Odon Planinšek

Advantages of celecoxib nanosuspension formulation and transformation into tablets.

Drugs with low aqueous solubility and high permeability (BCS class II) present a high proportion of all drugs. This study examines the critical issues regarding engineering of a nanosuspension tailored to increase drug dissolution rate and its transformation into dry powder suitable for tabletting. Nanosuspensions of celecoxib, a selective COX-2 inhibitor with low water solubility, were produced by the emulsion-diffusion method using three different stabilizers (Tween) 80, PVP K-30 and SDS) and characterized by particle size analysis, dissolution testing, scanning electron microscopy imaging, differential scanning calorimetry and X-ray powder diffraction. Spray-dried nanosuspension was blended with microcrystalline cellulose, and compressed to tablets, and their tensile strength, porosity and elastic recovery of tablets were investigated. The selection of solvent and stabilizers is critical, firstly to achieve controlled crystallization and size, and secondly to increase the wettability of the hydrophobic drug. The crystalline nano-sized celecoxib alone or in tablets showed a dramatic increase of dissolution rate and extent compared to micronized. SEM images showed that the nanoparticle morphology was influenced by the choice of stabilizers. Celecoxib nanosuspension stabilized with PVP K-30 and SDS showed advantages over Tween 80 due to sticking of the dried product and unexpected changes observed on DSC curves. Markedly lower compaction forces are needed for nano-sized compared to micro-sized celecoxib to produce tablets of equal tensile strength.

Carvedilol dissolution improvement by preparation of solid dispersions with porous silica.

Impregnation of porous SiO(2) (Sylysia) with carvedilol from acetone solution was used to improve dissolution of this poorly water-soluble drug. Solvent evaporation in a vacuum evaporator and adsorption from acetone solution were the methods used to load various amounts of carvedilol into the Sylysia pores. The impregnated carriers were characterized using nitrogen-adsorption experiments, X-ray diffraction, wettability measurements, attenuated total reflectance FTIR spectroscopy and thermal analysis. The impregnation procedures resulted in a significant improvement of drug release compared to dissolution of pure carvedilol or its physical mixtures with Sylysia. The results showed that when the drug precipitated in a thin layer within the carrier the dispersion retained a high specific surface area, micropore volume, and drug-release rate from the solid dispersion. Increasing the amount of drug in the solid dispersion caused particle precipitation within the pores that decreased the carriers specific surface area and pore volume and decreased the release rate of the drug. The results also suggest that the amorphous form of carvedilol, the improved wettability and weak interactions between the drug and carrier in the solid dispersion also contribute to improved dissolution of the drug from the dispersion.

Understanding controlled drug release from mesoporous silicates: theory and experiment.

Based on the results of carefully designed experiments upgraded with appropriate theoretical modeling, we present clear evidence that the release curves from mesoporous materials are significantly affected by drug-matrix interactions. In experimental curves, these interactions are manifested as a non-convergence at long times and an inverse dependence of release kinetics on pore size. Neither of these phenomena is expected in non-interacting systems. Although both phenomena have, rather sporadically, been observed in previous research, they have not been explained in terms of a general and consistent theoretical model. The concept is demonstrated on a model drug indomethacin embedded into SBA-15 and MCM-41 porous silicates. The experimental release curves agree exceptionally well with theoretical predictions in the case of significant drug-wall attractions. The latter are described using a 2D Fokker-Planck equation. One could say that the interactions affect the relative cross-section of pores where the local flux has a non-vanishing axial component and in turn control the effective transfer of drug into bulk solution. Finally, we identify the critical parameters determining the pore size dependence of release kinetics and construct a dynamic phase diagram of the various resulting transport regimes.

The dispersive component of the surface free energy of powders assessed using inverse gas chromatography and contact angle measurements.

The nonpolar parameter of solid surface free energy gamma(s)(d) has been determined for some pharmaceutical powders by means of contact angle measurement (Wilhelmy plate method) and inverse phase gas chromatography (IGC). For most samples, a good correlation between the results of the two methods was found. Additionally it was found that to get comparable results with the IGC method, contact angles obtained with totally nonpolar liquid should be used for calculating gamma(s)(d). Comparison of our results with those from the literature showed that the correlation depends on the method used for contact angle determination and the properties of the liquids used for contact angle measurements.

