New solid mucoadhesive systems for benzydamine vaginal administration

The aim of this work was the realization of new formulations for vaginal application to improve the pharmacological effect of benzydamine, displaying both anti-inflammatory and antiseptic activities. For this reasons, this drug was formulated in solid dispersions, by using the mucoadhesive polymers HPMC and/or Carbopol(?), then compressed. Tablets were characterized by studies of friability, hardness, hydration, DSC, mucoadhesion and in vitro release. Kinetics, responsible for drug delivery, was investigated as well. Tablets prepared by using only HPMC showed the best results in terms of swelling and mucoadhesion (time and force) together with prolonged and complete drug release, by diffusive mechanism, through gelled layer. Despite the good mucoadhesive properties, Carbopol(?) does not represent a good excipient because, after the contact with water, it generates a spongy gel layer, not homogeneous, stiff, brittle and with breaking tendency when highly swelled. This kind of gel does not guarantee a linear drug release and could provoke discomfort because of fragment release. HPMC mucoadhesive tablets could be a proper delivery system for benzydamine administration representing a good alternative to traditional dosage forms for vaginal topical therapy.     

Application of a new mathematical method for the estimation of the mean surface area to calculate the percolation threshold of lobenzarit disodium [correction of dissodium] salt in controlled release matrices

One of the practical handicaps for the application of the percolation theory to estimate the percolation threshold of drugs in controlled release systems is the fact that the dissolution studies must be carried out so that only one surface of the tablet is exposed to the dissolution medium. The aim of this work is to estimate the percolation threshold of the antiarthritic drug lobenzarit dissodium (LBD) in inert matrices prepared with the excipients Ethocel((R)) 100 and Eudragit((R)) RS-PO (10-75% w/w). Release assays were performed using the paddle method. The whole surface of the tablets was exposed to the dissolution medium. For the first time, a new mathematical method is developed to transform the amount of drug released in amount released per surface area in order to calculate the percolation thershold of LBD. The mathematical method proposed allows to calculate, using a new equation, the evolution of the mean surface area (O((t))). The new method was validated and three novel results were achieved: A constant value of (O((t))) at critical time (theta) in the matrices (O((theta))=1.272 cm(2)); a linear relationship between initial surface area (O((0))) and critical time; and a linear relationship between O((t)) and time. Employing the values of O((t)), it was possible to calculate for the first time, the percolation threshold (p(c1)) for LBD in Ethocel((R)) 100 (p(c1)=0.280+/-0.102) and Eudragit((R)) RS-PO (p(c1)=0.344+/-0.07) matrices.     

Solution calorimetry to monitor swelling and dissolution of polymers and polymer blends

The observed rate of drug release from a polymeric drug delivery system is governed by a combination of diffusion, swelling and erosion. It is thus not a simple task to determine the effects of the polymer on the observed drug release rate, because the swelling characteristics of the polymer are inferred from the drug release profile. Here we propose to use solution calorimetry to monitor swelling. Powdered polymer samples (HPMC E4M, K4M, K15M and NaCMC, both alone and in a blend) were dispersed into water or buffer (pH 2.2 and 6.8 McIlvaine citrate buffers) in a calorimeter and the heat associated with the swelling phenomena (hydration, swelling, gelation and dissolution) was recorded. Plots of normalised cumulative heat (i.e. q_t/Q, where q_t is the heat released up to time t and Q the total amount of heat released) versus time were analysed by the power law model, in which a fitting parameter, n, imparts information on the mechanism of swelling.

For all systems the values of n were greater than 1, which indicated that dissolution occurred immediately following hydration of the polymer. However, while not suitable for determining reaction mechanism, the values of n for each polymer were significantly different and, moreover, were observed to vary both as a function of particle size and dissolution medium pH. Thus, the values of n may serve as comparative parameters. Properties of the polymer blends were observed to be different from those of either constituent and correlated with the behaviour seen for polymer tablets during dissolution experiments. The data imply that solution calorimetry could be used to construct quantitative structure–activity relationships (QSARs) and hence to optimise selection of polymer blends for specific applications.     

Synthesis and immobilization of micro-scale drug particles in cellulosic films

The anti-solvent synthesis of micron-scale particles, their stabilization, and subsequent self-assembly into polymer films suitable for drug delivery is presented. The colloidal particles were stabilized using low molecular weight hydroxypropyl methylcellulose (HPMC), while drug encapsulation was carried out with high molecular weight HPMC and polyvinylpyrrolidone (PVP). Griseofulvin (GF) was used as the model drug compound, and the polymer films were evaluated in terms of their surface morphology, mechanical properties and in vitro drug release. In general, the release rates were best described by first-order and Hixson-Crowell kinetic models, and in a typical film containing 57% HPMC, 100% of GF was released within 50 min.     

