Formulation development and optimization of sustained release matrix tablet of Itopride HCl by response surface methodology and its evaluation of release kinetics

The objective of this present investigation was to develop and formulate sustained release (SR) matrix tablets of Itopride HCl, by using different polymer combinations and fillers, to optimize by Central Composite Design response surface methodology for different drug release variables and to evaluate drug release pattern of the optimized product. Sustained release matrix tablets of various combinations were prepared with cellulose-based polymers: hydroxy propyl methyl cellulose (HPMC) and polyvinyl pyrolidine (pvp) and lactose as fillers. Study of pre-compression and post-compression parameters facilitated the screening of a formulation with best characteristics that underwent here optimization study by response surface methodology (Central Composite Design). The optimized tablet was further subjected to scanning electron microscopy to reveal its release pattern. The in vitro study revealed that combining of HPMC K100M (24.65 MG) with pvp(20 mg)and use of LACTOSE as filler sustained the action more than 12 h. The developed sustained release matrix tablet of improved efficacy can perform therapeutically better than a conventional tablet.     

Development of orodispersible polymer films with focus on the solid state characterization of crystalline loperamide

The formulation of active pharmaceutical ingredients (API) as orodispersible films is gaining interest among novel oral drug delivery systems due to their small size, enhanced flexibility and improved patient compliance. The aim of this work was the preparation and characterization of orodispersible films containing loperamide hydrochloride (LPH) as model drug. As loperamide hydrochloride is poorly soluble in water it was used in crystalline form with a loading of 2 mg/6 cm² film.Hydroxypropyl methylcellulose (HPMC) and different types of hydroxypropyl cellulose (HPC) in different concentrations were used as film forming polymers whereas arabic gum, xanthan gum and tragacanth served as thickening agents. Films were characterized with respect to the content uniformity, morphology, thermal behavior and crystallinity. Suspensions were investigated regarding their viscosity using a rotational rheometer and the crystal structure of the Active Pharmaceutical Ingredient (API) was analyzed using polarized light microscopy. The development of flexible, non-brittle and homogeneous films of LPH was feasible.Two polymorphic forms of LPH appeared in the film formulations dependent on the utilized polymer. While in presence of HPMC the original polymorphic form I remained stable in suspension and films, the polymorphic form II occurred in presence of HPC. Both polymorphic forms were prepared separately and a solid state characterization was performed. Polymorph I showed isometric crystals whereas polymorph II showed needle shaped crystals. Tragacanth was able to prevent the transformation to polymorph II, if it was dissolved first before HPC. When HPC was added first to the suspension, the conversion to form II occurred irreversibly also after further addition of tragacanth.     

Gastroretentive hydrodynamically balanced systems of ofloxacin: In vitro evaluation

Hydrodynamically balanced systems (HBSs) of ofloxacin were prepared using lactose, HPMC K4M, PVP K 30, and liquid paraffin, which may increase the mean residence time in the gastrointestinal tract, and may be able to provide maximum drug at the site of absorption to improve oral bioavailability. All these formulated HBS capsules were floated well over 6 h with no floating lag time. They also showed sustained drug release over 6 h. Time for 50% release of ofloxacin was within the range, 2.47 ± 0.02 to 3.07 ± 0.08 h. The in vitro drug release from these HBS capsules was dependent on HPMC K4M, PVP K 30, and liquid paraffin content. The drug release pattern of these HBS capsules containing ofloxacin followed the Higuchi model with the anomalous transport mechanism.     

Indomethacin sustained release pellets prepared by extrusion-spheronization

Gastrointestinal side effects may interrupt essential therapy with indomethacin, a non-steroidal anti-inflammatory drug. Formulation of this drug into sustained release multiparticulate form may reduce some of these side effects by avoiding contact of drug crystals with gastrointestinal mucosa at high concentrations, as may happen with immediate release dosage forms. Indomethacin (IM) sustained release pellets containing 5 or 10 % w/w of the drug were prepared using an extrusion-spheronization technique. Different concentrations of hydrophilic polymers, polyethylene glycol 4000 (PEG 4000), hydroxypropyl methylcellulose E5 LV premium (HPMC) and polyvinyl pyrrolidone (PVP K30), were mixed at different concentrations (5,10 and 20 %) with Avicel PH 101 to prepare the sustained release formulae. Moreover, a mixer torque rheometer was used to quantitatively determine the suitable moisture content in the pastes before the extrusion process. The resulting pellets were characterized for content, particle size, shape and dissolution profile. The studies on the effect of the polymers used on Avicel rheological properties revealed that the magnitude of torque for the system was decreasing as the polymer concentration increased. The in vitro release of IM from the prepared Avicel pellets was found to be dependent upon the type and concentration of the added polymer. The rank order of IM release in the presence of the investigated polymers was as follows: PEG > HPMC > PVP. Furthermore, the magnitude of IM release rate from the pellet formulations was found to be dependent on the magnitude of the peak torque of the pellet forming paste, which in turn depends on the type and concentration of the added polymer. Increasing IM loading from 5 to 10 % has led to an increase in dissolution rates. At least two of the prepared pellet formulations showed dissolution profiles similar to the commercial product Bonidon 75 SR capsules. In conclusion, the formulation of IM sustained release pellets successfully controlled the drug release which might be beneficial in lowering the risk of side effects and improving patient convenience as an advantage of the pellets as a drug delivery system.     

