Polymerized rosin: novel film forming polymer for drug delivery

Polymerized rosin (PR) a novel film forming polymer is characterized and investigated in the present study for its application in drug delivery. Films were produced by a casting/solvent evaporation method from plasticizer free and plasticizer containing solutions. Films prepared from different formulations were studied for their mechanical (tensile strength, percent elongation and Young's modulus), water vapour transmission and moisture absorption characteristics. Neat PR films were slightly brittle and posed the problem of breaking during handling. Hydrophobic plasticizers, dibutyl sebacate and tributyl citrate, improved the mechanical properties of free films with both the plasticizers showing significant effects on film elongation. Release of diclofenac sodium (model drug) from coated pellets was sustained with high coating levels. Concentration of plasticizer was found to affect the release profile. PR films plasticized with hydrophobic plasticizers could therefore be used in coating processes for the design of oral sustained delivery dosage forms.     

药物制剂中薄膜包衣微丸的研究与应用

综述近年来薄膜包衣微丸在药物制剂中的研究与应用。微丸属于多单元型药物传递系统，具有众多优点。而将微丸制备技术和薄膜包衣技术相结合制成的具有特殊释药性质的薄膜包衣微丸，已经成为缓、控释制剂研究领域的热点。     

Influence of hydroxyethylcellulose on the drug release properties of theophylline pellets coated with Eudragit RS 30 D.

The objective of this study was to investigate the influence of a hydrophilic polymer, hydroxyethylcellulose (HEC), on the release properties of theophylline from pellets coated with Eudragit RS 30 D, and the physicochemical properties of Eudragit RS 30 D cast films. The release rate of theophylline from Eudragit RS 30 D coated pellets decreased during storage at 25 degrees C/60% RH due to the further coalescence of colloidal acrylic particles. In addition, water-vapor permeability and tensile strength of Eudragit RS 30 D cast film decreased after 1-month storage at 25 degrees C/60% RH. The presence of 10% hydroxyethylcellulose in the coating formulation was shown to stabilize the drug release rate from coated pellets, the water-vapor permeability and the tensile strength of free films. Atomic force microscopy and scanning electronic microscopy were used to demonstrate that the HEC was immiscible with Eudragit RS 30 D in the cast films. The stabilization effect of HEC was investigated and determined to be due to the formation of an incompatible phase between the latex particles which impaired further coalescence of the colloidal acrylic particles.     

Alginate-chitosan film for ocular drug delivery: effect of surface cross-linking on film properties and characterization

The characteristics of alginate-chitosan films intended for ocular drug delivery of gatifloxacin sesquihydrate were compared with the ionically surface cross-linked films of similar compositions. The effect of polymer ratios and cross-linking was studied relatively to various parameters of formulations including physicochemical, mechanical strength, swelling and bioadhesion. The drug release profiles and drug release mechanisms were compared. The folding endurance, tensile strength, bioadhesive strength considerably increased whereas swelling index, elongation at break decreased with surface cross-linking of the films. Surface cross-linked formulation F3 (2% w/v sodium alginate and 1% w/v chitosan) showed most prolonged drug release of 24 h indicating the potential of surface cross linking of the film to sustain drug release. As per the kinetic models both type of films showed a constant drug release, however the drug release mechanism transformed from erosion to diffusion after cross linking. These results demonstrate that the surface treated alginate-chitosan film could be a potential vehicle to enhance ocular GS bioavailability and patient compliance.     

Novel Film Modifiers to Alter the Physical Properties of Composite Ethylcellulose Films

No HeadingPurpose. Polyvinylpyrrolidone (PVP), molecular-composite PVP, and Plasdone S-630 copolyvidonum are potential polymeric film modifiers for achieving improved drug release. The aim of this study was to investigate how these polymeric additives would affect the physicomechanical properties of composite ethylcellulose films.Methods. The miscibility of these polymeric additives with ethylcellulose was determined from the differential scanning calorimetry (DSC) thermograms of various polymer blends formed from organic solvents. It was found that ethylcellulose (EC) was miscible with the polymeric additives up to a concentration of 50%. Ten percent to 30% w/w polymeric additives were then added to aqueous ethylcellulose dispersion to form composite films. The morphology, film transparency, dynamic mechanical analysis (DMA) thermograms, and mechanical properties of the composite ethylcellulose films were studied. In addition, puncture strength and % elongation of the dry and wet films were also compared from indentation test.Results. Significant reduction and change in film transparency and morphology was obtained for EC films blended with PVP of higher molecular weight (MW). The composite EC films also showed higher T_g, greater elastic modulus, tensile and puncture strength depending on the concentration and type of additives present.Conclusions. The interaction between ethylcellulose and the polymeric additives is dependent on the MW and concentration of additives. The composite films offer new opportunities for the use of ethylcellulose as modified release coatings for dosage forms.     

