Occlusive Properties of Monolayer Patches: In Vitro and in Vivo Evaluation

Purpose. Patches can cause a different grade of skin occlusion, depending on matrix composition and thickness, backing layer material. The aim of this work was to verify if in vitro water vapour permeability (WVP) values are predictive of transepidermal water loss (TEWL) and Fourier-transform infrared (FTIR) spectroscopy values measured in vivo after 24 h of methacrylic or acrylic monolayer patches application. The correlation between both in vivo methods has been evaluated. Methods. The WVP, TEWL and FTIR measurements were performed by using four patches made of a methacrylic or an acrylic polymeric system (250 and 500 m thickness on a polyurethane backing layer). A fifth patch was made of the methacrylic matrix on a polyvinyl chloride backing layer. Results. A good correlation was found between TEWL values and IR water/lipid absorbance ratios. The in vitro WVP values are in a good correlation with the results of both in vivo methods: TEWL = –0.01WVP + 21.31 (R² = 0.9312); FTIR water/lipid ratio = –0.01WVP + 27.15 (R² = 0.9447). Conclusions. The in vitro method proposed for measuring the WVP is predictive of the degree of occlusion resulting from the in vivo application of monolayer patches.     

Formulation Study of Oxybutynin Patches

The present feasibility study was designed to obtain a monolayer patch containing oxybutynin (OXY) avoiding chemical permeation enhancers. The highest flux was obtained with a polydimethylsiloxane matrix patch. Because OXY crystals were detected in the matrix within a week, two amino methylmethacrylate copolymers (Eudragit® E or Eudragit® RS) were used as OXY crystallization inhibitors. A preliminary in vivo study indicated that flux from the stabilized patches had to be increased about 30–40%. This goal was reached by occlusion with a polyethylene layer.     

Erodible Time‐Dependent Colon Delivery Systems with Improved Efficiency in Delaying the Onset of Drug Release

To prepare swellable/erodible time‐dependent colon delivery systems with improved efficiency in delaying drug release, the application of an outer Eudragit® NE film, which contained the superdisintegrant Explotab® V17 as a pore former, was attempted. Tablet cores were successively spray‐coated with a hydroxypropyl methylcellulose (HPMC) solution and diluted Eudragit® NE 30 D, wherein fixed amounts of Explotab® V17 were present. The resulting two‐layer systems yielded lag phases of extended duration as compared with formulations provided with the HPMC layer only. By raising the thickness of the outer film, longer lag times were generally observed, whereas the effectiveness in deferring the drug liberation was reduced by increasing the pore former content, which, however, also resulted in a lower data variability. The films containing 20% of Explotab® V17 effectively and consistently prolonged the in vitro lag phase imparted by HPMC as a function of their thickness. Stored for 3 years under ambient conditions, a two‐layer system with this outer film composition pointed out unmodified release patterns. The same system proved to meet gastroresistance criteria when enteric coated. The results obtained indicated that the proposed strategy would enable the preparation of erodible delivery systems with reduced size, possibly suitable as multiple‐unit dosage forms. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3585–3593, 2014     

Evaluation of films used in development of a novel controlled-release system for gastric retention

A novel gastric retention system was developed consisting of a tablet coated with a porous membrane. The membrane consisted of aqueous dispersions of methyl methacrylate copolymers, plasticizers, anti tacking and anti foaming agents. This article presents research work performed in order to characterize these membranes. The films were cast on glass plates coated with teflon. The films were dried at 30°C in a vacuum oven. The three main properties studied on these films were as follows: (1) Transport of drugs across the membrane; (2) mechanical properties; (3) thermo-mechanical properties. These properties were studied to produce a film having the desired characteristics for drug release and mechanical strength. It was observed that the permeability of the drug decreased slightly with increase in the Eudragit® NE 30D concentration. This result correlated well with dissolution rate constants of tablets at 15% coating level. The thermo-mechanical studies helped to understand the results from permeability studies. Based on mechanical properties, a 70:30 ratio of Eudragit® RL 30D and NE 30D was found to be optimum. The study has shown that the evaluation of films will be helpful in providing guidelines in selecting the membrane for the gastric retention system.     

