in vivo drug release behavior in dogs from a new colon-targeted delivery system

Journal of Controlled Release 57 (1999) 45–53

In vivo drug release behavior in dogs from a new colon-targeteddelivery system

*Takashi Ishibashi , Harumi Hatano, Masao Kobayashi, Masakazu Mizobe,Hiroyuki Yoshino

Pharmaceutics Research Laboratory, Tanabe Seiyaku Co. Ltd., 16-89, Kashima 3-chome, Yodogawa-ku, Osaka 532, Japan

Received 8 November 1997; received in revised form 18 March 1998; accepted 8 June 1998

Abstract

The colon-targeted delivery capsule (CTDC), a new capsule-type dosage form for colonic delivery of drugs, wasinvestigated for the in vivo drug release behavior in dogs. A CTDC formulation with prednisolone as a model drug andtheophylline as a marker substance for gastric emptying was prepared for this study. The enteric-coated capsule (ECC)formulation with a similar composition was also prepared as the reference. Both formulations were administered to fourbeagle dogs, and the drug release behavior thereof was compared. Under fasted condition, ECC released prednisolone andtheophylline at the same time within 1 h after the gastric emptying. On the other hand the CTDC released prednisolone at 3.2h after the gastric emptying. Such release behavior of CTDC was approximately consistent with the results obtained from thein vitro dissolution study, suggesting that the pH-sensing and timed-release functions imparted to the CTDC can work in thegastrointestinal tract of dogs as programmed. Under non-fasted condition, however, the gastric emptying of CTDC wasfound to be considerably delayed, up to about 14 h, and in this case the in vivo dissolution lag time of prednisolone at thesmall intestine was shortened to about 1.5 h. 1999 Elsevier Science B.V. All rights reserved.

Keywords: Colon-targeted delivery; Hard gelatin capsule; Beagle dog; Eudragit E; HPMC -AS; Gastric emptying; Foodeffect

1. Introduction targeting based on different principles, including pH-sensing release [1,2], timed-controlled release [3–6],

For the purpose of achieving the local treatment of and microbially-controlled release [7–10].a variety of bowel diseases by peroral administration, Besides potential selectivity to the colon, theand also to improve the oral bioavailability of some feasibility for large scale production and regulatorydrugs susceptible to enzymatic degradation in the issues are important factors to be considered in orderupper gastrointestinal tract, such as peptides and to offer such new delivery systems to clinics andproteins, colon-specific drug delivery has attracted hospitals as soon as possible. Formulations, there-much interest in recent years. Various technologies fore, should be designed using materials identified asand methodologies have been developed for colon safe in actual usage, and preparation methods should

apply technologies authorized in actual pharmaceu-* tical production. From such a practical point of view,Corresponding author. Tel: 181-6-300-2788; fax: 181-6-300-

2799; e-mail: [email protected] we recently tried to develop a new capsule-type

0168-3659/99/$ – see front matter 1999 Elsevier Science B.V. All rights reserved.PI I : S0168-3659( 98 )00106-0

46 T. Ishibashi et al. / Journal of Controlled Release 57 (1999) 45 –53

dosage form, called the colon-targeted delivery cap- colon-targeted delivery system based on the resultssule (CTDC). of those in vivo assessments in dogs.

Considering the physiological conditions andmovements of the human gastrointestinal tract, theCTDC was designed so as to impart a timed-release 2. Materials and methodsfunction and a pH-sensing function to a conventionalcapsule-type dosage form. The technical characteris- 2.1. Materialstics of this system are the containment of an organicacid in a hard gelatin capsule together with an active Prednisolone (Nacalai Tesque, Kyoto, Japan) wasingredient, and to coat the capsule with a three- used as a model drug. Theophylline (Shiratorilayered film consisting of an acid-soluble polymeric Seiyaku, Japan) was used as an indicator determininglayer, a water-soluble layer, and an enteric layer. the gastric emptying time of the dosage form. HardAfter ingestion of the CTDC, the outermost enteric gelatin capsules (size [2) were purchased fromcoating completely prevents the drug release in the Warner Lambert. Aminoalkyl-methacrylate copoly-

