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Design and Evaluation of a Dry Coated Drug Delivery System with Floating–Pulsatile Release
Design and Evaluation of a Dry Coated Drug Delivery System With Floating–Pulsatile Release HAO ZOU,1 XUETAO JIANG,1 LINGSHAN KONG,2 SHEN GAO1 1
Department of Pharmaceutics, School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, PR China 2
Department of Nuclear Medicine, Changhai Hospital of Second Military Medical University, No. 325 Changhai Road, Shanghai 200433, PR China
Received 30 October 2006; revised 26 January 2007; accepted 2 February 2007 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21083
ABSTRACT: The objective of this work was to develop and evaluate a floating–pulsatile drug delivery system intended for chronopharmacotherapy. Floating–pulsatile concept was applied to increase the gastric residence of the dosage form having lag phase followed by a burst release. To overcome limitations of various approaches for imparting buoyancy, we generated the system which consisted of three different parts, a core tablet, containing the active ingredient, an erodible outer shell and a top cover buoyant layer. The dry coated tablet consists in a drug-containing core, coated by a hydrophilic erodible polymer which is responsible for a lag phase in the onset of pulsatile release. The buoyant layer, prepared with Methocel1 K4M, Carbopol1 934P and sodium bicarbonate, provides buoyancy to increase the retention of the oral dosage form in the stomach. The effect of the hydrophilic erodible polymer characteristics on the lag time and drug release was investigated. Developed formulations were evaluated for their buoyancy, dissolution and pharmacokinetic, as well gamma-scintigraphically. The results showed that a certain lag time before the drug released generally due to the erosion of the dry coated layer. Floating time was controlled by the quantity and composition of the buoyant layer. Both pharmacokinetic and gamma-scintigraphic data point out the capability of the system of prolonged residence of the tablets in the stomach and releasing drugs after a programmed lag time. ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:263–273, 2008
Keywords: floating–pulsatile drug delivery; verapamil hydrochloride; gamma scintigraphy; pharmacokinetics; chronotherapy
INTRODUCTION Chronopharmacotherapy, the drug regime based on circadian rhythm, is recently gaining much attention worldwide. Various diseases like asthma, hypertension, arthritis show circadian variation, that demand time-scheduled drug release for effective drug action for example inflammations Correspondence to: Shen Gao (Telephone: þ86-21-25070392; Fax: þ86-21-6549-1664; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 97, 263–273 (2008) ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association
associated with morning body stiffness, asthma, and heart attack in early hours of the day.1 Results of several epidemiological studies demonstrate the elevated risk of different pathologies during a 24-h cycle. Specifically, symptoms of rheumatoid arthritis and osteoarthritis,2 dyspnoea,3 and epilepsy appear to have a peak during the night or early in the morning. Ischemic heart diseases, such as angina pectoris and myocardial infarction, are manifested more frequently during these times.4 Blood pressure which arises notably just before waking up5 is usually responsible for these attacks. Verapamil hydrochloride
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was chosen as a model drug, for it is a potent calcium-channel blocker and has been effective for preventing the time-related occurrence of ischemia.6 Verapamil HCl was widely accepted for its anti-hypertension and anti-anginal properties, since it is a calcium antagonist compound. So verapamil HCl is a typical example of drug, which is used in the therapy of symptoms or diseases as described. However, for such cases, conventional drug delivery systems are inappropriate for the delivery of verapamil HCl, as they cannot be administered just before the symptoms are worsened, because during this time the patients are asleep. To follow this principle one must have to design the dosage form so that it can be given at the convenient time for example bed time for the above mentioned diseases with the drug release in the morning. Using current release technology, it is possible for many drugs oral delivery for a pulsed or pulsatile release, which is defined as the rapid and transient release of a certain amount of drugs within a short time-period immediately after a predetermined off-release period.7–11 Chronotherapeutical devices based on osmotic pumps have been developed by MaGruder et al.12 and Cutler et al.13 A PulsincapTM system14 corresponds to a more sophisticated approach while it is composed by a capsule with an insoluble body and a hydrogel plug. Multiphasic drug release was achieved by using a three layer15 tablet while similar devices were also developed and evaluated in a later stage.16,17 Time controlled coating systems were also developed by Ueda et al.18 and Narisawa et al.,19 including single and multiple unit dosage forms. The disadvantage of these pulsatile release formulations is that they require a long residence time in the gastrointestinal track. With conventional pulsatile release dosage forms, the highly variable nature of gastric emptying process can result in in vivo variability and bioavailability problems. The advantages for gastro-retentive pulsatile dosage forms are also pH dependent drug solubility (in this case verapamil is good example) or better drug bioavailability in stomach, when compared with lower parts of GIT. Overall, these considerations led to the development of oral pulsatile release dosage forms possessing gastric retention capabilities.20–22 Low density multiparticulate systems for floating– pulsatile release were developed by Sharma et al.20 and Badve et al.22 A pulsatile release formulation with the mucoadhesive properties JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 1, JANUARY 2008
Figure 1. Schematic diagram of the floating–pulsatile release (FPRT) delivery system. A: the layer for buoyancy; B: the layer for drug pulsatile release; C: the rapid-release core tablet.
was developed by Karavas et al.21 However, at the present time little is known about the in vivo performances of the floating–pulsatile release system. More knowledge on the in vivo investigation of the system should be useful to devices based on these technologies becoming clinically available. Objective of this work was to develop and evaluate a pulsatile–floating drug delivery system. The system consists of three different parts, a core tablet, containing the active ingredient, an erodible outer shell, and a top cover buoyant layer (Fig. 1). One layer is for buoyancy and the other for drug pulsatile release. The pulsatile release system with various lag times was prepared by compression with different erodible polymeric layers (press-coated systems) as described previously.23–25 Combined usage of hydroxypropyl methylcellulose (HPMC) and carbomer in a gastric floating or mucoadhesive drug delivery system has been reported26,27 to improve the floating properties or mucoadhesiveness of the combined system. Ideally, the novel system could result in (1) a floating dosage form with a prolonged gastric residence time and in (2) a pulsatile dosage form, in which the drug is released rapidly in a timecontrolled fashion after rupturing of the coating. Developed formulations were evaluated for buoyancy studies, dissolution studies, gamma-scintigraphic evaluation and pharmacokinetic study.
MATERIALS AND METHODS Materials Verapamil hydrochloride (Ver) was purchased from Tianjin Central Pharmaceutical Factory, Tianjin, China. HPMC (Methocel1 E5, E15, E50, K4M, Colorcon, UK), ethylcellulose (Ethocel1 45cp, Colorcon, UK), crospovidone (Kollidon1 CL, DOI 10.1002/jps
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BASF, Ludwigshafen, Germany), polyvinylpyrrolidone (Kollidon1 30, BASF), lactose (Shanghai Lactose Factory, Shanghai, China), carbomer (Carbopol1 934P NF, BF Goodrich, Brecksville, OH), magnesium stearate (Shanghai Chemistry Reagents Factory, Shanghai, China) and other excipients used to prepare the tablets were of standard pharmaceutical grade. Ethanol and other reagents were analytical reagent grade. Technetium-99m (TcO4 ) was obtained from Department of Nuclear Medicine, Changhai Hospital, Shanghai, China.