Chitosan films incorporated with nettle (Urtica dioica L.) extract-loaded nanoliposomes: I. Physicochemical characterisation and antimicrobial properties

The objective of this study was to characterise and compare physical, mechanical and antimicrobial properties of chitosan-based films, containing free or nanoencapsulated nettle (Urtica dioica L.) extract (NE) at concentrations of 0, 0.5, 1 and 1.5% w/w. Nanoliposomes were prepared using soy-lecithin by thin-film hydration and sonication method to generate an average size of 107–136?nm with 70% encapsulation efficiency. The information on FT-IR reflected that some new interaction have occurred between chitosan and nanoliposomes. Despite the increasing yellowness and decreasing whiteness indexes, the nanoliposomes incorporation improved the thermal properties and mechanical stiffness and caused to decrease water vapour permeability (WVP), moisture uptake and water solubility. The possible antimicrobial activity of the films containing NE-loaded nanoliposomes against Staphylococcus aureus was decreased in comparison to free NE-incorporated films, which could be due to the inhibition effect of the encapsulation that prevents the release of NE from the matrix.     

Spherical Crystallization of Mebendazole to Improve Processability

Spherical crystallization technique combines crystallization and agglomeration directly to generate spherical crystals with improved micromeretic properties, thus obviating need for further processing by granulation and agglomeration. The present study was focused on spherical crystallization of an antihelmentic drug – Mebendazole (MBZ) – using spherical agglomeration technique. Apart from being poorly water-soluble, MBZ exhibits poor flow and compressibility owing to its needle shaped crystal habit and electrostatic charge. Spherical agglomeration was carried out in the presence of different bridging liquids (hexane, octanol, toluene, dichloromethane) and polymers (polyethylene glycol, cross-povidone, starch, cross carmellose sodium, hydroxyl propyl methyl cellulose (HPMC), hydroxyl propyl cellulose (HPC), ethyl cellulose (EC), Eudragit®S100, Eudragit®RLPO, Eudragit®RD100, Eudragit®E), by employing different crystallization conditions such as variation of polymer type, polymer concentration, and rate of stirring. The final parameters were optimized to obtain crystals with an aspect ratio in the range of 1–2 compared to a value of 12 for untreated MBZ. These agglomerates retained form C of MBZ, and exhibited good flow properties, high bulk density and improved compressibility. Lower elastic:plastic energy (EE/PE) ratio for spherical crystals generated in the presence of Eudragit®-S100 and Hydroxypropylcellulose (HPC) indicated better compressibilty of spherical crystals.     

Influence of Fumed Silicon Dioxide on the Stabilization of Eudragit® RS/RL 30 D Film-Coated Theophylline Pellets

The objective of this study was to investigate the influence of various grades of fumed silicon dioxide on the drug release rate and physical aging of theophylline pellets coated with Eudragit® RS 30 D and RL 30 D. Free films were assessed for both physicomechanical properties and water vapor permeability with respect to time and storage conditions. The release rate of theophylline was influenced by the physical properties of the silicon dioxide employed. As the particle size of the silica dioxide decreased, there was an increase in dispersion viscosity, as well as a decrease in the theophylline release rate from the coated pellets. Films prepared from formulas containing Aeroperl® 300 had twice the water vapor transmission rate of films prepared from formulas containing Aerosil® 200 VV and Cab-O-Sil® M-5P and showed consistent moisture permeability values during storage for up to 1 month at 25°C/0% relative humidity (RH). Scanning electron microscopy (SEM) imaging of pellets coated with a formulation containing Aerosil® 200 VV or Cab-O-Sil® M-5P demonstrated film structures that were homogenous, while those coated with a formulation containing Aeroperl® 300 produced heterogeneous films with large particles of the excipient present within the polymeric matrix of the film. Stability in the drug release rate exhibited by pellets coated with a formulation containing Eudragit® RS 30 D, 15% triethyl citrate (TEC), and 30% Aeroperl® 300 was attributed to the stabilization of the moisture vapor transmission rate of the acrylic films. Increasing the concentration of Aeroperl® 300 in the coating formulation increased the theophylline release rate from coated pellets.     

