A study of critical functionality-related characteristics of HPMC for sustained-release tablets.

The drug release profile from hydrophilic matrix tablets can be crucially affected by the variability of physicochemical properties of the controlled release agent. This study investigates and seeks to understand the functionality-related characteristics (FRCs) of hydroxypropyl methylcellulose (HPMC) type 2208, K4M grade, that influence the release rate of the model drug carvedilol from hydrophilic matrix tablets during the entire dissolution profile. The following FRCs were examined: particle size distribution, degree of substitution, and viscosity. Eight different HPMC samples were used to create a suitable design space. Multiple linear regression (MLR) and partial least squares regression (PLSR) analyses were used to create models for each time point. The PLSR results show that the first part of the drug release profiles is mainly regulated by the HPMC particle size. Apparent viscosity and hydroxypropoxy content (%HP) become important in later stages of the drug release profile, when the influence of particle size distribution decreases. These findings make it possible to better understand the importance of FRCs. Larger HPMC particles increase drug release in the first part of the drug release profile, whereas decreased apparent viscosity and a higher degree of %HP increase the drug release rate in the later part of the drug release profile.

Release mechanism of doxazosin from carrageenan matrix tablets: Effect of ionic strength and addition of sodium dodecyl sulphate.

The polyelectrolyte matrix tablets loaded with an oppositely charged drug exhibit complex drug-release mechanisms. In this study, the release mechanism of a cationic drug doxazosin mesylate (DM) from matrix tablets based on an anionic polyelectrolyte λ-carrageenan (λ-CARR) is investigated. The drug release rates from λ-CARR matrices are correlated with binding results based on potentiometric measurements using the DM ion-sensitive membrane electrode and with molecular characteristics of the DM-λ-CARR-complex particles through hydrodynamic size measurements. Experiments are performed in solutions with different ionic strength and with the addition of an anionic surfactant sodium dodecyl sulphate (SDS). It is demonstrated that in addition to swelling and erosion of tablets, the release rates depend strongly on cooperative interactions between DM and λ-CARR. Addition of SDS at concentrations below its critical micelle concentration (CMC) slows down the DM release through hydrophobic binding of SDS to the DM-λ-CARR complex. On the contrary, at concentrations above the CMC SDS pulls DM from the complex by forming mixed micelles with it and thus accelerates the release. Results involving SDS show that the concentration of surfactants that are naturally present in gastrointestinal environment may have a great impact on the drug release process.

Formulation and evaluation of chitosan/polyethylene oxide nanofibers loaded with metronidazole for local infections.

Nanofibers combined with an antimicrobial represent a powerful strategy for treatment of various infections. Local infections usually have a low fluid volume available for drug release, whereas pharmacopoeian dissolution tests include a much larger receptor volume. Therefore, the development of novel drug-release methods that more closely resemble the in-vivo conditions is necessary. We first developed novel biocompatible and biodegradable chitosan/polyethylene oxide nanofibers using environmentally friendly electrospinning of aqueous polymer solutions, with the inclusion of the antimicrobial metronidazole. Here, the focus is on the characterization of these nanofibers, which have high potential for bioadhesion and retention at the site of application. These can be used where prolonged retention of the delivery system at an infected target site is needed. Drug release was studied using three in-vitro methods: a dissolution apparatus (Apparatus 1 of the European Pharmacopoeia), vials, and a Franz diffusion cell. In contrast to other studies, here the Franz diffusion cell method was modified to introduce a small volume of medium with the nanofibers in the donor compartment, where the nanofibers swelled, eroded, and released the metronidazole, which then diffused into the receptor compartment. This set-up with nanofibers in a limited amount of medium released the drug more slowly compared to the other two in-vitro methods that included larger volumes of medium. These findings show that drug release from nanofibers strongly depends on the release method used. Therefore, in-vitro test methods should closely resemble the in-vivo conditions for more accurate prediction of drug release at a therapeutic site.