Compatibility study of quetiapine fumarate with widely used sustained release excipients

The drug-excipient compatibility study of quetiapine fumarate, with widely used sustained release excipients, was carried out employing differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). The selected excipients were HPMC K100M, sodium alginate, xanthan gum, Eudragit RSPO, hydrogenated castor oil, carnauba wax, and PEO WSR 303. Equal proportion of drug and excipients was utilized in the interaction study. FT-IR spectra indicated the absence of interaction between drug and excipients. The DSC curve showed a sharp endothermic melting peak at 173.26 °C for quetiapine fumarate. Post melting interaction was observed for carnauba wax, Eudragit RSPO, and hydrogenated castor oil probably due to solubilization of drug in the melted excipient. No interaction was observed for other excipients. The physical mixtures stored at 30 ± 2 °C/65 ± 5% RH did not show any significant degradation of the drug. The concept of systemically conducted preformulation studies will facilitate dossier submission to the drug control authority.     

Predicting the drug concentration in starch acetate matrix tablets from ATR-FTIR spectra using multi-way methods

The amounts of drug and excipient were predicted from ATR-FTIR spectra using two multi-way modelling techniques, parallel factor analysis (PARAFAC) and multi-linear partial least squares (N-PLS). Data matrices consisted of dissolved and undissolved parallel samples having different drug content and spectra, which were collected at axially cut surface of the flat-faced matrix tablets. Spectra were recorded comprehensively at different points on the axially cut surface of the tablet. The sample drug concentrations varied between 2 and 16% v/v. The multi-way methods together with ATR-FTIR spectra seemed to represent an applicable method for the determination of drug and excipient distribution in a tablet during the release process. The N-PLS calibration method was more robust for accurate quantification of the amount of components in the sample whereas the PARAFAC model provided approximate relative amounts of components.     

Thermal analysis applied in the osmotic tablets pre-formulation studies

Osmotically controlled and oral drug delivery systems utilize osmotic pressure for controlled delivery of active agent(s). Drug delivery from these systems, to a large extent, is independent of the physiological factors of the gastrointestinal tract and these systems can be utilized for systemic as well as targeted delivery of drugs. We apply the thermal methods and IR spectroscopy to study compatibility between atenolol and several excipients usually found in the osmotic systems formulations (Polyethylene oxide, MW 3350, 100000, 200000 and 5000000; HPMC K4000, magnesium stearate and cellulose acetate. Cellulose acetate, HPMC K4000 and magnesium stearate have essentially no interaction with atenolol otherwise all Polyethylene oxide excipients modifies significantly the drug melting point indicating some extend of interaction.     

Niflumic acid-collagen delivery systems used as anti-inflammatory drugs and analgesics in dentistry

Collagen sponges are known to be safe and well-characterized supports for drug delivery systems. The aim of this study was to prepare, characterize and test drug delivery systems that contain collagen as support and niflumic acid as a drug. Type-I collagen and niflumic acid gels were cross-linked with different concentrations of glutaraldehyde and then freeze-dried in order to obtain collagen matrices (spongious form). The physical-chemical properties were assessed by infrared spectroscopy (FTIR) and morphological properties were evaluated by water absorption. Niflumic acid release from cross-linked collagen spongious forms was also investigated and the kinetic mechanism was discussed.     

Preparation of hydroxypropylmethyl cellulose-based porous matrix for gastroretentive delivery of gabapentin using the freeze-drying method

The aims of the present study were to prepare hydroxypropylmethyl cellulose (HPMC)-based porous matrix tablets for gastroretentive drug delivery and to characterize their physicochemical properties. Gabapentin (GBP) was used as a model drug. Paste containing GBP, HPMC and water was molded and freeze-dried to prepare freeze-dried gastroretentive matrix tablet (FD-GRT). In vitro drug release and erosion studies were also performed. Although FD-GRT exhibited porous structure, they had good tablet strength and friability. Density of FD-GRT ranged from 0.402 to 0.509 g/cm³ and thus they could float on the medium surface without any lag time. FD-GRT was remained floated until the entire matrix erosion or end of drug release during in vitro release test. Release behavior of GBP could be modulated by the amount and the viscosity grade of HPMC. However, large amount and high viscosity of HPMC caused trouble in molding prior to freeze-drying. Addition of ethylcellulose could retard the release rate of GBP, with relatively low increase in viscosity of paste. Since pores generated by freeze drying imparted buoyancy for gastric retention to FD-GRT, additional materials for buoyancy was not necessary and FD-GRT had no lag time for buoyancy due to low density. Therefore it could be a promising tool for gastroretentive drug delivery.     

