pH-independent release of a basic drug from pellets coated with the extended release polymer dispersion Kollicoat SR 30 D and the enteric polymer dispersion Kollicoat MAE 30 DP.

The objective of this study was to obtain pH-independent release profiles from coated pellets containing drugs with pH-dependent solubility. pH-independent release of the basic model drug verapamil HCl was achieved by coating with a combination of the neutral polymer dispersions Kollicoat SR 30 D (aqueous dispersion of polyvinyl acetate) and the enteric polymer dispersion Kollicoat MAE 30 DP (aqueous dispersion of methacrylic acid and ethyl acrylate copolymer; methacrylic acid copolymer type C). The two polymers where applied either as separate layers (enteric polymer + extended release polymer or vice versa) or as a polymer blend. A careful balance of the ratios of the polymers allowed the achievement of a pH-independent release. Higher amounts of the enteric polymer in the polymer blend resulted in a reversal of the pH-dependency, e.g. a faster release at pH 6.8 than in 0.1 N HCl.     

Enteric polymers as acidifiers for the pH-independent sustained delivery of a weakly basic drug salt from coated pellets

Weakly basic drugs and their salts exhibit a decrease in aqueous solubility at higher pH, which can result in pH-dependent or even incomplete release of these drugs from extended release formulations. The objective of this study was to evaluate strategies to set-off the very strong pH-dependent solubility (solubility: 80 mg/ml at pH 2 and 0.02 mg/ml at pH 7.5, factor 4000) of a mesylate salt of weakly basic model drug (pK_a 6.5), in order to obtain pH-independent extended drug release. Three approaches for pH-independent release were investigated: (1) organic acid addition in the core, (2) enteric polymer addition to the extended release coating and (3) an enteric polymer subcoating below the extended release coating. The layering of aspartic acid onto drug cores as well as the coating of drug cores with an ethylcellulose/Eudragit L (enteric polymer) blend were not effective to avoid the formation of the free base at pH 7.5 and thus failed to significantly improve the completeness of the release compared to standard ethylcellulose/hydroxypropyl cellulose (EC/HPC)-coated drug pellets. Interestingly, the incorporation of an enteric polymer layer underneath the EC/HPC coating decreased the free base formation at pH 7.5 and thus resulted in a more complete release of up to 90% of the drug loading over 18 h. The release enhancing effect was attributed to an extended acidification through the enteric polymer layer. Flexible release patterns with approximately pH-independent characteristics were successfully achieved.     

The use of formulation technology to assess regional gastrointestinal drug absorption in humans.

The aim of this study was to assess the feasibility of using oral modified-release formulations for the purposes of site-specific targeting and regional drug absorption assessment in man. An immediate release pellet formulation containing ranitidine as the model drug of choice for the study was fabricated by extrusion-spheronisation, and then film coated with either the enteric polymer polyvinyl acetate phthalate or the bacteria-degradable polymer amylose, in combination with ethylcellulose, to effect drug release within the small intestine and colon, respectively. Optimised formulations were evaluated in vivo in ten healthy volunteers, who each received, on four separate occasions, the immediate release, small intestinal release and colonic release formulations (each equivalent to 150mg ranitidine), and an intravenous injection of ranitidine (equivalent to 50mg ranitidine). Blood samples were collected and assessed for ranitidine concentration, and radiolabelled placebo pellets were co-administered with the coated ranitidine pellets to monitor their gastrointestinal transit using a gamma camera. Ranitidine was rapidly released and absorbed from the immediate release formulation, whereas the enteric formulation (10% coat weight gain) delayed drug release until some or all of the pellets had emptied into the small intestine. The amylose-ethylcellulose coated formulation (coat ratio 1:3, coat weight gain 25%) retarded ranitidine release until the pellets had reached the colon. The mean absolute bioavailability of ranitidine from the immediate release, small intestinal release and colonic release formulations were 50.6, 46.1 and 5.5%, respectively. These data are in general agreement to those obtained from a previous regional intubation study. The present study therefore demonstrates the practical potential of utilising a non-invasive, formulation-based approach to assess drug absorption from different regions of the human gastrointestinal tract.     

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.     

