Chris Vervaet

This article examines the applicability of Fourier Transform Infrared (FTIR) spectroscopy to detect the applied virus medium volume (i.e., during sample filling), to evaluate the virus state and to distinguish between different vaccine doses in a freeze dried live, attenuated vaccine formulation. Therefore, different formulations were freeze dried after preparing them with different virus medium volumes (i.e., 30, 100, and 400 µl) or after applying different pre-freeze-drying sample treatments (resulting in different virus states); i.e., (i) as done for the commercial formulation; (ii) samples without virus medium (placebo); (iii) samples with virus medium but free from antigen; (iv) concentrated samples obtained via a centrifugal filter device; and (v) samples stressed by 96h exposure to room temperature; or by using different doses (placebo, 25-dose vials, 50-dose-vials and 125-dose vials). Each freeze-dried product was measured directly after freeze-drying with FTIR spectroscopy. The collected spectra were analyzed using principal component analysis (PCA) and evaluated at three spectral regions, which might provide information on the coated proteins of freeze dried live, attenuated viruses: (i) 1700-1600 cm(-1) (amide I band), 1600-1500 cm(-1) (amide II band) and 1200-1350 cm(-1) (amide III band). The latter spectral band does not overlap with water signals and is hence not influenced by residual moisture in the samples. It was proven that FTIR could distinguish between the freeze-dried samples prepared using different virus medium volumes, containing different doses and using different pre-freeze-drying sample treatments in the amide III region. © 2015 American Institute of Chemical Engineers Biotechnol. Prog., 2015.

The in vivo behaviour of 5% gentamicin sulphate ocular mini-tablets (2-mm diameter, 6.525 mg weight) was compared with gentamicin eye drops in six ponies. Two mini-tablets were inserted on the bulbar conjunctiva of the right eye while a similar dose of gentamicin was administered via eye drops in the left eye. Irritation induced by the mini-tablets and the eye drops was evaluated using a visual analogue scale (0-10). Tears were sampled with ophthalmologic absorption triangles for 1 min for the determination of the concentration of gentamicin sulphate using a microbiological plate diffusion method. Irritation induced by the tablets was minor and clinically acceptable (overall median score of 1.7 +/- 1.4). Eye drops induced a sharp increase in gentamicin sulphate concentration (364.4 microg/mL after 5 min) followed by a fast decline (10.8 microg/mL after 60 min). The increase in concentration induced by the ocular mini-tablets was less pronounced (up to 56.2 microg/mL after 30 min) and followed by a gradual decrease; the concentration remained above 15 microg/mL for 8 h. Ocular 5% gentamicin sulphate mini-tablets are clinically well-tolerated in ponies, assuring a constant concentration in the tears for at least 8 h.

A mucoadhesive combination of a maize starch (Amioca, mainly consisting of amylopectine) and a cross-linked acrylic acid-based polymer (Carbopol 974P) was spray-dried with metoprolol tartrate (used as model molecule) in order to develop a powder suitable for nasal drug delivery via a one-step manufacturing process. The bioavailability of metoprolol tartrate after nasal administration of this powder to rabbits was compared with powders manufactured via other procedures: (a) freeze-drying of a dispersion prepared using the co-spray-dried powder, (b) freeze-drying of a dispersion prepared using a physical mixture of drug and mucoadhesive polymers. After co-processing via spray-drying a low bioavailability (BA 10.8+/-2.3%) was obtained, whereas manufacturing procedures based on freeze-drying yielded a higher BA: 37.9+/-12.8% using the co-processed powder and 73.6+/-24.9% using the physical mixture. The higher bioavailability was due to the deprotonation of poly(acrylic acid) during neut...

