Cellulose Acetate Butyrate: Ammonio Methacrylate Copolymer Blends as a Novel Coating in Osmotic Tablets.

The objective of this work was the preparation of osmotic tablets using polymer blends of cellulose acetate butyrate (CAB) or ethylcellulose with ammonio methacrylate copolymer (Eudragit® RL). The advantage of these coatings in comparison to the traditionally used cellulose acetate is their solubility in safer organic solvents like ethanol. Polymer films were characterized with respect to their water uptake, dry mass loss, and mechanical properties. The effect of the polymer blend ratio on drug release and on the rupture force of the coating was investigated. In addition, the effect of drug solubility and content, pH and agitation rate of the release medium, and coating level and plasticizer content on the release were studied. With increased Eudragit® RL content in the coating blends, higher medium uptake of the film was observed, resulting in shorter lag times and faster drug release from the osmotic tablets. Replacing ethylcellulose with cellulose acetate butyrate as a coating material led to shorter lag times and faster drug release due to increased film permeability. In addition, CAB-based films had a higher strength and flexibility. The drug release was osmotically controlled and decreased with increasing coating level. It increased with increased drug solubility, plasticizer content, change of buffer species (acetate > phosphate), and decreased coating level. Agitation rate and drug content had no effect on the drug release. A 20% w/w coating level was sufficient for the tablet to tolerate forces of more than five times of the gastric destructive force reported in literature.

Poly vinyl acetate and ammonio methacrylate copolymer as unconventional polymer blends increase the mechanical robustness of HPMC matrix tablets.

The objective was to investigate poly vinyl acetate (Kollicoat® SR 30 D) and ammonio methacrylate copolymer (Eudragit® RL 30 D) blends as coatings to increase the mechanical robustness of hydroxypropyl methylcellulose (HPMC) matrix tablets. Poly vinyl acetate (Kollicoat® SR 30 D - KSR) was selected for its flexibility and ammonio methacrylate copolymer (Eudragit® RL 30 D - ERL) because of its high permeability. Films based on KSR:ERL blends were prepared by casting or spraying aqueous dispersions of these polymers and were characterized by water uptake, dry mass loss and mechanical properties. KSR:ERL blends were investigated as coating materials to improve the robustness, mechanical strength and drug release from the HPMC matrix tablets containing propranolol HCl, caffeine and carbamazepine as model drugs. Both HPMC and the polymer coating affected the propranolol release. The release and the mechanical properties could be easily adjusted by varying the polymer blend ratio. The flexibility increased with increasing KSR content. At an 8% w/w coating level, a force of 3.2N was required to rupture the coating of the swollen tablet after 16h in the release medium; the coated tablets were thus robust to withstand gastrointestinal forces. The coating level (6%-10%, w/w) and dissolution agitation rate (50rpm to 150rpm) had no effect on the drug release. The water-insoluble carbamazepine was not released from the coated tablets as HPMC erosion, which is necessary for the release of a poorly water-soluble drug was hindered by the coating. The release of the water-soluble propranolol increased with increasing drug content and decreased with increasing HPMC content. CONCLUSION: Poly vinyl acetate and ammonio methacrylate copolymer could be a proper polymer blend for coating HPMC matrix tablets to increase mechanical robustness, which characterized by its flexibility and permeability.

Polyvinyl acetate-based film coatings.

