Biomedical subjects

Thomas Rades

Publications and source records attributed to Thomas Rades.

At least 19 recordsLinked to original sources

PubMed2007

Influence of polymorphic form, morphology, and excipient interactions on the dissolution of carbamazepine compacts.

To gain a deeper understanding of the behavior of carbamazepine (CBZ) and CBZ dihydrate (DH) compacts during in vitro dissolution tests various factors were investigated: hydrate formation of CBZ, crystal morphology, surface area, and excipient influence. Dissolution tests were performed in three different dissolution media: distilled water, hydroxypropyl methylcellulose (HPMC), and polyethylene glycol (PEG) solutions. For the CBZ compacts, the dissolution rate of CBZ in water was fastest (0.338 mg L(-1) min(-1)). With increasing ability of the excipients to inhibit the hydration of CBZ (PEG < HPMC), surprisingly the dissolution rate of CBZ compacts decreased: PEG solution (0.314 mg L(-1) min(-1)) > HPMC solution (0.257 mg L(-1) min(-1)). This implies that DH formation resulted in an apparent increase in the dissolution rate rather than slowing it down. For the DH compacts, the dissolution rate in water (0.055 mg L(-1) min(-1)) was slower than that of PEG and HPMC solutions (0.174 and 0.178 mg L(-1) min(-1), respectively). The contact angle measurements showed a significantly higher value in water (61.0 degrees) than in PEG and HPMC solutions (44.8 degrees and 43.1 degrees, respectively). Although the dissolution of CBZ and DH compacts in various dissolution media are complex processes, the influence and relative importance of these factors were clearly detected providing better understanding of the dissolution behavior of the drug.

Carbamazepine↗

PubMed2007

Analysis of coating structures and interfaces in solid oral dosage forms by three dimensional terahertz pulsed imaging.

Three dimensional terahertz pulsed imaging (TPI) was evaluated as a novel tool for the nondestructive characterization of different solid oral dosage forms. The time-domain reflection signal of coherent pulsed light in the far infrared was used to investigate film-coated tablets, sugar-coated tablets, multilayered controlled release tablets, and soft gelatin capsules. It is possible to determine the spatial and statistical distribution of coating thickness in single and multiple coated products using 3D TPI. The measurements are nondestructive even for layers buried underneath other coating structures. The internal structure of coating materials can be analyzed. As the terahertz signal penetrates up to 3 mm into the dosage form interfaces between layers in multilayered tablets can be investigated. In soft gelatin capsules it is possible to measure the thickness of the gelatin layer and to characterize the seal between the gelatin layers for quality control. TPI is a unique approach for the nondestructive characterization and quality control of solid dosage forms. The measurements are fast and fully automated with the potential for much wider application of the technique in the process analytical technology scheme.

Capsules↗

PubMed2006

Preparation of glass solutions of three poorly water soluble drugs by spray drying, melt extrusion and ball milling.

The aim of this study was to investigate the influence of the manufacturing process on the physicochemical properties of three poorly water soluble compounds (carbamazepine, dipyridamole, and indomethacin) when processed with a polymer (polyvinylpyrrolidone K30 (PVP)) at a 1:2 drug to polymer ratio. Melt extrusion, spray drying, and ball milling techniques were used to prepare glass solutions. Product homogeneity, dissolution, physical stability, and drug/polymer interactions were investigated. Particular attention was paid to solid phase analysis using XRPD, modulated temperature DSC, optical microscopy, and Raman microscopy and the importance of using a combination of techniques was demonstrated. The latter technique when applied to freshly ball milled samples exhibited the presence of drug and polymer rich areas, indicating that complete glass solution formation had not occurred. The three compounds produced products with differing physical stability with indomethacin proving the most physically stable. These differences in physical stability were attributed to hydrogen bonding of drug and polymer. The manufacturing technique did not influence physical stability, but it did affect dissolution. The dissolution of the spray-dried material was generally poor, compared to melt extruded and ball milled products. This was probably due to rapid dissolution of PVP from the small particles of the spray-dried products.