Preparation of the Rapid-Release Tablet (RRT) The powder of 66% (w/w) Ver, 34% (w/w) Kollidon1 CL was passed through a 210-mm sieve to obtain a well-dispersed mixture and further was mixed thoroughly with a pestle and mortar. A 10% (wt/V) Kollidon1 30 alcoholic solution was added to this mixture dropwise with continuous mixing. The resultant powdered mixtures were compacted using a Roller Compactor equipped with 2.5 mm screens. Granules were then dried at 608C for 6 h using a convection oven. After adding magnesium stearate as a lubricant, the resulting dried and granules with size 25–60 mesh were directly compressed into tablets using a conventional single punch press (TDP type; First Pharmacy Machine, Shanghai, China). Sixty milligrams of RRT (6 mm in diameter, the mean height was 2.05 mm, RSD 1.92%) containing 40 mg of Ver was prepared and the tablet hardness was 30–50 N.
Preparation of the Pulsatile Release Tablet (PRT) RRT was taken as cores, respectively, and 260-mg coatings of Methocel1 E15 were used with two steps: the first 130-mg coatings were filled into the die, followed by RRT in the center of die, and slightly pressed to fix the coatings around and under the core, and then the rest of the coatings were filled and compressed. So PRT dry-coated with 260-mg Methocel1 E15 was prepared (10 mm in diameter, the mean height was 4.45 mm, RSD 0.82%) and the tablet hardness was 30–50 N.
Preparation of the Floating and Pulsatile Release Tablet (FPRT) FPRT was designed to comprise PRT and a top cover buoyant layer. PRT was taken as the layer DOI 10.1002/jps
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for pulsatile release. The buoyant layer included a hydrocolloid gelling agent such as carbomer, HPMC, which upon contact with gastric fluid formed a gelatinous mass, sufficient for cohesively binding the drug release layer. The buoyant layer also included effervescent components, for example, sodium bicarbonate, which is fabricated so that upon arrival in the stomach, carbon dioxide is liberated by the acidity of the gastric contents and is entrapped in the gellified hydrocolloid. This produces an upward motion of the dosage form and maintains its buoyancy. The buoyant powder of 50% (w/w) Carbopol1 934P, 40% (w/w) Methocel1 K4M and 10% (w/w) NaHCO3 was passed through a 210-mm sieve to obtain a well-dispersed mixture and followed by the addition of 1% (w/w) magnesium stearate. The 100-mg buoyant powder was filled into the die (10 mm in diameter, the mean height was 5.90 mm, RSD 0.95% and the mean height of the buoyant layer was 1.45 mm, RSD 1.25%), followed by PRT in the die, and then compressed. So FPRT was prepared by direct compression and the tablet hardness was 60–80 N.
Dissolution Testing of FPRT The rotating basket method (USP 28) was employed with a dissolution test apparatus (ZRS-8G type; Radio Equipment of Tianjing University, China). The medium was 900 mL (V) dissolution medium at 37 0.58C and the rotating speed was 100 rpm. At appropriate time intervals, 5 mL of the solution was withdrawn, filtered, and assayed by a UV spectrophotometer (UV2000 type; Third Analysis Machine, Shanghai, China) at 229 nm, while an equal volume of fresh dissolution medium was added into the apparatus. In certain studies, the dissolution medium (0.1 M HCl, pH 7.4 phosphate buffered saline, PBS and purified water) was varied. Dissolution tests were performed in triplicate. The lag time was determined by extrapolation of the upward part of release profile to the time axis.
Floating Behavior of FPRT The in vitro floating behavior of FPRT was studied by placing them in 900 mL containers (0.1 M HCl, 378C, 100 rpm, n ¼ 6). The floating onset time (time period between placing FPRT in the medium and buoyancy begining) and floating duration of FPRT were determined by visual observation. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 1, JANUARY 2008
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Gamma-Scintigraphic Study Choice of Radio-Label Technitium-99m (99mTcO 4 ) is the radioisotope of choice for nuclear medicine imaging studies. It has a short half-life of 6.03 h and is easy and inexpensive to produce. 99mTc is eluted as pertechnetate (99mTcO 4 ), with sodium chloride 0.9% from a molybdenum-99 generator.28,29 Preparation of the Radio-Labeled FPRT Granules of rapidly disintegrating core tablet containing 99mTc (1.5 MBq) (absorbed on dried sodium chloride, obtained from department of nuclear medicine, Changhai hospital, Shanghai, China) and super-disintegrant Kollidon1 CL (12 mg) were prepared. Quantity weighing 52 mg of the granules was taken and compressed individually into tablets using 6 mm flat plain punches on a single-punch tablet machine. Each tablet contained 1.5 MBq of 99mTcO 4 . Compression coating material Methocel1 E15 (260 mg) and buoyant material (100 mg) were applied over the core tablets. Preparation of the Radio-Labeled Non-Floating and Non-Pulsatile Release Tablet (NRT) Core tablets containing 99mTc (1.5 MBq) were prepared using the same procedure as for the radio-labeled FPRT. Instead of Methocel1 E15, Ethocel1 45cp (EC) was used as compression coating material of NRT and no buoyant material were applied. In Vivo Study Six healthy males with ranging ages (28–38), weights (63–75 kg) and heights (165–186 cm) were selected and they provided written consent to take part in the study in Changhai hospital of Second Military Medical University. No volunteer had a history of gastrointestinal disorders. Those volunteers who were smokers abstained during the study. The protocol was approved by the local Ethics Committee. FPRT and NRT were administered simultaneously to each volunteer, 4 h after dinner and then supine 8 h following the dose, with 200 mL of water containing 99mTc, to outline the gastrointestinal tract. Through the images taken at 30-min intervals by a gamma-camera the gastrointestinal transit of the dosage forms was followed JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 1, JANUARY 2008
and the site and time of their break-up were assessed. The Collection and Treatment of Gastric Emptying Data In vivo images were obtained with an Ohio Nuclear Sigma 410 gamma camera (Packard Instrument Company, Meridian, CT), which was fitted with a 40 cm parallel hole collimator. Data were collected on magnetic disk for future analysis using MAPS 2000 software. The gamma-scintigraphic images were assessed by visual examination. The time to the onset of gastric emptying was determined as the time that showed hotspots of radioactivity leaving the stomach and entering the small intestine. The time of FPRT breaking-up, as determined by spreading of radiolabel in the GI tract contents, was determined by examination of the scintiscans.