Development of Cetylpyridinium-Alginate Nanoparticles: A Binding and Formulation Study.

In this study the development of stable polyelectrolyte-surfactant complex nanoparticles composed of alginate and cetylpyridinium chloride (CPC), with and without ZnCl2, for therapeutic use, is investigated. The mechanism of CPC binding by alginate was analyzed using a cetylpyridinium cation (CP(+)) selective membrane electrode. The cooperative nature of the interaction between CP(+) and alginate was underlined by the sigmoidal shape of the binding isotherms. The presence of salts was shown to weaken interactions and, moreover, ZnCl2 reduced the cooperativity of binding. The CP(+) cations in the form of micellar associates acted as multivalent crosslinkers of the alginate chains where stable dispersions of CP-alginate nanoparticles were formed in water at CP(+)/alginate charge ratios from 0.2 to 0.8. Characterization of the nanoparticles showed hydrodynamic diameters from 140 to 200nm, a polydispersity index below 0.2, a negative zeta potential and spherical morphology. The entrapment efficiency of CPC was ∼94%, the loading capacity more than 50% and prolonged release over 7days were shown. The formulations with noted charge ratios resulted in stable CP-alginate nanoparticles with a potential of treating periodontal disease.

The Influence of High Drug Loading in Xanthan Tablets and Media with Different Physiological pH and Ionic Strength on Swelling and Release.

The formation of a gel coat around xanthan (Xan) tablets, empty or loaded with pentoxifylline (PF), and its release in media differing in pH and ionic strength by NMR, MR imaging, and two release methods were studied. The T1 and T2 NMR relaxation times in gels depend predominantly on Xan concentration; the presence of PF has negligible influence on them. It is interesting that the matrix swelling is primarily regulated by Xan despite high drug loading (25%, 50%). The gastric pH and high ionic strength of the media do not influence the position of the penetration and swelling fronts but do affect the erosion front and gel thickness. The different release profiles obtained in mixing and nonmixing in vitro methods are the consequence of matrix hydration level and erosion at the surface. In water and in diluted acid medium with low ionic strength, the main release mechanism is erosion, whereas in other media (pH 1.2, µ ≥ 0.20 M), anomalous transport dominates as was found out by fitting of measured data with theoretical model. Besides the in vitro investigation that mimics gastric conditions, mathematical modeling makes the product development more successful.

Contribution of Nanotechnology to Improved Treatment of Periodontal Disease.

Periodontal disease is chronic inflammation of periodontal tissues resulting in formation of periodontal pockets, periodontal attachment loss and progressive destruction of the ligament and alveolar bone. This review gives an update on periodontal disease pathogenesis, which is important for the development of novel methods and delivery systems for its treatment. The available treatment approaches, including removal of dental plaque, modulation of the host inflammatory response, and regeneration of periodontal tissue, are reviewed and their drawbacks discussed. Furthermore the latest achievements involving development of nanomedicines, which represent a new approach to better treatment of periodontal disease, are highlighted. They enable local drug delivery to particular tissues, cells, or subcellular compartments in periodontal pockets, either to biofilm pathogens or host cells, as well as control the release of incorporated drugs, usually antibiotic or anti-inflammatory. Specific examples of the nanocarriers or nanomaterials such as liposomes, lipid and polymeric nanoparticles, nanocrystals, dendrimers, and nanofibers under development for the treatment of periodontal disease are also clearly reviewed. Nanofibers are of special interest as nanodelivery systems and scaffolds for the regeneration of periodontal tissue. Finally, the future outlook of novel therapeutic approaches involving nanodelivery systems in the treatment of periodontal disease is provided.

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 drug's 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.

Determining the polymer threshold amount for achieving robust drug release from HPMC and HPC matrix tablets containing a high-dose BCS class I model drug: in vitro and in vivo studies.