Properties of enteric coated sodium valproate pellets

The influence of subcoat application and micro-environmental pH on the dissolution properties of enteric coated sodium valproate pellets was investigated. The pellets were prepared by solution-layering or wet-mass extrusion-spheronization methods. In order to pass the USP enteric test, the solution-layered and wet-mass extruded pellets required 35 and 25% weight gain of Eudragit L 30D-55, respectively. The application of a subcoat of either Methocel-E5 (HPMC) or Opadry AMB to the pellets resulted in a delay in sodium valproate release in 0.1N HCl. Further delay in drug release was observed when citric acid was present in a HPMC subcoat or when added to the core pellet formulation. The amount of drug released from coated pellets was a function of the level of citric acid in the pellet core or subcoat and subsequent micro-environmental pH of the pellets. Citric acid exerted a plasticizing effect on the enteric polymer film and improved film formation and polymer coalescence. When greater than 10% (w/w) citric acid was present in the pellets, a decrease in drug content was observed due to the conversion of sodium valproate to the volatile compound, valproic acid. Pellets containing less than 10% (w/w) citric acid maintained potency during processing.     

pH依赖—缓释型美沙拉秦结肠靶向小丸的制备与体外评价

以肠溶型和渗透型丙烯酸树脂为包衣材料制备ｐＨ依赖－缓释型美沙拉秦结肠靶向小丸,评价其体外释放特性。结果表明,包衣小丸在０．１ｍｏｌ／ＬＨＣｌ中２ｈ几乎不释放药物,在ｐＨ７．５缓冲液中具有较好的缓释作用。在模拟胃肠道各区段最高的和最低的ｐ变化的释放度试验中,均在对应小肠区段时开始缓慢释药。分别有４０％和７０％的药物进入结肠后释放。优于单独的肠溶或缓释制剂。     

Development of a single unit extended release formulation for ZK 811 752, a weakly basic drug.

ZK 811 752, a potent candidate for the treatment of autoimmune diseases, demonstrated pH-dependent solubility. The resulting release from conventional matrix tablets decreased with increasing pH-values of the dissolution medium. The aim of this study was to overcome this problem and to achieve pH-independent drug release. Three different polymers were used as matrix formers, the partly water-soluble and poorly swellable mixture of polyvinylacetate/polyvinylpyrrolidone, the water-insoluble and almost unswellable ethylcellulose (EC) and the water-soluble and highly swellable hydroxypropyl methylcellulose (HPMC). To solve the problem of pH-dependent solubility different organic acids, such as fumaric, tartaric, adipic, glutaric and sorbic acid were added to the drug-polymer system. The addition of organic acids to all three matrix formers was found to maintain low pH-values within the tablets during release of ZK 811 752 in phosphate buffer pH 6.8. Thus, the micro-environmental conditions for the dissolution of the weakly basic drug were kept almost constant. An extended release matrix tablet for ZK 811 752 consisting of drug, polymer and organic acid providing the desired pH-independent drug release has been developed.     

Evaluation of the drug release patterns and long term stability of aqueous and organic coated pellets by using blends of enteric and gastrointestinal insoluble polymers

The major aim of this study was to identify an efficient tool to adjust drug release patterns from aqueous and organic ethylcellulose (a gastrointestinal insoluble polymer) coated pellets and to evaluate the long term stability of the film coatings. Drug release was monitored during open and closed storage at 25 °C/60% RH (ambient conditions) and 40 °C/75% RH (stress conditions) for up to 24 months. Release of vatalanib succinate, a poorly soluble drug that demonstrates pH-dependent solubility, from pure ethylcellulose coated pellets was slow irrespectively of the type of coating and release medium. By addition of the enteric polymer methacrylic acid/ethyl acrylate copolymer (applied as aqueous Kollicoat MAE 30 DP dispersion or organic solution of Kollicoat MAE 100 P) to ethylcellulose broad ranges of drug release patterns could be achieved. For aqueous film coatings the addition of Kollicoat MAE 30 DP to ethylcellulose dispersions resulted in unaltered drug release kinetics during closed storage at ambient and stress conditions. The storage stabilizing effect of the added enteric polymer might be explained by the more hydrophilic nature of Kollicoat MAE 30 DP compared to ethylcellulose trapping water during film formation and improving polymer particle coalescence. However, during open storage of aqueous coated ethylcellulose:Kollicoat MAE 30 DP pellets at stress conditions drug release decreased due to further gradual polymer particle coalescence. In contrast, drug release rates from organic coated ethylcellulose:Kollicoat MAE 100 P pellets stored at ambient and stress conditions did not change which could be explained by differences in the film formation process. This clearly indicates that the presented concept of the addition of methacrylic acid/ethyl acrylate copolymer to ethylcellulose film coatings in combination with an organic coating process is able to achieve broad ranges of drug release patterns and to overcome storage instability.     

