Flocculated amorphous itraconazole nanoparticles for enhanced in vitro supersaturation and in vivo bioavailability

Rapid flocculation of nanoparticle dispersions of a poorly water soluble drug, itraconazole (Itz), was utilized to produce amorphous powders with desirable dissolution properties for high bioavailability in rats. Antisolvent precipitation (AP) was utilized to form Itz nanodispersions with high drug loadings stabilized with hydroxypropylmethylcellulose (HPMC) or the pH-sensitive Eudragit^® L100-55 (EL10055). The HPMC dispersions were flocculated by desolvating the polymer through the addition of a divalent salt, and the enteric EL10055 by reducing the pH. The formation of open flocs by diffusion limited aggregation facilitated redispersion of the flocs at pH 6.8. Upon redispersion of the flocculated nanoparticles at pH 6.8, the particle size was modestly larger than the original size, on the order of 1 μm. High in vitro supersaturation (AUC) of the flocculated nanoparticle dispersions was observed in micellar media at pH 6.8, after 2 hours initial exposure at pH 1.2 to simulate the stomach, relative to the AUC for a commercially available Itz formulation, Sporanox. Greater in vivo bioavailability in rats was correlated directly to the higher in vitro AUC at pH 6.8 with micelles during the pH shift experiment for the flocculated nanoparticle dispersions relative to Sporanox. The ability to generate and sustain high supersaturation in micellar media at pH 6.8, as shown with the in vitro pH shift dissolution test, is beneficial for increasing bioavailability of Itz by oral delivery.     

Preparation and in vivo evaluation of spray dried matrix type controlled-release microparticles of tamsulosin hydrochloride for orally disintegrating tablet

The objective of this study was to achieve an optimal formulation of spray dried matrix type controlled-release (MTCR) microparticles containing tamsulosin hydrochloride for orally disintegrating tablet. To control the release rate of tamsulosin hydrochloride, Acrylate-methacrylate copolymer (Eudragit^® L-100 or Eudragit^® S-100) and ethylcellulose were employed on the composition of MTCR microparticles. Physicochemical properties of MTCR microparticles such as particle size and SEM were characterized. Pharmacokinetic parameters of tamsulosin hydrochloride were evaluated in the rats after oral administration. MTCR microparticles were spherical microparticles of around 10 µm diameter with a corrugated surface. ODTs containing MTCR microparticles were disintegrated within 30 s and MTCR microparticles were able to control the release rate of tamsulosin hydrochloride following Fickian diffusion mechanism. The in vitro release rates of tamsulosin hydrochloride from MTCR microparticles were proportional to the ratio of Acrylate-methacrylate copolymer to ethylcellulose. Moreover, MTCR microparticles retarded the in vivo release rate of tamsulosin hydrochloride without reducing the bioavailability. Our results suggest that MTCR microparticles may be potential oral dosage forms to control the release and to improve the bioavailability of tamsulosin hydrochloride.     

New sustained release of Zidovudine Matrix tablets − cytotoxicity toward Caco-2 cells

Objective: The aim of this study was to adjust the zidovudine (AZT) release from solid tablets to an ideal profile, by developing matrices comprising swellable polymers with nonswellable ones.

Methods: Directly compressed matrices comprised different ratios of hydroxypropylmethylcellulose K15M and K100M, ethylcellulose, and methacrylic acid (Eudragit^® RS PO and Eudragit^® RL PO) were prepared. Technological characterization and evaluation of the in vitro release behavior were carried out. Cell density and viability following drug exposure were evaluated by the SRB method, for the Caco-2 line, while cell morphology was assessed upon Trypan blue staining.

Results: A specific formulation containing 5% of each excipient ? HPMC K15M, HPMC K100M, Eudragit^® RS PO, and Eudragit^® RL PO ? was found to yield the best release profile. Application of the Korsmeyer–Peppas model to the dissolution profile evidenced that a non-Fickian (anomalous) transport is involved in the drug release. Regarding the influence of the tablets’ composition on the drug’s cytotoxic effect toward the Caco-2 cell line, a reduction of cell biomass (0–15%) was verified for the distinct AZT formulations tested, F19 having displayed the highest cytotoxicity, after 24 and 48?h of incubation. Additionally, a high reversibility of the AZT effect was observed.