Cooperative hydration effect on the binding of organic vapors by a cross-linked polymer and beta-cyclodextrin

A cooperative hydration effect being favorable for the binding of organic vapors by cross-linked poly(N-6-aminohexylacrylamide) and beta-cyclodextrin was observed in ternary systems in the absence of liquid phase. For these systems the vapor sorption isotherms were determined by the static method of headspace gas chromatographic analysis at 298 K. The obtained isotherms show an increase of binding affinity for vapor of hydrophobic sorbates above a threshold value of receptor hydration. Further hydration gives a saturation of this affinity for the studied hydrophilic polyacrylamide derivative, while the affinity of beta-cyclodextrin for the hydrophilic sorbate ethanol even decreases. A similar behavior of this polymer and beta-cyclodextrin at the change of their hydration helps to explain the observed cooperative hydration effect in terms of clathrate formation.     

Nasal in situ gel containing hydroxy propyl ��-cyclodextrin inclusion complex of artemether: development and in vitro evaluation

The objective of the present investigation was to explore the formulation and evaluation of in situ gel for the nasal delivery of artemether (ARM), a poorly water-soluble antimalarial agent using temperature induced gelation technique using Pluronic with mucoadhesive polymer Hydroxy Propyl Methyl Cellulose (HPMC) K4M in different ratios. Initially, due to low water solubility, an inclusion complex of the antimalarial artemether (ARM) in hydroxypropyl-??-cyclodextrin (HP??CD) was prepared and characterized. The in situ gels so prepared were characterized for its gelation properties, viscosity, gel strength, mucoadhesion, drug content, drug release rate and for its histopathological studies. Pluronic and HPMC based in situ gel (PLH2) showed the effective gelation, viscosity, gel strength and drug release properties along with good mucoadhesive strength, it is further subjected for stability studies carried out at 30 ± 2 °C and 60 ± 5% RH for 90 days in order to know the influence of temperature and relative humidity on drug content and on drug release profile. Histological examination of formulations did not show any remarkable damage to nasal mucosa. The formulation also retained the good stability at accelerated conditions over the period of 90 days. Owing to these properties it can be used as an effective delivery system for the nasal route. These in situ gelling systems would be definitely useful for cerebral malaria.     

Supramolecular Proteoglycan Aggregate Mimics: Cyclodextrin‐Assisted Biodegradable Polymer Assemblies for Electrostatic‐Driven Drug Delivery

Self‐assembled, noncovalent polymeric biodegradable materials mimicking proteoglycan aggregates were synthesized from inclusion complexes of cationic surfactants with γ‐cyclodextrin and the natural anionic polymer hyaluronan. The amorphous structure of this ternary system was proven by X‐ray diffraction and thermal analysis. Light‐scattering measurements showed that there was a competition between hyaluronic acid and the surfactant for the cyclodextrin cavity. These self‐assembled supramolecular matrices were loaded with both hydrophilic and lipophilic drug substances for dissolution studies. The release of the entrapped drugs was found to be controlled by cations in the surrounding media and by biodegradation. Slow drug release in an ion‐free medium became faster in physiological salt solution in which the macroscopic polymer matrix was disassembled. In contrast, the enzymatic degradation of hyaluronan was hindered in the polymeric matrix. The supramolecular systems consisting of γ‐cyclodextrin as a macrocyclic host, a cationic surfactant guest, and hyaluronic acid as the anionic polymer electrostatically cross‐linked by the inclusion complex of the first two was found to be a novel drug‐delivery system for the controlled release of traditional drugs such as curcumin and ketotifen and proteins such as bovine serum albumin.     