Pharmacokinetic Study The trial was conducted on eight healthy male Beagle dogs (weight: 10.2 1.2 kg) according to a randomized cross-over treatment scheme. Each dog, 4 h after dinner, received a single oral administration of FPRT or RRT with 100 mL water, the wash-out period was 1 week. Blood samples were taken immediately before administering the drug and at designed time and immediately frozen until assay. The assay of Ver in dog plasma was analyzed with a HPLC method30–32 with a fluoremetric detector (Waters 510 HPLC pump; Waters 470 fluorescence detector; column Zorbax XDB-C18, 5 mm, 150 mm 4.6 mm, flow rate 1.0 mL/min; Fluorescence excitation 275 nm, emission 310 nm). Four hundred microliter plasma sample and 100 mL deproteinizing solution (a mixture of acetonitrile–perchloric acid, 8:2, v/v), were mixed by vortexing (30 s), and the suspension was centrifuged at 4000 rpm for 10 min. A 100 mL portion of the clear supernatant was injected into the liquid chromatograph. A standard calibration curve, linear in the 5–500 ng/mL range, was used to determine Ver concentration in dog plasma. Recoveries for the same drug concentrations from spiked dog plasma ranged from 80.1 to 86.3% (n ¼ 8). The accuracy values were <8% at all the investigated concentrations. The limit of quantitation of the analytical method was 1.9 ng/mL. The following calculations were performed on the plasma Ver concentration of all eight subjections: DOI 10.1002/jps
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P AUC01 ¼ (Ci þ Ci1) (ti ti1)/2 þ Cn/l; t1/2¼ 0.693/l; Cmax: observed maximal plasma concentration; tmax: time at which Cmax is observed; l: negative slope for the natural log of the detectable plasma concentration after Cmax versus time curve; lag time (tlag): the time elapsed between the administration of the system and the appearance of drug in plasma, which was determined by extrapolation of the upward part of plasma concentration versus time curve to the time axis.
Figure 3. In vitro release profiles of Ver from the pulsatile release tablet (PRT) coated with different amount of Methocel1 E15 in 0.1 M HCl.
RESULTS AND DISCUSSION Pulsatile Release Tablet (PRT) For this study, the core tablets containing Ver (RRT) were compression-coated with a low-viscosity HPMC (Methocel1 E5, E15, E50) up to 240 mg. The systems (PRT) showed satisfactory technological features in terms of surface and thickness homogeneity. The in vitro release profiles of Ver from HPMC-coated systems in 0.1 M HCl solution were provided in Figure 2. In the in vitro study, the three formulations were designed to have different tablet release profiles by changing weight (240, 260, 280 mg) of coating layers with Methocel1 E15. Consequently, differences in tablet release profiles were noted in the in vitro testing as Figure 3. As the coated tablet was placed in the aqueous medium, it was observed that the hydrophilic polymeric layer started erosion, which underwent progressive modification in terms of thickness and consistency. In the second phase of the dissolution procedure, the coating layer gradually starts to erode up to a limiting thickness. After this stage, a rapture of the shell was observed under the
pressure applied by the swelling of the core tablet and Ver released. All of this process corresponded to a lag time capable of exhibiting a pulsatile release of the drug. The profiles relevant to the coated tablet showed that a lag phase was followed by the quickly delivery of the active principle. The delay duration clearly depended on the kind and amount of hydrophilic polymer which was applied on the core. The lag time in vitro of the tablet coated with 260-mg HPMC E15 was 4.1 0.1 h.
Compositions of the Buoyant Layers The compositions of the buoyant layer of the FPRT for floating testing were shown in Table 1. All powdered excipients were mixed for 5 min using a mortar and pestle to form a homogenous directly compressible powder mix. When the system was immersed in a 0.1 M HCl solution at 378C, it sank at once in the solution and formed swollen tablet with a density much lower than 1 g/mL. The reaction was due to carbon dioxide generated by neutralization in the buoyant layer with the 0.1 M HCl solution. These systems (Tab. 1, F2, F3, F6, F7, F8) were found to float completely within 1 min and remained floating over a period of 12 h. The onset time of F1 floating was about 2–3 min because of no sodium bicarbonate including the buoyant layers. Table 1. The Composition of the Buoyant Layers for Floating Testing, Expressed as mg per Tablet No.
Figure 2. In vitro release profiles of Ver from the pulsatile release tablet (PRT) coated with 240-mg different kinds of HPMC in 0.1 M HCl. DOI 10.1002/jps
Carbopol1 934P Methocel1 K4M NaHCO3
F1
F2
F3
F4
F5
F6
F7
F8
50 40 0
50 40 10
40 40 20
30 30 40
25 20 5
40 50 10
20 70 10
70 20 10
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The duration time of F4 remaining floating was no more than 3 h because of too large amount of sodium bicarbonate including the buoyant layers. The formulation of F5 sank at once in the 0.1 M HCl solution and was not found to floating within 12 h, thus showing floating ability depending on the bulk density of a dosage form. It is worth mentioning here that sodium bicarbonate, in addition to imparting buoyancy to the novel formulation, provides the initial alkaline microenvironment for polymers to gel.33 Moreover, the release of CO2 helps to accelerate the hydration of the floating layer, which is essential for the formation of a bioadhesive hydrogel.34 This provides an additional mechanism (‘bioadhesion’) for retaining the dosage form in the stomach, apart from floatation.
Floating and Pulsatile Release Tablet (FPRT) The FPRT was manufactured as described above and consisted of the buoyant layer F2 (Tab. 2) combined with a PRT containing 40 mg Ver compression-coated with 260-mg Methocel1 E15. The FPRT coated with 260-mg HPMC E15 was 4.1 0.1 h, which was considered suitable lag time for Ver preventing the time-related occurrence of ischemic. The buoyant layer, prepared by 40mg Methocel1 K4M, 50-mg Carbopol1 934P and 10-mg sodium bicarbonate, provided buoyancy to increase the retention of the oral dosage form in the stomach. Since an orally administered FPRT comes into contact with gastro-intestinal fluids of different pH, it was important to investigate the lag time of FPRT in different media. The release pattern
Figure 4. In vitro release profiles of Ver from the floating–pulsatile release tablet (FPRT) coated with 260-mg Methocel1 E15 in different media.
and lag time (Fig. 4) are quite similar in 0.1 M HCl, pH 7.4 PBS and purified water. This could be attributed to pH-independent properties of coating layers with Methocel1 E15. The floating behavior of FPRT in different media was also investigated. In 0.1 M HCl, carbon dioxide generated in the buoyant layer was easily liberated by the acidity of the acidic environment and entrapped in the gellified hydrocolloid. As expected, the longer onset time of floating (5 min) was observed in purified water and pH 7.4 PBS than in 0.1 M HCl (<1 min). However, in all three media the FPRT could remain floating over a period of 12 h. These results indicated that lag times and floating duration of the FPRT appeared to be pH-independent.
Gamma-Scintigraphic Study Six healthy males took part in the study. Figure 5 shows the series of gamma-scintigraphic images
Table 2. Floating Ability of Various Formulation of Buoyant Granules of the Floating–Pulsatile Release Tablet (FPRT)
Formulation F1 F2 F3 F4 F5 F6 F7 F8
Floating Onset Time (min)a
Floating Duration (h)b
Integrity
2–3 <1 <1 <1 —c <1 <1 <1
>12 >12 >12 <3 —c >12 >12 >12
Intact Intact Intact Broken Intact Intact Intact Intact
a The floating onset time (time period between placing FPRT in the medium and buoyancy begining). b Floating duration of FPRT. c Not occured.
