Preparation and In-Vitro Evaluation of A Controlled Release Drug Delivery System of Theophylline Using An Aqueous Acrylic Resin Dispersion.

Abstract

Eudragit® E30D was utilized in conjunction with talc and xanthan gum to coat theophylline granules via a Wurster-type air suspension column. Since the resin is extremely tacky and cannot be used alone as a coating formulation, different amounts of talc and xanthan gum were incorporated into the Eudragit® E30D suspension to allow for coating of theophylline granules. The release profile of theophylline from the coated granules was found to be dependent on the ratio of the additives to the resin used in the coating suspension as well as on the coating level applied to the final product. A sample of theophylline granules coated with a film-coating suspension containing 1.5:1.0: :Talc: Eudragit® E30D resin (calculated on dry basis) exhibited a zero order release profile. However, the in-vitro release rates of this formulation decreased on storage. As the ratio of talc and Eudragit® E30D was changed to 1:1, the coated theophylline granules showed a release profile that remained unchanged even after exposure at room temperature, 30° C and 40° C for three months. A stable theophylline formulation was achieved by curing the coated product at 40°C for 24 hours.     

Manufacture of Slow-Release Matrix Granules by Wet Granulation with an Aqueous Dispersion of Quaternary Poly(meth)acrylates in the Fluidized Bed

ABSTRACT

Slow-release matrix granules were manufactured in the fluidized bed using an aqueous dispersion of quaternary poly(meth)acrylates (Eudragit® RS 30 D) as binder for granulation. A factorial design was carried out to investigate the influence of the following parameters, spraying rate, applied polymer amount, and inlet air temperature, on various granule properties. Prerequisites for a slow release of the model drug theophylline are high spraying rate, high amount of polymer, and low inlet air temperature. No considerable decrease of the drug release rate can be achieved without a subsequent curing of the dry granules. A clear correlation exists between the moisture content of the fluidized bed, indicated by the terminal moisture content (TMC), and the mean dissolution time for 80% of the drug (MDT₈₀).     

Evaluation of Ethylcellulose-Coated Pellets Optimized Using the Approach of Taguchi

Abstract

Spherical granules of theophylline with microcrystalline cellulose and lactose were prepared in a high-speed granulator. An original experimental design based on the philosophy of Taguchi was applied to optimize the yield of the produced granules. Successively, the optimized pellets were coated with an ethylcellulose pseudolatex preparation (Surelease®) in a fluid bed coating machine using a bottom spray noule and a Wurster® column. Finally, these granules were c ompressed into tablets of different hardnesses. The chosen statistical approach proved efficient not only to find the optimal operating conditions for granulation but it also appeared to define the characteristics of a process that was robust and no sensitive to noise factors. Dissolution studies revealed a zero-order release of theophylline from the coated granules, but after the compression step, the ethyl cellulose film was damaged and the drug release was immediate.     

The Influence of Formulation on the Dissolution Profile of Diclofenac Sodium Tablets

ABSTRACT

In attempts to design delayed-release tablets of diclofenac sodium, seven experimental batches were produced. The influence of super-disintegrant croscarmellose sodium (CCS), the granulation process, and the thickness of Eudragit® L 100 coating film were evaluated. The values of dissolution efficiency and the similarity factor were used to compare the dissolution profiles of each experimental batch and the reference Voltaren®. Both methods appear to be applicable and useful in comparing dissolution profiles. Based on such values four batches were considered similar when contrasted with the reference. The results suggest an optimal relationship between the amount of CCS and the thickness of the coating film, which provides appropriate dissolution rate of diclofenac sodium from the dosage forms.     

In Vitro Dissolution Studies of Sodium Diclofenac Granules Coated with Eudragit L-30D-55® by Fluidized-Bed System