¨stomach for many hours. After gastric emptying, mer E (Eudragit E100, Rhom Pharm, Darmstadt,though both the enteric and hydrophilic layers dis- Germany) was used as the acid-soluble polymer,solve quickly, the remaining acid-soluble polymeric which is soluble in the low pH aqueous medium uplayer still prevents the drug release. However, when to pH 5. Hydroxypropylmethylcellulose acetate suc-

the pH inside the capsule decreases by the dissolu- cinate (HPMC -AS, type MF, Shin-etsu Chemical,tion of organic acid, this layer dissolves and the drug Tokyo, Japan) was used as an enteric polymer.

contents are quickly released. Considering the above Hydroxypropylmethylcellulose (TC-5 , type EW,release mechanism, the CTDC can be applied to Shin-etsu Chemical) was used as a hydrophilicmost drugs, except the drugs extremely susceptible polymer. Ethylcellulose (10cp grade, Shin-etsuto degradation at low pH or to the interaction with Chemical) was used as a sealing agent of the hardorganic acid in solution form. gelatin capsule. Succinic acid (Katayama Chemical,

In a previous paper [11], we reported that the Osaka, Japan) was used as a pH-adjusting agent.onset time of drug release in vitro is delayed Betamethasone (Wako Chemical Industries, Osaka,depending on the thickness of the acid-soluble Japan) and 7-(2-hydroxyethyl)-theophylline (Tokyo

polymeric layer (Eudragit E layer). This suggested Kasei Kogyo, Tokyo, Japan) were used as thethat the CTDC has a potential for colon-targeted internal standards. Tetragastrin was purchased fromdelivery of drugs, when sufficient acid-resistibility Mecto (Tokyo, Japan). All other chemicals andand the suitable thickness of coating are given to solvents were of reagent grade.adjust the onset time of drug release to the smallintestinal transit time, which is known to be 361 h 2.2. Preparation of CTDC[12].

The purpose of the present study is to examine if The powder mixture of 40 mg of prednisolone andthe pH-sensing and timed-release concept of CTDC 100 mg of succinic acid was put into a hard gelatincan successfully work in the gastrointestinal tract as capsule, and the joint of the capsule body and capexpected. The CTDCs, containing prednisolone and was carefully sealed with a small amount of 5%theophylline as a model drug and an indicator for (w/w) ethylcellulose ethanolic solution. The sealedgastric emptying, respectively, were administered capsules obtained were spray-coated with

orally to beagle dogs. The gastric emptying time and Eudragit E (33 mg/capsule), then with TC-5 (50the onset time of drug release in the gastrointestinal mg/capsule) containing theophylline (9 mg/capsule)tract were estimated from the analysis of the plasma as the marker substance to indicate gastric emptying,

concentration level of both drugs. The effect of and finally with HPMC -AS (250 mg/capsule) usingfeeding on the gastrointestinal transit of CTDC and a coating machine (Hicoater , Type HCT-Mini,

the drug release behavior thereof is also examined. Freund, Tokyo, Japan). The formulation of theThis paper discusses the potential of CTDC as a polymeric coating solution and the operating con-

T. Ishibashi et al. / Journal of Controlled Release 57 (1999) 45 –53 47

Table 1 Formula of coating solution and standard operating conditions for the coatings of Eudragit E, TC-5 and HPMC -AS

Spray solution: Eudragit E coating TC-5 coating HPMC -AS coating Formula (%) Eudragit E 5.0 TC-5 5.0 HPMC -AS 5.0

Ethanol 95.0 Theophylline 0.4 Talc 2.5Water 94.6 Ethanol 55.8

Water 36.7

Operating conditions:Blower temperature (8C) 45 55 60Exhaust temperature (8C) 30 35 40

2Spray pressure (kg/cm ) 2 2 22Air flow rate (l /cm ) 30 30 30

Spray rate (g /min) 2.5 1.8 2.5Rotating speed of coating pan (rpm) 40 40 40

ditions of coating for each layer are described in HPLC conditions applied are given in Section 2.6.Table 1. All the experiments were carried out at least in

triplicate.

