Formulation of Sustained-Release Dosage Form of Verapamil Hydrochloride by Solid Dispersion Technique Using Eudragit RLPO or Kollidon®SR

The release of verapamil hydrochloride from tablets with Eudragit RLPO or Kollidon®SR with different drug-to-polymer ratios were investigated with a view to develop twice-daily sustained-release dosage form by solid dispersion (SD) technique. The SDs containing Eudragit RLPO or Kollidon®SR at drug-polymer ratios of 1:1, 1:2, and 1:3 with verapamil hydrochloride were developed using solvent evaporation technique. The physical mixtures of drug and both polymers were prepared by using simple mixing technique at the same ratio as solid dispersion. The physicochemical properties of solid dispersion were evaluated by using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and differential scanning calorimetry (DSC). The study of DSC, XRD, and FTIR could not show significant interaction between verapamil HCl and Kollidon®SR or Eudragit RLPO. The solid dispersions or physical mixtures were compressed to tablets. The tablets were prepared with solid dispersions containing Eudragit RLPO or Kollidon®SR, with all the official requirements of tablet dosage forms fulfilled. Tablets prepared were evaluated for the release of verapamil hydrochloride over a period of 12 h in pH 6.8 phosphate buffer using US Pharmacopoeia type II dissolution apparatus. The in vitro drug release study revealed that the tablet containing Eudragit has extended the release rate for 12 h whereas the tablet containing Kollidon®SR at the same concentration has extended the release rate up to 8 h. The in vitro release profile and the mathematical models indicate that release of verapamil hydrochloride can be effectively controlled from a tablet containing solid dispersions of Eudragit RLPO. The reduction of size fraction of the SD system from 200–250 to 75–125 μm had a great effect on the drug release.     

Development of Itraconazole Tablets Containing Viscous KinetiSol Solid Dispersions: <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Analysis in Dogs

The formulation factors relevant to developing immediate and controlled release dosage forms containing poorly soluble drugs dispersed in amorphous systems are poorly understood. While the utility of amorphous solid dispersions is becoming apparent in the pharmaceutical marketplace, literature reports tend to concentrate on the development of solid dispersion particulates, which then must be formulated into a tablet. Amorphous solid dispersions of itraconazole in high molecular weight hydroxypropyl methylcellulose were prepared by KinetiSol® Dispersing and tablets were formulated to immediately disintegrate or control the release of itraconazole. Formulated tablets were evaluated by two non-sink dissolution methodologies and the dosage form properties that controlled the gelling tendency of the dispersion carrier, hydroxypropyl methylcellulose, were investigated. Selected formulations were evaluated in an exploratory beagle dog pharmacokinetic study; the results of which indicate potential for a prolonged absorption phase relative to the commercially extruded control.     

Development of prednisone: Polyethylene glycol 6000 fast-release tablets from solid dispersions: Solid-state characterization, dissolution behavior, and formulation parameters

The aim of the current study was to design oral fast-release polymeric tablets of prednisone and to optimize the drug dissolution profile by modifying the carrier concentration. Solid dispersions were prepared by the solvent evaporation method at different drug:polymer ratios (wt/wt). The physical state and drug:carrier interactions were analyzed by X-ray diffraction, infrared spectroscopy, and scanning electron microscopy. The dissolution rate of prednisone from solid dispersions was markedly enhanced by increasing the polymer concentration. The tablets were prepared from solid dispersion systems using polyethylene glycol (PEG) 6000 as a carrier at low and high concentration. The results showed that PEG 6000-based tablets exhibited a significantly higher prednisone dissolution (80% within 30 minutes) than did conventional tablets prepared without PEG 6000 (<25% within 30 minutes). In addition, the good disintegration and very good dissolution performance of the developed tablets without the addition of superdisintegrant highlighted the suitability of these formulated dosage forms. The stability studies performed in normal and accelerated conditions during 12 months showed that prednisone exhibited high stability in PEG 6000 solid dispersion powders and tablets. The X-ray diffraction showed that the degree of crystallinity of prednisone in solid dispersions decreased when the ratio of the polymer increased, suggesting that the drug is present inside the samples in different physical states. The Fourier transform infrared spectroscopic studies showed the stability of prednisone and the absence of well-defined drug:polymer interactions. Scanning electron microscopy images showed a novel morphology of the dispersed systems in comparison with the pure components.     