Modulating pH-independent release from coated pellets: Effect of coating composition on solubilization processes and drug release

The aim of the study was to clarify the influences of three coating parameters on the drug release from chlorpheniramine maleate (CPM) pellets, coated with blends of poly(vinyl acetate) (PVAc) and poly(vinyl alcohol)-poly(ethylene glycol) (PVA-PEG) graft copolymer. A central composite design was implemented to investigate the effect of the polymer blend ratio, the film coat thickness and the plasticizer concentration on the drug release. The solubilization inside the pellets was monitored by EPR spectroscopy. The blending ratio of both the polymers and the film thickness were found to have a major influence on the drug release and the solubilization speed, in contrast to the plasticizer concentration. A pH-independent release profile was adjustable via modulating the polymer blend ratio and the coating thickness. A mathematical model was developed, providing a good predictability of the release profile, based on the film coat composition. This model offers the possibility to achieve a defined drug-release profile by selective adaptation of the film coat composition, in view of process times, feasibility or polymer costs.     

XEDS-mapping for explaining release patterns from single pellets

A common way to formulate controlled-release (CR) pharmaceuticals is to coat pellets of active substance with a polymer film, decrease the size of the pellets and distribute them as multiple-unit dosages in capsules. To increase the understanding of the release mechanism, the pellet shape and surface structure of pellets, before and after release in microtitre plates, have been studied by scanning electron microscope and X-ray energy-dispersive spectrometry. By performing these studies we associate release profiles during the first few hours to the microscopic structure. Pellets were divided into three classes (spherical pellets, dumbbell shaped pellets and twin-pellets) according to pellet form. Cases of burst release occurred for all three shape classes due to “open-window-defects” at the surface. Areas of thinner polymer film in the neck-region of dumbbell shaped pellets broaden the range of intermediate release rates for this pellet shape. The surface of twin pellets and dumbbell shaped pellets showed more defects, which increases the release rates in comparison to spherical pellets. All pellets with high release rates revealed ruptures in the polymer film, whereas only small cracks could be traced for pellets with slow release rates. The information gained is necessary for the development of future formulations and mathematical modelling of release patterns. The pharmaceutical used as model was remoxipride coated with a polymer film of ethyl cellulose and 10 wt.% triethyl citrate.     

Influence of an enteric polymer on drug release rates of theophylline from pellets coated with Eudragit RS 30D

The purpose of this research study was to investigate the influence of an enteric polymer on the drug release properties of theophylline pellets coated with Eudragit RS 30D. Theophylline pellets were coated with aqueous colloidal dispersions of Eudragit RS 30D containing various amounts of Eudragit L 100-55. The effect of storage conditions on the release of drug from coated pellets was determined as a function of the pH of the dissolution medium. The results from the dissolution study showed significant changes in the dissolution rate of theophylline from pellets coated with Eudragit RS 30D when cured at 40 degrees C for 4 days. No change in the drug release rate was observed when Eudragit L100-55 was present in the Eudragit RS 30D dispersion. Increasing the ratio of Eudragit L100-55 to Eudragit RS 30D resulted in faster drug release rates from the coated pellets. An increase in the pH of the dissolution medium was found to enhance drug release from the pellets coated with Eudragit RS 30D containing Eudragit L 100-55. Theophylline pellets when coated with Eudragit RS 30D containing the enteric polymer Eudragit L100-55 demonstrated no aging effects when stored at elevated temperatures. The overcoating of the pellets with Eudragit RD 100 did not affect the drug release profiles and prevented the particles from agglomerating during curing and storage.     

Drug-Polymer Mixed Coating: A New Approach for Controlling Drug Release Rates in Pellets

A new approach to developing a drug-polymer mixed coat for highly water-soluble diltiazem pellets was investigated at different coating levels. Drug layering and the coating procedures were performed using a bottom spray fluidized bed coater. Drug pellets were coated with Eudragit NE40 (NE40) alone and in combination with diltiazem and hydrophilic cellulose derivatives. Dissolution studies revealed that incorporation of hydrophilic substances such as methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), and the drug itself considerably increased the release rates. The release from mixed polymer coatings was fast compared to pellets coated with NE40 only. The major portion of the drug was released in about 2 hours in case of MC and NE40 mixed coat compared to hours from coated pellets containing HPMC or diltiazem. Incorporation of 15% to 25% drug with respect to the polymer coat helped to achieve a drug-release profile at a desirable rate over a 12 hour period. Moreover, the test formulation comprising 25% diltiazem with respect to 7% NE40 had a dissolution profile that matched the commercial product, Herbesser SR capsules. The release of diltiazem from the coated pellets was slightly affected by the pH of dissolution media.     

