Co-administration of Intravenous Drugs: Rapidly Troubleshooting the Solid Form Composition of a Precipitate in a Multi-drug Mixture Using On-Site Raman Spectroscopy.

Intravenous drugs are often co-administrated in the same intravenous catheter line due to which compatibility issues, such as complex precipitation processes in the catheter line, may occur. A well-known example that led to several neonatal deaths is the precipitation due to co-administration of ceftriaxone- and calcium-containing solutions. The current study is exploring the applicability of Raman spectroscopy for testing intravenous drug compatibility in hospital settings. The precipitation of ceftriaxone calcium was used as a model system and explored in several multi-drug mixtures containing both structurally similar and clinically relevant drugs for co-infusion. Equal molar concentrations of solutions containing ceftriaxone and calcium chloride dihydrate were mixed with solutions of cefotaxime, ampicillin, paracetamol, and metoclopramide. The precipitate formed was collected as an "unknown" material, dried, and analyzed. Several solid-state analytical methods, including X-ray powder diffraction, Raman spectroscopy, and thermogravimetric analysis, were used to characterize the precipitate. Raman microscopy was used to investigate the identity of single sub-visual particles precipitated from a mixture of ceftriaxone, cefotaxime, and calcium chloride. X-ray powder diffraction suggested that the precipitate was partially crystalline; however, the identity of the solid form of the precipitate could not be confirmed with this standard method. Raman spectroscopy combined with multi-variate analyses (principal component analysis and soft independent modelling class analogy) enabled the correct detection and identification of the precipitate as ceftriaxone calcium. Raman microscopy enabled the identification of ceftriaxone calcium single particles of sub-visual size (around 25 µm), which is in the size range that may occlude capillaries. This study indicates that Raman spectroscopy is a promising approach for supporting clinical decisions and especially for compatibility assessments of drug infusions in hospital settings.

Exploring a case of incompatibility in a complex regimen containing Plasma-Lyte 148 in the pediatric intensive care.

BACKGROUND: In the local pediatric intensive care unit, precipitation was observed in the intravenous catheter upon co-administration of four drugs together with the buffered electrolyte solution (Plasma-Lyte 148, Baxter). Co-infusion of incompatible combinations represents a safety concern. AIMS: To reproduce the clinical case of precipitation. To further explore and understand the risk of precipitation, different combinations of the components as well as the corresponding electrolyte solution with 5% glucose (Plasma-Lyte 148 with 5% glucose) should be investigated. METHODS: Physical compatibility of fentanyl, ketamine, midazolam, and potassium chloride was tested in combination with the buffered electrolyte solutions. The concentrations and infusion rates representative of children 10-40 kg were used to estimate mixing ratios. Analyses detecting visual particles (Tyndall beam) and sub-visual particles (light obscuration technology) were undertaken. Measured turbidity and pH in mixed samples were compared with unmixed controls. RESULTS: Both midazolam and ketamine showed formation of visual and sub-visual particles upon mixing with Plasma-Lyte 148, respectively. Particle formation was confirmed by increased turbidity and a distinct Tyndall effect. pH in mixed samples mirrored the pH of the buffered electrolyte, suggesting that the solubility limits of midazolam, and in some ratios also ketamine, were exceeded. Midazolam also precipitated in combination with the glucose-containing product that held a lower pH, more favorable for keeping midazolam dissolved. CONCLUSIONS: Replication of the case revealed that both midazolam and ketamine contributed to the precipitation. Midazolam and ketamine were both evaluated as incompatible with the buffered electrolyte solution and midazolam also with the buffered electrolyte-glucose solution and should not be co-administered in the same i.v.-catheter line. Fentanyl and potassium chloride were interpreted as compatible with both buffered electrolytes.

Co-administration of drugs with parenteral nutrition in the neonatal intensive care unit-physical compatibility between three components.