Design of a novel bilayered gastric mucoadhesive system for localized and unidirectional release of lamotrigine

Lamotrigine is a BCS class II drug with pH dependent solubility. The bilayered gastric mucoadhesive tablets of lamotrigine were designed such that the drug and controlled release polymers were incorporated in the upper layer and the lower layer had the mucoadhesive polymers. The major ingredients selected for the upper layer were the drug and control release polymer (either HPMC K15M or polyox) while the lower MA layer predominantly comprised of Carbopol 974P. A 2³ full factorial design was constructed for this study and the tablets were optimized for parameters like tablet size, shape, ex vivo mucoadhesive properties and unidirectional drug release. Oval tablets with an average size of 14 mm diameter were set optimum. Maximum mucoadhesive bond strength of 79.3 ± 0.91 * 10³ dyn/cm² was achieved with carbopol when used in combination with a synergistic resin polymer. All the tested formulations presented a mucoadhesion time of greater than 12 h. The incorporation of methacrylic polymers in the lower layer ensured unidirectional drug release from the bilayered tablets. The unidirectional drug release was confirmed after comparing the dissolution results of paddle method with those of a modified basket method. Model independent similarity and dissimilarity factor methods were used for the comparison of dissolution results. Controlled drug release profiles with zero order kinetics were obtained with polyox and HPMC K15M which reported t_90% at 6th and 12th hours, respectively. The “n” value with polyox was 0.992 and that with HPMC K15M was 0.946 indicating an approximate case II transport. These two formulations showed the potential for oral administration of lamotrigine as bilayered gastric mucoadhesive tablets by yielding highest similarity factor values, 96.06 and 92.47, respectively, between the paddle and modified basket method dissolution release profiles apart from reporting the best tablet physical properties and maximum mucoadhesive strength.     

Drug release behavior of polymeric matrix filled in capsule

A single unit sustainable drug release system was developed using hydroxypropyl methylcellulose (HPMC)-based matrices filled in capsule as the drug delivery device. Release behavior of propranolol HCl from these capsules was investigated and least square fitting was performed for the dissolution data with the different mathematical expressions. Effect of diluent, polymer, pH and hydrodynamic force on the drug release from the developed systems was investigated. The utilization of HPMC as a matrix former extended the drug release longer than 8 h. HPMC viscosity grades affected the drug release, that is, increasing the amount of fillers such as lactose and dibasic calcium phosphate enhanced the drug release rate of HPMC matrices. The hydrodynamic force, type and amount of incorporated polymer apparently influenced the drug release. The physiochemical properties of polymers and interaction between HPMC and other polymers were important factors for prolongation of the drug release. The release mechanism from HPMC-based matrices in capsules was the non-Fickian transport in which the sustainable drug release of HPMC capsules could be achieved by the addition of polymeric matrix.     

Design and In Vitro Evaluation of a Film-Controlled Dosage Form Self-Converted from Monolithic Tablet in Gastrointestinal Environment

The purpose of this study is to design an easily manufactured sustained drug delivery system, which can be converted to a film coated system during the dissolution process and then control the drug release according to near zero-order kinetics. Two kinds of pH- sensitive and oppositely charged hydrophilic polymers, chitosan and alginate, were physically mixed as the matrix. Slightly water-soluble drugs such as theophylline, aspirin, and acetaminophen were utilized as model drugs. In vitro drug release and swelling tests were undertaken in simulated gastrointestinal environments. The formation and properties of the film formed during the dissolution process were identified using different techniques. It was demonstrated that formation of the film was based on the interaction of the polymers on tablet surface with the change of system pH. In 0-4 h drug release depended on the intrinsic properties of the polymers, however, characteristics of the film played a leading role in controlling drug release after 4 h. By studying the ratio of relaxation over Fickian diffusion and relationship between tablets swelling and drug release, it was revealed that the film probably modified drug release behavior by limiting polymer erosion. The in vivo behavior of this hydrophilic matrix system will be investigated.     