A mucoadhesive spray-dried starch/poly(acrylic acid) powder underwent different heat treatments in order to induce cross-linking between the functional groups of starch (Amioca) and poly(acrylic acid) (Carbopol 974P). After heat treatment the water-absorbing capacity, viscosity and elasticity of the mucoadhesive powder increased. NMR analysis in combination with FT-IR indicated that heat treatment induced a low degree of cross-linking between the polymers. Nasal administration of Amioca/Carbopol 974P powders without heat treatment resulted in an absolute bioavailability in rabbits of 8.2+/-3.0% for insulin. Due to the difference in water-absorbing capacity (which opened the tight junctions of the nasal mucosa), elasticity and plasticity (which reduced mucociliairy clearance and prolonged residence time) heat treatment at 120 degrees C improved the bioavailability: 26.4+/-21.9, 36.5+/-11.0 and 19.3+/-17.3% after heat treatment during 30 min, 1 h and 4 h, respectively. Heat treatment ...

The influence of the deposition pattern and spray characteristics of nasal powder formulations on the insulin bioavailability was investigated in rabbits. The formulations were prepared by freeze drying a dispersion containing a physical mixture of drum dried waxy maize starch (DDWM)/Carbopol 974P (90/10, w/w) or a spray-dried mixture of Amioca starch/Carbopol 974P (25/75, w/w). The deposition in the nasal cavity of rabbits and in a silicone human nose model after actuation of three nasal delivery devices (Monopowder, Pfeiffer and experimental system) was compared and related to the insulin bioavailability. Posterior deposition of the powder formulation in the nasal cavity lowered the insulin bioavailability. To study the spray pattern, the shape and cross-section of the emitted powder cloud were analysed. It was concluded that the powder bulk density of the formulation influenced the spray pattern. Consequently, powders of different bulk density were prepared by changing the solid ...

The suitability of continuous twin screw extrusion for the wet granulation of alpha-lactose monohydrate was studied and compared with conventional high shear granulation. The influence of process parameters (screw speed and total input rate) and formulation variables (water and polyvinylpyrrolidone (PVP) concentration) on the properties of granules (yield, particle size distribution, friability and compressibility) and tablets (tablet tensile strength, friability and disintegration time) was investigated. Variation of the formulation and process parameters had a major effect on the process feasibility. Optimization of these parameters is required to allow continuous processing and to ensure a high yield. Total input rate, screw speed and water concentration had a minor influence on the granule and the tablet properties. The addition of PVP had no major influence on the granule properties, but significantly affected the tablet characteristics. For granules formulated with and without...

This study focuses on the thorough validation of an in-line NIR based moisture quantification method in the six-segmented fluid bed dryer of a continuous from-powder-to-tablet manufacturing line (ConsiGma™ 25, GEA Pharma Systems nv, Wommelgem, Belgium). The moisture assessment ability of an FT-NIR spectrometer (Matrix™-F Duplex, Bruker Optics Ltd, UK) equipped with a fiber-optic Lighthouse Probe™ (LHP, GEA Pharma Systems nv, Wommelgem, Belgium) was investigated. Although NIR spectroscopy is a widely used technique for in-process moisture determination, a minority of NIR spectroscopy methods is thoroughly validated. A moisture quantification PLS model was developed. Twenty calibration experiments were conducted, during which spectra were collected at-line and then regressed versus the corresponding residual moisture values obtained via Karl Fischer measurements. The developed NIR moisture quantification model was then validated by calculating the accuracy profiles on the basis of the...

The volume reduction behaviour of powders has been quantified by means of the ‘in-die’ yield pressure (YP) using Heckel analysis. However, because different YPs are reported for the same material, the experimental conditions influencing this material-constant were investigated. Silicified microcrystalline cellulose was compressed into flat-faced and convex tablets using a compaction simulator instrumented with load and displacement transducers. During compression,

The bioavailability of propranolol from a matrix-in-cylinder system for sustained drug delivery, consisting of a hot-melt extruded ethylcellulose pipe surrounding a drug-containing HPMC-Gelucire® 44/14 core, was determined. An oral dose of 80 mg propranolol hydrochloride was administered to healthy volunteers (n=10) in a randomized cross-over study design either as a commercial pellet formulation (Inderal retard mitis®) or as a matrix-in-cylinder

Placebo particles were mixed with film-coated diltiazem pellets to evaluate them as cushioning agents during tabletting in order to protect the film coat from damage. The cushioning properties of α-lactose monohydrate granules, microcrystalline cellulose pellets and wax/starch beads were evaluated by comparing the dissolution profile of the coated pellets before and after compression (compression force 10 kN). Only the tablet

... in the pellet formulation increased the release rate of hydrochlorothiazide (30% in 5 min) due to solubilisation of the ... Key words: Hydrochlorothiazide; Pellet; Dissolution rate enhancement; Polyethylene glycol; PEG-40 hydrogenated castor oil 1. Introduction order to increase the ...