Effect of Antiadherents on the Physical and Drug Release Properties of Acrylic Polymeric Films

Antiadherents are used to decrease tackiness of a polymer coating during both processing and subsequent storage. Despite being a common excipient in coating formulae, antiadherents may affect mechanical properties of the coating film as well as drug release from film-coated tablets, but how could addition of antiadherents affect these properties and to what extent and is there a relation between the physical characteristics of the tablet coat and the drug release mechanisms? The aim of this study was to evaluate physical characteristics of films containing different amounts of the antiadherents talc, glyceryl monostearate, and PlasACRYL^TM T20. Eudragit RL30D and Eudragit RS30D as sustained release polymers and Eudragit FS30D as a delayed release material were used. Polymer films were characterized by tensile testing, differential scanning calorimetry (DSC), microscopic examination, and water content as calculated from loss on drying. The effect of antiadherents on in vitro drug release for the model acetylsalicylic acid tablets coated with Eudragit FS30D was also determined. Increasing talc concentration was found to decrease the ability of the polymer films to resist mechanical stress. In contrast, glyceryl monostearate (GMS) and PlasACRYL produced more elastic films. Talc at concentrations higher than 25% caused negative effects, which make 25% concentration recommended to be used with acrylic polymers. All antiadherents delayed the drug release at all coating levels; hence, different tailoring of drug release may be achieved by adjusting antiadherent concentration with coating level.     

Eudragit E as excipient for production of granules and tablets from phyllanthus niruri L spray-dried extract

The aim of this study was to investigate the feasibility of using Eudragit E as a granulating agent for a spray-dried extract fromPhyllanthus niruri to obtain tablets containing a high dose of this product. The granules were developed by wet granulation and contained 2.5%, 5.0%, and 10.0% Eudragit E in the final product concentration. The tablets were produced on a single-punch tablet press by direct compression of granules using 0.5% magnesium stearate as a lubricant. The tablets were elaborated following a 2×3 factorial design, where Eudragit E concentration and compression force were the in-dependent variables, and tensile strength and the extract release of the tablets were the dependent variables. All granules showed better technological properties than the spray-dried extract, including less moisture sorption. The characteristics of the granules were directly dependent on the proportion of Eudragit E in the formulation. In general, all tablets showed high mechanical resistance with less than 1% friability, less moisture sorption, and a slower extract release profile. The Eudragit E concentration and compression force of the tablets significantly influenced both dependent variables studied. In conclusion, Eudragit E was efficient as a granulating agent for the spray-dried extract, but additional studies are needed to further optimize the formuations in order to achieve less water sorption and improve the release of the extract from the tablets. Published: April 27, 2007     

The Relationship of Dosage Schedule to the Blood Level of Quinidine,Using All Available Quinidine Preparations

Blood quinidine levels obtained by single and multiple dosage schedules of all available quinidine preparations were ascertained. A maintenance blood level of 4 to 7 mg./l. of quinidine was considered a desirable range to prevent recurrence of auricular fibrillation in patients previously converted to sinus rhythm. Quinidine sulfate, quinidine gluconate, dihydroquinidine gluconate and quinidine polygalacturonate were given in dosage schedules of one tablet (equivalent to 200 mg. quinidine) every eight hours for four days, then two tablets every eight hours for three days. Blood quinidine levels were determined the same time each day. Schedules of two tablets of quinidine sulfate or quinidine gluconate every eight hours resulted in blood levels between 4 and 7 mg./l. Similar dosage schedules of the other preparations did not produce levels of this order, nor did quinidine polygalacturonate administered in a 12-hourly schedule. Serious respiratory arrest occurred in one case following quinidine sulfate. No other toxic reactions were noted in this study.     