Clinical evaluation of novel buccoadhesive film containing ketorolac in dental and post-oral surgery pain management

Ketorolac tromethamine (KT), a non-steroidal anti-inflammatory drug, was formulated in buccoadhesive film to overcome the limitations in the currently available routes of administration which in sequence will increase patients' compliance. The film was formulated using aqueous solvents by means of two bioadhesive polymers namely: hydroxylpropyl methyl cellulose (HPMC) and Carbopol 934. The prepared film was subjected to investigations for its physical and mechanical properties, swelling behavior, in vitro bioadhesion, and in vitro, in situ and in vivo release. Anti-inflammatory efficacy and analgesic activity of the prepared buccoadhesive film were investigated in rats using the hind-paw oedema test and the hot plate method. The analgesic efficacy and tolerability of a single 30 mg dose of KT formulated into the buccoadhesive film was clinically evaluated using a standard, widely accepted post-oral surgery pain model. In this study, the prepared film has been administrated to dental post-operative patients for relieving pain in dental hospital clinic. Results indicate that the concentration of KT in the oral cavity was maintained above 4.0 microg/ml for a period of at least 6 h. The buccal KT film was excellently tolerated in all patients and no complains of GI side effects were reported. It is concluded from this clinical evaluation that KT formulated into a buccoadhesive film is effective as a potent analgesic in dental and postoperative oral surgery in a single dose of 30 mg with minimal GI side effects.     

The effect of sucrose and salts in combination on the drug release behaviour of an HPMC matrix

Previous work has shown how high concentrations of sugars can accelerate drug release from hydroxypropyl methylcellulose (HPMC) matrices by suppressing polymer hydration. This study investigates the effects of combining sugar and salts, using sucrose, sodium chloride and trisodium citrate, soluble ingredients commonly found in foods. A factorial study showed that each solute suppressed HPMC solution sol–gel transition temperature (a sensitive measure of molecular hydration) independently, and their effects reflected their rank order in the Hofmeister series. In mixtures, the effects were purely additive, with no evidence of antagonism or synergy. In dissolution tests, both salts significantly reduced the threshold sugar concentration required to elicit an acceleration of drug release, and when used in combination, 0.15 M sodium chloride with 0.015 M trisodium citrate reduced the threshold sucrose concentration from 0.7 M to 0.35–0.4 M, a reduction of almost 50%. The results show that food salts can significantly reduce the concentration required for sugar effects on HPMC matrices, and this may be a factor to consider when interpreting their in vivo behaviour in the fed state.     

The effect of sucrose and salts in combination on the drug release behaviour of an HPMC matrix

Previous work has shown how high concentrations of sugars can accelerate drug release from hydroxypropyl methylcellulose (HPMC) matrices by suppressing polymer hydration. This study investigates the effects of combining sugar and salts, using sucrose, sodium chloride and trisodium citrate, soluble ingredients commonly found in foods. A factorial study showed that each solute suppressed HPMC solution sol–gel transition temperature (a sensitive measure of molecular hydration) independently, and their effects reflected their rank order in the Hofmeister series. In mixtures, the effects were purely additive, with no evidence of antagonism or synergy. In dissolution tests, both salts significantly reduced the threshold sugar concentration required to elicit an acceleration of drug release, and when used in combination, 0.15 M sodium chloride with 0.015 M trisodium citrate reduced the threshold sucrose concentration from 0.7 M to 0.35–0.4 M, a reduction of almost 50%. The results show that food salts can significantly reduce the concentration required for sugar effects on HPMC matrices, and this may be a factor to consider when interpreting their in vivo behaviour in the fed state.     