There is a lack of compatibility data for intravenous therapy to neonatal intensive care unit (NICU) patients, and the purpose of this study was to contribute with documented physical compatibility data to ensure safe co-administration. We selected Numeta G13E, the 3-in-1 parenteral nutrition (PN) used at our NICU, together with the frequently used drugs morphine, dopamine and cefotaxime in two- but also three-component combinations. Incompatibility may lead to particle formation (precipitation) and oil-droplet growth (emulsion destabilisation), both which are undesirable and pose a safety risk to already unstable patients. We assessed potential particle formation of three mixing ratios for each combination (always including 1 + 1 ratio) using light obscuration, turbidity and pH measurements combined with visual inspection by focused Tyndall beam. Potential droplet-growth and emulsion destabilisation was assessed by estimating PFAT5 from droplet size measurements and counts, mean droplet diameter and polydispersity index from dynamic light scattering, and pH measurements. Mixed samples were always compared to unmixed controls to capture changes as a result of mixing and samples were analysed directly after mixing and after 4 h to simulate long contact time. None of the samples showed any sign of precipitation, neither in the drug-drug nor in the two- or three-component mixture with PN. Neither did we detect any form of emulsion destabilisation. CONCLUSION: Dopamine, morphine and cefotaxime were found to be compatible with NumetaG13E, and it is safe to co-administer these drugs together with this PN in NICU patients. WHAT IS KNOWN: • The need for co-administration of drugs and complex PN admixtures occurs frequently in NICU due to limited venous access. • Available compatibility data are scarce and for combinations of more than two components non-existent. WHAT IS NEW: • Here we report physical compatibility data of two- as well as three-component combinations of frequently used NICU drugs and a 3-in-1 PN admixture. • Co-administration of Numeta G13E with dopamine and morphine, but also with morphine and cefotaxime is safe in NICU.

Frequently acquired drugs in neonatal intensive care and their physical compatibility.

AIM: Incompatibility of intravenous drugs is dangerous and therefore undesirable. The aim of this study was to identify the most commonly acquired intravenous drugs in five neonatal intensive care units and test these for compatibility. METHODS: The most frequently acquired drugs in five key hospitals in the South-Eastern district of Norway for 2019 and 2020 served as a proxy for the prevalence of use. Representatives were selected from the three most prevalent groups based on the Anatomical Therapeutic Chemical classification system. Co-administration of drug pairs was simulated using clinically relevant concentrations and infusion rates representing mixing ratios in the catheter. Particle formation was assessed by particle counting and size measurement, by visual examination using Tyndall beam, by turbidity and by measuring pH of mixed samples. RESULTS: The most frequently acquired drug groups were anti-infectives, neurological agents and cardiovascular drugs. Compatibility testing revealed that both ampicillin and benzylpenicillin were incompatible with morphine. Flecainide and fluconazole showed no signs of incompatibility with morphine. No information on these combinations in a neonatal-relevant setting is available. CONCLUSION: We recommend to abstain from co-administering ampicillin and benzylpenicillin with morphine in neonatal intensive settings. Morphine co-administered with flecainide and fluconazole in neonatal patients were evaluated as safe.

Influence of Drug Load on the Printability and Solid-State Properties of 3D-Printed Naproxen-Based Amorphous Solid Dispersion.

Fused deposition modelling-based 3D printing of pharmaceutical products is facing challenges like brittleness and printability of the drug-loaded hot-melt extruded filament feedstock and stabilization of the solid-state form of the drug in the final product. The aim of this study was to investigate the influence of the drug load on printability and physical stability. The poor glass former naproxen (NAP) was hot-melt extruded with Kollidon® VA 64 at 10-30% w/w drug load. The extrudates (filaments) were characterised using differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), and thermogravimetric analysis (TGA). It was confirmed that an amorphous solid dispersion was formed. A temperature profile was developed based on the results from TGA, DSC, and DMA and temperatures used for 3D printing were selected from the profile. The 3D-printed tablets were characterised using DSC, X-ray computer microtomography (XµCT), and X-ray powder diffraction (XRPD). From the DSC and XRPD analysis, it was found that the drug in the 3D-printed tablets (20 and 30% NAP) was amorphous and remained amorphous after 23 weeks of storage (room temperature (RT), 37% relative humidity (RH)). This shows that adjusting the drug ratio can modulate the brittleness and improve printability without compromising the physical stability of the amorphous solid dispersion.