A method for the preparation of sustained release-coated Metoprolol Succinate pellet-containing tablets

The purpose of this study was to develop a method to prepare Metoprolol Succinate (MS) sustained release pellets and compress them into pellet-containing tablets without losing sustained release property. The drug layered pellets were coated with Eudragit NE 30D to obtain a sustained release (SR) property. The mechanical properties and permeability of the coating film were tailored by adjusting the proportion of talc in the coating dispersion and the weight gain of the coating film. Pellets with different MS release rates were tested and then mixed together by different ratios to optimize drug release rate. The mixed pellets were compressed into tablets with cushioning excipients. The results showed that when the ratio of talc and coating material was 1:4, the coating operation could be conducted successfully without pellet conglutination and the mechanical property of the coating film was enhanced to withstand the compress force during tableting. Blending SR-coated pellets of 20% weight gain with SR-coated pellets of 40% weight gain at the ratio of 1:5 could produce a constant and desired drug release rate. The formulation and the procedure developed in the study were suitable to prepare MS pellet-containing tablets with selected SR properties.     

Bacteria and pH-sensitive polysaccharide-polymer films for colon targeted delivery

The colon provides drug delivery opportunities for colon-specific and systemic delivery of various therapeutic agents. Different strategies have been utilized in targeting drugs to the colon. Recently, integrated systems which incorporate dual mechanisms in colon targeted delivery have received a lot of attention. Of particular interest is bacteria-aided biomaterials and pH-sensitive polymeric film (BPSF) coating for colon targeted drug delivery. The major constituents of these films are polysaccharides and pH-sensitive polymers. The pH-sensitive polymer retards drug release in the stomach and small intestine, while the polysaccharide is digested by colonic enzymes. Digestion of the polysaccharides by bacterial glycosidic enzymes increases the pore density in the film to facilitate drug release. Generally, bacteria-aided biomaterials and pH-sensitive films can be applied to the delivery of most small organic molecules to the colon. The review encompasses the pharmaceutical design parameters such as film digestibility, swelling index and dry mass loss (that provide molecular mechanistic analysis of film permeability) as well as tensile strength, elastic modulus, and elongation at break (that describe the desirable mechanical properties of the films). A critical analysis of formulation, techniques for characterization of film properties and drug-release kinetics from these systems are emphasized.     

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.     

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 degrees 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.     

Incorporation of surface-modified dry micronized poorly water-soluble drug powders into polymer strip films

Recent work has established polymer strip films as a robust platform for delivery of poorly water-soluble drugs via slurry casting, in particular using stable drug nanosuspensions. Here, a simpler, robust method to directly incorporate dry micronized poorly water-soluble drug, fenofibrate (FNB), is introduced. As a major novelty, simultaneous surface modification using hydrophilic silica along with micronization was done using fluid energy mill (FEM) in order to reduce FNB hydrophobicity and powder agglomeration. It is hypothesized that silica coating promotes easy, uniform dispersion of micronized and coated FNB (MC-FNB) during direct mixing with aqueous hydroxypropyl methylcellulose (HPMC-E15LV) and glycerin solutions. Uniform dispersion leads to improved film critical quality attributes (CQAs) such as appearance, drug content uniformity and drug dissolution. The impact of polymer solution viscosity (low and high), mixer type (low versus high shear), and FNB surface modification on film CQAs were also assessed. Films with as-received FNB (AR-FNB) and micronized uncoated FNB (MU-FNB) were prepared as control. When MC-FNB powders were used, films exhibited improved appearance (thickness uniformity, visible lumps/agglomerates), better drug content uniformity (expressed as relative standard deviation), fast and immediate drug release, and enhanced mechanical properties (tensile strength, elongation percentage), regardless of the polymer solution viscosity or mixer type. These results compare favorably with those reported using nanosuspensions of FNB, establishing the feasibility of directly incorporating surface modified-micronized poorly water-soluble drug powders in film manufacturing.     

Influence of film additives on stabilizing drug release rates from pellets coated with acrylic polymers.