Polyvinyl acetate-based colloidal aqueous polymer dispersion Kollicoat(®) SR 30 D results in coatings characterized by moderate swelling behaviour, lipophilicity, pH-independent permeability for actives and high flexibility to withstand mechanical stress and is therefore used for controlled release coating. The colloidal aqueous polymer dispersion of Kollicoat(®) SR 30 D can be easily processed due to an optimal low minimum film forming temperature (MFT) of 18 °C without plasticizer addition and a thermal after-treatment (curing) of coated pellets. The drug release from Kollicoat(®) SR 30 D coated pellets was almost pH independent. Drug release could be easily adjusted by coating level or addition of soluble pore forming polymers. Physically stable Kollicoat(®) SR 30 D dispersions were obtained with the water-soluble polymers Kollidon(®) 30 and Kollicoat(®) IR up to 50% w/w. The addition of only 10% w/w triethyl citrate as plasticizer improved the flexibility of the films significantly and allowed compaction of the pellets. The drug release was almost independent of the compression force and the pellet content of the tablets. The inclusion of various tableting excipients slightly affected the drug release, primarily because of a different disintegration rate of the tablets. A combination of Kollicoat(®) SR 30 D and Kollicoat(®) IR with higher coating levels>10 mg/cm(2) is a relatively new alternative to OROS system which does not require drilling.

Improved physical stability and injectability of non-aqueous in situ PLGA microparticle forming emulsions.

The goal of this study was to obtain physically stable non-aqueous in situ forming microparticle (ISM) emulsions capable of forming biodegradable microparticles upon injection. ISM emulsions consist of a biocompatible organic PLGA solution dispersed in a continuous oil phase prepared in a two-syringe/connector system prior to administration. A variety of parenteral approved excipients were tested for a stability-enhancing effect and possible stabilization mechanisms evaluated. Glycerol monostearate (GMS) showed superior stabilizing potential prolonging the emulsion stability from a few minutes to more than 12h. Flow behavior analysis, differential scanning calorimetry, polarized light- and Cryo-electron microscopy revealed, that the stabilization was caused by an immediate, more than 5-fold viscosity increase in the continuous phase after emulsification and by a stabilized interface through a liquid crystalline GMS layer around the polymer solution droplets. Despite the viscosity increase the injectability of the stabilized ISM emulsion was improved by about 30% compared to the corresponding highly viscous PLGA solution (in situ implant) due to a pronounced shear thinning of the GMS containing oil phase. The injectability improvement allows a faster administration or enables the use of thinner needles and hence reduced patient discomfort.

Cubic phase-forming dry powders for controlled drug delivery on mucosal surfaces.

The purpose of this study was to prepare and physicochemically characterize protein-loaded, glycerol monooleate (GMO)-based dry powder systems, which can be used for the controlled mucosal delivery of macromolecules (e.g., nasal, buccal, pulmonary). Bovine serum albumin (BSA)-loaded powders were prepared by spray-drying, freeze-drying and/or spray-freezing using different types of carrier materials, including mannitol, polyvinyl pyrrolidone (PVP 25) and polyethylene glycols (PEGs). The systems were characterized by optical and polarized light microscopy, X-ray powder diffraction, gel electrophoresis and diffusion studies. The type of carrier material strongly affected the resulting particle size and shape. The presence of GMO effectively slowed down BSA release. Importantly, broad ranges of release patterns could be achieved by varying the type of preparation method and composition of the dry powders. In all cases, the primary structure of the BSA remained intact. GMO, which is a wax solid at room temperature, has been successfully converted into dry powder formulations that offer potential for the controlled mucosal delivery of proteins.

Effect of unconventional curing conditions and storage on pellets coated with Aquacoat ECD.

PURPOSE: Purpose of this study was to develop storage stable pellets coated with the aqueous ethylcellulose dispersion Aquacoat ECD. METHODS: The influence of accelerated curing/storage conditions on the release behavior of Aquacoat/HPMC-coated drug pellets were investigated as a function of various formulations (sealing, plasticizer content, and pore-former type/amount) and process parameters (process humidity, thermal curing, and organic processing). RESULTS: Conventionally cured Aquacoat/hydroxypropyl methylcellulose- coated pellets were storage stable at ambient conditions and 25 degrees C/60% relative humidity (RH) but showed a decreasing drug release at 40 degrees C/75% RH, which is a required test condition according to ICH guidelines. CONCLUSION: Only organic processing of dried Aquacoat or unconventionally harsh curing conditions (60 degrees C/75% RH or 80 degrees C) improved the storage stability of Aquacoat-coated pellets at accelerated conditions.