The utilization of surface free-energy parameters for the selection of a suitable binder in fluidized bed granulation

Surface free energy was determined for model substances pentoxyfilline, acyclovir, lactose and binding agents (that were used in the granulation process) hydroxypropilmethyl cellulose (HPMC) and polyvinylpyrrolidone (PVP) were determined by contact angle measurements. The methods of Wu, Good-van Oss and Della Volpe were used for solid-surface free-energy calculation. Spreading coefficients (S) were calculated and correlated with granulate properties. Granulates consisted of model drug and binding agent, and were produced in fluid bed granulator Glatt powder coater granulator GPCG1 by means of spraying the colloidal solution of binder on the model substance. Granules contained either 5% or 10% binder. Inverse granules, however, were also produced by spraying the model drug (i.e. pentoxyfilline and lactose) on the binding agent (HPMC, PVP). Particle size distribution, friability, true density, bulk density and tapped density of the granulates were determined. Although many different parameters influence the granule properties, it has been found that the interactions between the drug and the binder play a very important role. Spreading coefficients were found to be in good correlation with the friability of granulates. Positive spreading coefficient values of the binder over the model substance correlate well with the low friability of the granules containing lower amount of binder, i.e. 5%. In the group of the same binder, the spreading coefficient values decrease from pentoxyfilline over lactose to acyclovir. Friability results show that, for the system under consideration, PVP offers certain advantages over the grade of HPMC employed. The increase of the binder amount from 5 to 10% resulted in more friable granulates. Lower work of cohesion of the binder (PVP and HPMC) than the work of adhesion between binder and the model substances is considered responsible for the higher friability of the granules. The inverse granulation process, where the suspension of the model substance was sprayed over the solid binder particles, proved more efficient with HPMC than with PVP. According to the spreading coefficient results, the binder should spread over the drug. However, the kinetics of wetting appears to play an important role in the granulation process. According to these results, the conclusion was made that water wets HPMC much faster than PVP.

Electrospun polycaprolactone nanofibers as a potential oromucosal delivery system for poorly water-soluble drugs

The number of poorly water-soluble drug candidates is rapidly increasing; this represents a major challenge for the pharmaceutical industry. As a consequence, novel formulation approaches are required. Furthermore, if such a drug candidate is intended for the therapy of a specific group of the population, such as geriatric or pediatric, the formulation challenge is even greater, with the need to produce a dosage form that is acceptable for specific patients. Therefore, the goal of our study was to explore electrospun polycaprolactone (PCL) nanofibers as a novel nanodelivery system adopted for the oromucosal administration of poorly water-soluble drugs. The nanofibers were evaluated in comparison with polymer films loaded with ibuprofen or carvedilol as the model drugs. Scanning electron microscopy revealed that the amount of incorporated drug affects the diameter and the morphology of the nanofibers. The average fiber diameter increased with a higher drug loading, whereas the morphology of the nanofibers was noticeably changed in the case of nanofibers with 50% and 60% ibuprofen. The incorporation of drugs into the electrospun PCL nanofibers was observed to reduce their crystallinity. Based on the morphology of the nanofibers and the films, and the differential scanning calorimetry results obtained in this study, it can be assumed that the drugs incorporated into the nanofibers were partially molecularly dispersed in the PCL matrix and partially in the form of dispersed nanocrystals. The incorporation of both model drugs into the PCL nanofibers significantly improved their dissolution rates. The PCL nanofibers released almost 100% of the incorporated ibuprofen in 4h, whereas only up to 77% of the incorporated carvedilol was released during the same time period, indicating the influence of the drugs properties, such as molecular weight and solubility, on its release from the PCL matrix. The obtained results clearly demonstrated the advantages of the new nanodelivery system compared to the drug-loaded polymer films that were used as the reference formulation. As a result, electrospinning was shown to be a very promising nanotechnology-based approach to the formulation of poorly water-soluble drugs in order to enhance their dissolution. In addition, the great potential of the produced drug-loaded PCL nanofiber mats for subsequent formulation as oromucosal drug delivery systems for children and the elderly was confirmed.