It is challenging to achieve mechanically robust drug-release profiles from hydrophilic matrices containing a high dose of a drug with good solubility. However, a mechanically robust drug release over prolonged period of time can be achieved, especially if the viscosity and amount of the polymer is sufficiently high, above the "threshold values." The goal of this research was to determine the hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) polymer threshold amount that would enable robust drug release from matrix tablets containing a high dose of levetiracetam as a class I model drug according to the Biopharmaceutical Classification System (BCS). For this purpose, formulations containing HPC or HPMC of similar viscosity range, but in different amounts, were prepared. Based on the dissolution results, two final formulations were selected for additional in vitro and in vivo evaluation to confirm the robustness and to show bioequivalence. Tablets were exposed to various stress conditions in vitro with the use of different mechanically stress-inducing dissolution methods. The in vitro results were compared with in vivo results obtained from fasted and fed bioequivalence studies. Under both conditions, the formulations were bioequivalent and food had a negligible influence on the pharmacokinetic parameters C max and area under the curve (AUC). It was concluded that the drug release from both selected formulations is mechanically robust and that HPC and HPMC polymers with intrinsic viscosities above 9 dL/g and in quantities above 30% enable good mechanical resistance, which ensures bioequivalence. In addition, HPC matrices were found to be more mechanically robust compared to HPMC.

Nanofibers and their biomedical use.

The idea of creating replacement for damaged or diseased tissue, which will mimic the physiological conditions and simultaneously promote regeneration by patients' own cells, has been a major challenge in the biomedicine for more than a decade. Therefore, nanofibers are a promising solution to address these challenges. These are solid polymer fibers with nanosized diameter, which show improved properties compared to the materials of larger dimensions or forms and therefore cause different biological responses. On the nanometric level, nanofibers provide a biomimetic environment, on the micrometric scale three-dimensional architecture with the desired surface properties regarding the intended application within the body, while on the macrometric scale mechanical strength and physiological acceptability. In the review, the development of nanofibers as tissue scaffolds, modern wound dressings for chronic wound therapy and drug delivery systems is highlighted. Research substantiates the effectiveness of nanofibers for enhanced tissue regeneration, but ascertains that evidences from clinical studies are currently lacking. Nevertheless, due to the development of nano- and bio-sciences, products on the market can be expected in the near future.

The impact of relative humidity during electrospinning on the morphology and mechanical properties of nanofibers.

Electrospinning is an efficient and flexible method for nanofiber production, but it is influenced by many systemic, process, and environmental parameters that govern the electrospun product morphology. This study systematically investigates the influence of relative humidity (RH) on the electrospinning process. The results showed that the morphology of the electrospun product (shape and diameter) can be manipulated with precise regulation of RH during electrospinning. Because the diameter of nanofibers correlates with their rigidity, it was shown that RH control can lead to manipulation of material mechanical properties. Finally, based on the solution's rheological parameter-namely, phase shift angle-we were able to predict the loss of homogenous nanofiber structure in correlation with RH conditions during electrospinning. This research addresses the mechanism of RH impact on the electrospinning process and offers the background to exploit it in order to better control nanomaterial properties and alter its applicability.

A novel beads-based dissolution method for the in vitro evaluation of extended release HPMC matrix tablets and the correlation with the in vivo data.

The aim of this work was to establish alternative in vitro dissolution method with good discrimination and in vivo predictability for the evaluation of HPMC extended release matrix tablets. For this purpose, two different HPMC matrix tablet formulations were first evaluated by a range of conventional dissolution testing methods using apparatus 1, apparatus 2, and apparatus 3 according to US Pharmacopoeia. Obtained results showed low discrimination between the tested samples. Afterward, a novel dissolution testing method which combines plastic beads and apparatus 3 was developed with the aim to better mimic the mechanical forces that occur in vivo. Results showed that sufficiently large mechanical stress with high dips per minute program setting (apparatus 3) was needed to obtain in vitro discriminative results, which are in accordance with the in vivo data. The in vivo relevance of the method was confirmed with the establishment of the level A in vitro-in vivo correlation.