Calorimetry, Differential Scanning↗

PubMed2006

Screening for differences in the amorphous state of indomethacin using multivariate visualization.

The aim of this study was to examine molecular-level differences in the amorphous state of indomethacin prepared from both alpha- and gamma-polymorphs using various preparative techniques: milling, quench cooling of a melt, slow cooling of a melt and spray drying. X-ray powder diffraction (XRPD), polarizing light microscopy (PLM), differential scanning calorimetry, as well as mid-infrared (MIR), near infrared (NIR) and Raman spectroscopy were used to analyze the samples after preparation. Principal component analysis (PCA) was used to visualize the differences in the spectroscopic data. According to the XRPD and PLM measurements, all samples except the spray dried indomethacin were amorphous after preparation. Spray dried indomethacin had some remaining residual crystallinity. Differences in the amorphous samples could be found on molecular level: the milled samples clustered separately from the other amorphous samples in the PCA of MIR, NIR and Raman spectra. This could be due to either small degrees of undetected crystallinity remaining in the samples after milling or differences in the hydrogen bonding in the different amorphous samples of indomethacin. The spectroscopic techniques revealed different information about the samples. Raman spectroscopy was most sensitive to differences caused by the preparation techniques and degradation products. Multivariate methods, such as PCA, offer an efficient tool to screen for these differences in the amorphous state.

Chemistry, Pharmaceutical↗

PubMed2006

Drug hydrate systems and dehydration processes studied by terahertz pulsed spectroscopy.

Terahertz pulsed spectroscopy was used to distinguish between different hydrate systems. In the example of four pharmaceutical materials lactose, carbamazepine, piroxicam and theophylline it was demonstrated that all different hydrate and anhydrate forms exhibit distinct spectra in the far infrared. Furthermore the dehydration of theophylline monohydrate was characterised in situ. Here, a phase transition from the monohydrate to the anhydrous form was observed, followed by evaporation of the hydrate water in a second step. The rotational spectrum of water vapour is very characteristic in the far infrared and can easily be discerned from the terahertz spectrum of the solid state form.

Carbamazepine↗

PubMed2006

Immunogenicity of liposomes containing lipid core peptides and the adjuvant Quil A.

PURPOSE: The purpose of this study was to investigate the immunogenicity of liposomes containing mannosylated lipid core peptide (manLCP) constructs, both in vitro and in vivo, with or without the addition of the immune stimulating adjuvant Quil A. METHODS: Mouse bone marrow dendritic cells (BMDC) were cultured with liposome formulations for 48 h, and the resulting level of BMDC activation was determined by flow cytometry. BMDC pulsed with liposome formulations were incubated with 5,6-carboxyfluoroscein diacetate succinimidyl ester-labeled T cells for 72 h and the resulting T cell proliferation was determined by flow cytometry. To investigate the immunogenicity of formulations in vivo, groups of C57Bl/6J mice were immunized by subcutaneous injection, and the resulting antigen-specific cytotoxic and protective immune responses toward tumor challenge evaluated. RESULTS: Despite being unable to demonstrate the activation of BMDC, BMDC pulsed with liposomes containing manLCP constructs were able to stimulate the proliferation of naïve T cells in vitro. However, in vivo only liposomes containing both manLCP and Quil A were able to stimulate a strong antigen-specific cytotoxic immune response. Liposomes containing manLCP and Quil A within the same particle were able to protect against the growth of tumor cells to a similar level as if the antigen was administered in alum with CD4 help. CONCLUSION: ManLCPs administered in liposomes are able to stimulate strong cytotoxic and protective immune responses if Quil A is also incorporated as an adjuvant.

Adjuvants, Immunologic↗

PubMed2006

Characterization of microemulsion structures in the pseudoternary phase diagram of isopropyl palmitate/water/Brij 97:1-butanol.

