the system's mucoadhesive potential, as compared to coating with higher concentrations. These results provide a good platform for further in vivo animal studies on mucoadhesive liposomes destined to localized vaginal therapy.

Pharmaceutics, 2014

Different non-ionic cellulose ethers (methyl cellulose, MC; hydroxyethyl cellulose, HEC; hydroxyp... more Different non-ionic cellulose ethers (methyl cellulose, MC; hydroxyethyl cellulose, HEC; hydroxypropyl cellulose, HPC; hydroxypropylmethyl cellulose, HPMC) and microcrystalline cellulose (MCC) were investigated as matrix formers for preparation of mini-tablets targeting vaginal drug delivery. Hexyl aminolevulinat hydrochloridum (HAL) was used as a model drug. The mini-tablets were characterized with respect to their mechanical strength, bioadhesion towards cow vaginal tissue in two independent tests (rotating cylinder test, detachment test using texture analyzer), and dissolution rate in two media mimicking the pH levels of fertile, healthy and post-menopausal women (vaginal fluid simulant pH 4.5, phosphate buffer pH 6.8). Mini-tablets with a matrix of either HPMC or HPC were found to possess adequate mechanical strength, superior bioadhesive behavior towards vaginal tissue, and pH independent controlled release of the model drug, suggesting that both systems would be suited for the treatment of women regardless of age, i.e., respective of their vaginal pH levels. Bioadhesive mini-tablets offer a potential for improved residence time in the vaginal cavity targeting contact with mucosal tissue and prolonged release of the drug.

Powder Technology, 2010

The present work evaluates the usefulness of “in die” elastic recovery descriptors as an indicato... more The present work evaluates the usefulness of “in die” elastic recovery descriptors as an indicator of tabletability. Tablet elastic recovery (“in die” and “out-of-die”) with respect to applied compression speed and dwell time were evaluated by applying 22-full factorial ...

Pharmaceutical Development and Technology, 2012

This study examines the effect of the degree of methoxylation (DM) and particle size on compressi... more This study examines the effect of the degree of methoxylation (DM) and particle size on compression properties and compactibility of pectin powders. A powder classification system based on sequential handling of compression parameters was applied. A single size fraction (90-125 μm) of pectin powders with DM values ranging from 5-72% was studied. For DM 25%, the effect of different particle size fractions (180-250, 125-180, 90-125, 63-90, 45-63, <45 μm) were investigated. Compression parameters were derived based on time-resolved force-displacement data using Heckel, Kawakita and Shapiro equations. Volume-specific surface area was estimated for powders and tablets. Tablet tensile strength was determined. It was found that all pectin powders displayed low degrees of particle rearrangement and relatively low degrees of fragmentation (class IIA materials). Pectin particles were found to be relatively soft, with a tendency towards softer particles for pectins of higher DM. The overall variation in fragmentation and deformation behavior was limited. Both DM and initial particle size affected the tensile strength of pectin tablets. The difference in surface hydrophobicity caused by the DM was suggested as being responsible for the variation in the mechanical strengths. The study shows that pectin grades with DM ≤ 40% are potential direct compression excipients.

Pharmaceutical Development and Technology, 2009

The present work challenges a newly developed approach to tablet formulation development by using... more The present work challenges a newly developed approach to tablet formulation development by using chemically identical materials (grades and brands of microcrystalline cellulose). Tablet properties with respect to process and formulation parameters (e.g. compression speed, added lubricant and Emcompress fractions) were evaluated by 2(3)-factorial designs. Tablets of constant true volume were prepared on a compaction simulator at constant pressure (approx. 100 MPa). The highly repeatable and accurate force-displacement data obtained was evaluated by simple 'in-die' Heckel method and work descriptors. Relationships and interactions between formulation, process and tablet parameters were identified and quantified by multivariate analysis techniques; principal component analysis (PCA) and partial least square regressions (PLS). The method proved to be able to distinguish between different grades of MCC and even between two different brands of the same grade (Avicel PH 101 and Vivapur 101). One example of interaction was studied in more detail by mixed level design: The interaction effect of lubricant and Emcompress on elastic recovery of Avicel PH 102 was demonstrated to be complex and non-linear using the development tool under investigation.

Journal of Pharmacy and Pharmacology, 2010

The phospholipid vesicle-based barrier has recently been introduced as an in-vitro permeation mod... more The phospholipid vesicle-based barrier has recently been introduced as an in-vitro permeation model mimicking gastro-epithelial barriers in terms of passive diffusion of drugs. The aim of this study was to investigate whether the phospholipid vesicle-based barrier was suitable for permeability screening of complex formulations such as solid dispersions. Methods Solid dispersions containing the poorly water-soluble drugs HIV-PI 1 (log P = 6.2, molar mass = 628.80 g/mol) and HIV-PI 2 (log P = 5.3, molar mass = 720.95 g/ mol), a hydrophilic polymer and different surfactants were tested with respect to their influence on integrity of the barrier in terms of electrical resistance and permeability for calcein. Furthermore, utilisation of a more biologically relevant medium, Hank's balanced salt solution supplemented with Mg 2+ -and Ca 2+ -ions (HBSS (Mg 2+ , Ca 2+ )), has been tested. Key findings Except for the polyoxyl 40 hydrogenated castor oil-containing solid dispersion, no influence on the phospholipid vesicle-based barrier could be observed from the tested samples. Presence of active pharmaceutical ingredients (APIs) in the solid dispersions led to the same results as the corresponding placebo results. First experiments analysing the passive diffusion of both APIs in HBSS (Mg 2+ , Ca 2+ ), evaluated as suitable transport medium, have shown promising results regarding the suitability of the phospholipid vesiclebased barrier for investigation of solid dispersions. Conclusions The study indicated that the phospholipid vesicle-based barrier was compatible with selected melt extrudate formulations. The model seemed capable to reveal different transport routes in comparison with Caco-2 cell permeability tests.

Journal of Pharmaceutical Sciences, 2012

Curcumin is a well-established natural antioxidant and anti-inflammatory agent. Up till now its p... more Curcumin is a well-established natural antioxidant and anti-inflammatory agent. Up till now its potential in treatment of vaginal inflammation has not been evaluated. We are aiming at developing liposomal delivery system for curcumin targeting vaginal administration. Liposomes as nanosized phospholipid-based vesicles are expected to solubilize curcumin and enhance its activity, thus serving as an advanced topical formulation in the treatment of vaginal inflammation. Curcumin and curcuminoids were analyzed by the high-performance liquid chromatography method. Liposomes containing curcumin/curcuminoids of various sizes were prepared and characterized. Antioxidant activities of curcumin and liposomal curcumin were compared based on 1,1-diphenyl-2-picrylhydrazyl radical scavenging and superoxide dismutase activities. The anti-inflammatory activities were determined by measuring the inhibition of lipopolysaccharide -induced nitric oxide, interleukin-1$, and tumor necrosis factor-" production in macrophage RAW 264.7 cells. Curcumin/curcuminoids were encapsulated in phosphatidylcholine vesicles with high yields. Vesicles in the size range around 200 nm were selected for stability and cell experiments. Liposomal curcumin were found to be twofold to sixfold more potent than corresponding curcuminoids. Moreover, the mixture of curcuminoids was found to be more potent than pure curcumin in regard to the antioxidant and anti-inflammatory activities. Liposomal delivery systems for curcumin are promising formulations for the treatment of vaginal inflammation.

Journal of Pharmaceutical and Biomedical Analysis, 2010

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