Formulation and in vitro, in vivo evaluation of extended- release matrix tablet of Zidovudine: Influence of combination of hydrophilic and hydrophobic matrix formers

The aim of the present study was to prepare and characterize extended-release matrix tablets of zidovudine using hydrophilic Eudragit RLPO and RSPO alone or their combination with hydrophobic ethyl cellulose. Release kinetics was evaluated by using United States Pharmacopeia (USP)-22 type I dissolution apparatus. Scanning electron microscopy was used to visualize the effect of dissolution medium on matrix tablet surface. Furthermore, the in vitro and in vivo newly formulated sustained-release zidovudine tablets were compared with conventional marketed tablet (Zidovir, Cipla Ltd, Mumbai, India). The in-vitro drug release study revealed that either Eudragit preparation was able to sustain the drug release only for 6 hours (94.3%±4.5% release). Combining Eudragit with ethyl cellulose sustained the drug release for 12 hours (88.1%±4.1% release). Fitting the in vitro drug release data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release. In vivo investigation in rabbits showed sustained-release pharmacokinetic profile of zidovudine from the matrix tablets formulated using combination of Eudragits and ethylcellulose. In conclusion, the results suggest that the developed sustained-release tablets of zidovudine could perform therapeutically better than conventional dosage forms, leading to improve efficacy and better patient compliance. Published: January 3, 2006     

Preparation and properties of soluble-insoluble immobilized proteases

In order to carry out an effective enzyme reaction, the preparation of soluble-insoluble immobilized enzyme was investigated. Proteases were selected as model enzymes, and their immobilization was carried out by using an enteric coating polymer as a carrier. Among the polymers tested, methacrylic acid-methylacrylate-methylmethacrylate copolymer (MPM-06) gave the most active soluble-insoluble immobilized papain. This immobilized papain showed insoluble from below pH 4.8 and soluble form above pH 5.8; it was also soluble in water-miscible organic solvent. It was reusable and more stable with heat and water-miscible organic solvents than native proteases. Furthermore, various proteases could be immobilized by using MPM-06 with high activity. Chymotrypsin immobilized by this method catalyzed the effective peptide synthesis in a heterogeneous reaction system containing water-miscible organic solvent.     

Monitoring tablet surface roughness during the film coating process

The purpose of this study was to evaluate the change of surface roughness and the development of the film during the film coating process using laser profilometer roughness measurements, SEM imaging, and energy dispersive X-ray (EDX) analysis. Surface roughness and texture changes developing during the process of film coating tablets were studied by noncontact laser profilometry and scanning electron microscopy (SEM). An EDX analysis was used to monitor the magnesium stearate and titanium dioxide of the tablets. The tablet cores were film coated with aqueous hydroxypropyl methylcellulose, and the film coating was performed using an instrumented pilot-scale side-vented drum coater. The SEM images of the film-coated tablets showed that within the first 30 minutes, the surface of the tablet cores was completely covered with a thin film. The magnesium signal that was monitored by SEM-EDX disappeared after ∼15 to 30 minutes, indicating that the tablet surface was homogeneously covered with film coating. The surface roughness started to increase from the beginning of the coating process, and the increase in the roughness broke off after 30 minutes of spraying. The results clearly showed that the surface roughness of the tablets increased until the film coating covered the whole surface area of the tablets, corresponding to a coating time period of 15 to 30 minutes (from the beginning of the spraying phase). Thereafter, the film only became thicker. The methods used in this study were applicable in the visualization of the changes caused by the film coating on the tablet surfaces.     

Comparison of Release-Controlling Efficiency of Polymeric Coating Materials Using Matrix-type Casted Films and Diffusion-Controlled Coated Tablet

