Renaat Kinget

Physical stabilisation of amorphous ketoconazole in solid dispersions with polyvinylpyrrolidone K25.

The glass forming properties of ketoconazole were investigated using differential scanning calorimetry (DSC), by quench cooling liquid ketoconazole from T(m)+10 to 273.1 K, followed by subsequent heating at 5 K/min to T(m)+10 K. It was shown that liquid ketoconazole forms a glass which did not recrystallise following reheating, indicating its stability; T(g) was found to be 317.5+/-0.3 K. However, the presence of a small amount of crystalline ketoconazole was able to convert the amorphous drug back to the crystalline state: the addition of only 4.1% (w/w) of crystalline material converted 77.1% of the glass back to the crystalline state, and this value increased as the amount of added crystals increased. PVP K25 was found to be highly effective in the prevention of such recrystallisation, but only if the amorphous drug was formulated in a solid dispersion, since physical mixing of amorphous ketoconazole with the polymer resulted in recrystallisation of the former compound. Storage of the solid dispersions for 30 days at 298.1 K (both 0 and 52% RH) in the presence or absence of crystals did not result in recrystallisation of the amorphous drug. Solid dispersions formed compatible blends as one single T(g) was observed, which gradually increased with increasing amounts of PVP K25, indicating the anti-plasticising property of the polymer. The values of T(g) followed the Gordon-Taylor equation, indicating no significant deviation from ideality and suggesting the absence of strong and specific drug-polymer interactions, which was further confirmed with 13C NMR and FT-IR. It can be concluded therefore that the physical mechanism of the protective effect is not caused by drug-polymer interactions but due to the polymer anti-plasticising effect, thereby increasing the viscosity of the binary system and decreasing the diffusion of drug molecules necessary to form a lattice.

The lung as a route for systemic delivery of therapeutic proteins and peptides

The large surface area, good vascularization, immense capacity for solute exchange and ultra-thinness of the alveolar epithelium are unique features of the lung that can facilitate systemic delivery via pulmonary administration of peptides and proteins. Physical and biochemical barriers, lack of optimal dosage forms and delivery devices limit the systemic delivery of biotherapeutic agents by inhalation. Current efforts to overcome these difficulties in order to deliver metabolic hormones (insulin, calcitonin, thyroid-stimulating hormone [TSH], follicle-stimulating hormone [FSH] and growth hormones) systemically, to induce systemic responses (immunoglobulins, cyclosporin A [CsA], recombinant-methionyl human granulocyte colony-stimulating factor [r-huG-CSF], pancreatic islet autoantigen) and to modulate other biological processes via the lung are reviewed. Safety aspects of pulmonary peptide and protein administration are also discussed.

The biopharmaceutical aspects of nasal mucoadhesive drug delivery

Nasal drug administration has frequently been proposed as the most feasible alternative to parenteral injections. This is due to the high permeability of the nasal epithelium, allowing a higher molecular mass cut‐off at approximately 1000 Da, and the rapid drug absorption rate with plasma drug profiles sometimes almost identical to those from intravenous injections. Despite the potential of nasal drug delivery, it has a number of limitations. In this review, the anatomy and physiology of the nasal cavity, as well as ciliary beating and mucociliary clearance as they relate to nasal drug absorption, are introduced. The rationale for nasal drug delivery and its limitations, some factors that influence nasal drug absorption, and the experimental models used in nasal drug delivery research are also reviewed. Nasal mucoadhesion as a promising method of nasal absorption enhancement is discussed, and factors that influence mucoadhesion, as well as safety of nasal mucoadhesive drug delivery systems are reviewed in detail.

Physicochemical characterization of solid dispersions of the antiviral agent UC-781 with polyethylene glycol 6000 and Gelucire 44/14