Conclusions: The results showed that the simultaneous application of both hydrophilic and hydrophobic polymers can modulate the drug release process, leading to an improved efficacy and patient compliance. All AZT formulations studied were found to be cytotoxic against Caco-2 cells, F19 being the most effective one.     

Preparation and evaluation of enteric coated tablets of hot-melt extruded lansoprazole

Abstract

The objective of this work was to use hot-melt extrusion (HME) technology to improve the physiochemical properties of lansoprazole (LNS) to prepare stable enteric coated LNS tablets. For the extrusion process, we chose Kollidon^® 12?PF (K12) polymeric matrix. Lutrol^® F 68 was selected as the plasticizer and magnesium oxide (MgO) as the alkalizer. With or without the alkalizer, LNS at 10% drug load was extruded with K12 and F68. LNS changed to the amorphous phase and showed better release compared to that of the pure crystalline drug. Inclusion of MgO improved LNS extrudability and release and resulted in over 80% drug release in the buffer stage. Hot-melt extruded LNS was physically and chemically stable after 12 months of storage. Both formulations were studied for compatibility with Eudragit^® L100-55. The optimized formulation was compressed into a tablet followed by coating process utilizing a pan coater using L100-55 as an enteric coating polymer. In a two-step dissolution study, the release profile of the enteric coated LNS tablets in the acidic stage was less than 10% of the LNS, while that in the buffer stage was more than 80%. Drug content analysis revealed the LNS content to be 97%, indicating the chemical stability of the enteric coated tablet after storage for six months. HME, which has not been previously used for LNS, is a valuable technique to reduce processing time in the manufacture of enteric coated formulations of an acid-sensitive active pharmaceutical ingredient as compared to the existing methods.     

Spray-dried pH-sensitive microparticles: effectual methodology to ameliorate the bioavailability of acid labile pravastatin

Pravastatin is a promising drug utilized in the treatment of hyperlipidemia, yet, its main clinical limitation is due to gastric liability which fractions its oral bioavailability to less than 18%. The purpose of the current study is to encapsulate pravastatin into Eudragit^®-based spray-dried microparticles aspiring to overcome its acid liability. With the aim to optimize the microparticles, formulation and process parameters were studied through acid resistance challenging test. Physicochemical characterization of the optimized spray-dried pH-sensitive microparticles namely; in-vitro dissolution, surface morphology, compatibility, and solid-state studies were performed. Moreover, in-vivo evaluation of the microparticles and accelerated stability studies were carried out. The results outlined that polymer to drug ratio at 5:1 and pravastatin concentration at 1%w/w in spray-drying feed solution showed 38.55% and 53.97% encapsulation efficiency, respectively. The significance of process parameters specifically; the flow rate and the inlet temperature on microparticles surface integrity were observed, and optimized until encapsulating efficiency reached 72.37%. The scanning electron microscopical examination of the optimized microparticles illustrate uniform smooth surface spheres entrapping the drug in an amorphous state as proved through Differential Scanning Calorimetry (DSC) and Fourier Transfer Infrared (FTIR) studies. The in-vivo evaluation demonstrated a 5-fold enhancement in pravastatin bioavailability compared to the marketed product. The results provided evidence for the significance of spray-dried pH-sensitive microparticles as a promising carrier for pravastatin, decreasing its acid liability, and improving its bioavailability.     