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DOI 10.1002/jps
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Figure 5. Gamma-scintigraphic images showing the movement of the floating– pulsatile release tablet (FPRT) and the non-floating and non-pulsatile release tablet (NRT) for volunteer 1 at selected time-points when the two tablets were administered simultaneously to the volunteer, 4 h after dinner and then supine 8 h following the dose, with 200 mL of water: (a) image at 6 min after administered showing FPRT and NRT with the intact tracer-containing core somewhere in the stomach, (b) image at 1.5 h after administered showing NRT had left the stomach and FPRT remain in the stomach, (c) image at 3.0 h after administered showing FPRT was found to still remain in the stomach, hotspots of radioactivity was not found to break-up, (d) image at 4.5 h after administered showing hotspots of radioactivity broke up, indicated the disintegration of the tracer-containing core from the FPRT with the spread in the stomach.
that were obtained for volunteer 1 when the FPRT and NRT were swallowed with 200 mL of water containing 99mTc, outlining the gastrointestinal tract. Within the series, the position of the two tablets in the stomach of the volunteer and the passage through to the intestine could clearly be seen. The red areas, indicating greater radioactivity, depicted the FPRT or NRT. The images and anatomical visualizations shown in Figure 5 were representative of all the volunteers. Figure 5 shows distinct areas of radioactivity with both stomach and intestinal areas highlighted. Gastric emptying was deemed complete when either two successive images of minimal radioactivity were collected or by noting the last time that two units were seen in the stomach and DOI 10.1002/jps
the next frame that clearly showed that one or both units had left the stomach.35 The window of time in all cases between the two points was 30 min, and therefore, the measure of gastric emptying was complete within a time error of 15 min. The gastric emptying times of NRT for volunteer 1 were reflected by Figure 5b and c for the current study. The lag time of FPRT was defined as the time at which all the radio labeled tablet dissipated in the GI tract and no signs of a distinct ‘‘core’’ remained. Scintigraphic images from the study showed that when the unit released in the stomach there was a marked increase in dispersion of the marker.36 Through the images taken at 30-min intervals by a gamma-camera the gastrointestinal transit JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 1, JANUARY 2008
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Table 3. The Onset Times to Gastric Emptying and the Pulsatile Release Time Obtained From the Series of Gamma-Scintigraphic Images for Six Volunteers Gastric Retention Timea (h) Subjects 1 2 3 4 5 6 Mean SD
Pulsatile Release Timeb(h)
Anatomical Position of Disintegration
NRTc
FPRTd
NRTc
FPRTd
FPRTd
1.5 1.0 1.0 0.5 1.5 2.5 1.3 0.7
>4.5 >4.0 >4.5 4.5 >4.0 >4.5
—e — — — — —
4.5 4.0 4.5 5.0 4.0 4.5 4.4 0.4
Stomach Stomach Stomach Small intestine Stomach Stomach
a
The time to the onset of gastric emptying, determined as the time that showed hotspots of radioactivity leaving the stomach and entering the small intestine. b The time of hotspots of radioactivity breaking-up, determined by spreading of radiolabel in the GI tract contents. c The radio-labeled floating and pulsatile release tablet. d The radio-labeled non-floating and non-pulsatile release tablet. e Not occured.
of the dosage forms was followed and the site and time of their break-up were assessed. The lag time of FPRT for volunteer 1 was reflected by Figure 5d for the current study. In all studies the two tablets (FPRT and NRT) remained as two distinct the signs with a distinct ‘‘core’’ whilst in the gastrointestinal tract before the pulsatile release occurred. But once the pulsatile release of FPRT occurred, all the radiolabeled tablets dissipated in the GI tract and no signs of a distinct ‘‘core’’ remained. Such observations were expected, as NRT, compression coated with Ethocel1 45cp instead of Methocel1 E15, could not release the intact tracer within the core at any time. So we were able to distinguish between FPRT and NRT by visualization of the spreading of the marker. A summary of the results showing the onset times to gastric emptying time and the lag time were obtained for the six volunteers taking part in the study and were shown in Table 3. Overall, Table 3 showed that the FPRT used in the study could be retained in the stomach for extended periods in the half-fed state (4 h after dinner). The gastric retention of the FPRT tablet was observed in six volunteers who took part in the study. When compared with the time to onset of emptying of the NRT tablet, the residence time of the FPRT tablet was found to increase in excess of 4 h. In addition to the times recorded for the onset of gastric emptying, the lag time from the FPRT tablet was also noted. The analysis of gamma-scintigraphic images for the volunteers showed that in vivo lag time values (4.4 0.4 h on JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 1, JANUARY 2008
average) of FPRT were found to be the relatively low variability and be consistent with the corresponding in vitro lag time (4.1 0.1 h).
Pharmacokinetic Study Figure 6 displayed the average plasma levels of Ver obtained following the oral administration of the FPRT tablet and the core tablet. In Table 4 the relevant pharmacokinetic parameters were collected. Also the in vivo behavior of the Methocel1 E15-coated tablet with the buoyant layer appeared quite different from that exhibited by the core tablet. The FPRT gave rise to a delayed appearance of model drugs in plasma. The AUC values of the FPRT tablet (4105 1318.94 ng h/
Figure 6. Mean Ver plasma concentration versus time after a single oral administration the core tablet and the floating–pulsatile release tablet coated with 260-mg Methocel1 E15 (FPRT) (80 mg) in 8 Beagle dogs. Bars represent standard deviation. DOI 10.1002/jps
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Table 4. Pharmacokinetic Data of Eight Beagle Dogs Relevant to the Core Tablet (RRT) and the Floating and Pulsatile Release Tablet (FPRT) Subject No.