Adjusting the dose in paediatric care by dispersing fragments of four different aspirin tablets.

AIM: Tablets can be manipulated in several ways to obtain a fraction as the dose-a practice frequently seen in paediatric care due to lack of suitable formulations. Splitting tablets prior to fragment dispersion in a small volume of liquid is one such method. The objective of this study was to investigate the accuracy and precision of this method. METHODS: Four different types of aspirin tablets (two dispersible, one conventional and one chewing) were split with a tablet splitter into half and quarter fragments. The fragments were dispersed in a medicine measure or an oral syringe. The amount recovered was determined by UHPLC analysis. RESULTS: The largest quarter fragments ranged from 26.7% to 31.5% of the full tablet weight. Dispersing the fragment in an oral syringe, the amount recovered was greater than 90.8% of the fragment manipulated for all four tablet types, when rinsing was performed. Dispersing the fragment in a medicine measure, the amounts recovered spanned from 32.9% for the conventional tablets to 98.7% for one of the dispersible tablets. CONCLUSION: Dispersion of half or quarter tablets directly in an oral syringe, but not a medicine measure, could give satisfactory recovery from fragments of all the investigated aspirin tablets.

Development of a bioadhesive nanoformulation with Glycyrrhiza glabra L. extract against Candida albicans.

Glycyrrhiza glabra L. is considered an important source of bioactive compounds. This study aimed at the development of an efficient solution for the treatment of oral candidiasis. Several extracts of Glycyrrhiza glabra L. were prepared using different solvents and their potential in vitro antifungal activity was assessed. Ethanolic extracts showed the most promising results against C. albicans. This extract was incorporated into mucoadhesive nanoparticles (PLA, PLGA and alginate), which were further included in an oral gel, an oral film and a toothpaste, respectively. The results showed that nanoparticles were successfully produced, presenting a mean size among 100-900 nm with high encapsulation efficiency. In vitro studies showed that the most bioadhesive formulation was the oral film with extract-loaded PLGA nanoparticles, followed by the toothpaste with extract-loaded alginate nanoparticles and the oral gel with extract-loaded PLA nanoparticles.

Viscosity reduction of isotonic solutions of the photosensitizer TPCS2a by cyclodextrin complexation.

Meso-tetraphenyl chlorin disulphonate (TPCS2a) is a photosensitizer (PS) particularly developed and patented for use in the technology of photochemical internalization (PCI) against cancer. TPCS2a is known to aggregate in aqueous media even at low concentrations (≥0.1 µM) and to form a high-viscosity network at clinically relevant concentrations (mM). The aim of this work was to evaluate the effect of two hydroxypropylated cyclodextrin derivatives of beta and gamma type, respectively i.e. HPßCD and HPγCD, on the aggregation and solubilization of TPCS2a in isotonic solutions. Samples containing micromolar concentrations of TPCS2a were studied spectrophotometrically, while samples containing a clinical relevant concentration (10 mM = 9 mg/ml) of TPCS2a were evaluated by dynamic viscosity measurements. HPßCD was determined to be a more suitable solubilizer of TPCS2a than HPγCD in aqueous media both in the absence and presence of salt. The complexation stoichiometry between TPCS2a/HPßCD at micromolar to millimolar concentrations of TPCS2a was determined to be 1:3 and 1:2 in the absence and presence of isotonic NaCl, respectively. The network of TPCS2a (10 mM) was broken down in the presence of 3% w/v (= 20 mM) HPßCD, i.e. a 1:2 molar ratio between TPCS2a and the cyclodextrin. Formation of the inclusion complex resulted in low viscosity samples both in water and in the presence of isotonic NaCl or phosphate buffered saline (PBS) at 25 °C and 37 °C.