Physicochemical properties of tadalafil solid dispersions – Impact of polymer on the apparent solubility and dissolution rate of tadalafil

To improve solubility of tadalafil (Td), a poorly soluble drug substance (3 μg/ml) belonging to the II class of the Biopharmaceutical Classification System, its six different solid dispersions (1:1, w/w) in the following polymers: HPMC, MC, PVP, PVP-VA, Kollicoat IR and Soluplus were successfully produced by freeze-drying. Scanning electron microscopy showed a morphological structure of solid dispersions typical of lyophilisates. Apparent solubility and intrinsic dissolution rate studies revealed the greatest, a 16-fold, increase in drug solubility (50 μg/ml) and a significant, 20-fold, dissolution rate enhancement for the Td/PVP-VA solid dispersion in comparison with crystalline Td. However, the longest duration of the supersaturation state in water (27 μg/ml) over 24 h was observed for the Td solid dispersion in HPMC. The improved dissolution of Td from Td/PVP-VA was confirmed in the standard dissolution test of capsules filled with solid dispersions. Powder X-ray diffraction and thermal analysis showed the amorphous nature of these binary systems and indicated the existence of dispersion at the molecular level and its supersaturated character, respectively. Nevertheless, as evidenced by film casting, the greatest ability to dissolve Td in polymer was determined for PVP-VA. The crystallization tendency of Td dispersed in Kollicoat IR could be explained by the low T_g (113 °C) of the solid dispersion and the highest difference in Hansen solubility parameters (6.8 MPa^0.5) between Td and the polymer, although this relationship was not satisfied for the partially crystalline dispersion in PVP. Similarly, no correlation was found between the strength of hydrogen bonds investigated using infrared spectroscopy and the physical stability of solid dispersions or the level of supersaturation in aqueous solution.     

An approach for lacidipine loaded gastroretentive formulation prepared by different methods for gastroparesis in diabetic patients

The present work deals with various attempts to prepare a gastroretentive formulation of lacidipine for treating gastroparesis. High density sucrose beads were modified by coating with certain polymers, but unfortunately sustained release could not be achieved. Granules were prepared by wet granulation technology using different combinations of polymers and a release of the drug was observed. The method failed to release the drug as per desired specifications. Polymeric coating followed by wet granulation was thought to be a better process to sustain the dissolution rate. The release rate can be modified by the incorporation of different polymeric coatings, but the mucoadhesive potential of granules was only 4.23% which might be due to its large size and the presence of other ingredients. Further, the lacidipine loaded microparticles were prepared by different methods such as compression, ionic gelation with TPP, ionic gelation with TPP and glutaraldehyde, spray drying and coacervation techniques. The formulations were evaluated for average particle size, surface morphology, entrapment efficiency, % yield and mucoadhesive potential. The microparticles prepared by compression method using HPMC K4M and SCMC as mucoadhesive polymers and BaSO₄ as high density diluent showed poor bioadhesion (8.3%) and poor release characteristics (100% in 120 min). Ionic gelation with tripolyphosphate yielded microspheres with poor mechanical strength. In order to improve its mechanical strength, TPP ionic gelation was combined with step-wise cross-linking with glutaraldehyde. The additional solidification step to improve mechanical strength left this procedure tedious, time consuming and cytotoxic. Spray drying method gave a very low yield with 46.67% bioadhesion. The method using CaCl₂ for ionotropic gelation showed the best results with regard to physical characteristics (well formed discrete, spherical surface microcapsule), particle size (88.57 ± 0.51), in vitro bioadhesion (67.33%), yield (>85%) and loading (>70%).     

Polymer incorporation method affects the physical stability of amorphous indomethacin in aqueous suspension

This study reports the potential of different polymers and polymer incorporation methods to inhibit crystallisation and maintain supersaturation of amorphous indomethacin (IND) in aqueous suspensions during storage. Three different polymers (poly(vinyl pyrrolidone) (PVP), hydroxypropyl methylcellulose (HPMC) and Soluplus® (SP)) were used and included in the suspensions either as a solid dispersion (SD) with IND or dissolved in the suspension medium prior to the addition of amorphous IND. The total concentrations of both IND and the polymer in the suspensions were kept the same for both methods of polymer incorporation. All the polymers (with both incorporation methods) inhibited crystallisation of the amorphous IND. The SDs were better than the predissolved polymer solutions at inhibiting crystallisation. The SDs were also better at maintaining drug supersaturation. SP showed a higher IND crystallisation inhibition and supersaturation potential than the other polymers. However, this depended on the method of addition. IND in SD with SP did not crystallise, nor did the SD generate any drug supersaturation, whereas IND in the corresponding predissolved SP solution crystallised (into the recently characterised η polymorphic form of the drug) but also led to a more than 20-fold higher IND solution concentration than that observed for crystalline IND. The ranking of the polymers with respect to crystallisation inhibition potential in SDs was SP ≫ PVP > HPMC. Overall, this study showed that both polymer type and polymer incorporation method strongly impact amorphous form stability and drug supersaturation in aqueous suspensions.     