Abstract

The objective of this work was to study the dissolution process of sodium diclofenac granules coated with a polymeric suspension of Eudragit L-30D-55® by fluidized bed. Methacrylic acid-methylmetacrylate copolymer, also known as Eudragit, has been used as a pH sensitive coating material to protect drug substances prior to delivery to the human intestines. The sodium diclofenac granules were prepared by wet granulation technology using microcrystalline cellulose (MICROCEL), sodium diclofenac, and polivinilpirrolidone K-30. The granules coating operation was carried out in a fluidized bed with top spraying by a double-fluid nozzle. The dissolutions studies of the coated granules were performed in triplicate in a dissolution test station according to “in vitro testing requirements” Method A (paddle method, rotation of 100 RPM and temperature fixed at 37°C). The dissolution mediums were 0.1N HCl solution and a pH 6.8 phosphate buffer solution, following the pH change dissolution procedure specified in USP for enteric-coated articles: 2 h of exposure to 750 mL of 0.1N HCl followed by testing in 1000 mL of pH 6.8 phosphate buffer, the pH being adjusted with 250 mL of 0.2 M tribasic sodium phosphate solution. The released amount of sodium diclofenac was periodically determined by UV spectrophotometry at wavelength of 276 nm, using a spectrophotometer UV-VIS HP 8453. The coated product showed gastric resistance properties confirming the feasibility of the fluidized bed for applying enteric coating in granules and pharmaceutical powders.     

Comparative Study of Aqueous and Organic Enteric Coatings of Chlorpheniramine Maleate Tablets

Abstract

Two acrylic polymers (Eudragit® L 12.5 P and L 30 D) and a cellulosic polymer (cellulose acetate trimellitate, CAT) in organic and aqueous formulations were used in order to obtain an enteric coating on tablets containing clorpheniramine maleate as a water-soluble model drug. The coating of tablets was executed in a coating pan in similar conditions for each kind of solvent. The coated tablets were tested according to the delayed-release test of USP 23 (Method A). In our experimental conditions different amounts of polymers were needed to obtain an enteric coating. The lowest amount was in the case of Eudragit L 30 D (aqueous), after which appeared Eudragit L 12.5 P (organic), CAT (organic), and finally, CAT (aqueous) as the polymer that needed to be of the highest amount. During the dissolution test differences in the size and aspect of the tablets were observed according to the polymers. Acrylic polymers did not show changes in size and aspect, but CAT polymers showed a notable increase in size. me different behavior of the tablets during the dissolution test can explain the differences observed in the adjustment of the release data. The release data were tested assuming common kinetic models. In the present study it was observed that Eudragit L polymers release the drug in a first-order kinetic and that CAT releases it according to a zero-order kinetic.     

A Comparison of the Dissolution Characteristics of Theophylline from Film Coated Granules and Mini-Tablets

Granules and mini-tablets containing theophylline were film coated by fluidised bed technology with various amounts of ethylcellulose and Eudragit RL. Scanning electron micrographs of both whole and fractured film coated granules and mini-tablets were taken. In vitro dissolution studies were carried out on encapsulated samples of film coated material equivalent to about 150mg of theophylline. Dissolution studies were also carried out on individual granules and mini-tablets and the time for 10% release (t10% values) of drug were determined. A comparison of the dissolution profiles showed that granules required about 2.5 to 3 times more coating material than mini-tablets to achieve the same release rate. It is also shown from the t10% values that drug release from mini-tablets is more consistent than from granules. Since the mini-tablets contain uniform weights of theophylline, their use allows precise adjustment of the number of encapsulated mini-tablets for individual dosage titration.     

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.     

Use of Proteins to Minimize the Physical Aging of EUDRAGIT® Sustained Release Films

ABSTRACT

The objective of this study was to investigate the influence of two proteins, albumin and type B gelatin, on the physical aging of EUDRAGIT® RS 30 D and RL 30 D coated theophylline pellets. The physicomechanical properties of sprayed films, thermal properties of cast films, influence of proteins on the zeta potential and particle size of the dispersion, and the release of proteins from cast films under simulated dissolution conditions were investigated. The release rate of theophylline decreased significantly over time from pellets coated with an acrylic dispersion containing 10% albumin when there was no acidification of the acrylic dispersion; however, when pellets were coated with an acidified EUDRAGIT®/albumin dispersion, the theophylline release rate was stable for dosage forms stored in the absence of humidity. The drug release rate was faster for pellets coated with acrylic dispersions containing 10% gelatin compared to the albumin–containing formulations. When sprayed films were stored at 40°C/75% RH, the water vapor permeability decreased significantly for both EUDRAGIT® films and those containing EUDRAGIT® and albumin; however, there was no significant change in this parameter when 10% gelatin was present. Albumin was released from the acrylic films when the pH of the dissolution media was below the isoelectric point of the protein while no quantitative release of gelatin was observed in pH 1.2 or 7.4 media. The effect of gelatin to prevent the decrease in drug release rate was due to stabilization in water vapor permeability of the film. Acidification of the polymeric dispersion resulted in electrostatic repulsive forces between albumin and the acrylic polymer, which stabilized the drug release rate when the dosage forms were stored in aluminum induction sealed containers at both 40°C/75% RH and 25°C/60% RH.     