Chitosan-Based Nanomedicine to Fight Genital Candida Infections: Chitosomes.

Vaginal infections are associated with high recurrence, which is often due to a lack of efficient treatment of complex vaginal infections comprised of several types of pathogens, especially fungi and bacteria. Chitosan, a mucoadhesive polymer with known antifungal effect, could offer a great improvement in vaginal therapy; the chitosan-based nanosystem could both provide antifungal effects and simultaneously deliver antibacterial drugs. We prepared chitosan-containing liposomes, chitosomes, where chitosan is both embedded in liposomes and surface-available as a coating layer. For antimicrobial activity, we entrapped metronidazole as a model drug. To prove that mucoadhesivness alone is not sufficient for successful delivery, we used Carbopol-containing liposomes as a control. All vesicles were characterized for their size, zeta potential, entrapment efficiency, and in vitro drug release. Chitosan-containing liposomes were able to assure the prolonged release of metronidazole. Their antifungal activity was evaluated in a C. albicans model; chitosan-containing liposomes exhibited a potent ability to inhibit the growth of C. albicans. The presence of chitosan was crucial for the system's antifungal activity. The antifungal efficacy of chitosomes combined with antibacterial potential of the entrapped metronidazole could offer improved efficacy in the treatment of mixed/complex vaginal infections.

Development and evaluation of a test program for Y-site compatibility testing of total parenteral nutrition and intravenous drugs.

BACKGROUND: There is no standardized procedure or consensus to which tests should be performed to judge compatibility/incompatibility of intravenous drugs. The purpose of this study was to establish and evaluate a test program of methods suitable for detection of physical incompatibility in Y-site administration of total parenteral nutrition (TPN) and drugs. METHODS: Eight frequently used methods (dynamic light scattering, laser diffraction, light obscuration, turbidimetry, zeta potential, light microscopy, pH-measurements and visual examination using Tyndall beams), were scrutinized to elucidate strengths and weaknesses for compatibility testing. The responses of the methods were tested with samples containing precipitation of calcium phosphate and with heat destabilized TPN emulsions. A selection of drugs (acyclovir, ampicillin, ondansetron and paracetamol) was mixed with 3-in-1 TPN admixtures (Olimel® N5E, Kabiven® and SmofKabiven®) to assess compatibility (i.e. potential precipitates and emulsion stability). The obtained compatibility data was interpreted according to theory and compared to existing compatibility literature to further check the validity of the methods. RESULTS: Light obscuration together with turbidimetry, visual inspection and pH-measurements were able to capture signs of precipitations. For the analysis of emulsion stability, light obscuration and estimation of percent droplets above 5 µm (PFAT5) seemed to be the most sensitive method; however laser diffraction and monitoring changes in pH might be a useful support. Samples should always be compared to unmixed controls to reveal changes induced by the mixing. General acceptance criteria are difficult to define, although some limits are suggested based on current experience. The experimental compatibility data was supported by scattered reports in literature, further confirming the suitability of the test program. However, conflicting data are common, which complicates the comparison to existing literature. CONCLUSIONS: Testing of these complex blends should be based on a combination of several methods and accompanied by theoretical considerations.

Chitosan in mucoadhesive drug delivery: focus on local vaginal therapy.

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 release and are expected to ensure prolonged residence time on the vaginal mucosa providing localized sustained release of entrapped model substances.

Impact of drug load and polymer molecular weight on the 3D microstructure of printed tablets.