This research was aimed to characterize microemulsion systems of isopropyl palmitate (IPP), water, and 2:1 Brij 97 and 1-butanol by different experimental techniques. A pseudoternary phase diagram was constructed using water titration method. At 45% wt/wt surfactant system, microemulsions containing various ratios of water and IPP were prepared and identified by electrical conductivity, viscosity, differential scanning calorimetry (DSC), cryo-field emission scanning electron microscopy (cryo-FESEM) and nuclear magnetic resonance (NMR). The results from conductivity and viscosity suggested a percolation transition from water-in-oil (water/oil) to oil-in-water (oil/water) microemulsions at 30% wt/wt water. From DSC results, the exothermic peak of water and the endothermic peak of IPP indicated that the transition of water/oil to oil/water microemulsions occurred at 30% wt/wt water. Cryo-FESEM photomicrographs revealed globular structures of microemulsions at higher than 15% wt/wt water. In addition, self-diffusion coefficients determined by NMR reflected that the diffusability of water increased at higher than 35% wt/wt water, while that of IPP was in reverse. Therefore, the results from all techniques are in good agreement and indicate that the water/oil and oil/water transition point occurred in the range of 30% to 35% wt/wt water.

1-Butanol↗

PubMed2006

On the preparation, microscopic investigation and application of ISCOMs.

ISCOM matrices constitute colloidal structures formed from Quillaja saponins, cholesterol and phospholipid. Addition of protein antigens to these matrices leads to the formation of ISCOMs. In this review we report on microscopic investigations of ISCOM matrices and ISCOMs as well as related colloidal structures, such as helices, worm-like micelles, ring-like micelles, and lamellae structures. We briefly outline the immunologic basis for the use of ISCOMs as vaccine delivery systems, and describe the various methods to form ISCOMs. Negative staining transmission electron micrographs of all colloidal structures are presented and described. On the basis of our microscopic investigations, different formation mechanisms of ISCOMS are discussed.

Adjuvants, Immunologic↗

PubMed2006

Structural investigations on nanoemulsions, solid lipid nanoparticles and nanostructured lipid carriers by cryo-field emission scanning electron microscopy and Raman spectroscopy.

Recently, colloidal dispersions based on solid lipids (solid lipid nanoparticles, SLN) and mixtures of solid and liquid lipids (nanostructured lipid carriers, NLC) were described as innovative carrier systems. A spherical particle shape is the basis of features such as a high loading capacity and controlled drug release characteristics due to smaller lipid-water interfaces and longer diffusion pathways when compared to thin platelets. The structures of SLN and the influence of oil load (NLC) on particle properties were investigated by photon correlation spectroscopy (PCS), laser diffractometry (LD), cryo-field emission scanning electron microscopy (cryo-FESEM), Raman spectroscopy and infrared spectroscopy (IR), and compared to a conventional nanoemulsion. PCS and LD data show similar size and size distribution for SLN and NLC (approximately 210 nm, polydispersity index approximately 0.15) and suggested a long term physical stability for the dispersions which had been stored for up to 12 months at different temperatures. Using cryo-FESEM droplets (for the nanoemulsion) and almost spherical particles for SLN and NLC were observed. Raman spectroscopy resulted in spectra for NLC that are weighted to the SLN spectra, suggesting an undisturbed crystal structure. Infrared spectra of the NLC are predominantly SLN in nature. Importantly the SLN bands are unshifted in the NLC spectrum indicating that the crystalline structure is unaffected by the presence of the oil.

Chemistry, Pharmaceutical↗

PubMed2006

Towards characterization and identification of solid state pharmaceutical mixtures through second harmonic generation.