Lag Time (h)
tmax (h)
The core tablet 1 0.02 2.0 2 0.11 2.0 3 0.17 1.5 4 0.04 2.0 5 0.18 1.5 6 0.19 1.0 7 0.14 1.5 8 0.21 1.0 Mean 0.13 1.6 SD 0.07 0.4 CV (%) 52.26 26.7 The floating and pulsatile release tablet 1 4.5 8.0 2 5.0 8.0 3 5.0 8.0 4 5.0 8.0 5 5.0 8.5 6 5.0 8.5 7 4.5 8.0 8 4.5 8.0 Mean 4.8 8.1 SD 0.3 0.2 CV (%) 5.4 2.9
mL) were lower than that of the core tablet (4630.48 1930.48 ng h/mL) since the peak plasma levels of the FPRT tablet (542.87 98.60 ng/mL) were very similar with that of the core tablet (546.28 147.68 ng/mL). With the FPRT configuration evaluated in this study it was possible that the sluggish stirring provided by the stomach could not cause the coated tablet complete dissolution and might limit dispersion of the core. In addition, it was interesting to underline that the lag time values in vivo (4.8 0.3 h) were similar with that in vitro (4.1 0.1 h) and this preliminary result might represent a suitable basis for the development of in vitro–in vivo correlations. Also in the case of FPRT formulations, good correlations were found between the pharmacokinetic result and gamma-scintigraphic evaluation. Finally, the average lag time of FPRT was of 4.8 0.3 h and the relatively low variability of this parameter pointed out the reproducibility of the in vivo performances of the system. Dressman reported that while the gastric pH in dogs and humans is very similar in the fasted state, the initial postprandial pH peak that occurs consistently in humans appears to be absent in DOI 10.1002/jps
Cmax (ng/mL)
AUC0<1 (ng h/mL)
667.45 566.72 502.58 350.92 819.80 399.61 512.43 550.75 546.28 147.68 27.03
5316.55 6598.12 4315.50 3358.86 8193.33 2795.84 3065.73 3397.43 4630.17 1930.48 41.69
527.50 493.66 547.89 748.47 438.06 544.93 446.48 596.00 542.87 98.60 18.16
5744.92 5863.53 3444.14 2597.57 3971.84 2477.84 3709.55 5034.88 4105.53 1318.94 32.13
dogs.37 Akimoto et al., reported that the gastric pH in fasting dogs fluctuated from 2.7 to 8.3, with a mean 6.8, which is higher than that in humans.38 As far as the pH values of in-vivo conditions, the values of pH in beagle dog or human stomach is still controversial. But the fact that in vivo lag time values of beagle dogs (4.8 0.3 h, Pharmacokinetic study) and volunteers (4.4 0.4 h, gamma-scintigraphic evaluation) are comparable to the corresponding in vitro lag times (4.1 0.1 h, dissolution profile) in this study, might partly be explained by the pH-independent lag times and floating duration of the FPRT.
CONCLUSIONS The FPRT containing the buoyant material, such as Methocel1 K4M, Carbopol1 934P and NaHCO3, achieved a satisfactory buoyant force in vitro, whereas the floating onset time was less than 1 min and the floating duration was more than 12 h. The pulsatile releasing mechanism of FPRT is based on the exploitation of the peculiar interaction between hydrophilic polymeric JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 1, JANUARY 2008
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coating and the aqueous gastrointestinal fluids. The in vitro release profiles of Ver from FPRT prepared using Methocel1 E15 as retarding polymer are characterized by a predetermined lag phase, the duration of which depends on the kind and amount of the polymeric layer applied on the cores. The developed system offers a simple and novel technique for pulse release of drugs in stomach or upper part of small intestine. Both the pharmacokinetic and gamma-scintigraphic data point out the capability of the system of prolonged residence of the tablets in the stomach and releasing drugs after a programmed lag time. From the results obtained we highlighted the following important points: the FPRT we prepared could achieve a rapid release after lag time in vivo, with the relatively low variability, which was consistent with the corresponding that in vitro.
ACKNOWLEDGMENTS Authors wish to acknowledge the National Natural Science Foundation of China (NSFC) (No. 30070898) and the Shanghai Science and Technology Commission (SSTC) for financial support.
REFERENCES 1. Lemmer B. 1999. Chronopharmacokinetics: Implications for drug treatment. J Pharm Pharmacol 51: 887–890. 2. Arvidson NG, Gudbjornson B, Elfman L, Ruden AC, Totternam H, Hallgren R. 1994. Circadian rhythm of secum interleucin-6 in rhematiod arthritis. Ann Rheum Dis 53:521–524. 3. Barnes JP. 1985. Circadian variation in airway function. Am J Med 79:5–9. 4. Fox KM, Mulcahy DA. 1991. Circadian rhythms in cardiovascular diseases. Postgrad Med J 67:S33– S36. 5. Millar-Craig MW, Bishop CN, Raftery EB. 1978. Circadian variation of blood pressure. Lancet 1: 795–797. 6. McTavish D, Sorkin EM. 1989. Verapamil an updated review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in hypertension. Drugs 38:19–76. 7. Bussemer T, Peppas NA, Bodmeier R. 2003. Evaluation of the swelling, hydration and rupturing properties of the swelling layer of a rupturable pulsatile drug delivery system. Eur J Pharm Biopharm 56:261–270. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 1, JANUARY 2008
8. Bussemer T, Dashevsky A, Bodmeier R. 2003. A pulsatile drug delivery system based on rupturable coated hard gelatin capsules. J Control Release 93:331–339. 9. Sungthongjeen S, Puttipipatkhachorn S, Paeratakul O, Dashevsky A, Bodmeier R. 2004. Development of pulsatile release tablets with swelling and rupturable layers. J Contr Rel 95:147–159. 10. Dashevsky A, Mohamad A. 2006. Development of pulsatile multiparticulate drug delivery system coated with aqueous dispersion Aquacoat ECD. Eur J Pharm Biopharm 318:124–131. 11. Karavas E, Georgarakis E. 2006. Felodipine nanodispersions as active core for predictable pulsatile chronotherapeutics using PVP/HPMC blends as coating layer. Int J Pharm 313:189–197. 12. MaGruder PR, Barclay B, Wong PSL, Theeuwes F. 1988. Composition comprising salbutamol. US Patent 4,751,071. 13. Cutler N, Anders R, Stanford S, Stramed J, Awan N, Bultas J, Lahari A, Woroszylska M. 1995. Placebo-controlled evaluation of three doses of a controlled-onset, extended-release formulation of verapamil in the treatment of stable angina pectoris. A MJ Cardiol 75:1102–1106. 14. Hedben J, Wilson C, Spiller R, Gilchrist P, Blackshaw E, Frier M, Perkins A. 1999. Regional differences in quinine absorption from the undisturbed human colon assessed using a timed release delivery system. Pharm Res 16:1087–1092. 15. Conte U, Colombo P, La Manna A, Gazzaniga A, Sangalli ME, Giuchedi P. 1989. A new ibuprofen pulsed release oral dosage form. Drug Dev Ind Pharm 15:2583–2596. 16. Conte U, Maggi L. 1996. Modulation of the dissolution profiles from Geomatrix multi-layer matrix tablets containing drug of different solubility. Biomaterials 17:889–896. 17. Ghika J, Gashoud JP, Gasser U. 1997. Clinical efficacy and tolerability of a new levodopa/benserazide dual-release formulation in parkinsonian patients. Clin Neuropharmacol 20:130–139. 18. Ueda S, Hata T, Asakura S, Yamaguchi H, Ueda Y. 1994. Development of a novel drug release system, time controlled explosion system (TES). Part 1. Concept and design. J Drug Target 2:35–44. 19. Narisawa S, Nagata M, Hirakawa Y, Kobayshi M, Yoshino H. 1996. An organic acid-induced sigmoidal release system for oral controlled release preparations. Permeability enhancement of Eudragit RS coating led by the physicochemical interactions with organic acid. J Pharm Sci 85:184– 188. 20. Sharma S, Pawar A. 2006. Low density multiparticulate system for pulsatile release of meloxicam. Int J Pharm 313:189–197. 21. Karavas E, Georgarakis E, Bikiaris D. 2006. Application of PVP/HPMC miscible blends with enhanced mucoadhesive properties for adjusting DOI 10.1002/jps
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drug release in predictable pulsatile chronotherapeutics. Eur J Pharm Biopharm 64:115–126. Badve SS, Sher P, Korde A, Pawar AP. Development of hollow/porous calcium pectinate beads for floating–pulsatile drug delivery. Eur J Pharm Biopharm doi: 10.1016/j.ejpb.2006.07.010. Conte U, Maggi L, Torre ML, Giunchedi P, La Manna A. 1993. Press-coated tablets for timeprogrammed release of drugs. Biomaterials 14: 1017–1023. Halsas M, Ervasti P, Veski P, Jurjenson H, Marvola M. 1998. Biopharmaceutical evaluation of time-controlled press-coated tablets containing polymers to adjust drug release. Eur J Drug Metab Pharmacokinet 23:190–196. Lin SY, Li MJ, Lin KH. 2004. Hydrophilic excipients modulate the time lag of time-controlled disintegrating press-coated tablets. AAPS Pharm Sci Tech 5:e54. Li S, Lin S, Daggy BP, Mirchandani HL, Chien YW. 2003. Effect of HPMC and Carbopol on the release and floating properties of Gastric Floating Drug Delivery System using factorial design. Int J Pharm 253:13–22. Khanna R, Agarwal SP, Ahuja A. 1997. Muco-adhesive buccal tablets of clotrimazole for oral candidiasis. Drug Dev Ind Pharm 23:831–837. Stops F, Fell JT, Collett JH, Martini LG, Sharma HL, Smith A. 2005. The use of citric acid to perolong the in vivo gastro-retention of a floating dosage form in the fasted state. Int J Pharm 308:8–13. Sinha VR, Mittal BR, Kumria R. 2005. In vivo evaluation of time and site of disintegration of polysaccharaeide tablet prepared for colon-specific drug delivery. Int J Pharm 289:79–85. Lau-Cam CA, Piemontese D. 1998. Simplified reversed-phase HPLC method with spectrophotometric detection for the assay of verapamil in rat plasma1. J Pharm Biomed Anal 2916:1029–1035.