Development and comparative evaluation of in vitro,in vivo properties of novel controlled release compositions of paroxetine hydrochloride hemihydrate as against Geomatrix™ platform technology

The objective of this study is to develop, in vitro and in vivo evaluation of novel approaches for controlled release of paroxetine hydrochloride hemihydrate (PHH) in comparison to patented formulation PAXIL CR^® tablets of GlaxoSmithKline (Geomatrix? technology). In one of the approaches, hydrophilic core matrix tablets containing 85% of the dose were prepared and further coated with methacrylic acid copolymer to delay the release. An immediate release coating of 15% was given as top coat. The tablets were further optionally coated using ethyl cellulose. In the second approach, hydrophobic matrix core tablets containing metharylic acid copolymer were prepared. In the third approach, PHH was granulated with enteric polymer and further hydrophobic matrix core tablets were prepared. The effect of polymer concentration, level of enteric coating on drug release was evaluated by in vitro dissolution study by varying dissolution apparatus and the rotation speeds. It was found that increase in concentration of high viscosity hydroxypropylmethylcellulose (HPMC) resulted in reduction of the release rate. The drug release was observed to be dependent on the level of enteric coating and ethyl cellulose coating, being slower at increased coating. The release mechanism of PHH followed zero-order shifting to dissolution dependent by the increase of HPMC content. The formulation was stable without change in drug release rate. In vivo study in human volunteers confirmed the similarity between test and innovator formulations. In conclusion, HPMC-based matrix tablets, which were further coated using methacrylic acid copolymer, were found to be suitable for the formulation of single layer-controlled release PHH.     

Development of a Tamsulosin Hydrochloride Controlled-Release Capsule Consisting of Two Different Coated Pellets

Tamsulosin hydrochloride (TSH) controlled-release capsule (pellets) was successfully prepared using a novel, simple, and flexible multiunit drug delivery system, which consisted of two different coated pellets. The TSH-loaded core pellets consisting of microcrystalline cellulose (MCC), lactose, Carbopol^® 974P, and the active agent, were prepared by extrusion/spheronization method. Eudragit^® NE30D and Eudragit^® L30D-55 were used as the coating materials to prepare sustained-release (SR) pellets and enteric-release (ER) pellets. The coated pellets were prepared using two different equipments: centrifugal coater and fluidized-bed coater. By adjusting the ratio of SR and ER pellets, more than one blend ratios, which meet the in vitro release criterion were obtained. A similarity factor (f₂) was employed to choose the optimum proportion compared with the commercial product (Harnal^® capsule). The morphology of the pellet surfaces was examined by scanning electron microscopy (SEM) before and after dissolution. The release profiles were significantly affected by changing the proportions of SR and ER. The optimum ratio is SR:ER?=?2:1 using a centrifugal coater (f₂?=?61.93) and SR:ER?=?3:1 using a fluidized coater (f₂?=?66.42). This result suggests that blending these two-part pellets (SR and ER) can provide an alternative to preparing a controlled-release dosage form, instead of blending of the coating polymer.     

Vitamin B12 buccoadhesive tablets: auspicious non-invasive substitute for intra muscular injection: formulation,in vitro and in vivo appraisal

Attempting to prepare a convenient bioavailable formulation of vitamin B₁₂ (cyanocobalamin), 17 tablet formulations were prepared by direct compression. Different concentrations of hydroxypropyl methyl cellulose (HPMC), carbopol 971p (CP971p), and chitosan (Cs) were used. The tablets were characterized for thickness, weight, drug content, hardness, friability, surface pH, in vitro drug release, and mucoadhesion. Kinetic analysis of the release data was conducted. Vitamin B₁₂ bioavailability from the optimized formulations was studied on rabbits by the aid of enzyme-linked immunosorbent assay. Neurotone^® I.M. injection was used for comparison. HPMC (F1-F4), CP971p (F5-F8), and HPMC/CP971p (F12-F15)-based formulations showed acceptable mechanical properties. The formulated tablets showed maximum swelling indices of 232?±?0.13. The surface pH values ranged from 5.3?±?0.03 to 6.6?±?0.02. Bioadhesive force ranged from 66?±?0.6 to 150?±?0.5?mN. Results showed that CP971p-based tablets had superior in vitro drug release, mechanical, and mucoadhesive properties. In vitro release date of selected formulations were fitted well to Peppas model. HPMC/CP971p-based formulations showed bioavailability up to 2.7-folds that of Neurotone^® I.M. injection.     