In this paper, we report improvements to a previously developed method based on optical nonlinearity for characterizing polymorphism and concentration of pharmaceuticals in powdered and tablet form. An apparatus that measures the nonlinear optical response of a sample through second harmonic generation (SHG) is described. The response of several enalapril maleate-polyvinylpyrrolidone (PVP) tablets was measured, the results of which were used to determine the concentration of the drug. The current limit of detection of the apparatus was found to be approximately 1%-2%. Ranitidine hydrochloride (RN) polymorph forms I and II were also characterized using SHG. It was found that pure samples of forms I and II could be clearly and rapidly distinguished. Mixtures consisting of 50% form I and 50% form II were also distinguishable from the respective pure forms. An investigation was performed into the size dependence of the SHG response for crystalline lactose. It was found that the SHG response was a slowly decreasing monotonic function of particle size. Additional investigation into the angular dependence of the scattered SHG light was also undertaken for crystalline lactose. This new technique based on optical nonlinearity offers promise for application in monitoring of pharmaceutical manufacturing processes.

Automation↗

PubMed2006

Characterization of temperature-induced phase transitions in five polymorphic forms of sulfathiazole by terahertz pulsed spectroscopy and differential scanning calorimetry.

The far-infrared properties of all five known polymorphic forms of the drug sulfathiazole have been studied by terahertz pulsed spectroscopy and low-frequency Raman spectroscopy. The observed spectra of the different polymorphs are distinctly different. Terahertz pulsed spectroscopy proves to be a rapid and complementary alternative to other physical characterization techniques reported in the literature for distinguishing between the five forms. Variable-temperature measurements (293-473 K) of all polymorphic forms have been performed. The phase transitions observed have been related to thermal analysis data. Form I is the form stable at high temperature of sulfathiazole with a melting point of about 475 K. Form II melts at around 470 K and recrystallizes at higher temperatures to form I. Forms III, IV, and V all convert to form I via a solid-solid phase transition at temperatures below 450 K. The phase transitions can be monitored by terahertz pulsed spectroscopy. Polymorphic impurities of the samples can be detected in the room temperature spectra and their effect on the phase transition behavior can be studied.

Calorimetry, Differential Scanning↗

PubMed2006

Preparation of poly (alkylcyanoacrylate) nanoparticles by polymerization of water-free microemulsions.

Phase diagrams of the pseudoternary systems ethyloleate, polyoxyethylene 20 sorbitan mono-oleate/sorbitan monolaurate and propylene glycol with and without butanol as a co-surfactant were prepared. Areas containing optically isotropic, one-phase systems were identified and samples therein designated as droplet, bicontinuous or solution type microemulsions using conductivity, viscosity and self-diffusion NMR. Nanoparticles were prepared by polymerization of selected microemulsions with ethyl-2-cyanoacrylate and the morphology of the particles was investigated. Addition of monomer to all types of microemulsions led to the formation of nanoparticles, which had an average size of 244 +/- 25 nm, an average polydispersity index of 0.15 +/- 0.04 and a zeta-potential of -17 +/- 3 mV. The formation of particles from water-free microemulsions of different types is surprising, particularly considering that polymerization is expected to occur at a water-oil interface by base-catalysed polymerization. It would appear that propylene glycol is sufficiently nucleophilic to initiate the polymerization. The use of water-free microemulsions as templates for the preparation of poly (alkylcyanoacrylate) nanoparticles opens up interesting opportunities for the encapsulation of bioactives which do not have suitable properties for encapsulation on the basis of water-containing microemulsions.

Cyanoacrylates↗

PubMed2006

Mannosylated liposomes as antigen delivery vehicles for targeting to dendritic cells.