Polymeric coating materials have been widely used to modify release rate of drug. We compared physical properties and release-controlling efficiency of polymeric coating materials using matrix-type casted film and diffusion-controlled coated tablet. Hydroxypropylmethyl cellulose (HPMC) with low or high viscosity grade, ethylcellulose (EC) and Eudragit® RS100 as pH-independent polymers and Eudragit S100 for enteric coatings were chosen to prepare the casted film and coated tablet. Tensile strength and contact angle of matrix-type casted film were invariably in the decreasing order: EC> Eudragit S100> HPMC 100000> Eudragit RS100>HPMC 4000. There was a strong linear correlation between tensile strength and contact angle of the casted films. In contrast, weight loss (film solubility) of the matrix-type casted films in three release media (gastric, intestinal fluid and water) was invariably in the increasing order: EC < HPMC 100000 < Eudragit RS100 < HPMC 4000 with an exception of Eudragit S100. The order of release rate of matrix-type casted films was EC > HPMC 100000 > Eudragit RS100 > HPMC 4000 > Eudragit S100. Interestingly, diffusion-controlled coated tablet also followed this rank order except Eudragit S100 although release profiles and lag time were highly dependent on the coating levels and type of polymeric coating materials. EC and Eudragit RS100 produced sustained release while HPMC and Eudragit S100 produced pulsed release. No molecular interactions occurred between drug and coating materials using ¹H-NMR analysis. The current information on release-controlling power of five different coating materials as matrix carrier or diffusion-controlled film could be applicable in designing oral sustained drug delivery.Key words: diffusion-controlled coated tablet, drug release rate, matrix-type casted film, polymeric coating materials, release-controlling power     

Effects of Processing on the Release Profiles of Matrix Systems Containing 5-Aminosalicylic Acid

The aim of this study was to investigate the influence of different processing methods on the profiles of 5-aminosalicylic acid dissolution from controlled-release matrix systems based on Eudragit® RL and Eudragit® RS water-insoluble polymers. The pure polymers and their mixtures were studied as matrix formers using different processing methods, i.e., direct compression, wet granulation of the active ingredient with the addition of polymer(s) to the external phase, wet granulation with water, and wet granulation with aqueous dispersions. In comparison with the directly compressed tablets, tablets made by wet granulation with water demonstrated a 6–19% increase in final drug dissolution, whereas when polymers were applied in the external phase during compression, a 0–13% decrease was observed in the amount of drug released. Wet granulation with aqueous polymer dispersions delayed the release of the drug; this was especially marked (a 54–56% decrease in drug release) in compositions, which contained a high amount of Eudragit RL 30D. The release profiles were mostly described by the Korsmeyer–Peppas model or the Hopfenberg model.KEY WORDS: controlled release, matrix tablet, polymethacrylates, release kinetics     

Improved dissolution of oleanolic acid with ternary solid dispersions

The purpose of this study was to enhance the dissolution of oleanolic acid by solid dispersions consisting of the drug, a polymeric carrier, and a surfactant. Binary solid dispersions consisting of oleanolic acid and polyvinylpyrrolidone were prepared for comparison. Polysorbate 80, a nonionic surfactant, was incorporated into binary solid dispersions as the third component to prepare ternary solid dispersions. Solid dispersions were characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, and dissolution tests. The crystallinization of OA was prohibited in solid dispersions. Both the binary and ternary solid dispersions enhanced the dissolution of OA. Moreover, the dissolution of ternary solid dispersion was faster compared with that of binary solid dispersion. Polysorbate 80 played an important positive role in dissolution of the solid dispersion.     

Release of phospholipids from colloidal particles to polymeric surfaces

This study presents a small-scale polymerization of high molecular weight methyl methacrylate/n-butyl acrylate (MMA/n-BA) colloidal particles that are synthesized in an aqueous environment in the presence of phospholipid hydrogenated soybean phosphatidylcholine (HSPC) molecules that also serve as the particle stabilizing agents. When such particles coalesce to form polymeric films, they release phospholipids, which, in turn, form organized structures near the film-air (F-A) interface. Diffusion and mobility of phospholipid molecules are affected not only by their compatibility with colloidal particles but also by electrolyte environments of colloidal dispersions. When Na(+), K(+), and Ca(2+) counterions are added to MMA/n-BA aqueous colloidal dispersions stabilized with HSPC, and such films are coalesced, different degrees of diffusion of HSPC to the F-A interface exist, depending on the counterion, and conformational changes of HSPC result. For example, in the presence of Ca(2+), HSPC molecules collapse entropically to form random surface layers, as opposed to smaller Na(+) and K(+), which force amphiphilic HSPC ends to align preferentially parallel to the film surface. These studies show that it is possible to design stimuli-response colloidal systems triggered by chemical environments of active molecules on colloidal polymer particles.     