Controlled Release Theophylline Tablet with Acrylic Polymers Prepared by Spray-Drying Technique in Aqueous System

Abstract

Sustained release and enteric theophylline tablets were prepared by directly compressing spray-dried microsphers with Eudragits L30D, L100-55 and E30D. The spray-drying process was free from using organic solvent. Drug dissolution of the enteric tablet in an acidic solution (pH 1.2) was highly dependent on the polymer content of the microsphere. Completely enteric function was observed with drug-to-polymer ratio of 1:3 using Eudragit L30D or L100-55. Tablet with Eudragit E30D formulated at the 2–40% level showed good sustained drug release which was throughly independent of the pH of dissolution media. The dissolution pattern was similar to that of Theo-dur and gave a straight line in Higuchi plot. In each tablet, the controlled drug release was attributed to continuous and well-dispersed polymer matrix formed by spray-drying and subsequent compressing process     

Optimization Studies on Floating Multiparticulate Gastroretentive Drug Delivery System of Famotidine

The objective of this study was to optimize floating microballoons of famotidine by the emulsion solvent diffusion technique using central composite design. Formulations F₁–F₁₅ were prepared using three independent variables (pH of medium, drug: Eudragit® S100 ratio and ethanol : dichloromethane ratio) and evaluated for dependent variables (shape, percentage buoyancy, and encapsulation). The optimized formulation F₉ was fractionated and a polymer combination of (Eudragit® S100 : Eudragit® L100-55, 9.5:0.5) resulted in microballoons that exhibited zero order release (94.73%) with 84.20% buoyancy at the end of the eighth hour when studied in the mesh-designed modified USP type II apparatus.     

The Influence of Polymeric Subcoats and Pellet Formulation on the Release of Chlorpheniramine Maleate from Enteric Coated Pellets

Abstract

The influences of aqueous polymeric subcoats and pellet composition on the release properties of a highly water-soluble drug, chlorpheniramine maleate (CPM), from enteric coated pellets were investigated. Three different aqueous polymeric subcoats, Eudragit® RD 100, Eudragit® RS 30D, and Opadry® AMB, were applied to 10% w/w CPM-loaded pellets that were then enteric coated with Eudragit® L 30D-55. Observed drug release from the coated pellets in acidic media correlated with water vapor transmission rates derived for the subcoat films. The influence of pellet composition on retarding the release of CPM from enteric coated pellets in 0.1 N HCl was investigated. The rate of drug release was greatest for pellets prepared with lactose, microcrystalline cellulose, or dibasic calcium phosphate compared with pellets formulated with citric acid and microcrystalline cellulose. Citric acid reduced the pellet micro-environmental pH, decreasing the amount of drug leakage in 0.1 N HCL during the first 2 hr of dissolution. Polymer flocculation was observed when CPM was added to the Eudragit L 30D-55 dispersion. An adsorption isotherm was generated for mixtures of CPM and the polymer and the data were found to fit the Freundlich model for adsorption. Adsorption of CPM to the polymer decreased with the addition of citric acid to the drug-polymer mixtures.     

Formulation and evaluation of injectable in situ forming microparticles for sustained delivery of lornoxicam

The objective of this study is to formulate biodegradable in situ microparticles (ISM) containing lornoxicam for post-operative and arthritic pain management. ISM emulsions were prepared according to 2⁵ full factorial experimental design to investigate the influence of formulation variables on the release profile of the drug. The independent variables studied are the polymer type, polymer inherent viscosity, polymer concentration, oil type and polymer:oil ratio. In vitro drug release, microscopical examination, particle size determination and syringeability measurement were selected as dependent variables. The effect of γ-sterilization on the prepared formulae was also examined. The prepared formulae showed extended drug release over two weeks, and flow time below 5?s/ml. Scanning electron microscope revealed that the prepared microparticles were spherical in shape, with diameter ranging from 3.45 to 22.78?µm. In vivo pharmacokinetic evaluation of two selected optimum formulations in rabbits showed prolonged drug absorption indicated by delayed T_max and the extended mean residence time. In conclusion, the prepared injectable ISM could be a promising approach for providing extended delivery of lornoxicam with low initial burst effect.     