Application of methyl methacrylate copolymers to the development of transdermal or loco-regional drug delivery systems

Introduction: Methyl methacrylate copolymers (Eudragit®) have been exploited to develop transdermal patches, medicated plasters (hereinafter patches) and, more recently, film-forming sprays, microsponges and nanoparticles intended to be applied on the skin.

Areas covered: The article reviews the information regarding the application of Eudragits in the design and development of these dosage forms focusing on the impact of formulative variables on the skin drug penetration and the patch adhesive properties.

Expert opinion: Eudragits combined with a large amount of plasticizers are used to design the pressure-sensitive adhesives, specialized materials used in the patch development. They have to assure the drug skin penetration and the contact with the skin. Most of the studies mainly deal with the former aspect. The authors used a Eudragit type opportunely plasticized to merely investigate the in vitro or in vivo skin permeability of a loaded drug. However, the summa of these data evidenced that a strict connection between the matrix hydrophilicity and drug penetration probably exists. The criticisms of adhesion are addressed in a limited number of papers reporting data on technological properties, namely tack, shear adhesion and peel adhesion, while the structural data of the Eudragit adhesives, rheology and surface free energy are not described, excepting the case of Eudragit E. Among other applications, micro- and nanosystems exploiting the ionizable nature of some Eudragits can offer novel opportunities to develop pH-sensitive drug delivery systems suitable for triggering its release onto the skin.     

Binary Medical Nanofluids by Combination of Polymeric Eudragit Nanoparticles for Vehiculization of Tobramycin and Resveratrol: Antimicrobial,Hemotoxicity and Protein Corona Studies

The development of smart nanoparticles (NPs) became a trend to enhance the delivery of drugs. In the present work, Tobramycin (TB), an aminoglycoside antibiotic that displays several undesirable side effects, has been encapsulated into cationic Eudragit®E100 (E100) NPs for the treatment of infections caused by Pseudomonas aeruginosa. Combination with neutral Eudragit®NE30D (NE30D) NPs containing resveratrol (RSV), a strong natural antioxidant, increased the antimicrobial activity of TB (75% higher than free TB). NPs were stabilized with 1.0% (w/v) poloxamer 188 (P188) or poloxamer 407 (P407) as surfactants. E100 NPs showed 83.3 ± 8.5%, and 70.1 ± 2.7 encapsulation efficiency (EE) of TB with P188 and P407 coatings, respectively. The presence of NPs was confirmed by DLS and TEM studies. TB was controlled released from NPs for 6 h. Hemotoxicity tests of NPs in the range of MIC values on human blood gave negative results. Analysis of Surface Plasmon Resonance verified that NE30D/P407/RSV does not interact with plasma proteins BSA, IgG or fibrinogen, besides E100/P188/TB interact with BSA, findings that are compatible with a negligible in vivo clearance of the nanovehicles. The obtained results show a potential binary fluid composed of two NPs to highly improve the effectiveness of conventional antibiotics.     

Development of local patches containing melilot extract and ex vivo-in vivo evaluation of skin permeation.

Melilot extract could be effective in treating localised varicose syndrome or capillary fragility. The monolayer patch was selected to obtain a prolonged release of coumarin contained in the phytocomplex. Two types of methacrylic patches (patch 1 based on a blend of Eudragit E100 and Eudragit NE; patch 2 based on Eudragit L100) were prepared. Both patches were equivalent in terms of coumarin release and ex vivo skin permeation profiles. The two patches differed significantly as regards respective adhesive properties. At low peel rate only patch 1 showed adhesive failure as confirmed by the in vivo performance. When comparing the behaviour of the patches containing melilot extract with analogous patches containing synthetic coumarin, no melilot phytocomplex enhancer effect was shown. The data of the ex vivo coumarin skin permeation and those obtained by the in vivo stripping technique showed a good correlation (r(2)=0.9727 for patch 1, r(2)=0.9835 for patch 2).     

