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avai lab le at www.sc iencedi rec t .com

journa l homepage: www.e lsev ier .com/ locate /e jps

Gastrointestinal transit and disintegration of enteric coatedmagnetic tablets assessed by ac biosusceptometry

Luciana A. Coraa, Fernando G. Romeiroa, Madileine F. Americoc,Ricardo Brandt Oliveirac, Oswaldo Baffad, Murilo Stelzera,Jose Ricardo de Arruda Mirandaa,∗

a Department of Physics and Biophysics, Biosciences Institute, IBB, Laboratorio de Biomagnetismo, Universidade Estadual Paulista,UNESP, CXP 510, Botucatu, Sao Paulo CEP 18618-000, Brazilb Department of Medical Clinics, FMB, Universidade Estadual Paulista, UNESP, Botucatu, Sao Paulo, Brazilc Department of Medical Clinics, FMRP, Universidade de Sao Paulo, USP, Ribeirao Preto, Sao Paulo, Brazild Department of Physics and Mathematics, FFCLRP, Universidade de Sao Paulo, USP, Ribeirao Preto, Sao Paulo, Brazil

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rticle history:

eceived 2 August 2004

eceived in revised form 11 January

005

ccepted 4 August 2005

vailable online 26 September 2005

eywords:

iosusceptometry

isintegration

ablets

astrointestinal motility

olonic drug delivery

agnetic images

a b s t r a c t

The oral administration is a common route in the drug therapy and the solid pharmaceutical

forms are widely used. Although much about the performance of these formulations can

be learned from in vitro studies using conventional methods, evaluation in vivo is essential

in product development. The knowledge of the gastrointestinal transit and how the physio-

logical variables can interfere with the disintegration and drug absorption is a prerequisite

for development of dosage forms. The aim of this work was to employing the ac biosus-

ceptometry (ACB) to monitoring magnetic tablets in the human gastrointestinal tract and

to obtain the magnetic images of the disintegration process in the colonic region. The ac

biosusceptometry showed accuracy in the quantification of the gastric residence time, the

intestinal transit time and the disintegration time (DT) of the magnetic formulations in the

human gastrointestinal tract. Moreover, ac biosusceptometry is a non-invasive technique,

radiation-free and harmless to the volunteers, as well as an important research tool in the

pharmaceutical, pharmacological and physiological investigations.

© 2005 Elsevier B.V. All rights reserved.

. Introduction

he drug delivery systems are intended for optimize the actionf the pharmacological agent, for improving therapeutic effec-iveness and for minimizing adverse effects (Rouge et al.,996; Levy, 1998; Urquhart, 2000; Chourasia and Jain, 2003).olonic drug delivery is potentially useful not just for the top-

cal treatment of intestinal diseases especially inflammatoryowel disease (IBD) including Chron’s disease and ulcerativeolitis, but also for the delivery of therapeutic peptides androteins due to the low proteolytic enzyme activities (Kenyon

∗ Corresponding author. Tel.: +55 14 3811 6254; fax: +55 14 3811 6346.E-mail address: jmiranda@ibb.unesp.br (J.R. de Arruda Miranda).

et al.,1997; Wikberg et al., 1997; Friend, 1998; Yang et al.,2002).

However, before reaching the colon, the enteric dosageforms should overcome many physiological changes along thegastrointestinal (GI) tract, such as motility pattern and thegradual variation in pH (Dressman et al., 1993; Lipka and Ami-don, 1999). The oral absorption from a solid dosage form canbe regarded as part of a process that includes the drug releasefor the disintegration, the drug solubility and its permeabilityto the GI mucosa (Melia and Davis, 1989; Lipka and Amidon,1999). Traditionally, these processes may be investigated by in

928-0987/$ – see front matter © 2005 Elsevier B.V. All rights reserved.oi:10.1016/j.ejps.2005.08.009

2 e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 1–8

vitro tests; however, in vivo studies provide more reliable datafor the clinical development of a new product (Zahirul andKhan, 1996) and should be used at least in the latest stage ofdevelopment.