2.3. Preparation of ECC2.5. In vivo release study

The powder mixture of 40 mg of prednisolone andThe in vivo absorption studies were carried out

100 mg of succinic acid was filled into a hard gelatinusing acidity-controlled beagle dogs in order to

capsule. The joint of the capsule body and cap wasminimize the individual difference in gastric acidity.

carefully sealed with a small amount of 5% (w/w)Four healthy male beagle dogs, 11–12 kg, were used

ethylcellulose ethanolic solution, exactly in the samein this study under fasted and non-fasted conditions.

manner as with CTDC. The sealed capsules obtainedTetragastrin (10 mg/kg) was injected intramuscular-were spray-coated with TC-5 (50 mg/capsule)ly twice, 15 min before and 45 min after oral

containing theophylline (9 mg/capsule), and thenadministration of CTDC or ECC. The fasted dogswith HPMC -AS (250 mg/capsule) using a coatingreceived no food, but had free access to water for 18machine (Hicoater , Type HCT-Mini). The formula-h before the administration. The CTDC or ECC was

tion of the polymeric coating solution and theorally administered to four male beagle dogs along

operating conditions of the coating were identicalwith 50 ml of water. Blood samples (4.0 ml) were

with those described above.collected every hour until 12 h, and again after 24 h.The plasma was immediately obtained by centrifug-

2.4. In vitro release study ing the blood samples at 3000 rpm for 5 min. All thesamples were frozen at 2208C until analysis.

The drug release profiles from the capsules wereinvestigated according to the procedure described in 2.6. Assay methodsthe Japanese Pharmacopoeia JP XIII (the paddlemethod). The capsules were placed in a vessel with 2.6.1. Prednisolone900 ml of the JP 1st-fluid (pH 1.2) or 2nd-fluid (pH The prednisolone concentration in plasma was6.8) at 3760.58C rotating at 100 rpm. The aliquots determined according to the HPLC method reportedwere removed periodically and assayed for theo- by Sugawara et al. [13]. Betamethasone methanolicphylline and prednisolone using the high perform- solution (0.2 ml; 6 mg/ml) as an internal standard,ance liquid chromatography (HPLC) method. The 0.1 ml of 0.2 N sodium hydroxide aqueous solution,


and 10 ml of dichloromethane were added to 0.5 ml 3. Results and discussionof plasma. After shaking for 10 min, the mixture wascentrifuged at 2000 rpm for 10 min, and the di- 3.1. In vitro release characteristicschloromethane layer (organic phase) was taken out.One ml of 0.02 N hydrochloride aqueous solution The fundamental structures of CTDC and ECCwas added to 8 ml of the organic phase. After used in this study are depicted schematically in Fig.shaking for 10 min, the mixture was centrifuged at 1. The CTDC is coated with a three-layered film

the rate of 2000 rpm for 10 min. Six ml of the consisting of Eudragit E, TC-5 and HPMC -AS,organic phase were taken out and evaporated to as an acid-soluble layer, a water-soluble hydrophilicdryness at 408C under a continuous N gas flow. The layer and an enteric layer, respectively. On the other2

residue was dissolved with 0.5 ml of the metha- hand, ECC is coated with a two-layered film consist- nol:water (1:1) mixture to make the sample solution. ing of TC-5 and HPMC -AS. In both formulations,