Protection of moisture-sensitive drugs with aqueous polymer coatings: importance of coating and curing conditions.

The aim of this study was to better understand the importance of coating and curing conditions of moisture-protective polymer coatings. Tablets containing freeze-dried garlic powder were coated with aqueous solutions/dispersions of hydroxypropyl methylcellulose (HPMC), poly(vinyl alcohol), ethyl cellulose and poly(methacrylate-methylmethacrylates). The water content of the tablets during coating and during storage at different temperatures and relative humidities (RH) was determined gravimetrically. In addition, changes in the allicin (active ingredient in garlic powder) content were monitored. During the coating process, the water uptake was below 2.7% and no drug degradation was detectable. Thermally induced drug degradation occurred only at temperatures above the coating temperatures. Different polymer coatings effectively decreased the rate, but not the extent of water uptake during open storage at room temperature and 75% RH. Tablets coated with poly(vinyl alcohol) and poly(methacrylate-methylmethacrylates) showed the lowest moisture uptake rates (0.49 and 0.57%/d, respectively). Curing at elevated temperature after coating did not improve the moisture-protective ability of the polymeric films, but reduced the water content of the tablets. Drug stability was significantly improved with tablets coated with poly(vinyl alcohol) and poly(methacrylate-methylmethacrylates).

Importance of glassy-to-rubbery state transitions in moisture-protective polymer coatings.

The aim of this study was to better understand the mechanisms governing water transport in polymeric film coatings used for moisture protection. Tablets containing garlic powder were coated with Methocel E5 (hydroxypropyl methylcellulose), Opadry AMB [poly(vinylalcohol)-based formulation] and Eudragit E PO [poly(methacrylate-methylmethacrylate)]. Their water content at different temperatures and relative humidities were determined. The polymers were characterized by X-ray powder diffraction and differential scanning calorimetry (DSC). The latter revealed significant physical changes in Opadry AMB during storage, while Eudragit E PO remained unchanged. For Opadry AMB, a strong dependence of the vapor permeability on the water content of the system was observed. The water uptake drastically increased with increasing relative humidity and storage temperature due to structural polymer changes (glassy-to-rubbery state transition). Linear relationships between the initial uptake rate and the relative humidity or temperature were established. Storage below critical threshold values of 66% RH (at room temperature) and 16 degrees C (at 75% RH) significantly reduced water imbibition. Opadry AMB-based film coatings undergo a glassy-to-rubbery state transition upon storage at room temperature and elevated relative humidity, resulting in significantly increased mobility of the polymer chains and, thus, increased water uptake rates.

Injectability of biodegradable in situ forming microparticle systems (ISM).

In situ forming microparticle (ISM) systems offer a new encapsulation technique that provide a prolonged release of drug along with much greater ease of preparation and administration than conventional microparticles and surgically implanted systems. In this study, the forces required to inject biodegradable emulsions of the ISM systems via different sizes of syringe and needle into a newly developed chicken meat model, were determined using a compression mode of Texture Analyzer. The obtained injection forces were finally correlated with the injectability of the formulations into living rats. Results indicated that the flow of the ISM formulations through the needle could be described by the well-known Poiseuille equation. The injection forces were directly proportional to the formulations' viscosity, injection speed, the second power of the syringe plunger radius and inversely proportional to the forth power of the needle radius. This test method could differentiate very well the required forces from various formulations and injection conditions as well as different injection sites (muscle, subcutaneous tissues or air). In comparison to the polymer solutions that form implants in situ, the ISM systems were more easily injectable with smaller needle size thus expected to be less painful and give better patient comfort/compliance.

Characterization of moisture-protective polymer coatings using differential scanning calorimetry and dynamic vapor sorption.