This study investigates the influence of drug load and polymer molecular weight on the structure of tablets three-dimensionally (3D) printed from the binary mixture of prednisolone and hydroxypropyl methylcellulose (HPMC). Three different HPMC grades, (AFFINISOLTM HPMC HME 15LV, 90 Da (HPMC 15LV); 100LV, 180 Da (HPMC 100LV); 4M, 500 Da (HPMC 4M)), which are suitable for hot-melt extrusion (HME), were used in this study. HME was used to fabricate feedstock material, i.e., filaments, at the lowest possible extrusion temperature. Filaments of the three HPMC grades were prepared to contain 2.5, 5, 10 and 20 % (w/w) prednisolone. The thermal degradation of the filaments was studied with thermogravimetric analysis, while solid-state properties of the drug-loaded filaments were assessed with the use of X-ray powder diffraction. Prednisolone in the freshly extruded filaments was determined to be amorphous for drug loads up to 10%. It remained physically stable for at least 6 months of storage, except for the filament containing 10% drug with HPMC 15LV, where recrystallization of prednisolone was detected. Fused deposition modeling was utilized to print honeycomb-shaped tablets from the HME filaments of HPMC 15LV and 100LV. The structural characteristics of the tablets were evaluated using X-ray microcomputed tomography, specifically porosity and size of structural elements were investigated. The tablets printed from HPMC 15LV possessed in general lower total porosity and pores of smaller size than tablets printed from the HPMC 100LV. The studied drug loads were shown to have minor effect on the total porosity of the tablets, though the lower the drug load was, the higher the variance of porosity along the height of the tablet was observed. It was found that tablets printed with HPMC 15LV showed higher structural similarity with the virtually designed model than tablets printed from HPMC 100LV. These findings highlight the relevance of the drug load and polymer molecular weight on the microstructure and structural properties of 3D printed tablets.

A unifying approach to drug-in-polymer solubility prediction: Streamlining experimental workflow and analysis.

This method paper describes currently used experimental methods to predict the drug-in-polymer solubility of amorphous solid dispersions and offers a combined approach for applying the Melting-point-depression method, the Recrystallization method, and the Melting-and-mixing method. It aims to describe and expand on the theoretical basis as well as the analytical methodology of the recently published Melting-and-mixing method. This solubility method relies on determining the relationship between drug loads and the enthalpy of melting and mixing of a crystalline drug in the presence of an amorphous polymer. This relationship is used to determine the soluble drug load of an amorphous solid dispersion from the recorded enthalpy of melting and mixing of the crystalline drug portion in a drug-polymer sample at equilibrium solubility. Due to the complex analytical methodology of the Melting-and-mixing method, a software solution called the Glass Solution Companion app was developed. Using this new tool, it is possible to calculate the predicted drug-in-polymer solubility and Flory-Huggins interaction parameter from experimental samples, as well as to generate the resulting solubility-temperature curve. This software can be used for calculations for all three experimental methods, which would be useful for comparing the applicability of the methods on a given drug-polymer system. Since it is difficult to predict the suitability of these drug-in-polymer solubility methods for a specific drug-polymer system in silico, some experimental investigation is necessary. By optimizing the experimental protocol, it is possible to collect data for the three experimental methods simultaneously for a specific drug-polymer system. These results can then be readily analyzed using the Glass Solution Companion app to find the most appropriate method for the drug-polymer system, and therefore, the most reliable drug-in-polymer solubility prediction.

Towards personalized drug delivery via semi-solid extrusion: Exploring poly(vinyl alcohol-co-vinyl acetate) copolymers for hydrochlorothiazide-loaded films.