The immune stimulating ability of mannosylated liposomes containing FITC-ovalbumin as a model antigen and displaying either a branched tri-mannose or a mono-mannose ligand on the liposome surface was investigated in human monocyte-derived dendritic cells (MoDCs) and murine bone-marrow-derived dendritic cells (BMDCs). Uptake of liposomes, dendritic cell activation and proliferation of CD8(+) T cells from OT-I transgenic mice were determined by flow cytometry. Uptake of liposomes displaying the tri-mannose ligand was enhanced in human MoDCs compared with both non-mannosylated liposomes and liposomes displaying mono-mannose ligands. However, this increased uptake did not result in an increase in expression of CD80 or CD86 on the surface of the MoDCs. In contrast, neither tri-mannose- nor mono-mannose-containing liposomes were taken up by murine BMDCs to a greater extent than non-mannose-containing liposomes. The expression of CD86 and CD40 on the surface of BMDCs was not increased after exposure to mannosylated liposomes and BMDCs incubated with mannosylated liposomes were not able to stimulate proliferation of CD8(+) T cells to any greater extent than BMDCs incubated with non-mannosylated liposomes. These findings suggest that while mannose-containing ligands can enhance the uptake of antigen-containing liposomes by some dendritic cells, important differences in the affinity of carbohydrate-binding receptors for mannose-containing ligands do exist between species. In addition, the increase in uptake of antigen by dendritic cells using mannosylated liposomes does not necessarily result in enhanced dendritic cell activation.

Animals↗

PubMed2006

Immunostimulatory colloidal delivery systems for cancer vaccines.

Cancer vaccine delivery is a multidisciplinary scientific field that is currently undergoing rapid development. An important component of cancer vaccines is the development of novel vaccine delivery strategies, such as colloidal immunostimulatory delivery systems. The importance of formulation strategies for cancer vaccines can be explained by the poor immunogenicity of tumour antigens. Colloidal vaccine delivery systems modify the kinetics, body distribution, uptake and release of the vaccine. This review explores recent research that is directed towards more targeted treatments of cancer through to colloidal vaccine delivery systems. Widely investigated carrier systems include polymeric micro- and nanoparticles, liposomes, archaeal lipid liposomes (archaeosomes), immune-stimulating complexes and virus-like particles. These systems are evaluated in terms of their formulation techniques, immunological mechanisms of action as well as the potential and limitations of such colloidal systems in the field of cancer vaccines.

Adjuvants, Immunologic↗

PubMed2005

Dose-related effects of lauric acid on antropyloroduodenal motility, gastrointestinal hormone release, appetite, and energy intake in healthy men.

We recently reported that intraduodenal infusion of lauric acid (C12) (0.375 kcal/min, 106 mM) stimulates isolated pyloric pressure waves (IPPWs), inhibits antral and duodenal pressure waves (PWs), stimulates release of cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1), and suppresses energy intake and that these effects are much greater than those seen in response to isocaloric decanoic acid (C10) infusion. Administration of C12 was, however, associated with nausea, confounding interpretation of the results. The aim of this study was to evaluate the effects of different intraduodenal doses of C12 on antropyloroduodenal (APD) motility, plasma CCK and GLP-1 concentrations, appetite, and energy intake. Thirteen healthy males were studied on 4 days in double-blind, randomized fashion. APD pressures, plasma CCK and GLP-1 concentrations, and appetite perceptions were measured during 90-min ID infusion of C12 at 0.1 (14 mM), 0.2 (28 mM), or 0.4 (56 mM) kcal/min or saline (control; rate 4 ml/min). Energy intake was determined at a buffet meal immediately following infusion. C12 dose-dependently stimulated IPPWs, decreased antral and duodenal motility, and stimulated secretion of CCK and GLP-1 (r > 0.4, P < 0.05 for all). C12 (0.4 kcal/min) suppressed energy intake compared with control, C12 (0.1 kcal/min), and C12 (0.2 kcal/min) (P < 0.05). These effects were observed in the absence of nausea. In conclusion, intraduodenal C12 dose-dependently modulated APD motility and gastrointestinal hormone release in healthy male subjects, whereas effects on energy intake were only apparent with the highest dose infused (0.4 kcal/min), possibly because only at this dose was modulation of APD motility and gastrointestinal hormone secretion sufficient for a suppressant effect on energy intake.

Adult↗

PubMed2005

Quil A-lipid powder formulations releasing ISCOMs and related colloidal structures upon hydration.