Multivariate Analysis of Variance of Dissolution Data in the Development of Oral Sustained Release Formulations

Abstract

A multivariate analysis of variance applied to polinomial interpretation of growth curves in used for the interpretation of dissolution curves of four experimental, sustained release, wax type theophylline tablets.

The factors under study were glyceril palmitic stearate, carboxypol imethylene contents and compression force. The tablets were formulated according an experimental design based on 4 × 4 Hadamard matrix. The USP type I apparatus for dissolution test and CHI 0.1 N plus O.1%. polysorbate 80 as dissolution medium was used.

The statistical interpretation of results showed: first, that dissolution rates were almost constant for the four formulations during 8 h; second, the main difference between formulation dissolution rates can be inputed to fat excipient content and in much lesser extent to carboxipolymethylene content; third, the theopylline release rate was unaffected by compression force.     

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     

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.     

Effect of Viscosity Increasing Agent and Electrolyte Concentration on the Release Rate of Theophylline from a HPMC Based Sustained Release Capsules

Abstract

Sustained release (SR) granules (250-650～) containing theophylline were prepared using hydroxypropyl methylcellulose (HPMC) as a rate retarding polymer. The effect of variable ionic strength and viscosity increasing agent on the theophylline release rate have been investigated. Irrespective of dissolution media the theophylline release kinetics was found to be dependent on square root of time. Thc Higuchian release rate (K) was found to increase exponentially with the increase in ionic strength of the dissolution fluid. An opposite effect was observed with the viscosity increasing agent sodium carboxy methyl cellulose (Na-CMC) in the dissolution fluid. The release rate dccreased linearly with the increase of Na-CMC concentration in the dissolution fluid.     

Sustained-Release Dosage Form of Nicardipine Hydrochloride: Application of Factorial Design and Effect of Surfactant on Release Kinetics

Abstract

Microcapsules of nicardipine hydrochloride with core:wall ratios of 1:1, 2:1, and 1:2 were prepared by the coacervation-phase separation method, using ethyl-cellulose as the coating material. Two batches of nicardipine hydrochloride microscapsules were divided into size fraction by using standard sieves ranging from 840 μm to 476 pn. Dissolution rate studies from microcapsules were performed using the USP XXII basket method. The kinetic model according to the Rosin-Rammler-Sperling-Bennet-Weibull (RRSBW) distribution was applied for the parametric representation of the dissolution curves. Preparation and dissolution rate studies on the nicardipine hydrochloride microcapsules were pellformed and the influence of particle size, core:wall ratio, and the amount of nicardipine hydrochloride on the release rate was examined by 2³ factorial design. The sign@cance of the observed effects was tested with the F test. A surface active substance was added in the dissolution medium to understand how this substance effects the release of drug from ideal microcapsule form which is found by the findings of the 2³ factorial design. Dissolution studies were repeated with this ideal formulation using different ratio of Tween 20.

The results of this study suggested that the solubility and bioavailability of the sustained-release dosage forms of nicardipine hydrochloride using sullface active substances could be increased.     

Manufacture of slow-release matrix granules by wet granulation with an aqueous dispersion of quaternary poly(meth)acrylates in the fluidized bed

Slow-release matrix granules were manufactured in the fluidized bed using an aqueous dispersion of quaternary poly(meth)acrylates (Eudragit® RS 30 D) as binder for granulation. A factorial design was carried out to investigate the influence of the following parameters, spraying rate, applied polymer amount, and inlet air temperature, on various granule properties. Prerequisites for a slow release of the model drug theophylline are high spraying rate, high amount of polymer, and low inlet air temperature. No considerable decrease of the drug release rate can be achieved without a subsequent curing of the dry granules. A clear correlation exists between the moisture content of the fluidized bed, indicated by the terminal moisture content (TMC), and the mean dissolution time for 80% of the drug (MDT₈₀).     