The aim of this study was to evaluate the moisture-protective ability of different polymeric coatings. Free films and film-coated tablets (with cores containing freeze-dried garlic powder) were prepared using aqueous solutions/dispersions of hydroxypropyl methylcellulose (HPMC), Opadry AMB [a poly(vinylalcohol)-based formulation] and Eudragit E PO [a poly(methacrylate-methylmethacrylate)]. The water content of the systems upon open storage at 75% relative humidity (RH) and 22 degrees C (room temperature) was followed gravimetrically. Furthermore, polymer powders, free films and coated tablets were analyzed by differential scanning calorimetry (DSC) and dynamic vapor sorption (DVS). The type of polymer strongly affected the resulting water uptake kinetics of the free films and coated tablets. DSC analysis revealed whether or not significant physical changes occurred in the coatings during storage, and whether the water vapor permeability was water concentration dependent. Using DVS analysis the critical glass transition RH of Opadry AMB powder and Opadry AMB-coated tablets at 25 degrees C could be determined: 44.0% and 72.9% RH. Storage below these threshold values significantly reduces water penetration. Thus, DVS and DSC measurements can provide valuable information on the nature of polymers used for moisture protection.

Structure formation and characterization of injectable drug loaded biodegradable devices: in situ implants versus in situ microparticles.

The objective of the study was to investigate key formulation variables affecting the release of bupivacaine hydrochloride, a local anesthetic, from different in situ forming biodegradable drug delivery devices. The formulations included ISM systems [in situ microparticles, a poly(lactide)-solvent phase dispersed into an external oil phase] and poly(lactide) solutions (in situ implant systems). The solubility of the biodegradable polymer poly(d,l-lactide) (PLA) in various organic solvents was determined using the Hansen multicomponent solubility parameter concept. The solvent release from ISM and polymer solutions into phosphate buffer which influences the polymer precipitation rate was investigated as a function of the type of solvent, polymer concentration and polymer:oil phase ratio by using a HPLC assay. Scanning electron microscopy (SEM) was performed in order to relate the drug release to the surface properties of the precipitated implants or microparticles. Suitable solvents for the preparation of the in situ forming drug delivery systems, such as N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO) and 2-pyrrolidone were found using the Hansen multicomponent solubility parameter concept. The injection of the polymer solutions (in situ implants) into the aqueous medium led to a rapid solvent/non-solvent exchange. The resulting in situ implants were porous, thus explaining the rapid initial drug release. Upon contact with the release medium, the internal polymer phase of the ISM system solidified and formed microparticles as shown by SEM measurements. Due to the presence of an external oil phase the solvent release into the buffer medium from ISM was significantly slower compared to the polymer solutions. The solvent release of the ISM systems into the phosphate buffer decreased with increasing polymer concentration and decreasing polymer:oil phase ratio. The type of solvent used also affected the solvent release. A slower solvent release into the aqueous medium resulted in less porous microparticles, thus explaining the reduced initial drug release from ISM systems compared to the polymer solutions.

Polymer blends for controlled release coatings.

The use of polymer blends as coating materials for controlled drug delivery systems can offer major advantages, including: (i) facilitated adjustment of desired drug release patterns, mechanical properties and drug release mechanisms, (ii) improved film formation and storage stability, and (iii) the possibility to develop novel strategies for site specific drug delivery within the gastro intestinal tract (e.g., colon targeting). However, these systems are more complex than coatings based on only one polymer and care has to be taken when using this type of formulations. For instance, the blended polymers can be incompatible, aqueous polymer dispersions might flocculate and plasticizers potentially redistribute from one polymer into the other during curing and/or long term storage. This article gives an overview on the current state of the art of the use of polymer blends as coating materials for controlled drug delivery, explaining the major advantages and potential pitfalls. Special emphasis is laid on the underlying drug release mechanisms and practical examples for various types of applications are given. Due to the higher complexity of the systems, a thorough understanding of the most important mass transport phenomena involved in the control of drug release can be very helpful to render the optimization of this type of advanced delivery systems more efficient.

A novel in situ forming drug delivery system for controlled parenteral drug delivery.