Preparation and In Vitro/In Vivo Evaluation of Gliclazide Loaded Eudragit Nanoparticles as a Sustained Release Carriers

ABSTRACT

The aim of this study was to formulate and optimize gliclazide-loaded Eudragit nanoparticles (Eudragit L100 and Eudragit RS) as a sustained release carrier with enhanced efficacy. Eudragit L 100 nanoparticles (ELNP) were prepared by controlled precipitation method whereas Eudragit RSPO nanoparticles (ERSNP) were prepared by solvent evaporation method. The influence of various formulation factors (stirring speed, drug:polymer ratio, homogenization, and addition of surfactants) on particle size, drug loading, and encapsulation efficiency were investigated. The developed Eudragit nanoparticles (L100 and RS) showed high drug loading and encapsulation efficiencies with nanosize. Mean particle size altered by changing the drug:polymer ratio and stirring speed. Addition of surfactants showed a promise to increase drug loading, encapsulation efficiency, and decreased particle size of ELNP as well as ERSNP. Dissolution study revealed sustained release of gliclazide from Eudragit L100 as well as Eudragit RSPO NP. SEM study revealed spherical morphology of the developed Eudragit (L100 and RS) NP. FT-IR and DSC studies showed no interaction of gliclazide with polymers. Stability studies revealed that the gliclazide-loaded nanoparticles were stable at the end of 6 months. Developed Eudragit NPs revealed a decreased t_min (ELNP), and enhanced bioavailability and sustained activity (ELNP and ERSNP) and hence superior activity as compared to plain gliclazide in streptozotocin induced diabetic rat model and glucose-loaded diabetic rat model. The developed Eudragit (L100 and RSPO) NP could reduce dose frequency, decrease side effects, and improve patient compliance.     

Comparison of simple Eudragit microparticles loaded with prednisolone and Eudragit-coated chitosan-succinyl-prednisolone conjugate microparticles: Part I. Particle characteristics and in vitro evaluation as a colonic delivery system

Objective: Simple Eudragit microparticles loaded with prednisolone and chitosan-succinyl-prednisolone conjugate microparticles coated with Eudragit were prepared and characterized in vitro in order to obtain their basic features as a colonic delivery system.

Materials and methods: Both types of microparticles were prepared by the emulsification-solvent evaporation modified somewhat from the previous one. Their particle size, shape and their drug content were investigated, and in vitro release profiles were examined using JP-15 1st fluid (pH 1.2), JP-15 2nd fluid (pH 6.8) and PBS (pH 7.4) as release media. Furthermore, the regeneration of conjugate microparticles from Eudragit-coated microparticles was investigated under the same incubation conditions.

Results: Simple Eudragit S100 (EuS) microparticles (ES-M) were almost spherical, ca. 1.2 μm diameter, and PD content ca. 3.7% (w/w). Conjugate microparticles (CS-M1) and EuS-coated conjugate microparticles (CS-M1/S) had particle sizes of ca. 2.8 and 15.3 μm, respectively, and PD contents of 5.4 and 2.1% (w/w), respectively. ES-M exhibited suppressed release at pH 1.2, gradual release at pH 6.8 and rapid release at pH 7.4. CS-M1 showed no release at pH 1.2, and very slow release at pH 6.8 and 7.4. CS-M1 regenerated poorly from CS-M1/S at pH 6.8.

Conclusions: Simple Eudragit micrparticles and Eudragit-caoted conjugate microparticles, prepared by the present methods, were found in vitro to be possibly useful as the delivery systems of PD to the lower intestine, although there were differences in their release rate and morphological features.     

Preliminary investigation on the design of biodegradable microparticles for ivermectin delivery: set up of formulation parameters

The aim was to design sterile biodegradable microparticulate drug delivery systems based on poly(dl-lactide) (PLA) and poly(?-caprolactone) (PCL) and containing ivermectin (IVM), an antiparasitic drug, for subcutaneous administration in dogs. The drug delivery system should: (i) ensure a full 12-month protection upon single dose administration; (ii) be safe with particular attention regarding IVM dosage and its release, in order to prevent over dosage side effects. This preliminary work involves: polymer selection, evaluation of the effects of γ-irradiation on the polymers and IVM, investigation and set up of suitable microparticle preparation process and parameters, IVM-loaded microparticles in vitro release evaluation.