A pharmacoscintigraphic study of three time-delayed capsule formulations in healthy male volunteers

Three time-delayed capsule (TDC) formulations were investigated in a pharmacoscintigraphic study, using a three-way crossover design in eight healthy male volunteers. Additionally, the pulsed release of a TDC was investigated with time-lapse photography, using a nondisintegrating riboflavin tablet. The photographic study indicated how the release characteristics of the TDC relied on the erosion of a tablet containing hypromellose (HPMC). Each TDC was duel radio labelled with indium-111 and technetium-99 m DTPA complexes, to observe drug release scintigraphically (theophylline was a marker compound). Three formulations, having in vitro dissolution release times of 1.8, 2.9 or 4.0 h were shown to compare favourably with mean in vivo scintigraphic release times of 2.7, 3.0 and 4.0 h for each formulation containing 20, 24 or 35% (w/w) HPMC concentrations respectively. An increase in HPMC concentration was associated with a delayed technetium release time, and followed the same rank order as the in vitro dissolution study. Observed radiolabel dispersion always occurred in the small intestine. In conclusion, the study established that the TDC performs and demonstrates an in vitro–in vivo correlation. Additionally, time and site of release were accurately visualized by gamma scintigraphy, and confirmed with determination of theophylline absorption. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4251–4263, 2009     

Development of Mucoadhesive Films for Buccal Administration of Flufenamic Acid: Effect of Cyclodextrin Complexation

A new mucoadhesive film for topical administration in the oral cavity of flufenamic acid, a poorly soluble anti-inflammatory drug, has been developed, using complexation with hydroxypropyl-β-cyclodextrin (HPβCD) to improve drug dissolution and release rate. Buccal films were prepared utilising chitosan as mucoadhesive polymer, KollicoatIR® as film-forming polymer and glycerol as plasticiser. Different combinations of these components were used and the obtained films were characterised for weight, thickness, swelling, mucoadhesive and mechanical properties. The film containing chitosan 2%, glycerol 7.5% and KollicoatIR® 1% showed the best properties for the development of the film formulation. The selected film was loaded with the plain drug and its colyophilised and coground products with HPβCD, and in vitro release studies in simulated saliva were performed. The improved drug dissolution properties, obtained by complexation with HPβCD, were critical to achieve complete release from film formulation during 4–5 h. On the contrary, film loaded with the plain drug showed incomplete release, not exceeding 70% release after 5 h. The developed film formulation containing the drug as complex with HPβCD can assure a prolonged drug release directly at the inflammation site and can be proposed as a new therapeutic tool in the treatment of oral mucosa inflammations.     

Floating matrix dosage form for dextromethorphan hydrobromide based on gas forming technique: In vitro and in vivo evaluation in healthy volunteers

The objective of this study was to develop the dextromethorphan hydrobromide sustained-release (DMB-SR) tablets using floating technique to prolong the gastric residence time and compared their pharmacokinetic behavior with conventional sustained release tablets. DMB-SR floating tablets were prepared employing hydroxypropyl methylcellulose (HPMC) as hydrophilic gel material, sodium bicarbonate as gas-generating agent and hexadecanol as floating assistant agent. An orthogonal experiment design method was used to select the optimized formulation. The floating tablets were evaluated for uniformity of weight, hardness, friability, drug content, floating characteristics, in vitro release and in vivo bioavailability. The optimized tablets were prepared with HPMC K4M 25 mg, sodium bicarbonate 20 mg and hexadecanol 18 mg. The prepared tablets could float within 3 min and maintain for more than 24 h. The data of physical parameters were all lie within the limits. Drug release at 12 h was more than 85%. The comparative pharmacokinetic study was performed by administration of the DMB-SR floating tablets and conventional DMB-SR tablets. The area under curve of plasma concentration–time (AUC) of floating tablets was slightly higher than that of reference tablets, T_max was prolonged apparently. The results showed the floating tablets are a feasible approach for the sustained-release preparation of drugs, which have limited absorption sites in the stomach.     

Characterization of cellulosic hot-melt extruded films containing lidocaine.