Two hundred ml of the sample solution was loaded theophylline was embedded in the TC-5 layer so asonto a HPLC system to determine the plasma to be released immediately after the dissolution ofconcentration of prednisolone. The HPLC conditions the outermost enteric layer. The gastric emptyingwere as follows: pump, L-6200 (Hitachi, Tokyo, after ingestion, therefore, can be detected by moni-Japan); UV detection, SPD-1OA (Shimadzu, Kyoto, toring the absorption of theophylline. As was shown,Japan); column, Inertsil ODS-2 (5 mm, 4.6 mm both formulations were almost the same; except fori.d.3150 mm; GL Science, Osaka, Japan); mobile the composition of the coating, so that the impact of

phase, methanol:water (1:1); flow rate, 1 ml /min; the Eudragit E layer on the in vitro or in vivodetection, wavelength 250 nm; and column tempera- performance of CTDC could be highlighted in thisture, 408C. study.

Fig. 2 shows the comparison of in vitro releaseprofiles of prednisolone and theophylline from ECC

2.6.2. Theophylline in the JP 1st-fluid (pH 1.2) and JP 2nd-fluid (pHThe theophylline concentration in plasma was 6.8). In the 1st-fluid, both drugs were not released

determined according to the HPLC method reported for over 10 h, whereas they were quickly releasedby Nakano et al. [14]. 7-(2-Hydroxy- after a short lag time in the 2nd-fluid, suggesting thatethyl)theophylline methanolic solution (0.5 ml; 4 an excellent acid-resistibility was given by themg/ml) as an internal standard was added to 0.5 mlof plasma. Then, the mixture was shaken with 4 mlof the iso-propanol:chloroform (5:95) mixture for 5min prior to centrifugation at 2000 rev. /min for 5min. Three ml of the organic layer were evaporatedand dried at 408C under N gas flow, and the residue2

was dissolved with 0.5 ml of the mixture ofacetonitrile:0.01 M sodium acetate (pH 4) (1:12) tomake the sample solution for analysis. Next, 200 mlof the sample solution was loaded onto a HPLCsystem to determine the plasma concentration oftheophylline. The HPLC conditions were as follows:pump, L-6200 (Hitachi); UV detection, SPD-1OA(Shimadzu); column, TSK-GEL ODS-120T (4.6

Fig. 1. Schematic representation of the fundamental structures ofmm3250 mm; TOSOH, Tokyo, Japan); mobilethe colon-targeted delivery capsule (CTDC) and the enteric coated

phase, acetonitrile:0.01 M sodium acetate (pH 4) capsule (ECC). (a) prednisolone, (b) succinic acid, (c) sealing(1:12); flow rate, 0.5 ml /min; detection, wavelength (ethylcellulose), (d) TC-5 layer (theophylline contained), (e)

273 nm; and column temperature, 508C. HPMC-AS layer, (f) Eudragit E layer.


Fig. 2. Release profiles of prednisolone and theophylline from ECC. (a) theophylline, (b) prednisolone; s, in the JP 1st-fluid (pH 1.2); d, inthe JP 2nd-fluid (pH 6.8). The vertical lines show standard errors.

enteric coating with HPMC -AS. The observed lag released quickly in the 2nd-fluid similar to the casetime, about 20 min, should correspond to the time of ECC. However, it was noted that the onset time of

required for dissolving the HPMC -AS layer. A prednisolone release was extended up to about 3 h.good coincident in the release behavior of both drugs This unique drug-release behavior of CTDC was

means that the capsule wall of gelatin and the TC-5 brought about by the interaction between the layer quickly dissolved after disappearance of the Eudragit E layer and succinic acid. Eudragit E does

enteric layer, and hence both layers do not function not dissolve in an aqueous medium over pH 5 inessentially as a dissolution barrier. nature, so that a long lag phase can be produced in

The release profiles of both drugs from the CTDC the JP 2nd-fluid. However, the timed-collapse of thisare also compared in Fig. 3. Theophylline was not polymeric layer was triggered when the microen-released for over 10 h in the 1st-fluid, but was vironmental pH inside the capsule decreased under