Drug-polymer mixed coating: a new approach for controlling drug release rates in pellets

A new approach to developing a drug-polymer mixed coat for highly water-soluble diltiazem pellets was investigated at different coating levels. Drug layering and the coating procedures were performed using a bottom spray fluidized bed coater. Drug pellets were coated with Eudragit NE40 (NE40) alone and in combination with diltiazem and hydrophilic cellulose derivatives. Dissolution studies revealed that incorporation of hydrophilic substances such as methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), and the drug itself considerably increased the release rates. The release from mixed polymer coatings was fast compared to pellets coated with NE40 only. The major portion of the drug was released in about 2 hours in case of MC and NE40 mixed coat compared to hours from coated pellets containing HPMC or diltiazem. Incorporation of 15% to 25% drug with respect to the polymer coat helped to achieve a drug-release profile at a desirable rate over a 12 hour period. Moreover, the test formulation comprising 25% diltiazem with respect to 7% NE40 had a dissolution profile that matched the commercial product, Herbesser SR capsules. The release of diltiazem from the coated pellets was slightly affected by the pH of dissolution media.     

<Emphasis Type="Italic">In vitro</Emphasis> and <Emphasis Type="Italic">in vivo</Emphasis> evaluations of ketoprofen extended release pellets prepared using powder layering technique in a rotary centrifugal granulator

In the present study, an extended release pellet dosage form of ketoprofen was prepared using powder layering technique. A combination of ethyl cellulose (45 cps) and shellac polymers was used as a binder (12% w/w polymer) during drug layering and an extended release coating (1:3 ratio at 2%, 4% and 7% w/w polymer) within the same apparatus. The coated pellets were characterized for sphericity, Hardness-Friability Index, and drug content, and also underwent scanning electron microscopy. In vitro dissolution was performed in 900 mL of phosphate buffer (pH 6.8) using paddle apparatus at 100 rpm. Ethyl cellulose and shellac when used as binders during drug loading did not extend ketoprofen release beyond 3 h. However, coating of the drug loaded pellets using ethyl cellulose and shellac resulted in an extended release profile of about 10 h. Using Higuchi’s model and the Korsmeyer equation, the drug release mechanism from the pellets was found to be an anomalous type involving diffusion and erosion. Scanning electron microscopy was used to visualize the pellet morphology and drug release mechanism during dissolution testing. In vivo evaluations of the extended release pellets in rats indicated a significant increase in the time to reach maximum concentration (t_max) and extent of absorption (AUC_0-∞) compared to the ketoprofen immediate release tablet blend dispersed and dosed. In conclusion, extended release pellets of ketoprofen could perform therapeutically better than conventional dosage forms, leading to improved efficacy for a prolonged period.     

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 °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.     

An in vitro drug release rate method for lipoidal materials

A multiparticulate preparation of an osmotically mediated, controlled release system for lipoidal materials is described. Spherical beads containing a lipid carrier, an osmotic agent and a lipid soluble model drug were made and a microporous, polymeric coating applied. When placed in an aqueous medium, the coated beads controllably released first the lipid carrier (containing the model drug), then the osmotic agent. A technique is described for measuring the in vitro release rate profile of the lipoidal components of the beads using microporous polypropylene films. Sorption of the lipoidal components by the film occurred following release from the beads in an aqueous medium. Films were removed at specific times for analysis. The lipoidal components were extracted from the film with ethanol and the model drug content determined by spectrophotometry. This technique may be useful for other systems requiring release rate/dissolution testing of lipoidal agents in an aqueous medium.     

Influence of water soluble additives and HPMCP on drug release from sureleaseê-coated pellets containing tamsulosin hydrochloride

The objective of this study was to investigate the influence of various water-soluble additives and HPMCP as an enteric polymer into Surelease for the developement of oral controlled release system containg tamsulosin hydrochloride. The drug loaded pellets were coated with only Surelease or Surelease containing HPMC, PEG 4000, mannitol and HPMCP (20% w/w). In case of HPMC and PEG 4000 as additives into Surelease film, the rapid drug release was observed in pH 1.2 while the higher drug release was achieved by adding HPMCP into Surelease as well as by increasing the amount of HPMCP (10, 20, and 30% w/w) in pH 7.2. The incorporation of HPMCP into Surelease showed pH-denpendent drug release due to its pH-dependent nature. Therefore, the incorporation of HPMCP into Surelease based on aqueous coating formulation is an effective way to develop oral controlled release delivery systems containing tamsulosin hydrochloride.     