The objective of this study was to investigate the influence of talc and triethyl citrate (TEC) on stabilizing the drug release rates following curing and storage at elevated temperature of pellets coated with an aqueous acrylic polymeric dispersion. Core pellets containing anhydrous theophylline (20%), microcrystalline cellulose, and polyvinylpyrrolidone were prepared by extrusion-spheronization. The aqueous dispersions were prepared by adding up to 30% TEC as a plasticizer and talc up to 200% as an antiadherent to a mixture of Eudragit RS 30D/RL 30D (95:5). The theophylline pellets were coated in a fluidized-bed coating unit and then cured at elevated temperatures. Theophylline pellets were successfully coated with the Eudragit dispersions that contained up to 200% talc, based on the dry polymer weight, and the coating efficiency was greater than 93%. Our results demonstrated that the polymer, which was plasticized by TEC, was able to function as a film-forming agent for dispersions containing high levels of talc. No sticking of the coated pellets was observed during the coating process or during the curing or equilibrating phase, even with high levels of TEC in the film. The dissolution rate of theophylline from the coated pellets was delayed when the film coating dispersion contained high levels of talc. Additionally, the stability of the drug release profiles from the coated pellets after storage was significantly improved. Furthermore, a modified dissolution testing used to simulate mechanical stresses that may be encountered in vivo showed the film coated pellets would have sufficient strength. The results of this study demonstrated that high levels of film additives in the acrylic dispersion contributed to the stabilization of the drug release rates as well as the reproducibility of the coating process.     

Non-traditional plasticization of polymeric films

The objective of this study was to investigate the influence of methylparaben, ibuprofen, chlorpheniramine maleate and theophylline on the thermal and mechanical properties of polymeric films of Eudragit RS 30 D. The effects of methylparaben and ibuprofen in the film coating on the rate of drug release from Eudragit RS 30 D coated beads were also studied. The physical and mechanical properties of the cast films and coated beads were investigated using thermal analysis, tensile testing, X-ray diffraction analysis and dissolution testing. The results demonstrated that the glass transition temperature of the Eudragit RS 30 D decreased with increasing levels of methylparaben, ibuprofen and chlorpheniramine maleate in the film. Theophylline exerted no influence on the thermal properties of the polymer. The higher levels of the ibuprofen and methylparaben incorporated into the film resulted in a decrease in the tensile strength of the film. The decrease in Young's modulus of Eudragit RS 30 D coated beads was attributed to an increase in the flexibility of the polymeric films when the level of methylparaben or ibuprofen in the polymeric dispersion was increased. The dissolution data demonstrated that the rate of release of the ibuprofen from coated beads was decreased by increasing the amount of ibuprofen and methylparaben in the polymeric film coating.     

Corn starches as film formers in aqueous-based film coating

The purpose of this study was to evaluate the film formation ability and mechanical stress-strain properties of aqueous native corn starches, using free films and film coatings applied to tablets. Free films were prepared from high-amylose corn (Hylon VII), corn and waxy corn starches, using sorbitol and glycerol as plasticizers. The tablets and pellets were film-coated using an air-suspension coater, and characterized with respect to the film coating surface topography, cross-sectional structure and thickness (SEM), and dissolution in vitro. The amylose content of the starch film formers affected both the tensile strength and the elongation. The elongations were under 5% for even the plasticized starches, and in most cases, no plasticization effect was seen by either of the plasticizers. Dissolution of native corn starch film-coated tablets (weight gain 1%) did not differ from uncoated ones. A notable delay in dissolution of the drug was found by increasing Hylon VII film coating thickness, suggesting controlled-release characteristics.     

Suppression of agglomeration in fluidized bed coating. IV. Effects of sodium citrate concentration on the suppression of particle agglomeration and the physical properties of HPMC film