Interfacial rheology: an overview of measuring techniques and its role in dispersions and electrospinning.

Interfacial rheological properties have yet to be thoroughly explored. Only recently, methods have been introduced that provide sufficient sensitivity to reliably determine viscoelastic interfacial properties. In general, interfacial rheology describes the relationship between the deformation of an interface and the stresses exerted on it. Due to the variety in deformations of the interfacial layer (shear and expansions or compressions), the field of interfacial rheology is divided into the subcategories of shear and dilatational rheology. While shear rheology is primarily linked to the long-term stability of dispersions, dilatational rheology provides information regarding short-term stability. Interfacial rheological characteristics become relevant in systems with large interfacial areas, such as emulsions and foams, and in processes that lead to a large increase in the interfacial area, such as electrospinning of nanofibers.

Correlating cellulose derivative intrinsic viscosity with mechanical susceptibility of swollen hydrophilic matrix tablets.

Hydrophilic matrix tablets are prone to mechanical stress while passing through the gastrointestinal tract, which may result in inappropriate drug-release characteristics. Intrinsic viscosity is a physical polymer property that can be directly compared across various types and grades of polymers and correlated with the mechanical susceptibility of swollen matrix tablets. Five tablet formulations containing different HPMC and HPC polymers were prepared and analyzed using an in vitro glass bead manipulation test. The dissolution rate results were modeled using the Korsmeyer-Peppas equation and a correlation was found between the fit constants k and n, goodness-of-fit measure parameters, and intrinsic viscosity. Moreover, the dissolution profiles were used to calculate the degree of mechanical susceptibility for each formulation, defined as the ratio of the average dissolution rate after manipulation and the initial dissolution rate before manipulation. It was confirmed that an increased intrinsic viscosity polymer value resulted in a decrease in mechanical susceptibility. Considering this, two simple rules were defined for designing robust matrix tablets with respect to mechanical stresses.

Addressing potent single molecule AFM study in prediction of swelling and dissolution rate in polymer matrix tablets.

Our goal was to understand and thus be able to predict the swelling behavior of xanthan matrix tablets in media of various pH and ionic strengths using data obtained from single xanthan molecules and films with atomic force microscopy. Imaging was performed in 1-butanol using contact mode AFM in order to characterize single xanthan chains prepared from various solutions. Image analysis was used to calculate the molecular contour, persistence length, and radius of gyration. Nanoindentation measurements of xanthan films were carried out to evaluate their mechanical properties. Increasing the ionic strength of solutions induced reductions in chain parameters such as molecular contour, persistence length, and radius of gyration. Nanomechanical measurements demonstrated that Young's moduli of xanthan films prepared from solutions with higher ionic strengths are twice as large as those prepared at lower ionic strengths. This may help explain xanthan matrix tablets' reduced degree of swelling and faster dissolution rate in the presence of salts or ions. We successfully come to conclusion that microscopic polymer properties such as radius of gyration and persistence length are responsible for the macroscopic polymer behavior. For instance, longer persistence lengths and radius of gyration of xanthan's chains result in a higher degree of swelling, corresponding to softer polymer films, increased gel layers in matrix, and a slower release rate of the incorporated drug from the tablets.

A compressibility and compactibility study of real tableting mixtures: the effect of granule particle size.

This study investigates the effect of particle size on the compression characteristics of wet- (fluid-bed granulation - FBG) and dry-granulated (slugging - DGS) tableting mixtures. Particle-size distribution, flowability, compressibility, using the Heckel and Walker model, compactibility and elastic recovery as well as friability and disintegration were determined and compared between the two particle size fractions (180-400 µm, 400-710 µm) and initial unsieved mixtures. The results showed that the particle size of granules had no effect on the compressibility of the FBG and DGS mixtures, due to the high fragmenting nature of the formulation used in this study. On the other hand, compactibility was particle size dependent, as larger-sized fractions showed higher crushing strength, lower friability, and lower elastic recovery. This was attributed to increased fragmentation of larger particles, allowing stronger bonding between uncontaminated surface areas. As a result of better rearrangement of particles, both initial tableting mixtures showed lower compressibility and lower compactibility compared to their sieved fractions.