Jet milling--a new technique for microparticle preparation

The effect of an aqueous amylopectin subcoating on the acidic resistance and dissolution behaviour of enteric-coated pellets was studied. Freely water-soluble riboflavin sodium phosphate (RSP) was used as a model drug, and microcrystalline cellulose (MCC) and lactose as fillers in the pellet cores. The pellets were subcoated with 5% aqueous amylopectin solution or with 5% hydroxypropyl methylcellulose (HPMC) solution, and subsequently film-coated with aqueous dispersion of cellulose acetate phthalate (CAP). Drug release of enteric-coated pellets was investigated by confocal laser scanning microscopy (CLSM). Dissolution tests showed that amylopectin subcoating improved the acidic resistance of the enteric-coated pellets in 0.1 N hydrochloric acid (HCl) compared with HPMC subcoating. As the amylopectin subcoating load was increased to 4% and the aqueous CAP coating load to 35%, the coated pellets resisted in 0.1 N HCl solution for approximately 1 h (the amount of drug released was below 10%), and they dissolved in the SIF without enzymes in less than 10 min. Confocal microscopy images and profiles of mean fluorescence intensities of RSP (obtained in the range of the interface of the pellet core and the film and the film coating surface) showed consistent results with dissolution tests. It seems that amylopectin subcoating can prevent the influx of the dissolution medium into the pellet core, and thus decrease the premature dissolution and release of the drug from the enteric-coated pellets in 0.1 N HCl solution. The drug release mechanism appeared to be osmotically driven release, and followed by diffusion through the polymer film.     

Influence of Plasticization Time,Curing Conditions,Storage Time,and Core Properties on the Drug Release from Aquacoat-Coated Pellets

Theophylline or chlorpheniramine maleate pellets were coated with an aqueous ethylcellulose dispersion, Aquacoat. The influence of the plasticization time, curing conditions, storage time, and core properties on the drug release were investigated. The plasticization time (time between plasticizer addition to the polymer dispersion and the spraying process) did not affect the drug release, when the water-soluble plasticizer, triethyl citrate, was used because of its rapid uptake by the colloidal polymer particles. In contrast, with the water-insoluble plasticizer, acetyltributyl citrate (ATBC), plasticization time (1/2 h vs 24 h) influenced the drug release, the longer plasticization time resulted in a slower drug release because of a more complete plasticizer uptake prior to the coating step. However, a thermal aftertreatment of the coated pellets at elevated temperatures (curing step) reduced/eliminated the effect of the plasticization time with ATBC. In general, curing reduced the drug release and resulted in stable drug release profiles. The time period between the coating and the curing step was not critical when the pellets were cured for a longer time. The structure of the pellet core (high dose matrix vs low dose layered pellet) strongly affected the drug release. A slow, zero-order drug release was obtained with high dose theophylline pellets, while a more rapid, first-order release pattern was obtained with low dose theophylline-layered nonpareil pellets.     

Influence of plasticization time, curing conditions, storage time, and core properties on the drug release from Aquacoat-coated pellets

Theophylline or chlorpheniramine maleate pellets were coated with an aqueous ethylcellulose dispersion, Aquacoat. The influence of the plasticization time, curing conditions, storage time, and core properties on the drug release were investigated. The plasticization time (time between plasticizer addition to the polymer dispersion and the spraying process) did not affect the drug release, when the water-soluble plasticizer triethyl citrate, was used because of its rapid uptake by the colloidal polymer particles. In contrast, with the water-insoluble plasticizer acetyltributyl citrate (ATBC), plasticization time (1/2 h vs 24 h) influenced the drug release, the longer plasticization time resulted in a slower drug release because of a more complete plasticizer uptake prior to the coating step. However a thermal aftertreatment of the coated pellets at eleylated temperatures (curing step) reduced/eliminated the effect of the plasticization time with ATBC. In general, curing reduced the drug release and resulted in stable drug release profiles. The time period between the coating and the curing step was not critical when the pellets were cured for a longer time. The structure of the pellet core (high dose matrix vs low dose layered pellet) strongly affected the drug release. A slow, zero-order drug release was obtained with high dose theophylline pellets, while a more rapid, first-order release pattern was obtained with low dose theophylline-layered nonpareil pellets.