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31. Hanada K, Akimoto S, Mitsui K, Hashiguchi M, Ogata H. 1998. Quantitative determination of disopyramide, verapamil and flocainide enantiomers in rat plasma and tissues by high-performance liquid chromatography. J Chromatogr 710:129– 135. 32. Garcia MA, Aramayona JJ, Bregante MA, Fraile LJ, Solans C. 1997. Simultaneous determination of verapamil and norverapamil in biological samples by highperformance liqiud chromatography using ultraviolet detection. J Chromatogr 693: 377–382. 33. Deshpande AA, Shah NH, Rhodes CT, Malick W. 1997. Development of a novel controlled-release system for gastric retention. Pharm Res 14:815– 819. 34. Brahma NS, Kwon HK. 2000. Floating drug delivery systems: An approach to oral controlled drug delivery via gastric retention. J Control Release 63:235–259. 35. Sato Y, Kawashima Y, Takeuchi H, Yamamotob H, Fujibayashic Y. 2004. Pharmacoscintigraphic evaluation of riboflavin-containing microballoons for a floating controlled drug delivery system in healthy humans. J Control Release 98:75–85. 36. Stevens H, Wilson C, Welling P, Bakhshaee M, Binns J, Perkins A, Frier M, Blackshaw E, Framed M, Nichols D, Humphrey M, Wicks S. 2002. Evaluation of PulsincapTM to provide regional delivery of dofetilide to the human GI tract. Int J Pharm 236:27–33. 37. Dressman JB. 1986. Comparison of canine and human gastrointestinal physiology. Pharm Res 3: 123–131. 38. Akimoto M, Nagahata N, Furuya A, Fukushima K, Higuchi S, Suwa T. 2000. Gastric pH profiles of beagle dogs and their use as an alternative to human testing. Eur J Pharm Biopharm 49:99– 102.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 1, JANUARY 2008
Department of Pharmaceutics, School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, PR China 2
Department of Nuclear Medicine, Changhai Hospital of Second Military Medical University, No. 325 Changhai Road, Shanghai 200433, PR China
Received 30 October 2006; revised 26 January 2007; accepted 2 February 2007 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21083
ABSTRACT: The objective of this work was to develop and evaluate a floating–pulsatile drug delivery system intended for chronopharmacotherapy. Floating–pulsatile concept was applied to increase the gastric residence of the dosage form having lag phase followed by a burst release. To overcome limitations of various approaches for imparting buoyancy, we generated the system which consisted of three different parts, a core tablet, containing the active ingredient, an erodible outer shell and a top cover buoyant layer. The dry coated tablet consists in a drug-containing core, coated by a hydrophilic erodible polymer which is responsible for a lag phase in the onset of pulsatile release. The buoyant layer, prepared with Methocel1 K4M, Carbopol1 934P and sodium bicarbonate, provides buoyancy to increase the retention of the oral dosage form in the stomach. The effect of the hydrophilic erodible polymer characteristics on the lag time and drug release was investigated. Developed formulations were evaluated for their buoyancy, dissolution and pharmacokinetic, as well gamma-scintigraphically. The results showed that a certain lag time before the drug released generally due to the erosion of the dry coated layer. Floating time was controlled by the quantity and composition of the buoyant layer. Both pharmacokinetic and gamma-scintigraphic data point out the capability of the system of prolonged residence of the tablets in the stomach and releasing drugs after a programmed lag time. ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:263–273, 2008
Keywords: floating–pulsatile drug delivery; verapamil hydrochloride; gamma scintigraphy; pharmacokinetics; chronotherapy
INTRODUCTION Chronopharmacotherapy, the drug regime based on circadian rhythm, is recently gaining much attention worldwide. Various diseases like asthma, hypertension, arthritis show circadian variation, that demand time-scheduled drug release for effective drug action for example inflammations Correspondence to: Shen Gao (Telephone: þ86-21-25070392; Fax: þ86-21-6549-1664; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 97, 263–273 (2008) ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association
associated with morning body stiffness, asthma, and heart attack in early hours of the day.1 Results of several epidemiological studies demonstrate the elevated risk of different pathologies during a 24-h cycle. Specifically, symptoms of rheumatoid arthritis and osteoarthritis,2 dyspnoea,3 and epilepsy appear to have a peak during the night or early in the morning. Ischemic heart diseases, such as angina pectoris and myocardial infarction, are manifested more frequently during these times.4 Blood pressure which arises notably just before waking up5 is usually responsible for these attacks. Verapamil hydrochloride
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was chosen as a model drug, for it is a potent calcium-channel blocker and has been effective for preventing the time-related occurrence of ischemia.6 Verapamil HCl was widely accepted for its anti-hypertension and anti-anginal properties, since it is a calcium antagonist compound. So verapamil HCl is a typical example of drug, which is used in the therapy of symptoms or diseases as described. However, for such cases, conventional drug delivery systems are inappropriate for the delivery of verapamil HCl, as they cannot be administered just before the symptoms are worsened, because during this time the patients are asleep. To follow this principle one must have to design the dosage form so that it can be given at the convenient time for example bed time for the above mentioned diseases with the drug release in the morning. Using current release technology, it is possible for many drugs oral delivery for a pulsed or pulsatile release, which is defined as the rapid and transient release of a certain amount of drugs within a short time-period immediately after a predetermined off-release period.7–11 Chronotherapeutical devices based on osmotic pumps have been developed by MaGruder et al.12 and Cutler et al.13 A PulsincapTM system14 corresponds to a more sophisticated approach while it is composed by a capsule with an insoluble body and a hydrogel plug. Multiphasic drug release was achieved by using a three layer15 tablet while similar devices were also developed and evaluated in a later stage.16,17 Time controlled coating systems were also developed by Ueda et al.18 and Narisawa et al.,19 including single and multiple unit dosage forms. The disadvantage of these pulsatile release formulations is that they require a long residence time in the gastrointestinal track. With conventional pulsatile release dosage forms, the highly variable nature of gastric emptying process can result in in vivo variability and bioavailability problems. The advantages for gastro-retentive pulsatile dosage forms are also pH dependent drug solubility (in this case verapamil is good example) or better drug bioavailability in stomach, when compared with lower parts of GIT. Overall, these considerations led to the development of oral pulsatile release dosage forms possessing gastric retention capabilities.20–22 Low density multiparticulate systems for floating– pulsatile release were developed by Sharma et al.20 and Badve et al.22 A pulsatile release formulation with the mucoadhesive properties JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 1, JANUARY 2008
Figure 1. Schematic diagram of the floating–pulsatile release (FPRT) delivery system. A: the layer for buoyancy; B: the layer for drug pulsatile release; C: the rapid-release core tablet.