The increasing need for personalized drug delivery requires developing systems with tailorable properties. The copolymer poly(vinyl alcohol-co-vinyl acetate) (PVA/PVAc) allows for adjusting the monomer ratio. This study explored the effect of vinyl alcohol (VA) and vinyl acetate (VAc) monomer ratio on the properties of hydrochlorothiazide (HCT) films. Five copolymers with different VA/VAc ratios were selected and characterized. Semi-solid extrusion was employed as a method for the preparation of HCT-PVA/PVAc films to address the challenges of HCT´s low water solubility, high melting point, and low permeability. All copolymers were suitable for semi-solid extrusion, however, the mechanical properties of films with higher VA proportions were more suitable. The drug was found to be homogeneously distributed on a micrometer level throughout the prepared films. It was found that using different monomer ratios in the copolymer allows for drug release tuning - higher VA proportions showed an increased rate of drug release. Experiments through HT29-MTX cell monolayers revealed differences in HCT permeability between the different formulations. In addition, no cytotoxicity was observed for the tested formulations. The results highlight the effect of monomer ratio on film properties, providing valuable guidance for formulators in selecting PVA/PVAc copolymers for achieving desired high-quality films. In addition, varying the monomer ratio allows tuning of the film properties, and can be applied for personalization, with flexible-dose adjustment and design of appealing shapes of the pharmaceutics, not least attractive for pediatric drug delivery.

Co-release of paclitaxel and encequidar from amorphous solid dispersions increase oral paclitaxel bioavailability in rats.

The oral bioavailability of paclitaxel is limited due to low solubility and high affinity for the P-glycoprotein (P-gp) efflux transporter. Here we hypothesized that maximizing the intestinal paclitaxel levels through apparent solubility enhancement and controlling thesimultaneous release of both paclitaxel and the P-gp inhibitor encequidar from amorphous solid dispersions (ASDs) would increase the oral bioavailability of paclitaxel. ASDs of paclitaxel and encequidar in polyvinylpyrrolidone K30 (PVP-K30), hydroxypropylmethylcellulose 5 (HPMC-5), and hydroxypropylmethylcellulose 4 K (HPMC-4K) were hence prepared by freeze-drying. In vitro dissolution studies showed that both compounds were released fastest from PVP-K30, then from HPMC-5, and slowest from HPMC-4K ASDs. The dissolution of paclitaxel from all polymers resulted in stable concentration levels above the apparent solubility. The pharmacokinetics of paclitaxel after oral administration to male Sprague-Dawley rats was investigated with or without 1 mg/kg encequidar, as amorphous solids or polymer-based ASDs. The bioavailability of paclitaxel increased 3- to 4-fold when administered as polymer-based ASDs relative to solid amorphous paclitaxel. However, when amorphous paclitaxel was co-administered with encequidar, either as an amorphous powder or as a polymer-based ASD, the bioavailability increased 2- to 4-fold, respectively. Interestingly, a noticeable increase in paclitaxel bioavailability of 24-fold was observed when paclitaxel and encequidar were co-administered as HPMC-5-based ASDs. We, therefore, suggest that controlling the dissolution rate of paclitaxel and encequidar in order to obtain simultaneous and timed release from polymer-based ASDs is a strategy to increase oral paclitaxel bioavailability.

Shifting the Focus from Dissolution to Permeation: Introducing the Meso-fluidic Chip for Permeability Assessment (MCPA).

In response to the growing ethical and environmental concerns associated with animal testing, numerous in vitro tools of varying complexity and biorelevance have been developed and adopted in pharmaceutical research and development. In this work, we present one of these tools, i.e., the Meso-fluidic Chip for Permeability Assessment (MCPA), for the first time. The MCPA combines an artificial barrier (PermeaPad®) with an organ-on-chip device (MIVO®) and real-time automated concentration measurements, to yield a sustainable, yet effortless method for permeation testing. The system offers three major physiological aspects, i.e., a biomimetic membrane, an optimal membrane interfacial area-to-donor-volume-ratio (A/V) and a physiological flow on the acceptor/basolateral side, which makes the MPCA an ideal candidate for mechanistic studies and excellent in vivo bioavailability predictions. We validated the method with a handful of assorted drug compounds in unstirred and stirred donor conditions, before exploring its applicability as a tool for dissolution/permeation testing on a BCS class III/I drug (pyrazinamide) crystalline adducts and BCS class II/IV (hydrocortisone) amorphous solid dispersions. The results were highly reproducible and clearly displayed the method's potential for evaluating the performance of enabling formulations, and possibly even predicting in vivo performance. We believe that, upon further development, the MCPA will serve as a useful in vitro tool that could push sustainability into pharmaceutics by refining, reducing and replacing animal testing in early-stage drug development.