Several techniques, including imaging methods, play animportant role in the evaluation of drug delivery and are ableto demonstrate how pharmaceutical dosage forms behave inthe human GI tract (Digenis et al., 1998a,b; Wilson, 1998; Singhand Waluch, 2000; Wilding et al., 2001; Newman et al., 2003).The �-scintigraphy is the standard method for this purpose;however, the main drawbacks of this technique are the expo-sure of the patient to ionizing radiation and the complicatedpreparation of radiopharmaceuticals.

Biomagnetic techniques are currently available as animportant tool in the clinical, physiological and pharmaceuti-cal research since they are non-invasive and radiation-free,allowing to evaluate the properties of biological systems,including the monitoring of dosage forms. Multichan-nel superconducting quantum interference device (SQUID)devices are employed for the measurement of the magneticfield, after ingestion of a magnetically marked dosage form(Weitschies et al., 1997, 2001; Hu et al., 2000). This system wasdeveloped to detect the extremely weak biomagnetic fieldsgenerally in a magnetically shielded environment. In addition,the SQUID has an expensive operational cost, which limits itsuse in a wide scale.

The alternate current biosusceptometry (ACB) is a promis-

Fig. 1 – (A) Single sensor ACB system with the excitationcoil (1) and the detection coil (2). (B) Multi-sensor ACBsystem showing the individual detection coils (internal)and the single excitation coil (external).

and a detection coil (internal), in the first-order gradiomet-ric configuration (Fig. 1A). Consequently, when no magneticmaterial is near to the measurement system, the output sig-nal will be minimized. When there is an approximation of amagnetic mass an unbalancing in the magnetic flux of the gra-diometric system occurs, and the magnetic material can bemonitored. In this study, the single sensor ACB was employedto obtain the GI transit time and the magnetic images of thetablets.

The multi-sensor ACB uses only a pair of excitation coil(� = 11 cm) and seven pairs of detection coils (� = 2.9 cm), coax-ially arranged (Fig. 1B) (Cora et al., 2003, 2005). This system isfixed in a vertical support with adjustment to be positionedon the abdominal surface to characterize the GI motility, thepattern of frequency and the tablet translocations. As the mag-netic signal is dependent of the distance, the movement ofthe gastric wall causes a variation in the distance between theabdominal surface and the magnetic material ingested. Thisvariation characterizes the motor activity of the GI tract thatit can be registered for the sensors in different points.

The magnetic signals are acquired through “lock-in” ampli-fiers (Stanford Research Systems) digitalized to an A/D board

ing technique and has shown accuracy when evaluatingphysiological properties of the GI tract (Miranda et al., 1992,1997; Baffa et al., 1995; Oliveira et al., 1996; Moraes et al.,2003). The ACB uses the induction coils to record the mag-netic flux variation obtained by the response of a magneticmaterial (ferrite—MnFe2O3) ingested. This technique was alsoemployed to acquire the magnetic images of the ferromagneticphantoms (Moreira et al., 2000).

The continuous improvement of the ACB allowed toincrease gradually the sensitivity and to implement a newinstrumental arrangement. The multi-sensor ACB was sug-gested originally to characterize the disintegration process ofmagnetic tablets in the human stomach (Cora et al., 2003,2005).

The aim of this study was to employ the single andmulti-sensor ACB systems to monitor enteric coated mag-netic tablets in the human GI tract and to obtain the magneticimages of the disintegration process.

2. Materials and methods

2.1. Fundamentals

The working principle of ac biosusceptometry, according toFaraday’s Induction Law, is based on a double magneticflux transformer with air nucleus, in which the pair (excita-tion/detection), located more distant from a magnetic material(ferrite), acts as reference (Miranda et al., 1992, 1997; Baffa etal., 1995; Oliveira et al., 1996). The single sensor ac biosus-ceptometer (single sensor ACB) consists of two pairs of coils(� = 3.0 cm) separated by a fixed distance (baseline), where eachpair of coils are compounded of an excitation coil (external)

e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 1–8 3

of 16 bits (PCI-MIO-16XE-10, National Instruments Inc.) and amicrocomputer.