Poly(propylene imine) dendrimer caps on mesoporous silica nanoparticles for redox-responsive release: smaller is better

To elucidate the importance of the size of capping agents in stimulus-induced release systems from mesoporous silica nanoparticles (MSNs), the effectiveness of poly(propylene imine) dendrimers in controlling the model drug release was studied. MCM-41-type MSNs were synthesized and characterized. Fluorescent compounds (fluorescein disodium salt and carboxyfluorescein) were loaded in the porous structure of the MSNs and entrapped in the silica matrix with the dendrimers of generations I through V by anchoring dendrimers on the MSN surface through disulfide bonds. Stimulus-induced release of the cargo was studied in the presence of dithiothreitol (DTT). Dendrimers of generations I and II were found to be more effective in model drug retention and subsequent release than higher generations. Moreover, MSNs modified with larger amounts of dendrimers lowered the cargo release in the presence of DTT. These findings are of importance for optimizing drug delivery systems based on responsive MSNs as they enable tuning of the amount of the released cargo by choosing the capping agent of appropriate size.

Shape optimization and characterization of polysaccharide beads prepared by ionotropic gelation.

The shape of drug loaded polysaccharide beads produced by ionotropic gelation has been optimized, with the aim of producing spherical beads suitable for further technological operations, such as coating. The optimization was performed on a model system sodium alginate/theophylline by inclusion of various fillers. Incorporation of excipients markedly influenced the morphological characteristics of the beads. The undesired irregular shape of beads caused by incorporation of the drug could only be improved by incorporating a combination of polycarbophil (PK) and polyvinylpyrrolidone (PVP). The spherical shape of these beads was stabilized mechanically by numerous air bubbles trapped inside the beads, which prevented the collapse of the beads during drying. The optimized method was shown to be applicable to a target system of pectin and an anti-inflammatory drug, LK-423.

Methods of amorphization and investigation of the amorphous state.

Abstract The amorphous form of pharmaceutical materials represents the most energetic solid state of a material. It provides advantages in terms of dissolution rate and bioavailability. This review presents the methods of solid- -state amorphization described in literature (supercooling of liquids, milling, lyophilization, spray drying, dehydration of crystalline hydrates), with the emphasis on milling. Furthermore, we describe how amorphous state of pharmaceuticals differ depending on the method of preparation and how these differences can be screened by a variety of spectroscopic (X-ray powder diffraction, solid state nuclear magnetic resonance, atomic pairwise distribution, infrared spectroscopy, terahertz spectroscopy) and calorimetry methods.

Mini-tablets: a contemporary system for oral drug delivery in targeted patient groups

Introduction: Mini-tablets represent a new trend in solid dosage form design, with the main goal of overcoming some therapeutic obstacles such as impaired swallowing and polypharmacy therapy, and also offering some therapeutic benefits such as dose flexibility and combined release patterns. Mini-tablets are a promising patient-friendly drug delivery system. Areas covered: Mini-tablets are tablets with a diameter ≤ 3 mm produced on conventional tablet presses equipped with multiple tooling. Mini-tablet production is similar to the production of standard tablets but requires excellent powder flow due to the small dies, exact control of process parameters and special caution during tablet press assembly in order to avoid tool damage. Mini-tablets (coated or uncoated and single- or multiple-unit systems) are mainly developed as patient-friendly systems for pediatric and geriatric patients and also for personalized medicine because they offer improved swallowing and flexible dosing, combining various release kinetics, doses and active compounds in only one system. Mini-tablets may also be successfully used as multiple-unit modified release systems (extended release, delayed-colon release, pulsatile and bi-modal release and gastroretentive systems) providing improved drug bioavailability compared with single-unit systems. Expert opinion: Mini-tablets used as single- or multiple-unit oral dosage forms have enormous potential as a patient-friendly drug delivery system for targeted populations, providing improved swallowing, flexible dosing and a combination of different release patterns and/or different active compounds (decreasing dosing frequency and/or polypharmacy therapy problems). In terms of complete expression of the benefits of mini-tablets over other oral dosage forms on the market, further investigation in formulation possibilities and development of suitable dosing devices is of essential importance.