Physicochemical properties and mechanisms of drug release from melt-extruded granules consisting of chlorpheniramine maleate and Eudragit FS

Abstract

The objective of this research project was to characterize the drug release profiles, physicochemical properties and drug–polymer interaction of melt-extruded granules consisting of chlorpheniramine maleate (CPM) and Eudragit® FS. Melt extrusion was performed using a single screw extruder at a processing temperature of 65–75?°C. The melt extrudate was milled, blended with lactose monohydrate and then filled into hard gelatin capsules. Each capsule contained 300?mg CPM granules. The release of CPM was determined with the United States Pharmacopeia dissolution apparatus II using a three-stage dissolution medium testing in order to simulate the pH conditions of the gastrointestinal tract. Pore structure, thermal properties and surface morphologies of CPM granules were studied using mercury and helium pycnometer, differential scanning calorimeter and scanning electron microscope. Sustained release of CPM over 10?h was achieved. The release of CPM was a function of drug loading and the size of the milled granules. The complexation between CPM and Eudragit® FS as the result of counterion condensation was observed, and the interaction was characterized using membrane dialysis and H¹ NMR techniques. In both 0.1?N HCl and phosphate buffer pH 6.8, CPM was released via a diffusion mechanism and the release rate was controlled by the pore structure of the melt-extruded granules. In phosphate buffer pH 7.4, CPM release was controlled by the low pH micro-environment created by CPM, the pore structure of the granules and the in situ complexation between CPM and Eudragit® FS.     

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.     

Preparing of aspirin sustained-release granules by hot-melt granulation and micro-crystal coating

In this work, aspirin (ASP) sustained granules were prepared using micro-crystal coating and hot-melt granulation, respectively. In the process of micro-crystal coating, PVP was used to form the isolation layer and then coated with either Eudragit RS/RL30D or ethyl cellulose (EC) as sustained-release layers to prepare sustained granules (the granules from this method were denoted m-cG). And in the process of hot-melt granulation, the granules were obtained with stearyl alcohol as a binder and EC as matrix material to prepare sustained granules (the granules were denoted h-mG). The in vitro release of ASP sustained-release granules was investigated by dissolution apparatus and the stability of the granules was studied. Since both methods effectively prevented the hydrolysis of ASP, the sustained granules by micro-crystal coating and hot-melt granulation were stable. However, there was a clear difference in the in vitro release of h-mG and m-cG. The h-mG was completely released in 4?h, while the m-cG with EC as sustained-release layer released 80% in 24?h and the m-cG with the Eudragit RS/RL 30?D as sustained-release layer released completely in 5?h. The results showed that micro-crystal coating was more suitable for the preparation of ASP sustained granules, and the granules with EC as sustained layer could achieve a better sustained-release effect.     

Aquesons Films Coating Stuied of Sustabined Release Niciotine Acid Fellets: An In-Vitro Evalutiion

Abstract

Numerous batches of nicotinic acid (niacin) pellets were coated to determine the optimum level of Surelease® coating which would exhibit in-vitro release patterns suitable for BID dosing. Various levels of Surelease, with and without the incorporation of a hydrophilic material, were studied. It was expected that a significantly high level of Surelease would be needed to obtain the desired in-vitro dissolution release rate for the water soluble drug. However, a coating level of 1.2% Surelease coating was found to have an in-vitro dissolution profile approximating that of a BID product. Scanning electron microscopic examination has shown that the surface of coating is smooth and uniform with the coating thickness of about 2 μm. The 2 months stability data showed no significant changes in the dissolution profiles.     

Release of Theophylline from Ethyl Cellulose Mecrocapsues Alone and in Conjuction with Fat Embedded (Precirol®) Granules and Hydroxypropyl Methycellulose

Abstract

Microcapsules of theophylline with ethyl cellulose were prepared by coacervation technique using cabosil® (silicon dioxide) as separant. Tablets were prepared from microcapsules, microcapsules + theophylline fat embedded granules, and microcapsules and hydroxypropyl methylcellulose 4000 (HPMC). Release was studied in vitro by the rotating basket method. Prolonged release of theophylline was observed from microcapsules with no drug dumping. The release from microcapsules was of first-order whereas that from all the tablet formulation was diffusion controlled according to the Higuchi model. Good correlation was found between release rate and core:wall ratio for all the systems. Decrease in hardness of tablets made from microcapsules alone decreased the release rate, indicating damage of microcapsules during compression. The tablets compressed from fat embedded granules, microcapsules with fat embedded granules, and microcapsules with HPMC gave a desired release for a 74 hour sustained release preparation.