The objective of this study was to investigate the in vitro drug (diltiazem hydrochloride and buserelin acetate) release from different in situ forming biodegradable drug delivery systems, namely polymer solutions (in situ implants) and in situ microparticle (ISM) systems. The drug release from ISM systems [poly(d,l-lactide) (PLA) or poly(d,l-lactide-co-glycolide) (PLGA)-solution dispersed into an external oil phase] was investigated as a function of the type of solvent and polymer, polymer concentration and internal polymer phase:external oil phase ratio and was compared to the drug release from in situ implant systems and microparticles prepared by conventional methods (solvent evaporation or film grinding). Upon contact with the release medium, the internal polymer phase of the ISM system solidified and formed microparticles. The initial drug release from ISM systems decreased with increasing polymer concentration and decreasing polymer phase:external oil phase ratio. The type of biocompatible solvent also affected the drug release. It decreased in the rank order DMSO>NMP>2-pyrrolidone. In contrast to the release of the low molecular weight diltiazem hydrochloride, the peptide release (buserelin acetate) was strongly dependent on the polymer degradation/erosion. One advantage of the ISM system when compared to in situ implant systems was the significantly reduced burst effect because of the presence of an external oil phase. ISM systems resulted in drug release profiles comparable to the drug release of microparticles prepared by the solvent evaporation method. Therefore, the ISM systems are an attractive alternative to existing complicated microencapsulation methods.

In vitro and in vivo evaluation of carbamazepine-loaded enteric microparticles.

The objective of the study was to prepare and evaluate carbamazepine-loaded enteric microparticles produced by a novel coacervation method. An aqueous polymeric stabilizer solution was added to an organic carbamazepine/Eudragit L100-55 solution. Water, which is a non-solvent for the drug and the enteric polymer, caused phase separation and the formation of coacervate droplets. These droplets hardened into microparticles upon further addition of the aqueous phase. The microparticles were characterized with respect to particle size distribution, morphology, encapsulation efficiency, yield, physical state and physical stability of the drug, wettability, in vitro release and in vivo bioavailability. Microparticles with a smooth surface and dense structure were obtained with high encapsulation efficiency (>85%) and yield (>90%). The drug was in a non-crystalline state in the matrix and physically stable for 5 months at room temperature. Under sink conditions, the drug dissolution rate from the microparticles was significantly enhanced compared to the physical mixture and to the pure drug; the release profile of the microparticles was stable after 5 months. Under non-sink conditions, an unstable supersaturated solution of carbamazepine was obtained from microparticles with the subsequent formation of needle-shaped crystals. The high surface area and good wettability of the microparticles, the non-crystalline state of the drug in the matrix and the fast dissolution rate contributed to a significantly enhanced oral bioavailability from the microparticles when compared to the physical mixture.

Stability of poly(D,L-lactide-co-glycolide) and leuprolide acetate in in-situ forming drug delivery systems.

In-situ forming drug delivery systems are prepared by dissolving a drug and a biodegradable polymer (poly(D,L-lactide-co-glycolide), PLGA) in a biocompatible organic solvent (In-situ implant, ISI) or further emulsified into an external phase (oil or aqueous solution), resulting in oil-in-oil or oil-in-water emulsions (In-situ forming microparticles, ISM). The chemical stability of PLGA and the drug is a major concern. In this study, the stability of PLGA and leuprolide acetate in the in-situ forming systems and lyophilized sponges was investigated. The degradation of PLGA increased with increasing storage temperature and water content in the biocompatible solvents. A faster degradation occurred in polar protic solvents (2-pyrrolidone, PEG 400, triethyl citrate) than in polar aprotic solvents (N-methyl-2-pyrrolidone, DMSO, triacetin, ethyl acetate). The presence of leuprolide acetate significantly accelerated PLGA degradation, especially in solution state. PLGA was stable in oily suspensions at 4 degrees C and degraded only slightly faster than solid powder at 25 degrees C. No interaction between the oils and the PLGA was observed as indicated by an unchanged T(g) of approx. 47 degrees C. PLGA underwent a slight degradation at 4 degrees C after 150 days in water and saturated sodium chloride solution. The degradation was slower in saturated sodium chloride solution than in water at 25 degrees C. Residual acetic acid in lyophilized sponges facilitated the PLGA degradation in contrast to dioxane. Leuprolide acetate did not affect the PLGA stability negatively. However, lidocaine significantly enhanced the polymer degradation in the sponges. Finally, leuprolide acetate was chemically stable in the sponges, the oils and the polymer solutions in suspension state, but unstable (aggregation) when dissolved in the polymer solutions and stored at 25 degrees C and 40 degrees C.