We previously reported that sodium citrate (Na citrate), which is a high order salt in the Hofmeister's series, greatly suppressed particle agglomeration in fluidized bed coating (Pharm. Res., 16 (1999), 1616-1620). In this paper, we studied the effects of Na citrate concentration on the particle agglomeration in fluidized bed coating and on the structure of coated film on the particles. Spherical granules made of crystalline cellulose (Celphere) containing phenacetin were coated in a fluidized bed with the aqueous coating solution of hydroxypropylmethyl cellulose (HPMC) containing Na citrate at various concentrations. The particle diameter and drug release profile of coated particles, and the physical properties, i.e. tensile strength, elongation percentage at break, porosity and pore size distribution, of the HPMC cast film were investigated. The particle agglomeration was suppressed with the increasing Na citrate concentration. It is considered that the increase in the suppression effect was caused by the salting-out effect of the increased Na citrate. In the HPMC cast film system, the tensile strength and elongation percentage decreased and the porosity and cumulative pore volume increased with an increase in Na citrate concentration. It is considered that the increase in the porosity by adding Na citrate resulted from a phase separation due to the salting-out during the film forming process. The drug release rate from coated particles also increased with the increasing Na citrate concentration. It can be concluded that the increase in the release rate was due to the increase in porosity of the HPMC coated film caused by the increased Na citrate concentration.     

Polymer Blends Used for the Coating of Multiparticulates: Comparison of Aqueous and Organic Coating Techniques

PURPOSE: The purpose of this study was to use polymer blends for the coating of pellets and to study the effects of the type of coating technique (aqueous vs. organic) on drug release. METHODS: Propranolol HCl-loaded pellets were coated with blends of a water-insoluble and an enteric polymer (ethyl cellulose and Eudragit L). Drug release from the pellets as well as the mechanical properties, water uptake, and dry weight loss behavior of thin polymeric films were determined in 0.1 M HCI and phosphate buffer, pH 7.4. RESULTS: Drug release strongly depended on the type of coating technique. Interestingly, not only the slope, but also the shape of the release curves was affected, indicating changes in the underlying drug release mechanisms. The observed effects could be explained by the higher mobility of the macromolecules in organic solutions compared to aqueous dispersions, resulting in higher degrees of polymer-polymer interpenetration and, thus, tougher and less permeable film coatings. The physicochemical properties of the latter were of major importance for the control of drug release, which was governed by diffusion through the intact polymeric films and/or water-filled cracks. CONCLUSIONS: The type of coating technique strongly affects the film microstructure and, thus, the release mechanism and rate from pellets coated with polymer blends.     

Relationship between drug dissolution and leaching of plasticizer for pellets coated with an aqueous Eudragit S100:L100 dispersion

In order to investigate the relationship between drug dissolution and leaching of plasticizer, theophylline pellets coated with 30% (w/w) Eudragit S100:L100 (1:1) plasticized with different levels of triethyl citrate (TEC) were prepared. The influence of storage conditions on the dissolution profile of theophylline and leaching of TEC was determined. Theophylline was found to dissolve completely from pellets coated with Eudragit S100:L100 (1:1) plasticized with 50% TEC at pH 6.0 after 2h. The shape of the pellets was maintained during dissolution testing. Cracks due to the leaching of TEC were observed in the scanning electron micrographs (SEMs) following dissolution testing at pH 6.0. Both the dissolution of theophylline and the leaching of TEC decreased during storage due to further coalescence of the acrylic polymers. The dissolution profiles of theophylline showed a biphasic pattern and the lag times were estimated as the time points at which a second, rapid release of theophylline was initiated. Subsequently, the percent of TEC leached at the lag time was calculated. While the lag time was increased by storage time and humidity, the percent of TEC leached at the lag time was unchanged as a function of storage condition and was dependent on the initial TEC levels in the films. In conclusion, the plasticizer content in the film coating influenced the dissolution profile of theophylline from pellets coated with Eudragit S100:L100 (1:1). A large amount of the TEC was leached from the enteric films before drug release was initiated and a TEC level of approximately 30% in the films, based on the polymer weight, was the critical amount of TEC for initiating drug release during dissolution testing at pH 6.0. While enteric films are more soluble and dissolve faster at higher pH values, the kinetics of plasticizer release was one of the important factors controlling the dissolution of drugs at pH 6.0, at which pH the enteric polymers were insoluble.     