Hot-melt extrusion technology was used to produce thin films containing a model drug, lidocaine, and the cellulosic polymers hydroxypropyl cellulose (HPC) and hydroxypropyl methyl cellulose (HPMC). Two film formulations were extruded and compared, one containing only HPC and the other containing HPC:HPMC (80:20). Thermal analysis of the films using differential scanning calorimetry (DSC) suggested that the drug existed in the amorphous condition, which was confirmed by wide angle X-ray diffractometry. Sustained release of the drug was observed from both of the polymer matrices. Dissolution profiles suggested that HPMC retarded the drug release from HPC:HPMC (80:20) films. However, the mechanism of drug release from both of the films was predominantly diffusion of the drug through the polymer matrices. Incorporation of HPMC also increased both adhesive strength and work of adhesion as compared to the HPC-only films.     

Quantitative Ultra-Fast MRI of HPMC Swelling and Dissolution

For the first time quantitative Rapid Acquisition with Relaxation Enhancement (RARE) based ultra-fast two-dimensional magnetic resonance imaging has been used to follow the dissolution of hydroxypropylmethyl cellulose (HPMC) in water. Quantitative maps of absolute water concentration, spin-spin relaxation times and water self-diffusion coefficient are obtained at a spatial resolution of 469 mm in less than 3 min each. These maps allow the dynamic development of the medium release rate HPMC/water system to be followed. It is demonstrated that the evolution of the gel layer and, in particular, the gradient in water concentration across it, is significantly different when comparing the quantitative RARE sequence with a standard (nonquantitative) implementation of RARE. The total gel thickness in the axial direction grows faster than that in the radial direction and that the dry core initially expands anisotropically. Additionally, while HPMC absorbs a large amount of water during the dissolution process, the concentration gradient of water within the gel layer is relatively small. For the first time MRI evidence is presented for a transition swollen glassy layer which resides between the outer edge of the dry tablet core and the inner edge of the gel layer.     

Atomistic simulation study of surfactant and polymer interactions on the surface of a fenofibrate crystal

It is currently of great interest to the pharmaceutical industry to control the size and agglomeration of nano- and micro-particles for the enhancement of drug delivery. Typically, surfactants and polymers are used as additives to interact with and stabilize the growing crystal surface, thus controlling size and agglomeration; however, selection is traditionally done empirically or using heuristics. The objective of this study was to use molecular dynamic simulations to investigate and predict additive interactions, and thus, evaluate the stabilization potential of individual and multiple additives on the surface of the model drug fenofibrate. Non-ionic surfactant Tween 80, anionic surfactant sodium dodecyl sulfate (SDS), and polymers hydroxypropyl methylcellulose (HPMC) and Pullulan were evaluated individually on three distinct crystal surfaces [(0 0 1), (0 1 0), (1 0 0)], as well as in surfactant-polymer combinations. HPMC was determined to have the strongest interaction with the surfaces of the fenofibrate crystal, and therefore, was predicted to be the most effective individual additive. A mixture of HPMC with SDS was determined to be the most effective mixture of additives, and more effective than HPMC alone, indicating a synergistic effect. The predictions of mixed additives indicated a relative order of effectiveness as follows: HPMC–SDS > HPMC–Tween 80 > Pullulan–Tween 80 > Pullulan–SDS. The simulations were subsequently validated by an anti-solvent crystallization of fenofibrate where it was found that HPMC individually, and a mixture of HPMC–SDS, produced the smallest and most stable crystals, as measured by laser diffraction; this, in combination with measurements of the crystal growth rate in the presence and absence of additives confirmed the results of the simulations.     

Cytotoxic evaluation of nanostructured zinc oxide (ZnO) thin films and leachates

Nanostructured ZnO films have potential use as coatings on medical devices and food packaging due to their antimicrobial and UV-protection properties. However, their influence on mammalian cells during clinical use is not fully understood. This study investigated the potential cytotoxicity of ZnO thin films in RAW 264.7 macrophages. ZnO thin films (∼96 nm thick with a 50 nm grain) were deposited onto silicon wafers using pulsed laser deposition. Cells grown directly on ZnO thin film coatings exhibited less toxicity than cells exposed to extracts of the coatings. Cells on ZnO thin films exhibited a 43% and 68% decrease in cell viability using the MTT and 7-AAD/Annexin V flow cytometry assays, respectively, after a 24-h exposure as compared to controls. Undiluted 100% 24- and 48-h extracts decreased viability by 89%, increased cell death by LDH release to 76% 24 h after treatment, and increased ROS after 5–24 h of exposure. In contrast, no cytotoxicity or ROS were observed for 25% and 50% extracts, indicating a tolerable concentration. Roughly 24 and 34 μg/m² Zn leached off the surfaces after 24 and 48 h of incubation, respectively. ZnO coatings may produce gradual ion release which becomes toxic after a certain level and should be evaluated using both direct exposure and extraction methods.