Doxazosin-carrageenan interactions: a novel approach for studying drug-polymer interactions and relation to controlled drug release.

When a cationic drug like doxazosin mesylate (DM) is incorporated into matrix tablets made of anionic polyelectrolytes carrageenans (CARRs) of different types (κ-, ι-, λ-CARR), DM-CARR interactions have a strong impact on drug release. To investigate these interactions, special DM ion-selective membrane electrode was made and applied for construction of binding isotherms. Isotherms were treated by the Zimm-Bragg theory and cooperative binding model. It was demonstrated that binding of doxazosin cations, DH(+), to CARRs is cooperative. It starts at very low drug concentrations with strong electrostatic interactions followed by aggregation of DH(+) ions. Hydrophobic interactions between bound DH(+) substantially contribute to the extent of binding. The strength of interactions increases with increasing negative charge of CARRs. At saturation, the number of DM molecules bound per repeat unit depends on the charge and steric distribution of binding sites on CARRs. Drug release rates of DM from CARR matrices were in accordance with the cooperativity binding constants: the weakest binding resulted in the fastest release. However it was proven that prolonged drug release is possible only by several processes running simultaneously, i.e., by swelling and erosion of CARR matrices on one side and electrostatic interactions and cooperativity effects on the other.

A compressibility and compactibility study of real tableting mixtures: the impact of wet and dry granulation versus a direct tableting mixture.

The purpose of this study was to investigate the influence of various powder agglomeration processes on tableting mixture flow and compaction properties. Four different granulation methods of the same model placebo formulation were tested at a semi-industrial scale and their properties were compared to those of the directly compressed mixture. The wet granulated mixtures had superior flow properties compared to other mixtures and showed better compressibility, measured by the Heckel and Walker models. This was attributed to work hardening due to the double particle processing and also to shorter contact times due to higher initial densities of dry granulated mixtures, allowing a shorter time for deformation. A strong linear correlation was established between the Heckel and Walker coefficients, which was further confirmed by the net energy results of force-displacement measurements. It was shown that the Walker model had slightly better discriminative power to differentiate tableting mixtures according to compressibility. The compactibility was considerably lower for the slugged mixture; however, the roller-compacted mixture produced tablets with unexpectedly high tensile strength. In conclusion, it is important to emphasize that general assumptions like higher porosity => better compressibility or better compressibility => better compactibility cannot be established for complex tableting mixtures.

Using quantitative magnetic resonance methods to understand better the gel-layer formation on polymer-matrix tablets.

INTRODUCTION: Magnetic resonance imaging is a powerful, non-invasive technique that can help improve our understanding of the hydrogel layer formed on swellable, polymer-matrix tablets, as well as the layer's properties and its influence on drug release. AREAS COVERED: In this paper, the authors review the NMR and MRI investigations of hydrophilic, swellable polymers published since 1994. The review covers NMR studies on the properties of water and drugs within hydrated polymers. In addition, MRI studies using techniques for determining the different moving-front positions within the swollen tablets, the polymer concentration profiles across them, the influence of the incorporated drug, and so on, are presented. Some complementary methods are also briefly presented and discussed. EXPERT OPINION: Using MRI, the formation of a hydrogel along with simultaneous determination of the drug's position within it can be observed non-invasively. However, the MRI parameters can influence the signal's intensity and therefore they need to be considered carefully in order to prevent any misinterpretation of the results. MRI makes possible an in situ investigation of swollen-matrix tablets and provides valuable information that can lead, when combined with other techniques, to a better understanding of polymeric systems and a more effective development of optimal dosage forms.