Water-soluble chitosan eases development of mucoadhesive buccal films and wafers for children.

Oromucosal films and wafers are user-friendly solid dosage forms offering easy and convenient administration, as well as rapid or controlled drug delivery. The aim of this study was to develop prednisolone containing child-friendly chitosan-based mucoadhesive films and wafers with a prolonged residence time on the buccal mucosa. Four different chitosan types (different molecular weights, degree of deacetylation (DDA), pattern of deacetylation) were studied for films prepared by solvent-cast-evaporation and wafers by freeze-drying. Mucoadhesive properties correlated with swelling abilities and were dependent on the chitosan type, the solvent, and the preparation method. Mucoadhesive forces were higher for formulations containing chitosan with higher DDA and for wafers compared to films. The drug release was relatively fast, especially for films (approx. 90 % in 15 minutes) and steadier for wafers (90 % in 45-120 minutes). Permeability was evaluated using artificial membranes and HT29-MTX cell-monolayers. The developed formulations exhibited good biocompatibility. Organoleptic properties can be improved by choosing a homogenously deacetylated chitosan type that provides a more neutral pH. Using hydroxypropyl-beta-cyclodextrin-complexation for taste masking of bitter drugs also reduced wafers' drug release rate. Mucoadhesive wafers are promising alternatives to films with a slower drug release rate and stronger mucoadhesion.

Increased bioavailability of a P-gp substrate: Co-release of etoposide and zosuquidar from amorphous solid dispersions.

P-glycoprotein (P-gp) inhibitors, like zosuquidar, partly increase oral bioavailability of P-gp substrates, such as etoposide. Here, it was hypothesised that co-release of etoposide and zosuquidar from amorphous solid dispersions (ASDs) may further increase oral etoposide bioavailability. This was envisioned through simultaneous co-release and subsequent spatiotemporal association of etoposide and zosuquidar in the small intestinal lumen. To further achieve this, ASDs of etoposide and zosuquidar in polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC) 5, and HPMC 4 k were prepared by freeze-drying. From these ASDs, etoposide release was fastest from PVP, then HPMC 5 and slowest from HPMC 4. Release from PVP and HPMC5 resulted in stable supersaturations of etoposide. In transcellular permeability studies across MDCKII-MDR1 cell monolayers, the accumulated amount of etoposide increased 3.7-4.9-fold from amorphous etoposide or when incorporated into PVP- or HPMC 5-based ASDs, compared to crystalline etoposide. In vivo, the oral bioavailability in Sprague Dawley rats increased from 1.0 to 2.4-3.4 %, when etoposide was administered as amorphous drug or in ASDs. However, when etoposide and zosuquidar were co-administered, the oral bioavailability increased further to 8.2-18 %. Interestingly, a distinct increase in oral etoposide bioavailability to 26 % was observed when etoposide and zosuquidar were co-administration in HPMC5-based ASDs. The supersaturation of etoposide as well as the simultaneous co-release of etoposide and zosuquidar in the small intestinal lumen may explain the observed bioavailability increase. Overall, this study suggested that simultaneous co-release of an amorphous P-gp substrate and inhibitor may be a novel and viable formulation strategy to increase the bioavailability P-gp substrates.

Effect of degree of methoxylation and particle size on compression properties and compactibility of pectin powders.

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.

[Orally disintegrating tablets--advantages and drawbacks]. / Smeltetabletter--fordeler og ulemper.

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.