Design and Evaluation of a Monolithic Drug-in-Adhesive Patch for Testosterone Based on Styrene–Isoprene–Styrene Block Copolymer

The purpose of the present study was to design and evaluate a monolithic drug-in-adhesive patch with a novel pressure-sensitive adhesive (PSA) matrix based on styrene–isoprene-styrene (SIS) block copolymer. Testosterone was selected as the model drug. The orthogonal array design for ternary mixtures was employed to optimize the amounts of SIS, C-5 hydrocarbon resin, and liquid paraffin. The drug release percentage, water vapor permeability, adhesive properties were chosen as response variables. The patch formulation was optimized by investigating the effects of the drug loading capacity, the type, and amount of permeation enhancer on the adhesive properties and skin permeation. The compositions of the optimal matrix were: 120 g of SIS copolymer, 120 g of C-5 hydrocarbon resin, 60 g of liquid paraffin. An optimized formulation with maximum skin permeation and acceptable adhesive properties was developed incorporating 2% testosterone and 6% isopropyl myristate. No significant differences for in vitro release, skin permeation, and in vivo absorption were observed between the optimal formulation and Testopatch®. The stability evaluation showed that the patches were stable at 25°C/60% relative humidity for 6 months. The result indicated that SIS copolymer was a suitable and compatible polymer for the development of PSA. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2221–2234, 2013     

Salmon calcitonin-loaded Eudragit® and Eudragit®-PLGA nanoparticles: in vitro and in vivo evaluation

The main objective of this study was to prepare salmon calcitonin (sCT)-loaded Eudragit®RSPO, Eudragit®L100 and Eudragit®-poly(lactic-co-glycolic acid) blend nanoparticles for in vitro and in vivo evaluation as an oral drug delivery system. The prepared nanoparticles ranged in size from 179.7 to 308.9?nm with a polydispersity index between 0.051 and 2.75, and had surface charges ? ?11 to +6?mV. Efficient sCT encapsulation and release was observed with all the nanoparticle formulations. The polymer type was an important factor that influenced the release characteristics and the in vivo hypocalcemic effect. Nanoparticle formulations were also prepared with sodium taurodeoxycholate (NaTDC) and characterized. No statistically significant difference was noted between the hypocalcemic effect of any of the nanoparticle formulations with and without NaTDC (p?>?0.05). The use of Eudragit®RSPO nanoparticles appears to be a potential approach for the oral delivery of sCT.     

Application of viscometry and solubility parameters in miconazole patches development

Nine binary mixtures of seven different methacrylic copolymer systems (Plastoid^® E 35 L (PLE) and Plastoid^® L 50 (PLL); Eudragit^® (Eu) NE, RL, RS, L, S) were tested as components of monolayer patches containing miconazole. Only three mixtures (PLE:EuNE, PLE:EuRL and PLE:EuRS) were suitable for the preparation of placebo matrices. Miconazole patches with good technological characteristics were obtained by using mixtures of PLE:EuNE and PLE:EuRL. The in vitro miconazole release rate from the two patches and from the patch prepared using only PLE were significantly different. The amounts of drug released in 24 h were quite satisfactory. A mathematical model based on capillary viscometry data was used for the evaluation of interactions between copolymers. This was useful to predict and understand the mechanisms related to the instability of the prepared mixture. The solubility parameters of the drug and of the matrix were also calculated. Miconazole release was faster when the difference between the solubility parameters of the matrix and of the drug was higher. A relationship between miconazole release rate and the difference of drug and matrix solubility parameters was found. Therefore, the solubility parameter could be applied in formulation studies of patches.     

Eudragit® microparticles as a possible tool for ophthalmic administration of acyclovir

This paper describes the production and characterization of polyacrylic polymer (Eudragit® RL, RS and NE) microparticles by spray drying method. Microparticles were designed for ophthalmic administration of acyclovir. Microparticle morphology was characterized by optical and electron microscopy. The release kinetics of the drug from microspheres were determined by a dialysis method. The spray drying method described allows the production of microparticles with acceptable encapsulation efficiency and appropriate dimensional characteristics for ophthalmic administration. Release profile data indicate that acyclovir is released from microparticles in a controlled manner. In addition the release pattern of the drug is influenced by the type of Eudragit® used for microparticle production. Moreover the plaque reduction efficiency of acyclovir containing microparticles (except for RS/NE microspheres) is comparable to that displayed by the free drug. Finally our results suggest that acyclovir containing microparticles could represent an interesting system for the release of this antiviral drug at the eye site.     