Results of gel permeation chromatography analysis on the irradiated polymers and IVM mixtures showed that combination of IVM with the antioxidant α-tocopherol (TCP) reduces the damage extent induced by irradiation treatment, independently on the polymer type.

Solvent evaporation process was successfully used for the preparation of PLA microparticles and appropriately modified; it was recognized as suitable for the preparation of PCL microparticles. Good process yields were achieved ranging from 76.08% to 94.72%; encapsulation efficiency was between 85.76% and 91.25%, independently from the polymer used. The type of polymer and the consequent preparation process parameters affected microparticle size that was bigger for PCL microparticles (480–800?µm) and solvent residual that was >500?ppm for PLA microparticles. In vitro release test showed significantly faster IVM release rates from PCL microparticles, with respect to PLA microparticles, suggesting that a combination of the polymers could be used to obtain the suitable drug release rate.     

Carbamazepine Modified Release Dosage Forms

Abstract

The preparation of sustained release dosage forms of Carbamazepine (anti-epileptic drug characterized by a very low water solubility and by a short half life on chronique dosing) was carried out.

These formulations were obtained in two different steps:

a) modified release granules were prepared by the loading of cross-linked sodium carboxymethylcellulose (swellable polymer), with the drug and an enteric polymer. Cellulose acetate phthalate, methacrylic acid – methacrylic acid methyl ester copolymer (usually employed as enteric coating agents) and cellulose acetate trimellitate (a new enteric polymer) were used in different weight ratios.

b) some sustained release dosage forms were prepared tabletting physical mixtures of the modified release granules with different weight ratios of hydroxypropylmethylcellulose.

In vitro dissolution tests of modified release granules in gastric fluid (USP XXI) showed a modulation of the drug release, while in intestinal fluid (USP XXI) a quick drug dissolution was observed.

In vitro dissolution tests of sustained release dosage forms, performed varying during the test, the pH of the dissolution medium, (hydrochloric acid pH 1 from 0 to 2 hours and phosphate buffer pH 6.8 from 2 to 18 hours) showed that the determining factors in the controlling release of the drug are: the type and amount of enteric polymer constituting the granules and the amount of hydroxy-propylmethylcellulose mixed with them.     

Drug Release Kinetics from Tablet Matrices Based Upon Ethylcellulose Ether-Derivatives: A Comparison Between Different Formulations

ABSTRACT

The present study involved the preparation of ibuprofen-containing controlled release tablets formulated from either the established granular product, Ethocel®Standard Premium, or the novel finely-milled product, Ethocel®Standard FP Premium. The tablets were prepared by either direct compression or wet granulation. The aim was to explore the influence of different parameters on the kinetics and mechanisms of ibuprofen release from the tablets. These parameters were; polymer particle size, polymer molecular weight, drug : polymer ratio, preparation methodology and partial replacement of lactose with the coexcipient—hydroxypropyl methylcellulose (HPMC). The derived drug release data were analyzed with reference to various established mathematical models while the f₂-metric technique was used in order to determine profile equivalency. It was found that drug release was mostly modulated by several interactive factors apparently exhibiting crosstalk. Nevertheless, it was possible to identify some simple rules. Incorporation of Ethocel® FP polymers and application of the wet granulation technique facilitated greater efficiency in controlling ibuprofen release behavior from the matrices. Furthermore, drug release profiles could be modulated by partial substitution of the primary excipient with HPMC. Polymer concentrations and particle sizes, rather than viscosity grade, were found to be decisive factors in controlling drug release rates.     

Preparation and evaluation of posaconazole-loaded enteric microparticles in rats

Objectives: Posaconazole (POS) is an antifungal compound which has a low oral bioavailability. The aim of this study was to prepare POS enteric microparticles to enhance its oral bioavailability.

Methods: POS enteric microparticles were prepared with hypromellose acetate succinate (HPMCAS) via the spray drying method. The solvent mixtures of acetone and ethanol used in the preparation of the microparticles were optimized to produce the ideal POS enteric microparticles. Multivariate data analysis using a principal component analysis (PCA) was used to find the relationship among the HPMCAS molecular characteristics, particle properties and drug release kinetics from the spray dried microparticles.