Release behavior of tanshinone IIA sustained-release pellets based on crack formation theory

The objective of this study was to investigate the drug release mechanism and in vivo performance of Tanshinone IIA sustained-release pellets, coated with blends of polyvinyl acetate (PVAc) and poly(vinyl alcohol)-poly(ethylene glycol) (PVA-PEG) graft copolymer. A formulation screening study showed that pellets coated with PVAc-PVA-PEG at a ratio of 70:30 (w/w) succeeded in achieving a 24 h sustained release, irrespective of the coating weight (from 2% to 10%). Both the microscopic observation and mathematical model gave further insight into the underlying release mechanism, indicating that diffusion through water-filled cracks was dominant for the control of drug release. In vivo test showed that the maximum plasma concentration of sustained-release pellets was decreased from 82.13 ± 17.05 to 40.50 ± 11.72 ng mL as that of quick-release pellets. The time of maximum concentration, half time, and mean residence time were all prolonged from 3.80 ± 0.40 to 8.02 ± 0.81 h, 4.28 ± 1.21 to 8.18 ± 2.06 h, and 8.60 ± 1.59 to 17.50 ± 2.78 h, compared with uncoated preparations. A good in vitro-in vivo correlation was characterized by a high coefficient of determination (r = 0.9772). In conclusion, pellets coated with PVAc-PVA-PEG could achieve a satisfactory sustained-release behavior based on crack formation theory.     

Aqueous ethyl cellulose dispersion containing plasticizers of different water solubility and hydroxypropyl methyl-cellulose as coating material for diffusion pellets II: properties of sprayed films.

This study investigates the properties of sprayed films prepared from aqueous ethyl cellulose dispersions (ECD) containing hydroxypropyl methylcellulose (HPMC) and plasticizers of different water solubility in order to clarify the drug release mechanisms of pellets coated with the respective material. It is of special interest to measure the migration of the water soluble components as well as the physical properties of the swollen ethyl cellulose film. Swelling experiments with sprayed films in 0.1 N-HCl at 37 degrees C show that fairly water soluble plasticizers and the pore forming agent (HPMC) migrated rapidly and almost completely out of the films. The water insoluble plasticizers remain predominantly in the film and the migration rate of HPMC is reduced in a release medium of high ionic strength. The glass transition temperature (T(g)) and the softening temperature (T(s)) of these films after swelling are dependent on the water solubility of the plasticizer. The T(g) of ECD films plasticized with triethyl citrate is above the swelling temperature of 37 degrees C after migration of the plasticizer, transforming the polymer in the glassy state. In contrast, dibutyl phthalate-containing ECD films demonstrate a T(g) below the swelling temperature, leaving the polymer in the rubbery state. The mechanical properties of dry and wet films are studied as a function of the state of curing of the films and of the swelling temperature. On contact with water, a pronounced shrinkage of ECD/HPMC films plasticized with water insoluble plasticizers is observed. All these results are used to explain the different drug release mechanisms of the coated pellets and to enable the prediction and optimization of drug release-rates from coated pellets.     

Compression of pellets coated with various aqueous polymer dispersions

Pellets coated with a new aqueous polyvinyl acetate dispersion, Kollicoat SR 30 D, could be compressed into tablets without rupture of the coating providing unchanged release profiles. In contrast, the compression of pellets coated with the ethylcellulose dispersion, Aquacoat ECD 30, resulted in rupture of the coating and an increase in drug release. Plasticizer-free Kollicoat SR coatings were too brittle and ruptured during compression. 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 tabletting excipients slightly affected the drug release, primarily because of a different disintegration rate of the tablets. The core size of the starting pellets had no influence on the drug release. Pellets coated with the enteric polymer dispersion Kollicoat 30 D MAE 30 DP [poly(methacrylic acid, ethyl acrylate) 1:1] lost their enteric properties after compression because of the brittle properties of this enteric polymer. Coating of pellets with a mixture of Kollicoat MAE 30 DP and Kollicoat EMM 30 D [poly(ethyl acrylate, methyl methacrylate) 2:1] at a ratio of 70/30 and compaction of the pellets resulted in sufficient enteric properties.     

Corn Starches as Film Formers in Aqueous-Based Film Coating

The purpose of this study was to evaluate the film formation ability and mechanical stress–strain properties of aqueous native corn starches, using free films and film coatings applied to tablets. Free films were prepared from high-amylose corn (Hylon VII), corn and waxy corn starches, using sorbitol and glycerol as plasticizers. The tablets and pellets were film-coated using an air-suspension coater, and characterized with respect to the film coating surface topography, cross-sectional structure and thickness (SEM), and dissolution in vitro. The amylose content of the starch film formers affected both the tensile strength and the elongation. The elongations were under 5% for even the plasticized starches, and in most cases, no plasticization effect was seen by either of the plasticizers. Dissolution of native corn starch film-coated tablets (weight gain 1%) did not differ from uncoated ones. A notable delay in dissolution of the drug was found by increasing Hylon VII film coating thickness, suggesting controlled-release characteristics.