Fig. 3. Release profiles of prednisolone and theophylline from CTDC. (a) theophylline, (b) prednisolone; s, in the JP 1st-fluid (pH 1.2); d,in the JP 2nd-fluid (pH 6.8). The vertical lines show standard errors.


pH 5 due to the dissolution of succinic acid. Our study. This is because, if the capsules were adminis-previous study indicated that there was an excellent tered to the normal dogs with higher gastric pH, thelinear relationship between the lag time of drug enteric layer of CTDC might be dissolved or dam-

release and the thickness of the Eudragit E layer aged in the stomach, resulting in a misjudgment of[11]. This finding suggests that the timed-release gastric emptying time.function may be achieved after gastric emptying of The prednisolone-loaded ECC and CTDC werethe CTDC by adjusting the thickness of the orally administered to four beagle dogs under fasted

Eudragit E layer. condition. Fig. 4 and Fig. 5 show the plasmaconcentrations vs. time profiles of theophylline and

3.2. In vivo release study prednisolone after the administration. Phar-macokinetic parameters necessary for discussion,

The in vivo release study was performed to see if calculated from the plasma drug concentration vs.the pH-sensing functions and time-release functions time profiles, are listed in Table 2. The in vivo lagof CTDC could work in the gastrointestinal tract as time of theophylline, corresponding to the gastricexpected. To minimize the variation of gastric pH, emptying time (GET), and the in vivo lag time ofacidity-controlled beagle dogs were used for this prednisolone (LTP) were defined as the first appear-

Fig. 4. Individual plasma concentration vs. time profile of prednisolone and theophylline after oral administration of ECC to beagle dogs. j,prednisolone, d, theophylline. Each capsule contains 40 mg of prednisolone and 9 mg of theophylline.


Fig. 5. Individual plasma concentration vs. time profiles of prednisolone and theophylline after oral administration of CTDC. j,prednisolone; d, theophylline. Each capsule contains 40 mg of prednisolone and 9 mg of theophylline.

ance times of theophylline and prednisolone in the C . MRT is an abbreviation of mean residencemax

plasma, respectively. C was the maximum drug time. AUC is the area under the plasma concen-max

concentration and T was the time taken to reach tration vs. time curve.max

Table 2Pharmacokinetic parameters of prednisolone obtained after oral administrations of ECC and CTDC to four beagle dogs under fastedcondition

a bDosage form GET (h) LTP (h) T (h) C (mg/ml) MRT (h) AUC (mg h/ml)max max

ECC Average 4.3 4.3 5.0 0.82 5.92 2.01S.E. 1.7 1.7 0.7 0.24 0.84 0.45

CTDC Average 4.3 7.5 9.3 0.41 10.06 1.84S.E. 1.7 1.9 1.2 0.02 0.99 0.36

aGastric emptying time, detection time of theophylline in the serum after oral administration.bLTP, the time of appearance of prednisolone in the plasma after oral administration.


When the ECC was administered, both drugs vivo performance, CTDC was also administeredappeared in the plasma approximately at the same orally to four beagle dogs under a non-fasted con-time in each dog, after a certain lag time. This dition. The GET, LTP and the difference of bothsuggested that theophylline and prednisolone were parameters were compared with those obtained underreleased immediately after the gastric emptying (Fig. fasting condition as shown in Table 3. A drastic4). The GET estimated from the in vivo lag time of delay of the GET and LTP were observed; 14.3 andtheophylline was 4.361.7 h, ranging from 1 h (dog 15.8 h, respectively. There are many papers reportingno. 4) to 5 h (dog no. 3). Although values are the prolongation of gastric emptying by feeding. Forsomehow greater than those reported by Kaniwa et instance, it was reported that large particles greateral. (2.0660.55 h) [15], this may be due to the large than 5 mm were emptied from the stomach associ-size of the dosage form applied in this study. LTP ated with the interdigestive migratory myoelectricwas exactly the same as GET, suggesting that complex which occurred about 7.5 h after feeding inprednisolone in the capsule was released quickly beagle dogs [17]. In another report, the gastricafter the dissolving of the enteric coating, similar to emptying rate of granules and tablets was found tothe case under the in vitro condition. be delayed longer by feeding in beagle dogs than in