Encapsulation of lipophilic drugs within enteric microparticles by a novel coacervation method.

Enteric microparticles were prepared by a novel microencapsulation method in order to improve the oral bioavailability of lipophilic drugs. This method involved the addition of an aqueous polymer solution to an organic enteric polymer solution containing lipophilic drugs. In contrast to classical coacervation microencapsulation methods, the drugs were initially also dissolved and not dispersed in the organic polymer solution. The hydrophilic polymer (hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) and Poloxamer 407) was dissolved in the aqueous phase and acted as a stabilizer for the coacervate droplets, preventing their coalescence and leading to the formation of enteric microparticles. The size of the enteric microparticles decreased with higher concentrations of the hydrophilic polymers, a higher pH of the aqueous polymer solution, a higher content of carboxyl groups of the enteric polymer and with better polymer solvents. Amide-containing lipophilic drugs, such as carbamazepine, lidocaine and cyclosporine A, were successfully encapsulated in the enteric microparticles in a non-crystalline state and were physically stable for 5 months. The high solubility of carbamazepine in the enteric polymer (>30%, w/w), a high partition coefficient between polymer-rich/-poor regions and strong drug/polymer interactions contributed to the high drug encapsulation efficiency (90%, w/w). In contrast, carboxyl-containing drugs (indomethacin, ibuprofen) and hydroxyl-containing drug (17beta-estradiol hemihydrate) crystallized inside or outside the polymeric matrix due to their low solubility in the enteric polymer.

Blends of aqueous polymer dispersions used for pellet coating: importance of the particle size.

Blends of aqueous dispersions of a water-insoluble and an enteric polymer, namely ethyl cellulose:hydroxypropyl methylcellulose acetate succinate (EC:HPMCAS) and ethyl cellulose:methacrylic acid ethyl acrylate copolymer (EC:Eudragit L), were used as coating materials to control theophylline release from matrix pellets. Varying the polymer blend ratio, broad ranges of drug release patterns were obtained at low as well as at high pH. Interestingly, the resulting release profiles were rather similar for both types of blends in 0.1 M HCl, whereas significant differences were observed in phosphate buffer pH 7.4. Surprisingly, drug release at high pH was much slower for EC:HPMCAS blends compared to EC:Eudragit L blends, although HPMCAS leached out more rapidly (and to a higher extent) from the film coatings than Eudragit L. To explain these phenomena and to better understand the underlying drug release mechanisms, thin polymeric films of identical composition as the pellet coatings were prepared and physicochemically characterized before and upon exposure to the release media. Importantly, the polymer particle size was identified to be a very crucial formulation parameter, determining the resulting film coating structure and properties. The Eudragit L particles are much smaller than the HPMCAS particles (nano- vs. micrometer size range) and, thus, more effectively hinder the formation of a continuous and mechanically stable EC network. Consequently, the EC structures remaining after enteric polymer leaching at high pH are mechanically much weaker in the case of Eudragit L. Upon exposure to phosphate buffer, water-filled cracks are formed, through which the drug rapidly diffuses out. In contrast, the EC structures remaining upon HPMCAS leaching are mechanically stronger and drug release is controlled by diffusion through the polymeric remnants.