2.2. Magnetic formulations

Magnetic tablets (10 mm diameter, 1.54 g weight) were pre-pared by direct compression from 1.00 g of ferrite (MnFe2O3),0.50 g of microcrystalline cellulose (Merck, Germany), 0.01 g ofmagnesium stearate (Merck, Germany) and 0.03 g of sodiumstarch glycolate—Explotab® (Penwest, USA), coated by spray-drying with a solution of enterosoluble polymer—Eudragit®

S100 (Rohm, Germany). The ferrite is an inert material that isnot absorbed by the GI tract, harmless to the organism and,therefore without biological side effects (Forsman, 1998).

2.3. Study subject

Studies were performed in nine healthy volunteers, both gen-ders and ages ranged from 21 to 41 years, with a meanbody weight of 65 ± 4 kg and body mass indices (BMI) of21.14 ± 0.8 kg m−2. All of the volunteers had no history of gas-trointestinal symptoms or abdominal surgery.

Written informed consent of participation in the studieshad been obtained. The in vivo investigation was carried outaccording to the Declaration of Helsinki, promulgated in 1964and was approved by the Ethic Committee in Research of theMedical School, Universidade Estadual Paulista (UNESP).

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intestinal transit time (SITT). When locating the tablet incolon, the multi-sensor ACB was positioned in the regiondelimited by the McBurney’s point and iliac right crest(Fig. 2B) for acquisition of the magnetic signals during20 min.

Besides that, the single-sensor ACB was used to real-ize a scanning every 10 min, in a correspondent area of12 cm × 12 cm, drawn in the colonic region of the volunteers(Fig. 2C). This scanning was carried out in 2 min to obtain theinitial matrix (9 × 9). The square matrix (144 points) was cal-culated considering null the external points in initial matrix(Miranda et al., 1992; Baffa et al., 1995; Moreira et al., 2000; Coraet al., 2005).

2.5. Data Analysis

The magnetic signals were recorded by the multi-sensor ACB,with acquisition frequency of 10 Hz/channel, stored in ASCIIformat and analyzed in MatLab (Mathworks, Inc.). The signalswere filtered using bi-directional Butterworth low-pass filterwith cutoff frequency of 0.2 Hz to minimize the artifacts of thebreathing. The gastrointestinal motility was analyzed by fastFourier transform (FFT) and running spectral analysis (RSA).

The gastric residence time (GRT) and the small intestinaltransit time (SITT) were determined through the mapping ofthe abdominal surface, carried out with single-sensor ACB.The GRT was determined as the time interval between the

F in g1

.4. Procedure

iomagnetic studies were carried out in distinct stages,mploying the single and multi-sensor ACB systems. All vol-nteers fasted at least 12 h prior to the administration of theagnetic tablets. Each volunteer, in orthostatic position in

he measurement system, swallowed a magnetic tablet with00 ml of water. The multi-sensor ACB system was positionedn the gastric region and the magnetic signals was acquired,oncomitantly, during 20 min. The xiphoid process and thembilicus were the anatomic references (Fig. 2A).

The single-sensor ACB was employing to monitoring theagnetic tablet between the measurements of the GI motil-

ty. This procedure consisted of mapping the abdominalurface to each 10 min to locate magnetic tablet and toetermine the gastric residence time (GRT) and the small

ig. 2 – Positioning of the sensors in volunteers. (A) Sensors2 cm × 12 cm where the scanning was done.

arrival of the magnetic tablet in the stomach and its gas-tric emptying. The SITT was calculated by subtracting theGRT from the total transit time in which the magnetic tabletreached the colonic region.

Each square matrix (144 points) was interpolated(256 × 256) by the spline method and with the applicationof routines implemented in MatLab, the degraded images ofthe disintegration process of magnetic enteric coated tabletswere obtained. The images processing consisted only of thesubtraction of background and adjustments of brightnessand contrasts. The analyses of magnetic images were basedon procedures employed in scintigraphic studies (Perkinset al., 2001). The onset of disintegration was defined asthe time in which a 50% increase in image area occurred.The complete disintegration was indicated as the time inwhich the magnetic material was spreading in the colonicregion.

astric projection. (B) Sensors in colonic projection. (C) Area

4 e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 7 ( 2 0 0 6 ) 1–8

Fig. 3 – (A) Gastric activity contraction. The arrow indicatesthe arrival of a magnetic tablet in the distal stomach. (B)FFT of the sensor 5 showing the frequency in 0.05 Hz (3cycles/min).