Matrix tablets based on carrageenans with dual controlled release of doxazosin mesylate.

The use of polymeric polyelectrolytes as matrix-forming agents is far from optimally or fully understood. Polyelectrolyte carrageenan (CARR) matrices loaded with oppositely charged active substance doxazosin mesylate (DM) were investigated according to their water-uptake/erosion properties, in situ complexation ability of CARR with DM, and the possibility to achieve dual drug release control. Interactions between different CARR types (ι-, κ-, and λ-) and DM were confirmed by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and zeta potential measurements. Combination of water-uptake/erosion with in situ complexation prolonged DM release from CARR matrices for more than 24 h. The rate order of drug release was in accordance with the number of ester sulfate moieties per disaccharide unit of CARRs (κ (1)>ι (2)>λ (3)). The higher the charge on the CARR backbone, the higher the number of interactions with DM and the slower the drug release. Low pH, more vigorous hydrodynamics, and higher ionic strength resulted in faster drug release. Based on zeta potential measurements of DM and CARRs, proposed influence of counterion condensation and its effect on screening polyelectrolyte-drug interactions was confirmed to lower in situ DM-CARR complexation. Dual drug release control from polyelectrolyte matrices by water-uptake/erosion and in situ complexation offers many new approaches for designing controlled-release systems.

A new approach combining different MRI methods to provide detailed view on swelling dynamics of xanthan tablets influencing drug release at different pH and ionic strength.

The key element in drug release from hydrophilic matrix tablets is the gel layer that regulates the penetration of water and controls drug dissolution and diffusion. We have selected magnetic resonance imaging (MRI) as the method of choice for visualizing the dynamic processes occurring during the swelling of xanthan tablets in a variety of media. The aims were (i) to develop a new method using MRI for accurate determination of penetration, swelling and erosion fronts, (ii) to investigate the effects of pH and ionic strength on swelling, and (iii) to study the influence of structural changes in xanthan gel on drug release. Two dimensional (2D) MRI and one dimensional single point imaging (SPI) of swollen xanthan tablets were recorded, together with T(2) mapping. The border between dry and hydrated glassy xanthan-the penetration front-was determined from 1D SPI signal intensity profiles. The erosion front was obtained from signal intensity profiles of 2D MR images. The swelling front, where xanthan is transformed from a glassy to a rubbery state (gel formation), was determined from T(2) profiles. Further, the new combination of MRI methods for swelling front determination enables to explain the appearance of the unusual "bright front" observed on 2D MR images in tablets swollen in HCl pH 1.2 media, which represents the position of swelling front. All six media studied, differing in pH and ionic strength, penetrate through the whole tablet in 4h+/-0.3h, but formation of the gel layer is significantly delayed. Unexpectedly, the position of the swelling front was the same, independently of the different xanthan gel structures formed under different conditions of pH and ionic strength. The position of the erosion front, on the other hand, is strongly dependent on pH and ionic strength, as reflected in different thicknesses of the gel layers. The latter are seen to be the consequence of the different hydrodynamic radii of the xanthan molecules, which affect the drug release kinetics. The slowest release of pentoxifylline was observed in water where the thickest gel was formed, whereas the fastest release was observed in HCl pH 1.2, in which the gel layer was thinnest. Moreover, experiments simulating physiological conditions showed that changes of pH and ionic strength influence the xanthan gel structure relatively quickly, and consequently the drug release kinetics. It is therefore concluded that drug release is greatly influenced by changes in the xanthan molecular conformation, as reflected in changed thickness of the gel layer. A new method utilizing combination of SPI, multi-echo MRI and T(2) mapping eliminates the limitations of standard methods used in previous studies for determining moving fronts and improves current understanding of the dynamic processes involved in polymer swelling.