Enhancement of dissolution profile by solid dispersion (kneading) technique

This article investigates enhancement of the dissolution profile of valdecoxib using solid dispersion with PVP. The article also describes the preparation of fast-dissolving tablets of valdecoxib by using a high amount of superdisintegrants. A phase solubility method was used to evaluate the effect of various water-soluble polymers on aqueous solubility of valdecoxib. Polyvinyl pyrrolidone (PVP K-30) was selected and solid dispersions were prepared by the method of kneading. Dissolution studies, using the USP paddle method were performed for solid dispersions of valdecoxib. Infrared (IR) spectroscopy, differential scanning calorimetry (DSC), and x-ray diffractometry (XRD) were performed to identify the physicochemical interaction between drug and carrier, hence its effect on dissolution. Tablets were formulated containing solid dispersion products and compared with commercial products. IR spectroscopy, XRD, and DSC showed no change in the crystal structure of valdecoxib. Dissolution of valdecoxib improved significantly in solid dispersion products (<85% in 5 minutes). Tablets containing solid dispersion exhibited better dissolution profile than commercial tablets. Thus, the solid dispersion technique can be successfully used for improvement of dissolution of valdecoxib. Published: August 18, 2006     

Properties and stability of tetracycline hydrochloride tablets

Three forms of tetracycline hydrochloride tablets were studied, i.e. the uncoated tablets, sugar-coated tablets and the tablets with gastric-soluble film coating. The film-coated tablets had advantages in the main quality characteristics, i.e. the contents of the tetracycline-like admixtures, the active substance and solubility rate. The possibility of the tablet stability investigation by the method of "accelerated aging" was shown.     

Polymersome encapsulated hemoglobin: a novel type of oxygen carrier

Bovine hemoglobin (Hb) was encapsulated inside polymer vesicles (polymersomes) to form polymersome encapsulated Hb (PEH) dispersions. PEH particles are 100% surface PEGylated with longer PEG chains and possess thicker hydrophobic membranes as compared to conventional liposomes. Polymersomes were self-assembled from poly(butadiene)-poly(ethylene glycol) (PBD-PEO) amphiphilic diblock copolymers with PBD-PEO molecular weights of 22-12.6, 5-2.3, 2.5-1.3, and 1.8-0.9 kDa. The first two diblock copolymers possessed linear hydrophobic PBD blocks, while the later possessed branched PBD blocks. PEH dispersions were extruded through 100 and 200 nm pore radii membranes. The size distribution, Hb encapsulation efficiency, P(50), cooperativity coefficient, and methemoglobin (metHb) level of PEH dispersions were consistent with values required for efficient oxygen delivery in the systemic circulation. The influence of different molecular weight diblock copolymers on the physical properties of PEH dispersions was analyzed. PBD-PEO copolymers with molecular weights of 22-12.6 and 2.5-1.3 kDa completely dissolved in aqueous solution to form polymersomes, while the other two copolymers formed a mixture of solid copolymer precipitates and polymersomes. PEHs self-assembled from 22-12.6 and 2.5-1.3 kDa PBD-PEO copolymers possessed Hb loading capacities greater than PEG-LEHs, PEGylated actin-containing LEHs, and nonmodified LEHs, although their sizes were smaller and their hydrophobic membranes were thicker. The Hb loading capacities of these polymersomes were also higher than lipogel encapsulated hemoglobin particles and nanoscale hydrogel encapsulated hemoglobin particles. PEH dispersions exhibited average radii larger than 50 nm and exhibited oxygen affinities comparable to human erythrocytes. Polymersomes did not induce Hb oxidation. The interaction between Hb and the membrane of 2.5-1.3 kDa PBD-PEO polymersomes improved the monodispersity of these particular PEH dispersions. These results suggest that PEHs could serve as efficient oxygen therapeutics.     