was developed by Karavas et al.21 However, at the present time little is known about the in vivo performances of the floating–pulsatile release system. More knowledge on the in vivo investigation of the system should be useful to devices based on these technologies becoming clinically available. Objective of this work was to develop and evaluate a pulsatile–floating drug delivery system. The system consists of three different parts, a core tablet, containing the active ingredient, an erodible outer shell, and a top cover buoyant layer (Fig. 1). One layer is for buoyancy and the other for drug pulsatile release. The pulsatile release system with various lag times was prepared by compression with different erodible polymeric layers (press-coated systems) as described previously.23–25 Combined usage of hydroxypropyl methylcellulose (HPMC) and carbomer in a gastric floating or mucoadhesive drug delivery system has been reported26,27 to improve the floating properties or mucoadhesiveness of the combined system. Ideally, the novel system could result in (1) a floating dosage form with a prolonged gastric residence time and in (2) a pulsatile dosage form, in which the drug is released rapidly in a timecontrolled fashion after rupturing of the coating. Developed formulations were evaluated for buoyancy studies, dissolution studies, gamma-scintigraphic evaluation and pharmacokinetic study.
MATERIALS AND METHODS Materials Verapamil hydrochloride (Ver) was purchased from Tianjin Central Pharmaceutical Factory, Tianjin, China. HPMC (Methocel1 E5, E15, E50, K4M, Colorcon, UK), ethylcellulose (Ethocel1 45cp, Colorcon, UK), crospovidone (Kollidon1 CL, DOI 10.1002/jps
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BASF, Ludwigshafen, Germany), polyvinylpyrrolidone (Kollidon1 30, BASF), lactose (Shanghai Lactose Factory, Shanghai, China), carbomer (Carbopol1 934P NF, BF Goodrich, Brecksville, OH), magnesium stearate (Shanghai Chemistry Reagents Factory, Shanghai, China) and other excipients used to prepare the tablets were of standard pharmaceutical grade. Ethanol and other reagents were analytical reagent grade. Technetium-99m (TcO4 ) was obtained from Department of Nuclear Medicine, Changhai Hospital, Shanghai, China.
Preparation of the Rapid-Release Tablet (RRT) The powder of 66% (w/w) Ver, 34% (w/w) Kollidon1 CL was passed through a 210-mm sieve to obtain a well-dispersed mixture and further was mixed thoroughly with a pestle and mortar. A 10% (wt/V) Kollidon1 30 alcoholic solution was added to this mixture dropwise with continuous mixing. The resultant powdered mixtures were compacted using a Roller Compactor equipped with 2.5 mm screens. Granules were then dried at 608C for 6 h using a convection oven. After adding magnesium stearate as a lubricant, the resulting dried and granules with size 25–60 mesh were directly compressed into tablets using a conventional single punch press (TDP type; First Pharmacy Machine, Shanghai, China). Sixty milligrams of RRT (6 mm in diameter, the mean height was 2.05 mm, RSD 1.92%) containing 40 mg of Ver was prepared and the tablet hardness was 30–50 N.
Preparation of the Pulsatile Release Tablet (PRT) RRT was taken as cores, respectively, and 260-mg coatings of Methocel1 E15 were used with two steps: the first 130-mg coatings were filled into the die, followed by RRT in the center of die, and slightly pressed to fix the coatings around and under the core, and then the rest of the coatings were filled and compressed. So PRT dry-coated with 260-mg Methocel1 E15 was prepared (10 mm in diameter, the mean height was 4.45 mm, RSD 0.82%) and the tablet hardness was 30–50 N.
Preparation of the Floating and Pulsatile Release Tablet (FPRT) FPRT was designed to comprise PRT and a top cover buoyant layer. PRT was taken as the layer DOI 10.1002/jps
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for pulsatile release. The buoyant layer included a hydrocolloid gelling agent such as carbomer, HPMC, which upon contact with gastric fluid formed a gelatinous mass, sufficient for cohesively binding the drug release layer. The buoyant layer also included effervescent components, for example, sodium bicarbonate, which is fabricated so that upon arrival in the stomach, carbon dioxide is liberated by the acidity of the gastric contents and is entrapped in the gellified hydrocolloid. This produces an upward motion of the dosage form and maintains its buoyancy. The buoyant powder of 50% (w/w) Carbopol1 934P, 40% (w/w) Methocel1 K4M and 10% (w/w) NaHCO3 was passed through a 210-mm sieve to obtain a well-dispersed mixture and followed by the addition of 1% (w/w) magnesium stearate. The 100-mg buoyant powder was filled into the die (10 mm in diameter, the mean height was 5.90 mm, RSD 0.95% and the mean height of the buoyant layer was 1.45 mm, RSD 1.25%), followed by PRT in the die, and then compressed. So FPRT was prepared by direct compression and the tablet hardness was 60–80 N.