Solvent-Free Melt Electrospinning for Preparation of Fast Dissolving Drug Delivery System and Comparison with Solvent-Based Electrospun and Melt Extruded Systems

The solvent-free melt electrospinning (MES) method was developed to prepare a drug delivery system with fast release of carvedilol (CAR), a drug with poor water solubility. To the authors knowledge, this is the first report for preparing drug-loaded melt electrospun fibers. Cationic methacrylate copolymer of Eudragit® E type was used as a fiber forming polymer matrix. For comparison, ethanol-based electrospinning and melt extrusion (EX) methods were used to produce samples that had the same composition as the melt electrospun system. According to the results of scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and Fourier transformed infrared spectrometry investigations, amorphous solid nanodispersions/solutions of CAR in Eudragit® E matrix were obtained in all cases with 20 ^m/_m% drug content. In vitro drug release in acidic media from the extrudates was significantly faster (5 min) than that from crystalline CAR. Moreover, ultrafast drug release was achieved from the solvent-free melt and ethanol-based electrospun samples because of their huge surface area and the soluble polymer matrix in the acidic media. These results demonstrate that solvent-free MES is a promising, novel technique for the production of drug delivery systems with enhanced dissolution because it can combine the advantages of EX (e.g., solvent-free, continuous process, and effective amorphization) and solvent-based electrospinning (huge product surface area).     

Influence of Plasticizer Level on the Drug Release from Sustained Release Film Coated and Hot-Melt Extruded Dosage Forms

In the current study, the influence of plasticizer level on drug release was investigated for solid dosage forms prepared by hot-melt extrusion and film coating. The properties of two highly water-soluble compounds, diltiazem hydrochloride (DTZ) and chlorpheniramine maleate (CPM), and a poorly water-soluble drug, indomethacin (IDM), were investigated in the melt extrudates containing either Eudragit® RSPO or Eudragit® RD 100 and triethyl citrate (TEC) as the plasticizer. In addition, pellets containing DTZ were film coated with Eudragit® RS 30D and varying levels of TEC using a fluidized bed coating unit. Differential scanning calorimetry (DSC) demonstrated that both CPM and IDM exhibited a plasticization effect on the acrylic polymers, whereas no plasticizing effect by DTZ on Eudragit® RSPO was observed. Thermogravimetric analysis (TGA) was used to investigate the thermal stability of the DTZ, Eudragit® RSPO and TEC at 140 °C, the maximum temperature used in the hot-melt extrusion process. The chemical stability of DTZ and IDM in the extrudate following hot-melt processing was determined by high pressure liquid chromatography (HPLC). Drug release rates of both DTZ and CPM from hot-melt extrudates increased with an increase in the TEC level in the formulations, while the release rate of DTZ from the Eudragit® RS 30D–coated pellets decreased with an increase in TEC in the coating dispersion. This phenomenon was due to the formation of a reservoir polymeric structure as a result of the thermal stress and shear stress involved in the hot-melt extrusion process regardless of the TEC level. In contrast, coalescence of the polymer particles in the film coating process was enhanced with higher levels of TEC, as demonstrated by scanning electron microscopy (SEM). The addition of TEC (0% to 8%) in the IDM hot-melt extrudate formulation had no influence on the drug release rate as the drug release rate was controlled by drug diffusion through the inside of the polymeric materials rather than between the polymer particles.     

氟比洛芬压敏胶分散型贴剂的制备及体外经皮渗透性考察

目的:研制氟比洛芬压敏胶分散型贴剂并考察其体外经皮渗透性。方法:将氟比洛芬及各种促渗剂直接溶于压敏胶中制备压敏胶分散性贴剂,采用卧式双室扩散池,研究其体外经皮渗透行为。结果:由Duro-Tak 87-9301型压敏胶制备的贴刺具有较好的稳态渗透速率。5%氯酮与10%豆蔻酸异丙酯合用对氟比洛芬促渗效果明显,经皮渗透速率为（3.35±0.53）μg·cm^-2·h^-1,促渗倍率达2.68倍。贴剂中氟比洛芬的含量由5%增加到10%,经皮渗透速率明显增大,含量增加到15%和20%时,渗透速率无明显变化。结论:所得处方中各因素的组合有利于氟比洛芬的经皮吸收。     

Formulation and in vitro characterization of poly(dl-lactide-co-glycolide)/Eudragit RLPO or RS30D nanoparticles as an oral carrier of levofloxacin hemihydrate