Mucosal vaccination has several advantages over parenteral vaccination. In this study, viscosity-enhancing mucosal delivery systems for the induction of an adaptive immune response against viral antigen were investigated. Powder formulations based on spray-dried mixtures of starch (Amioca)/poly(acrylic acid) (Carbopol 974P) in different ratios were used as carriers of the viral antigen. A comparison of these formulations for intranasal delivery of heat-inactivated influenza virus combined with LTR192G adjuvant was made in vivo in a rabbit model. Individual rabbit sera were tested for seroconversion against hemagglutinin (HA), the major surface antigen of influenza. The powder vaccine formulations were able to induce systemic anti-HA IgG responses. The presence of Carbopol 974P improved the kinetics of the immune responses and the level of IgG titers in a dose-dependent way which was correlated with moderately irritating capacities of the formulation. In contrast, mucosal IgA responses were not detected. In conclusion, it was demonstrated that the use of bioadhesive carriers based on Amioca starch and poly(acrylic acid) facilitates the induction of a systemic anti-HA antibody response after intranasal vaccination with a whole virus influenza vaccine.

Vaccination of chickens with dispersable dry powder vaccines was compared with commercial liquid vaccines. A Clone 30 Newcastle disease vaccine virus was spray dried with mannitol or with a mixture of trehalose, polyvinylpyrrolidone and bovine serum albumin. A coarse (+/-30 microm) and fine (+/-7 microm) powder were produced with both formulations. A commercial reconstituted Clone 30 vaccine was applied as coarse liquid spray (+/-222 microm) or fine liquid aerosol (+/-24 microm). Reduction of virus concentration in the air after dispersion/nebulization was monitored by air sampling and was explained by sedimentation of coarse particles/droplets and evaporation of fine droplets. The vaccine formulations induced high haemagglutination inhibition antibody titres in the serum of 4-week-old broilers (2(7) at 4 weeks post-vaccination). The good serum antibody response with the fine liquid aerosol despite extensive inactivation of virus due to evaporation of droplets, suggested that powder formulations (without inactivation due to evaporation) might allow a significant reduction of vaccine dose, thereby offering new options for fine aerosol vaccination with low-titre vaccines.

The aim of the present study was to examine the possibilities/advantages of using recently introduced in-line spectroscopic process analyzers (Raman, NIR and plasma emission spectroscopy), within well-designed experiments, for the optimization of a pharmaceutical formulation and its freeze-drying process. The formulation under investigation was a mannitol (crystalline bulking agent)-sucrose (lyo- and cryoprotector) excipient system. The effects of two formulation variables (mannitol/sucrose ratio and amount of NaCl) and three process variables (freezing rate, annealing temperature and secondary drying temperature) upon several critical process and product responses (onset and duration of ice crystallization, onset and duration of mannitol crystallization, duration of primary drying, residual moisture content and amount of mannitol hemi-hydrate in end product) were examined using a design of experiments (DOE) methodology. A 2-level fractional factorial design (2(5-1)=16 experiments+3 center points=19 experiments) was employed. All experiments were monitored in-line using Raman, NIR and plasma emission spectroscopy, which supply continuous process and product information during freeze-drying. Off-line X-ray powder diffraction analysis and Karl-Fisher titration were performed to determine the morphology and residual moisture content of the end product, respectively. In first instance, the results showed that - besides the previous described findings in De Beer et al., Anal. Chem. 81 (2009) 7639-7649 - Raman and NIR spectroscopy are able to monitor the product behavior throughout the complete annealing step during freeze-drying. The DOE approach allowed predicting the optimum combination of process and formulation parameters leading to the desired responses. Applying a mannitol/sucrose ratio of 4, without adding NaCl and processing the formulation without an annealing step, using a freezing rate of 0.9°C/min and a secondary drying temperature of 40°C resulted in efficient freeze-drying supplying end products with a residual moisture content below 2% and a mannitol hemi-hydrate content below 20%. Finally, using Monte Carlo simulations it became possible to determine how varying the factor settings around their optimum still leads to fulfilled response criteria, herewith having an idea about the probability to exceed the acceptable response limits. This multi-dimensional combination and interaction of input variables (factor ranges) leading to acceptable response criteria with an acceptable probability reflects the process design space.