Physicochemical and release properties of pellets coated with Kollicoat SR 30 D, a new aqueous polyvinyl acetate dispersion for extended release.

Kollicoat SR 30 D is a new aqueous colloidal polyvinyl acetate dispersion used for extended release coatings. Kollicoat SR 30 D is stable against sedimentation, has a low viscosity (54 mPas) and a negative zeta potential of -23.2 mV because of the presence of the anionic surfactant, sodium dodecyl sulfate. Because of its low minimum film formation temperature (MFT = 18 degrees C), plasticizer addition and a thermal after-treatment (curing) of coated pellets was not required. Coated pellets showed no aging or curing effect. The rate of release could be easily adjusted by varying the coating level. A subcoating layer of the hydrophilic polymer, polyvinyl alcohol, between an ibuprofen-containing core and the Kollicoat SR coating prevented the diffusion of the lipophilic, low melting ibuprofen into the polymer coating during storage. The drug release from Kollicoat SR 30 D coated pellets was almost independent of the pH and ionic strength of release medium.

Oral evaluation in rabbits of cyclosporin-loaded Eudragit RS or RL nanoparticles.

The hydrophobic cyclic undecapeptide cyclosporin A (CyA) used in the prevention of graft rejection and in the treatment of autoimmune diseases was encapsulated by nanoprecipitation within non-biodegradable polymeric nanoparticles. The effect of polymers (Eudragit RS or RL) and additives within the alcoholic phase (fatty acid esters and polyoxyethylated castor oil) on the size, zeta potential and the encapsulation efficiency of the nanoparticles was investigated. The mean diameter of the various CyA nanoparticles ranged from 170 to 310 nm. The size as well as the zeta potential increased by adding fatty acid ester and polyoxyethylated castor oil within the organic phase. No significant differences in surface potential were observed for all formulations tested. Probably due to the very low water solubility of the drug, high encapsulation efficiencies were observed in a range from 70 to 85%. The oral absorption of CyA from these polymeric nanoparticles was studied in rabbits and compared to that of Neoral capsule. Based on comparison of the area under the blood concentration-time curve values, the relative bioavailability of CyA from each nanoparticulate formulation ranged from 20 to 35%.

Polymer blends used for the aqueous coating of solid dosage forms: importance of the type of plasticizer.

The aim of this study was to investigate the importance of the type of plasticizer in polymer blends used for the coating of solid dosage forms, comparing a lipophilic and a hydrophilic plasticizer (dibutyl sebacate (DBS) and triethyl citrate (TEC)). In vitro drug release from propranolol hydrochloride (propranolol HCl)-loaded pellets coated with blends of ethyl cellulose (EC) and Eudragit L (100:0, 75:25, 50:50, 25:75 and 0:100 w/w) was investigated at low as well as at high pH. To better understand the underlying mass transport mechanisms, the physicochemical properties of the film coatings (e.g. mechanical resistance, water uptake and dry weight loss behavior) were determined. Interestingly, drug release strongly depended on the type of plasticizer. Importantly, not only the slope but also the shape of the release curves was affected, indicating that the chemical nature of the plasticizer plays a major role for the underlying drug release mechanisms. Diffusion through the intact polymer coatings and/or through water-filled cracks was found to be dominating for the control of drug release. The relative importance of these pathways strongly depended on the polymer blend ratio and type of plasticizer. In contrast to DBS, TEC rapidly leached out of the coatings, resulting in decreasing mechanical resistances of the films and, thus, facilitated crack formation. In addition, the hydrophilicity of the plasticizer significantly affected the water uptake behavior of the film coatings and, hence, changes in the coatings' toughness and drug permeability. Also the relative affinity of the plasticizer to the different polymers was found to be of significance. In contrast to TEC, DBS has a higher affinity to EC than to Eudragit L, resulting in potential redistributions of this plasticizer within the polymeric systems and changes in the release profiles during storage. Importantly, these effects could be avoided with appropriate curing conditions and preparation techniques for the coating dispersions.