The aim of the present study was to prepare solid Quil A-cholesterol-phospholipid formulations (as powder mixtures or compressed to pellets) by physical mixing or by freeze-drying of aqueous dispersions of these components in ratios that allow spontaneous formation of ISCOMs and other colloidal structures upon hydration. The effect of addition of excess cholesterol to the lipid mixtures on the release of a model antigen (PE-FITC-OVA) from the pellets was also investigated. Physical properties were evaluated by X-ray powder diffractometry (XPRD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and polarized light microscopy (PLM). Characterization of aqueous colloidal dispersions was performed by negative staining transmission electron microscopy (TEM). Physically mixed powders (with or without PE-FITC-OVA) and pellets prepared from the same powders did not spontaneously form ISCOM matrices and related colloidal structures such as worm-like micelles, ring-like micelles, lipidic/layered structures and lamellae (hexagonal array of ring-like micelles) upon hydration as expected from the pseudo-ternary diagram for aqueous mixtures of Quil A, cholesterol and phospholipid. In contrast, spontaneous formation of the expected colloids was demonstrated for the freeze-dried lipid mixtures. Pellets prepared by compression of freeze-dried powders released PE-FITC-OVA slower than those prepared from physically mixed powders. TEM investigations revealed that the antigen was released in the form of colloidal particles (ISCOMs) from pellets prepared by compression of freeze-dried powders. The addition of excess cholesterol slowed down the release of antigen. The findings obtained in this study are important for the formulation of solid Quil A-containing lipid articles as controlled particulate adjuvant containing antigen delivery systems.

Adjuvants, Pharmaceutic↗

PubMed2005

Using terahertz pulsed spectroscopy to quantify pharmaceutical polymorphism and crystallinity.

Terahertz pulsed spectroscopy (TPS) is a new technique that is capable of eliciting rich information when investigating pharmaceutical materials. In solids, it probes long-range crystalline lattice vibrations and low energy torsion and hydrogen bonding vibrations. These properties make TPS potentially an ideal tool to investigate crystallinity and polymorphism. In this study four drugs with different solid-state properties were analyzed using TPS and levels of polymorphism and crystallinity were quantified. Carbamazepine and enalapril maleate polymorphs, amorphous, and crystalline indomethacin, and thermotropic liquid crystalline and crystalline fenoprofen calcium mixtures were quantified using partial least-squares analysis. Root-mean-squared errors of cross validation as low as 0.349% and limits of detection as low as approximately 1% were obtained, demonstrating that TPS is an analytical technique of potential in quantifying solid-state properties of pharmaceutical compounds.

Carbamazepine↗

PubMed2005

Cationic cage-like complexes formed by DC-cholesterol, Quil-A, and phospholipid.

This study describes the formation of cationic, cage-like complexes which have a structure similar to classic anionic ISCOMs. In order to prepare these complexes cholesterol, a major component of classic ISCOM formulations, was substituted with a cationic derivative, 3beta-[N-(N',N'-dimethylaminoethane)-carbamoyl]-cholesterol (DC-CHOL). Colloidal dispersions with varying compositions of DC-CHOL, phosphatidylcholine, and Quil-A, which is a mixture of anionic triterpene saponins, were prepared by the lipid-film hydration method and characterised by transmission electron microscopy and laser Doppler electrophoresis. The colloidal structures obtained are presented in pseudo-ternary phase diagrams with two buffer systems as the pseudo-component. It was found that the formation of cationic, cage-like particles is highly depending on the formulation buffer. With TRIS buffered saline (TBS) pH 7.4, cage-like particles formed at compositions with high proportions of DC-CHOL and had a strongly positive zeta-potential. These could be purified by differential centrifugation. With phosphate buffered saline pH 7.4, the formation of cage-like particles was much reduced. It was shown that the formation of cage-like particles with a positive charge depended on suitable concentrations of TRIS in the hydration buffer.

Adjuvants, Immunologic↗