Fig. 4 – (A) Gastric contractile waves in fasting state. (B) FFTof the sensor 4 showing the frequency in 0.05 Hz (3cycles/min).

Fig. 5 – (A) Colonic motility. The arrows indicate thedisplacement of the magnetic tablet between the sensors.(B) FFT of the sensor 5 showing the frequency in 0.12 Hz (6cycles/min).

The disintegration process is characterized, basically,in transition between a magnetic marker (MM, non-disintegrating tablet) and a magnetic tracer (MT, disintegratingtablet). These modifications can be observed in the images,where the magnetic marker presents clearly outlines and theMT is the spreading of the magnetic material in the colonicregion.

Table 1 – Gastrointestinal transit times (minutes) anddisintegration time (DT) for magnetic enteric coatedtablets

Subject Time (min)

GRT SITT OCTT DT

1 70 120 190 1502 130 150 280 903 60 160 220 604 40 200 240 505 30 150 180 1806 50 180 230 607 60 210 270 1208 30 180 210 709 80 180 260 90X 60 170 230 90S.D. 30 30 40 40CV (%) 50 18 18 45

X: mean; S.D.: standard deviation; CV (%): coefficient of variation% = (S.D./X) × 100.

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Fig. 6 – Images of the disintegration process of the magnetic tablet in the colon obtained for two distinct volunteers. Eachsquare in the grid corresponds to 1 cm.

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3. Results and discussion

The GI tract presents regional differences that must be takeninto account for evaluation of the pharmaceutical form due tothe impact that the physiological variables have on its in vivoperformance (Lipka and Amidon, 1999; Urquhart, 2000). Themain factor that influences the drug delivery is the GI motility,which could be divided into two distinct modes, according tothe prandial state. In the interdigestive period, the motility ischaracterized by a cyclical motor pattern known as migratingmyolectric complex (MMC) (Quigley, 1996; Rao and Schulze-Delrieu, 1993).

With the multi-sensor ACB positioned on the abdominalsurface (Fig. 2A) the gastric activity contraction (GAC) duringthe MMC (Fig. 3A) was recorded. It is observed, through thevariation of the intensity and of the basal level of the magneticsignals recorded by the sensors located more distally, thatthe tablet arrived in the distal stomach (arrow). The gastricmotility of the interdigestive period was recorded in real-timeafter the ingestion of the magnetic tablet (Fig. 3A) and wascharacterized for the onset of intense and continuous con-tractile waves with dominant frequency of three cycles/min(Fig. 3B).

According to other studies (Khosla et al., 1989; Coupe etal., 1991a), the phase III of the MMC, the so-called “house-keeper wave”, promotes the emptying of indigestible parti-

the intestinal transit are variables that must be considered forcolonic drug delivery (Price et al., 1993).

The results obtained in this study showed that the colonicarrival time for the magnetic tablets, represented by orocaecaltransit time (OCTT) ranged from 180 to 280 min (mean 230 ± 40)(Table 1). This variation in the OCTT is attributed mainly tothe GRT, because the SITT is relatively constant as discussedearlier.

Similarly to that it occurs in other segments of the humanGI tract, the colonic motility is modulated by the prandial stateand presents strong propulsive waves that promotes the abo-rally movement of its contents (Edwards, 1997).

The multi-sensor ACB, positioned in the colonic region(Fig. 2C), characterized the colonic motility in real-time(Fig. 5A), obtaining a frequency pattern around the6 cycles/min (Fig. 5B).

The disintegration of solid pharmaceutical forms in thecolon is characterized by a slow process and initiates aftera lag time necessary for the coating dissolution. The disin-tegration process of magnetic tablets was analyzed throughthe magnetic images obtained by the scanning of the colonicregion. The images were represented in a temporal sequencethat allowed to visualize the magnetic tablet in the humancolon and to quantify the disintegration time (DT).

The instant t1 illustrates the magnetic tablet after thearrival to colon (Fig. 6A and B). The onset of the disintegrationcan be verified in t4 (Fig. 6A) and t3 (Fig. 6B). The spreading

cles, including the pharmaceutical dosage forms. Analyzingthe magnetic recordings (Fig. 4A and B), it is inferred that thetablets emptied from the stomach in this period of activity,since during the study the GAC presented high amplitude andnot been registered periods of motor quiescence.