Design and evaluation of bioadhesive in-situ nasal gel of ketorolac tromethamine

The present study was aimed at developing safe and effective bioadhesive gelling systems of ketorolac tromethamine, a potent non-narcotic analgesic with moderate anti-inflammatory activity for nasal systemic delivery. Chitosan and pectin based gelling systems were prepared with variables like polymer concentration and type. These systems were characterized in terms of their physical properties, in vitro bioadhesion, in vitro drug release and long-term stability. The anti-inflammatory activity and mucosal irritancy of selected gels were also evaluated in rats and these results were compared with per oral, intraperitoneal and nasal solution administration of ketorolac tromethamine. All the prepared formulations gelled immediately at the nasal mucosal pH and showed longer contact time. Addition of hydroxypropyl methylcellulose (HPMC) in both chitosan and pectin based gelling systems increased the viscosity and gel strength. All the formulated gels exhibited pseudoplastic rheology and diffusion-controlled drug release. The results from stability studies revealed that the prepared thermogels showed marginal decrease in viscosity but at the same time, no significant difference in drug content, and in vitro release characteristics were observed before and after accelerated studies. The developed gelling systems produced only mild to negligible irritant effect to nasal mucosae as compared to control group.     

Relationship between diffusivity of water molecules inside hydrating tablets and their drug release behavior elucidated by magnetic resonance imaging

We reported previously that sustained release matrix tablets showed zero-order drug release without being affected by pH change. To understand drug release mechanisms more fully, we monitored the swelling and erosion of hydrating tablets using magnetic resonance imaging (MRI). Three different types of tablets comprised of polyion complex-forming materials and a hydroxypropyl methylcellulose (HPMC) were used. Proton density- and diffusion-weighted images of the hydrating tablets were acquired at intervals. Furthermore, apparent self-diffusion coefficient maps were generated from diffusion-weighted imaging to evaluate the state of hydrating tablets. Our findings indicated that water penetration into polyion complex tablets was faster than that into HPMC matrix tablets. In polyion complex tablets, water molecules were dispersed homogeneously and their diffusivity was relatively high, whereas in HPMC matrix tablets, water molecule movement was tightly restricted within the gel. An optimal tablet formulation determined in a previous study had water molecule penetration and diffusivity properties that appeared intermediate to those of polyion complex and HPMC matrix tablets; water molecules were capable of penetrating throughout the tablets and relatively high diffusivity was similar to that in the polyion complex tablet, whereas like the HPMC matrix tablet, it was well swollen. This study succeeded in characterizing the tablet hydration process. MRI provides profound insight into the state of water molecules in hydrating tablets; thus, it is a useful tool for understanding drug release mechanisms at a molecular level.     

Bilayer tablets of atorvastatin calcium and nicotinic acid: formulation and evaluation

The objective of the study is to formulate bilayer tablets consisting of atorvastatin calcium (AT) as an immediate release layer and nicotinic acid (NA) as an extended release layer. The immediate release layer was prepared using super disintegrant croscarmellose sodium and extended release layer using hydroxypropylmethyl cellulose (HPMC K100M). Both the matrix and bilayer tablets were evaluated for hardness, friability, weight variation, thickness, and drug content uniformity and subjected to in vitro drug release studies. The amount of AT and NA released at different time intervals were estimated by HPLC method. The bilayer tablets showed no significant change either in physical appearance, drug content or in dissolution pattern after storing at 40 degrees C/75% relative humiding (RH) for 3 months. The release of the drug from the tablet was influenced by the polymer content and it was much evident from thermogravimetry/differential thermal analysis (TG/DTA) analysis. The results indicated that the bilayer tablets could be a potential dosage form for delivering AT and NA.     

Influence of Crosslinking Agent on the Release of Drug from the Matrix Transdermal Patches of HPMC/Eudragit RL 100 Polymer Blends

The present work was designed to develop suitable transdermal matrix patches using the polymer blends of hydroxy propyl methyl cellulose (HPMC) and Eudragit RL100 (ERL) with triethyl citrate as a plasticizer in group A and in group B, other than HPMC and ERL, crosslinking agent, succinic acid was added. A 3² full factorial design was employed for both groups. The concentration of HPMC and ERL were used as independent variables, while percentage drug release was selected as dependent variable. Physical evaluation was performed such as moisture content, moisture uptake, tensile strength, flatness and folding endurance. In vitro diffusion studies were performed using cellulose acetate membrane (pore size 0.45 μ) in a Franz's diffusion cell. The concentration of diffused drug was measured using UV-visible spectrophotometer (V-530, Jasco) at λ _max 272 nm. The experimental results shows that the transdermal drug delivery system (TDDS) containing ERL in higher proportion gives sustained the release of drug and patches containing crosslinking agent shows more release than those do not contains succinic acid.     