The main objective of this study was to design positively charged Levofloxacin Hemihydrate (Levo-h)-loaded nanoparticles with improved entrapment efficiency and antibacterial activity. PLGA alone or in combinations with Eudragit® RLPO or RS30D with or without positively charged inducing agent; 1,2-dioleoyl-3-trimethylammonium-propane, chloride salt (DOTAP); were used for preparation of nanoparticles. Blending between PLGA and Eudragit® RLPO or RS30D with inclusion of DOTAP caused a marked increase in entrapment efficiency and switched zeta potential from negative to positive. Nanoparticle formulations; NR3 (Levo-h:PLGA:Eudragit® RLPO; 1:1:1 w/w with DOTAP) and NS3 (Levo-h:PLGA:Eudragit® RS30D; 1:1:1 w/w with DOTAP) that possess high positive zeta potential (59.3?±?7.5 and 55.1?±?8.2?mV, respectively) and Efficient Levo-h entrapment (89.54?±?1.5 and 77.65?±?1.8%, respectively) were selected for further examinations; in vitro release, physical stability and microbiological study. NR3 and NS3 showed significant sustained release of Levo-h. NR3 and NS3 exhibited good stability after storage at room temperature. Microbiological assay showed strengthened antibacterial activity of NR3 against both types of gram-negative bacteria (E. coli, Ps. aeruginosa) and of NS3 against Ps. aeruginosa compared to free Levo-h solution. NR3 and NS3 appear to be promising oral delivery system for Levo-h.     

Evaluation of potential environmental toxicity of polymeric nanomaterials and surfactants

Nanomaterials have gained huge importance in various fields including nanomedicine. Nanoformulations of drugs and nanocarriers are used to increase pharmaceutical potency. However, it was seen that polymeric nanomaterials can cause negative effects. Thus, it is essential to identify nanomaterials with the least adverse effects on aquatic organisms. To determine the toxicity of polymeric nanomaterials, we investigated the effects of poly(lactic-co-glycolid) acid (PLGA), Eudragit® E 100 and hydroxylpropyl methylcellulose phthalate (HPMCP) on zebrafish embryos using the fish embryo toxicity test (FET). Furthermore, we studied Cremophor® RH40, Cremophor® A25, Pluronic® F127 and Pluronic® F68 applied in the generation of nanoformulations to identify the surfactant with minimal toxic impact. The order of ecotoxicty was HPMCP < PLGA < Eudragit® E100 and Pluronic® F68 < Pluronic® F127 < Cremophor® RH40 < Cremophor® A25. In summary, HPMCP and Pluronic® F68 displayed the least toxic impact, thus suggesting adequate environmental compatibility for the generation of nanomedicines.     

Evaluation of water uptake and mechanical properties of blended polymer films for preparing gas-generated multiple-unit floating drug delivery systems

Among various strategies of gastroretentive drug delivery systems (DDSs) developed to prolong the gastric residence time and to increase the overall bioavailability, effervescent multiple‐unit floating DDSs (muFDDSs) were studied here. These systems consist of drug (losartan)‐ and effervescent (sodium bicarbonate)‐containing pellets coated with a blended polymeric membrane, which was a mixture of gastrointestinal tract (GIT)‐soluble and GIT‐insoluble polymers. The addition of GIT‐soluble polymers, such as hydroxypropyl methylcellulose, polyethylene glycol (PEG) 6000, PEG 600, and Kollicoat® IR, greatly increased the water uptake ability of the GIT‐insoluble polymers (Eudragit® NE, RS, and RL; Surelease®; and Kollicoat® SR) and caused them to immediately initiate the effervescent reaction and float, but the hydrated films should also be impermeable to the generated CO₂ to maintain floatation and sufficiently flexible to withstand the pressure of carbon dioxide to avoid rupturing. The study demonstrated that the water uptake ability and mechanical properties could be applied as screening tools during the development of effervescent muFDDSs. The optimized system of SRT(5)P600(5) (i.e., a mixture of 5% Kollicoat® SR and 5% PEG 600) with a 20% coating level began to completely float within 15 min and maintained its buoyancy over a period of 12 h with a sustained‐release effect.