The determination of the arrival of the magnetic tablet inthe stomach and the recording of its emptying allowed thequantification of the gastric residence time for these tablets(Table 1). The GRT ranged from 30 to 130 min (mean 60 ± 30),showed a significant variation intervolunteers. In addition, theprotocol utilized in this study was designed to minimize theinterference of any external factor in the gastric emptying ofthe magnetic tablets.

Different of the GRT, the small intestinal transit time formagnetic tablets was relatively constant and the intersubjects’variation was less expressive. The SITT for magnetic tabletsranged from 120 to 210 min (mean 170 ± 30 min) (Table 1). Thecoefficient of variation for the SITT is lesser in relation tothe observed for the GRT demonstrating that intestinal tran-sit is affected by fewer physiological factors than it is gastricemptying. Several studies showed that the transit of differ-ent pharmaceutical dosage forms through the small intestineis independent of both the physical properties of the dosageform and the feeding conditions, and the transit time is gen-erally from 2 to 4 h (Davis et al., 1986; Coupe et al., 1991b).

Although the small intestine presents the main surface forthe drugs absorption orally administered, the colon appearsas a specific targeting for drug delivery, with significant ther-apeutic advantages (Stubbs et al., 1991; Kenyon et al., 1997;Friend, 1998; Shareef et al., 2003). However, for successfulcolonic drug delivery, many physiological barriers must beovercome. Beyond the appropriate coating that resists to thegradual changes along of the GI tract the gastric emptying and

of magnetic material in the region can be visualized fromthe instant t7 (Fig. 6A and B) and characterizes the completedisintegration of the tablet. The DT to the magnetic tabletsranged from 50 to 180 min (mean 90 ± 40) (Table 1) with expres-sive intersubjects’ variability, that also was observed in scinti-graphic studies (Kenyon et al., 1997; Krishnaiah et al., 1998).These findings reflect the importance of the in vivo studies tocharacterize the behaviour of the solid pharmaceutical formsand the drug release in the human GI tract.

The magnetic images (Fig. 6A and B) consisted in an originaland relevant approach to evaluate the disintegration processof the solid dosage forms in vivo, because allowed the visu-alization of this process suitably, although the digital imageprocessing (DIP) has not been totally explored. The DIP con-sists on use of filters like Wiener, for the restoration of thedegraded images (Kondo et al., 1977; Moreira et al., 2000). Inorder to improve the quality of the magnetic images, restora-tion techniques will be potentially advantageous.

4. Conclusions

When developing an oral dosage form, it is important to eval-uate the physiological parameters to understand how the for-mulation performs in the GI tract. Nevertheless, to followingthe involved processes in the drug delivery also is neces-sary to refine the available techniques and to develop othersfor this kind of analysis. In this context, this study demon-strated that through of a non-invasive technique, like theACB, it was possible to characterize the behaviour of mag-netic tablets in the human GI tract under normal physio-logical conditions, obtaining information regarding to in vivoperformance.

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As well as characterizing the gastric residence time andthe intestinal transit of magnetic tablets with the ACB, it waspossible to obtain the images from the magnetic tablets in thehuman colon, visualizing and quantifying the disintegrationprocess. Our data confirmed the ability of the ACB to obtainthe magnetic images in the human intestine; furthermore,applying digital image processing and the development ofnovel instrumentations increasing number of sensors, couldimprove the quality of the images.

The results presented are comparable with results obtainedby established methods, showing that the ACB is a suit-able technique for evaluation of solid pharmaceutical forms.In summary, this study allows to conclude that this tech-nique has enough potential to evaluate not only the mag-netic tablets as also magnetic controlled release dosage formsin the human gastrointestinal tract. Moreover, the ACB istotally safe, radiation-free and presents low cost; such char-acteristics had become it in an attractive tool to be usedin the physiological and pharmaceutical research, constitut-ing a new approaching for the investigation of drug deliverysystems.

Acknowledgements

The authors are grateful to FAPESP (01/11539-0), PRONEX(03/10107-5), CAPES and FUNDUNESP for financial support.E–

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