The purpose of this study was to prepare and characterize solid dispersions of the antiviral thiocarboxanilide UC-781 with PEG 6000 and Gelucire 44/14 with the intention of improving its dissolution properties. The solid dispersions were prepared by the fusion method. Evaluation of the properties of the dispersions was performed using dissolution studies, differential scanning calorimetry, Fourier-transform infrared spectroscopy and X-ray powder diffraction. To investigate the possible formation of solid solutions of the drug in the carriers, the lattice spacings [d] of PEG 6000 and Gelucire 44/14 were determined in different concentrations of UC-781. The results obtained showed that the rate of dissolution of UC-781 was considerably improved when formulated in solid dispersions with PEG 6000 and Gelucire 44/14 as compared to pure UC-781. From the phase diagrams of PEG 6000 and Gelucire 44/14 it could be noted that up to approximately 25% w/w of the drug was dissolved in the liquid phase in the case of PEG 6000 and Gelucire 44/14. The data from the X-ray diffraction showed that the drug was still detectable in the solid state below a concentration of 5% w/w in the presence of PEG 6000 and Gelucire 44/14, while no significant changes in the lattice spacings of PEG 6000 or Gelucire 44/14 were observed. Therefore, the possibility of UC-781 to form solid solutions with the carriers under investigation was ruled out. The results from infrared spectroscopy together with those from X-ray diffraction and differential scanning calorimetry showed the absence of well-defined drug-polymer interactions.

Physico-chemical characterization of solid dispersions of temazepam with polyethylene glycol 6000 and PVP K30

Abstract In order to increase the dissolution of temazepam, solid dispersions were prepared using polyethylene glycol 6000 (PEG 6000) and polyvinylpyrrolidone K30 (PVP K30). Dispersions with PEG 6000 were prepared by fusion-cooling and co-evaporation, while dispersions containing PVP K30 were prepared by co-evaporation. In contrast to the very slow dissolution rate of pure temazepam, the dispersion of the drug in the polymers considerably enhanced the dissolution rate. This can be attributed to improved wettability and dispersibility, as well as particle size reduction and decrease of the crystalline fraction of the drug. The aqueous solubility of temazepam was favoured by the presence of PEG 6000. The negative values of the Gibbs free energy and enthalpy of transfer explained the spontaneous transfer from pure water to the aqueous polymer environment. It was found that temazepam was decomposed in the presence of aqueous solutions of PVP K30 to at least two unidentified degradation products. Drug–polymer interactions in the solid state were investigated using differential scanning calorimetry, X-ray powder diffraction, and fourier-transform infrared spectroscopy. PEG 6000 gave a eutectic system in which liquid polymer could dissolve approximately 10% of temazepam. On the other hand, X-ray powder diffraction patterns and thermal analysis indicated that the drug was in the amorphous state up to a concentration of 40% w/w when dispersed in PVP K30; the infrared spectra indicated solid state interactions between the OH of temazepam and the CO of PVP K30.

Colonic drug targeting

Specific targeting of drugs to the colon is recognized to have several therapeutic advantages. Drugs which are destroyed by the stomach acid and/or metabolized by pancreatic enzymes are slightly affected in the colon, and sustained colonic release of drugs can be useful in the treatment of nocturnal asthma, angina and arthritis. Treatment of colonic diseases such as ulcerative colitis, colorectal cancer and Crohns disease is more effective with direct delivery of drugs to the affected area. Likewise, colonic delivery of vermicides and colonic diagnostic agents require smaller doses. This article is aimed at providing insight into the design considerations and evaluation of colonic drug delivery systems. For this purpose, the anatomy and physiology of the lower gastrointestinal tract are surveyed. Furthermore, the biopharmaceutical aspects are considered in relation to drug absorption in the colon and hence various approaches to colon-specific drug delivery are discussed.

Mechanism of increased dissolution of diazepam and temazepam from polyethylene glycol 6000 solid dispersions