Solitary maxillary or mandibular bone cysts are rare benign lesions. They are usually localized in the mandible of young men. In some cases, a traumatic risk factor can be documented. A young 13-year-old female patient consulted in the orthodontics unit. An orthopantomogram showed a large cystic lesion in the ramus and posterior part of the left mandible corpus. No reossification of the cavity was observed one year after curettage. A second curettage was performed combined with PRF filling. Six months later, the cavity was completely reossified. Curettage is the first line treatment of isolated cystic lesions and generally followed by complete reossification of the cavity. Incomplete healing is observed in 20% of the cases. PRF may induce the healing of non-reossified cystic cavity by supplying local growth factors.

To evaluate the tumour growth delay of a peritoneal carcinomatosis (PC) of colorectal origin after intraperitoneal chemotherapy with paclitaxel/randomly-methylated-β-cyclodextrin (Pac/RAME-β-CD) versus Taxol® at normo- and hyperthermic conditions in rats. Hyperthermic intraperitoneal chemotherapy (HIPEC) was performed 7 days post implantation of the tumour with both formulations at a Pac concentration of 0.24 mg/ml. Tumour evaluation was performed via positron emission tomography (PET) and magnetic resonance imaging (MRI) imaging, measuring tumour activity and tumour volume, respectively. Scans were taken at 2 and 7 days post treatment. PET and MRI data showed a significant reduction in tumour activity and tumour volume for rats treated with Pac/RAME-β-CD (at normo- and hyperthermic conditions), compared to the control group. Treatment with Taxol® did not result in a significant reduction of tumour activity and tumour volume. No significant differences between the normo- and hyperthermic conditions were observed for both formulations, indicating that hyperthermia and paclitaxel were not synergistic despite the direct cytotoxic effect of hyperthermia. Monitoring tumour growth via PET and MRI indicated that Pac/RAME-β-CD inclusion complexes had a significantly higher efficacy compared to Taxol® in a rat model for peritoneal carcinomatosis.

This study describes the characterization of the plasticizing properties of ibuprofen (IBP) on hot-melt extruded ethyl cellulose (EC). The thermal behavior of hot-melt extrudates containing 0, 5, 10, and 20% (w/w) IBP was evaluated using modulated temperature differential scanning calorimetry. By means of comparison, co-evaporates containing the same concentrations of IBP and EC, were also evaluated. Both methods yielded solid solutions having one glass transition temperature indicating compatibility between drug and polymer. A similar decrease in glass transition temperature was noticed with increasing IBP concentration in the solid solutions prepared via both methods, indicating its plasticizing effect. The plasticizing efficiency was of the same magnitude as for the traditionally used plasticizers. Infrared spectroscopy was performed for better understanding of the chemical interactions in the molecular dispersions and confirmed the existence of hydrogen bonds between IBP and EC. Overall, the study has highlighted the plasticizing properties of IBP on EC during hot-melt extrusion.

Sustained-release matrix tablets were developed by injection moulding using metoprolol tartrate (MPT) and ethylcellulose (EC) as sustained-release agent. Dibutyl sebacate was selected as plasticiser. The influence of matrix composition, plasticiser concentration, and drug load on drug release was evaluated. The influence of plasticiser addition was assessed on processability and drug release: Dibutyl sebacate was added to a dichloromethane/EC solution and subsequently spray-dried, or was mixed as a liquid with EC powder. Hydrated tablets were evaluated by frequency sweep and creep rheological tests to correlate the results with drug release. Xanthan gum (XG) was added to the formulation because drug release was too slow (<50%, 24 h) from EC/MPT matrices (70%/30%, w/w). Increasing XG concentrations provided faster MPT release rates characterised by zero-order release kinetics, no burst release was observed. Lower plasticiser concentrations and higher drug loads increased drug release substantially. The plasticiser addition method did not affect drug release. Matrix composition, drug load, and plasticiser level affected the rheological properties of the swollen matrix tablets. X-ray diffraction demonstrated the formation of solid dispersions. Formulations composed of XG/EC (ratio 1:1.5) and 30% (w/w) MPT had a low relative bioavailability compared with the commercial product Lopressor®, which significantly improved at higher MPT concentration (50%, w/w).