Application of Ethylcellulose Coating to Hydrophilic Matrices: A Strategy to Modulate Drug Release Profile and Reduce Drug Release Variability

Hydrophilic matrix tablets are commonly used for extended release dosage forms. For low aqueous-solubility drugs, there may be challenges in modulation of release profiles and achieving consistent release in physiological conditions. To evaluate potential formulation strategies, matrix tablets of a low-soluble drug, hydrochlorothiazide, were developed using hypromellose and two fillers of different solubility, lactose (soluble) or partially pregelatinized maize starch (partially soluble). Additionally, application of an insoluble barrier membrane, aqueous ethylcellulose coating system, and a hydrophilic pore former onto matrix tablets was evaluated. Drug release from uncoated matrix tablets was variable at different agitation rates. Evaluation of tablets in bio-relevant media using physiologically relevant residence time indicated variable and higher initial release rate for uncoated matrices containing lactose but more robust behavior for tablets containing partially pregelatinized starch. Such in vitro behavior may lead to erratic drug release in vivo, when comparing fed versus fasted conditions. Dissolution profiles from barrier membrane-coated tablets showed initial delay, followed by zero-order release kinetics, with reduction or elimination of variability compared to uncoated matrices. Such reduced variability may mitigate mechanical effects of post-prandial stomach. Effects of coating weight gain and inclusion levels of pore former were evaluated and found to be critical in achieving robust and stable release profiles.     

Preparation and Evaluation of Sustained-Release Matrix Tablets Based on Metoprolol and an Acrylic Carrier Using Injection Moulding

Sustained-release matrix tablets based on Eudragit RL and RS were manufactured by injection moulding. The influence of process temperature; matrix composition; drug load, plasticizer level; and salt form of metoprolol: tartrate (MPT), fumarate (MPF) and succinate (MPS) on ease of processing and drug release were evaluated. Formulations composed of 70/30% Eudragit RL/MPT showed the fastest drug release, substituting part of Eudragit RL by RS resulted in slower drug release, all following first-order release kinetics. Drug load only affected drug release of matrices composed of Eudragit RS: a higher MPT concentration yielded faster release rates. Adding triethyl citrate enhanced the processability, but was detrimental to long-term stability. The process temperature and plasticizer level had no effect on drug release, whereas metoprolol salt form significantly influenced release properties. The moulded tablets had a low porosity and a smooth surface morphology. A plasticizing effect of MPT, MPS and MPF on Eudragit RS and Eudragit RL was observed via DSC and DMA. Solubility parameter assessment, thermal analysis and X-ray diffraction demonstrated the formation of a solid solution immediately after production, in which H-bonds were formed between metoprolol and Eudragit as evidenced by near-infrared spectroscopy. However, high drug loadings of MPS and MPF showed a tendency to recrystallise during storage. The in vivo performance of injection-moulded tablets was strongly dependent upon drug loading.     

Erythromycin pharmacokinetics in children after rectal and oral administration

Pharmacokinetics of erythromycin base was studied clinically in children not older than 14 years treated with new children dosage forms of the antibiotic i. e. 0.1 and 0.25 g enteric coated tablets and 0.06 and 0.125 g suppositories. It was noted that the new dosage forms were characterized by higher availability which was 2.5-3 times higher than that after using the erythromycin base tablets without the coating. Systematic increasing of erythromycin availability after the use of the rectal suppositories was observed with increasing of the children age. Absolute absorption in newborns, sucklings and children over 1 year amounted to 28, 36 and 54 per cent respectively.     

Purification of recombinant protein A by aqueous two-phase extraction integrated with affinity precipitation

Aqueous two-phase extraction incorporated affinity precipitation was examined as a technique for protein purification. An enteric coating polymer, Eudragit S100, was employed as a ligand carrier. Eudragit was specifically partitioned to the top phase in the aqueous two-phase systems. For application of this method to purification of recombinant protein A using human IgG coupled to Eudragit in an aqueous two-phase system, 80% of protein A added was recovered with 81% purity. The purity was enhanced 26-fold by thid method. The IgG-Eudragit could be used repeatedly for the purification process. This seperation method should be applicable to industrial-scale purification as a new purification procedure combining the advantages and compensating for the disadvantages of the aqueous two-phase method and affinity precipitation method. (c) 1992 John Wiley & Sons, Inc.