Solid dispersion literature, describing the mechanism of dissolution of drug-polyethylene glycol dispersions, still shows some gaps; (A). only few studies include experiments evaluating solid solution formation and the particle size of the drug in the dispersion particles, two factors that can have a profound effect on the dissolution. (B). Solid dispersion preparation involves a recrystallisation process (which is known to be highly sensitive to the recrystallisation conditions) of polyethylene glycol and possibly also of the drug. Therefore, it is of extreme importance that all experiments are performed on dispersion aliquots, which can be believed to be physico-chemical identical. This is not always the case. (C). Polyethylene glycol 6000 (PEG6000) crystallises forming lamellae with chains either fully extended or folded once or twice depending on the crystallisation conditions. Recently, a high resolution differential scanning calorimetry (DSC)-method, capable of evaluating qualitatively and quantitatively the polymorphic behaviour of PEG6000, has been reported. Unraveling the relationship between the polymorphic behavior of PEG6000 in a solid dispersion and the dissolution characteristics of that dispersion, is a real gain to our knowledge of solid dispersions, since this has never been thoroughly investigated. The aim of the present study was to fill up the three above mentioned gaps in solid dispersion literature. Therefore, physical mixtures and solid dispersions were prepared and in order to unravel the relationship between their physico-chemical properties and dissolution characteristics, pure drugs (diazepam, temazepam), polymer (PEG6000), solid dispersions and physical mixtures were characterised by DSC, X-ray powder diffraction (Guinier and Bragg-Brentano method), FT-IR spectroscopy, dissolution and solubility experiments and the particle size of the drug in the dispersion particles was estimated using a newly developed method. Addition of PEG6000 improves the dissolution rate of both drugs. Mechanisms involved are solubilisation and improved wetting of the drug in the polyethylene glycol rich micro-environment formed at the surface of drug crystals after dissolution of the polymer. Formulation of solid dispersions did not further improve the dissolution rate compared with physical mixtures. X-ray spectra show that both drugs are in a highly crystalline state in the solid dispersions, while no significant changes in the lattice spacings of PEG6000 indicate the absence of solid solution formation. IR spectra show the absence of a hydrogen bonding interaction between the benzodiazepines and PEG6000. Furthermore, it was concluded that the reduction of the mean drug particle size by preparing solid dispersions with PEG6000 is limited and that the influence of the polymorphic behavior of PEG6000 (as observed by DSC) on the dissolution was negligible.

Swelling and drug release behaviour of xanthan gum matrix tablets

Abstract The swelling and drug release behaviour of xanthan gum matrix tablets were studied using three drugs having different properties, i.e., caffeine as a soluble neutral drug, indomethacin as an insoluble acidic drug, and the sodium salt of indomethacin as a soluble acidic drug. Swelling was ascertained by measuring the axial and the radial expansion of matrix tablets following exposure to media of physiological ionic strength. The mean drug dissolution time and swelling rate were calculated from dissolution and swelling experiments, respectively, and were used as responses for comparison under different experimental conditions. The dependence of drug release on the swelling of the polymer matrix and on the type of the drugs added was established. The former is mainly influenced by the ionic strength and buffer concentrations. The latter is affected by the solubility of the drug. The mechanism of matrix swelling follows Case I diffusion, whereas drug release from this polymer matrix conforms to Case II diffusion.

Comparative study on xanthan gum and hydroxypropylmethyl cellulose as matrices for controlled-release drug delivery I. Compaction and in vitro drug release behaviour

A comparative investigation has been undertaken to assess the performance of xanthan gum (XG) and hydroxypropylmethyl cellulose (HPMC) as hydrophilic matrix-forming agents in respect of compaction characteristics and in vitro drug release behaviour. The overall compaction characteristics are found to be quite similar to each other and typical of polymer behaviour. But the flow characteristics are different, i.e., XG is more readily flowable than HPMC. The observed difference in drug release profiles between these two potential excipients are explored and explained by the difference in their hydrophilicity and subsequent hydration properties.

Investigation of thermal properties of glassy itraconazole: identification of a monotropic mesophase

Abstract The purpose of the present work is the elucidation of two endothermic transitions at 74 and 90°C, respectively, observed during differential scanning calorimetry of glassy itraconazole. Modulated temperature DSC (MTDSC), hot-stage microscopy (HSM), HPLC and high temperature X-ray diffraction (HT-X ray) were used to examine the thermal properties of glassy itraconazole. It was found that the preparation mode of the glass does not seem to influence the appearance of both endothermic transitions since they were present during heating of glassy itraconazole which was prepared by cooling the melt or by rapid solvent evaporation of an itraconazole solution. These observations suggest that the appearance of the two endothermic transitions require the liquid state prior to glass formation. The transitions are not due to impurities in the starting material, nor are they caused by thermal decomposition. This was further confirmed by HPLC-analysis. HSM showed structure formation following cooling of the melt, at approximately 87°C; cooling the product further showed a second change in optical contrast. HT-X ray confirmed and identified the formation of a nematic mesophase. The appearance of the two endothermic signals during scanning of glassy itraconazole points to the formation of a mesophase. Due to the nature of itraconazole, it appears as a chiral nematic phase of which the mobility is frozen into a glass upon cooling below 59°C thereby impeding further crystallization.