Adjusting drug release by using miscible polymer blends as effective drug carries

In the present study PVP/HPMC and PVP/Chitosan polymer blends were prepared by using the solvent evaporation technique. From DSC studies were revealed that both blends are completed miscible in the entire composition range since only one glass transition temperature was detected. Miscibility can be attributed to the strong interactions evolved between the carbonyl group of PVP, which acts as strong proton acceptor, with hydroxyl and amino-groups of HPMC and Chitosan, which are proton donors. Thus hydrogen bonds are easily formed, as was verified by FTIR, producing miscible blends. However, the extent of interactions depends from polymer composition and mainly from the ratio and the kind of reactive groups. In PVP/HPMC blends a negative variation of T_g is recorded while in PVP/Chitosan the variation has a sigma form. The miscibility of these systems creates matrixes with completely different physical properties in order to use as effective drug carriers. PVP/HPMC blends can be used as pulsatile chronotherapeutics systems adjusting exactly the time of the drug release while PVP/Chitosan blends can be used to control the release profile of a poorly water soluble drug. In these blends HPMC and Chitosan respectively are the control factors for the corresponding applications.     

Formation of spanning water networks on protein surfaces via 2D percolation transition

The formation of spanning hydrogen-bonded water networks on protein surfaces by a percolation transition is closely connected with the onset of their biological activity. To analyze the structure of the hydration water at this important threshold, we performed the first computer simulation study of the percolation transition of water in a model protein powder and on the surface of a single protein molecule. The formation of an infinite water network in the protein powder occurs as a 2D percolation transition at a critical hydration level, which is close to the values observed experimentally. The formation of a spanning 2D water network on a single rigid protein molecule can be described by adapting the cluster analysis of conventional percolation studies to the characterization of the connectivity of the hydration water on the surface of finite objects. Strong fluctuations of the surface water network are observed close to the percolation threshold. Our simulations also furnish a microscopic picture for understanding the specific values of the experimentally observed hydration levels, where different steps of increasing mobility in the hydrated powder are observed.     

Percolation, phase separation, and gelation in fluids and mixtures of spheres and rods

The relationship between kinetic arrest, connectivity percolation, structure and phase separation in protein, nanoparticle, and colloidal suspensions is a rich and complex problem. Using a combination of integral equation theory, connectivity percolation methods, nai?ve mode coupling theory, and the activated dynamics nonlinear Langevin equation approach, we study this problem for isotropic one-component fluids of spheres and variable aspect ratio rigid rods, and also percolation in rod-sphere mixtures. The key control parameters are interparticle attraction strength and its (short) spatial range, total packing fraction, and mixture composition. For spherical particles, formation of a homogeneous one-phase kinetically stable and percolated physical gel is predicted to be possible, but depends on non-universal factors. On the other hand, the dynamic crossover to activated dynamics and physical bond formation, which signals discrete cluster formation below the percolation threshold, almost always occurs in the one phase region. Rods more easily gel in the homogeneous isotropic regime, but whether a percolation or kinetic arrest boundary is reached first upon increasing interparticle attraction depends sensitively on packing fraction, rod aspect ratio and attraction range. Overall, the connectivity percolation threshold is much more sensitive to attraction range than either the kinetic arrest or phase separation boundaries. Our results appear to be qualitatively consistent with recent experiments on polymer-colloid depletion systems and brush mediated attractive nanoparticle suspensions.     

Screening of mucoadhesive microparticles containing hydroxypropyl-beta-cyclodextrin for the nasal delivery of risperidone

Interaction of the antipsychotic drug risperidone with hydroxypropyl-beta-cyclodextrin (HPBCD) in solution and in the solid state was studied with the aim of overcoming the limitations associated with nasal administration of low solubility drugs. Risperidone solubility studies revealed inclusion complex formation with a 1:1 stoichiometry. Low concentrations (0.1 w/v %) of hydroxypropylmethyl cellulose (HPMC) and carbomer affected risperidone solubility in water. No formation of a ternary complex was detected. The solid inclusion complex was prepared by spray drying and was characterised by thermal (DSC) and spectral (FTIR) analyses. Risperidone and the inclusion complex were loaded into microparticles by spray drying using HPMC, carbomer and HPMC/carbomer interpolymer complex (IPC) as mucoadhesive components. The microparticles were characterised with respect to drug loading, particle size distribution, thermal analysis, and zeta potential measurements. Mucoadhesive properties of the microparticles were studied by measuring the work of adhesion. Carbomer and IPC based microparticles revealed superior mucoadhesive microparticles compared to HPMC based microparticles. Drug incorporation into microparticles reduced their mucoadhesive properties, while incorporation of the cyclodextrin complex caused no additional reduction in mucoadhesion. The in vitro dissolution studies showed that formation of the inclusion complex significantly increased the risperidone dissolution rate from the microparticles, thus providing sustained drug release.