Key findings: The optimal spray solvent mixtures were critical to produce the POS microparticles with the defined polymer entanglement index, drug surface enrichment, particle size and drug loading. The HPMCAS molecular characteristics affected the microscopic connectivity and diffusivity of polymer matrix and eventually influenced the drug release behavior, and enhanced the bioavailability of POS.

Conclusions: These studies suggested that the selection of suitable solvent mixtures of acetone and ethanol used in the spray drying of the microparticles was quite important to produce the entangled polymer structures with preferred polymer molecular properties of polymer coiling, overlap concentration and entanglement index. Additional studies on particle size and surface drug enrichment eventually produced HPMCAS-based enteric microparticles to enhance the oral bioavailability of POS.     

Formulation and Characterization of a Compacted Multiparticulate System for Modified Release of Water-Soluble Drugs—Part II Theophylline and Cimetidine

The purpose was to investigate the effectiveness of an ethylcellulose (EC) bead matrix and different film-coating polymers in delaying drug release from compacted multiparticulate systems. Formulations containing theophylline or cimetidine granulated with Eudragit^® RS 30D were developed and beads were produced by extrusion–spheronization. Drug beads were coated using 15% wt/wt Surelease^® or Eudragit^® NE 30D and were evaluated for true density, particle size, and sphericity. Lipid-based placebo beads and drug beads were blended together and compacted on an instrumented Stokes B2 rotary tablet press. Although placebo beads were significantly less spherical, their true density of 1.21 g/cm³ and size of 855 μm were quite close to Surelease^®-coated drug beads. Curing improved the crushing strength and friability values for theophylline tablets containing Surelease^®-coated beads; 5.7 ± 1.0 kP and 0.26 ± 0.07%, respectively. Dissolution profiles showed that the EC matrix only provided 3 h of drug release. Although tablets containing Surelease^®-coated theophylline beads released drug fastest overall (t_44.2% = 8 h), profiles showed that coating damage was still minimal. Size and density differences indicated a minimal segregation potential during tableting for blends containing Surelease^®-coated drug beads. Although modified release profiles >8 h were achievable in tablets for both drugs using either coating polymer, Surelease^®-coated theophylline beads released drug fastest overall. This is likely because of the increased solubility of theophylline and the intrinsic properties of the Surelease^® films. Furthermore, the lipid-based placebos served as effective cushioning agents by protecting coating integrity of drug beads under a number of different conditions while tableting.     

Effect of aminoalkyl methacrylate copolymer E/ HCl on in vivo absorption of poorly water-soluble drug

This study aimed to investigate in vivo absorption of tacrolimus formulated as a solid dispersion using Eudragit E^®/HCl (E-SD). E-SD is an aminoalkyl methacrylate copolymer that can be dissolved under neutral pH conditions. E-SD was used alone as a solid dispersion carrier and/or was mixed with tacrolimus primarily dispersed with hydroxypropylmethylcellulose (HPMC). Tacrolimus was formulated with E-SD at several different ratios. Formulations with tacrolimus/E-SD ratio of 1/3 showed higher in vivo absorption, compared to tacrolimus dispersed in the excipients (primarily HPMC) found in commercially available tacrolimus capsules, using a rat in situ closed loop method. Good correlation was observed between in vitro drug solubility and in vivo drug absorption. In vitro solubility tests and rat oral absorption studies of tacrolimus/HPMC solid dispersion formulations were also conducted after mixing the HPMC dispersion with several ratios of E-SD. E-SD/tacrolimus/HPMC formulations yielded high in vitro drug solubility but comparatively low in vivo absorption. Dog oral absorption studies were conducted using capsules containing a formulation of tacrolimus/E-SD at a ratio of 1/5. The E-SD formulation-containing capsule showed higher in vivo drug absorption than tacrolimus dispersed in the standard HPMC capsule. These studies report enhancement of the in vivo absorption of a poorly water-soluble drug following dispersion with E-SD when compared to formulation in HPMC.