Jaw osteonecrosis is, in most cases, caused by external irradiation. It is otherwise a rare occurrence.A 52-year-old patient was referred to this hospital for several tooth extractions. In the procedure follow-up, the external aspect of the mandible was more and more exposed. This led to the spontaneous loss of a voluminous bone fragment. The patient had never undergone radiotherapy or a course of bisphosphonates but had a long-term cardio-vascular history. He had undergone endarterectomy of both carotids, an ilio-femoral by-pass, and a coronary dilatation. The diagnosis of bone infarction on a chronic osteomyelitis was made.Blood coagulation disorders are responsible for most cases of bone infarction. Other risk factors include local trauma, chemotherapy, corticoids, and bisphosphonates. Necrosis of the jawbones is rare even though these are prone to trauma and infections. Symptoms are not specific and imaging is contributive late in the evolution. The results of medical treatment (antibiotherapy, vasodilators, and hyperbaric oxygenotherapy) and surgical debridement are very inconsistent.Les ostéonécroses maxillomandibulaires sont souvent la conséquence de l'irradiation d'une tumeur cervicofaciale. Il est inhabituel d'en rencontrer en dehors de ce contexte.Un patient de 52 ans nous a été adressé pour extractions dentaires. Les suites opératoires ont été marquées par une exposition osseuse progressive de la face externe de la mandibule droite ayant abouti à la perte spontanée d'un volumineux fragment osseux. Le patient n'avait jamais été traité par radiothérapie ni par bisphosphonates, mais on notait une endartériectomie des carotides, un pontage iliofémoral et une dilatation coronaire. Nous avons conclu à un infarctus osseux avec comme facteur aggravant la présence d'une ostéomyélite chronique.Différents facteurs locaux traumatiques ou iatrogènes peuvent amener une interruption de la vascularisation locale. Dans les facteurs généraux, nous retenons que les coagulopathies semblent être un facteur de risque majeur dans la physiopathologie des ostéonécroses. Des comorbidités thérapeutiques peuvent être relevées comme la chimiothérapie, la corticothérapie et l'usage de bisphosphonates. La localisation maxillofaciale des ostéonécroses est relativement rare, bien que cette région soit souvent le siège de traumatismes répétés et d'infection. La symptomatologie est peu spécifique et l'imagerie médicale n'est contributive que tardivement. Les différents traitements, qu'il s'agisse de l'antibiothérapie, des vasodilatateurs, de l'oxygénothérapie hyperbare, du curetage avec avivement des berges s'avèrent décevants.

To obtain a sustained-release dosage form with a lack of gastric unwanted effects, wax microspheres containing propranolol (I) were prepared by a congealable dispersion microencapsulation technique. The effects of the process variables; type of wax, speed of emulsification, amount of drug loaded, type and amount of emulsifier, were studied on the entrapment efficiency, angle of repose, dissolution efficiency (DE), in-vitro drug release and mean particle size of (I) microspheres, by a factorial design. The results showed that changes in the amount of emulsifier (Tween), 0.04% and 0.08%, the type of Tween (80 and 20) and the wax type; beeswax or ceresine, caused a significant decrease in the entrapment efficiency. All the variables had an effect on the angle of repose and particle size of the (I) microspheres. The only significant parameter affecting the DE was the nature of the wax. The drug release in pH 6.8 was affected by all the variables except the amount of emulsifier. The formulation with a 0.25:4 ratio of drug:ceresine wax and 0.04% of Tween 80 in 600 rpm emulsification speed showed a suitable multiparticulate delivery system for the retarded dissolution of entrapped active ingredients, allowing absorption only in the intestinal tract.