In the case of CTDC, GET was well coincident humans [15]. Therefore, the delay of gastric empty-with that of ECC, but the delay of LTP was clearly ing of CTDC observed in this study is thought to berecognized in each dog (Fig. 5), of which the a physiological phenomenon of dogs.average value was 7.5 h. The difference between It is notable that the lag time of prednisolone afterGET and LTP (LTP2GET), which is thought to gastric emptying (LTP2GET) was shortened tocorrespond to the lag time after gastric emptying, about 1.5 h, with almost half of that obtained underwas about 3.2 h, almost the same as that obtained the fast condition. This phenomenon could be muchfrom the in vitro dissolution study (3.3 h). This result concerned with the fact previously reported [11], insuggests that CTDC started the prednisolone release which the lag time of CTDC in the JP 2nd-fluid gotat about 3 h after discharge from the stomach, as shorter, depending on the immersing time in acidicexpected from the in vitro release characteristics. fluid, even though an excellent acid-resistibility was

There was no clear difference in AUC between observed. Therefore, the shortening of lag time inboth dosage forms. Nevertheless, as shown in Table vivo may be caused by the elongation of contact time2, considerable differences were found in other with gastric juice due to the delay of gastric empty-pharmacokinetic parameters. The T of ECC was ing by feeding. This problem may be minimizedmax

about 5.0 h, whereas that of CTDC extended up to technically either by increasing the coating amount9.3 h. The C of CTDC was 0.41 mg/ml, which of the HPMC -AS layer, modifying the compositionmax

was almost the half of that of the ECC. The MRTs of of the coating or applying more acid-resistibleECC and CTDC were 5.9260.84 and 10.0660.99 h, polymers.respectively. All these results imply that the CTDC Besides our delivery system, similar technologiestakes a longer time for drug absorption in the of capsule form have been proposed for colon-target-

gastrointestinal tract, and this is probably brought ing. The Pulsincap system is a typical example,about from the difference in the anatomical positionof drug release. CTDC was thought to release

Table 3prednisolone only at the lower part of the intestine Comparison of gastric emptying time and in vivo lag time of(probably to the colon) because the onset time of CTDC under fasted and non-fasted conditionsdrug release was considerably delayed. It was often Fasted condition Fed conditionpointed out that drug absorption from the lower

aGET 4.360.9 14.360.3intestine tended to decrease due to the lower water bLTP 7.561.0 15.860.3content [16].

cLTP2GET 3.260.6 1.560.33.3. Effect of food on drug release from CTDC aTheophylline appeared in plasma (h).

bPrednisolone appeared in plasma (h).cIn order to examine the effect of food on the in Lag time of prednisolone after gastric emptying (h).


[4] T. Takaya, C. Ikeda, N. Imagawa, K. Niwa, K. Takada,which was designed based on the timed-ejectionDevelopment of a colon delivery capsule and the pharmaco-induced by a swelling of the hydrogel plug, and waslogical activity of recombinant human granulocyte colony-

known to achieve a pulsatile release in the gastroin- stimulating factor (rhG-CSF) in beagle dogs, J. Pharm.testinal tract. Mooter et al. reported the capsules that Pharmacol. 47 (1995) 474–478.were coated with azo polymers [10]. With this [5] A. Gazzaniga, C. Busetti, M.E. Sangalli, F. Giordano, Time-

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in vivo drug release behavior in dogs from a new colon-targeted delivery system

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