Dissolution Testing of FPRT The rotating basket method (USP 28) was employed with a dissolution test apparatus (ZRS-8G type; Radio Equipment of Tianjing University, China). The medium was 900 mL (V) dissolution medium at 37 0.58C and the rotating speed was 100 rpm. At appropriate time intervals, 5 mL of the solution was withdrawn, filtered, and assayed by a UV spectrophotometer (UV2000 type; Third Analysis Machine, Shanghai, China) at 229 nm, while an equal volume of fresh dissolution medium was added into the apparatus. In certain studies, the dissolution medium (0.1 M HCl, pH 7.4 phosphate buffered saline, PBS and purified water) was varied. Dissolution tests were performed in triplicate. The lag time was determined by extrapolation of the upward part of release profile to the time axis.
Floating Behavior of FPRT The in vitro floating behavior of FPRT was studied by placing them in 900 mL containers (0.1 M HCl, 378C, 100 rpm, n ¼ 6). The floating onset time (time period between placing FPRT in the medium and buoyancy begining) and floating duration of FPRT were determined by visual observation. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 1, JANUARY 2008
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Gamma-Scintigraphic Study Choice of Radio-Label Technitium-99m (99mTcO 4 ) is the radioisotope of choice for nuclear medicine imaging studies. It has a short half-life of 6.03 h and is easy and inexpensive to produce. 99mTc is eluted as pertechnetate (99mTcO 4 ), with sodium chloride 0.9% from a molybdenum-99 generator.28,29 Preparation of the Radio-Labeled FPRT Granules of rapidly disintegrating core tablet containing 99mTc (1.5 MBq) (absorbed on dried sodium chloride, obtained from department of nuclear medicine, Changhai hospital, Shanghai, China) and super-disintegrant Kollidon1 CL (12 mg) were prepared. Quantity weighing 52 mg of the granules was taken and compressed individually into tablets using 6 mm flat plain punches on a single-punch tablet machine. Each tablet contained 1.5 MBq of 99mTcO 4 . Compression coating material Methocel1 E15 (260 mg) and buoyant material (100 mg) were applied over the core tablets. Preparation of the Radio-Labeled Non-Floating and Non-Pulsatile Release Tablet (NRT) Core tablets containing 99mTc (1.5 MBq) were prepared using the same procedure as for the radio-labeled FPRT. Instead of Methocel1 E15, Ethocel1 45cp (EC) was used as compression coating material of NRT and no buoyant material were applied. In Vivo Study Six healthy males with ranging ages (28–38), weights (63–75 kg) and heights (165–186 cm) were selected and they provided written consent to take part in the study in Changhai hospital of Second Military Medical University. No volunteer had a history of gastrointestinal disorders. Those volunteers who were smokers abstained during the study. The protocol was approved by the local Ethics Committee. FPRT and NRT were administered simultaneously to each volunteer, 4 h after dinner and then supine 8 h following the dose, with 200 mL of water containing 99mTc, to outline the gastrointestinal tract. Through the images taken at 30-min intervals by a gamma-camera the gastrointestinal transit of the dosage forms was followed JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 1, JANUARY 2008
and the site and time of their break-up were assessed. The Collection and Treatment of Gastric Emptying Data In vivo images were obtained with an Ohio Nuclear Sigma 410 gamma camera (Packard Instrument Company, Meridian, CT), which was fitted with a 40 cm parallel hole collimator. Data were collected on magnetic disk for future analysis using MAPS 2000 software. The gamma-scintigraphic images were assessed by visual examination. The time to the onset of gastric emptying was determined as the time that showed hotspots of radioactivity leaving the stomach and entering the small intestine. The time of FPRT breaking-up, as determined by spreading of radiolabel in the GI tract contents, was determined by examination of the scintiscans.
Pharmacokinetic Study The trial was conducted on eight healthy male Beagle dogs (weight: 10.2 1.2 kg) according to a randomized cross-over treatment scheme. Each dog, 4 h after dinner, received a single oral administration of FPRT or RRT with 100 mL water, the wash-out period was 1 week. Blood samples were taken immediately before administering the drug and at designed time and immediately frozen until assay. The assay of Ver in dog plasma was analyzed with a HPLC method30–32 with a fluoremetric detector (Waters 510 HPLC pump; Waters 470 fluorescence detector; column Zorbax XDB-C18, 5 mm, 150 mm 4.6 mm, flow rate 1.0 mL/min; Fluorescence excitation 275 nm, emission 310 nm). Four hundred microliter plasma sample and 100 mL deproteinizing solution (a mixture of acetonitrile–perchloric acid, 8:2, v/v), were mixed by vortexing (30 s), and the suspension was centrifuged at 4000 rpm for 10 min. A 100 mL portion of the clear supernatant was injected into the liquid chromatograph. A standard calibration curve, linear in the 5–500 ng/mL range, was used to determine Ver concentration in dog plasma. Recoveries for the same drug concentrations from spiked dog plasma ranged from 80.1 to 86.3% (n ¼ 8). The accuracy values were <8% at all the investigated concentrations. The limit of quantitation of the analytical method was 1.9 ng/mL. The following calculations were performed on the plasma Ver concentration of all eight subjections: DOI 10.1002/jps
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P AUC01 ¼ (Ci þ Ci1) (ti ti1)/2 þ Cn/l; t1/2¼ 0.693/l; Cmax: observed maximal plasma concentration; tmax: time at which Cmax is observed; l: negative slope for the natural log of the detectable plasma concentration after Cmax versus time curve; lag time (tlag): the time elapsed between the administration of the system and the appearance of drug in plasma, which was determined by extrapolation of the upward part of plasma concentration versus time curve to the time axis.
Figure 3. In vitro release profiles of Ver from the pulsatile release tablet (PRT) coated with different amount of Methocel1 E15 in 0.1 M HCl.
RESULTS AND DISCUSSION Pulsatile Release Tablet (PRT) For this study, the core tablets containing Ver (RRT) were compression-coated with a low-viscosity HPMC (Methocel1 E5, E15, E50) up to 240 mg. The systems (PRT) showed satisfactory technological features in terms of surface and thickness homogeneity. The in vitro release profiles of Ver from HPMC-coated systems in 0.1 M HCl solution were provided in Figure 2. In the in vitro study, the three formulations were designed to have different tablet release profiles by changing weight (240, 260, 280 mg) of coating layers with Methocel1 E15. Consequently, differences in tablet release profiles were noted in the in vitro testing as Figure 3. As the coated tablet was placed in the aqueous medium, it was observed that the hydrophilic polymeric layer started erosion, which underwent progressive modification in terms of thickness and consistency. In the second phase of the dissolution procedure, the coating layer gradually starts to erode up to a limiting thickness. After this stage, a rapture of the shell was observed under the
pressure applied by the swelling of the core tablet and Ver released. All of this process corresponded to a lag time capable of exhibiting a pulsatile release of the drug. The profiles relevant to the coated tablet showed that a lag phase was followed by the quickly delivery of the active principle. The delay duration clearly depended on the kind and amount of hydrophilic polymer which was applied on the core. The lag time in vitro of the tablet coated with 260-mg HPMC E15 was 4.1 0.1 h.
Compositions of the Buoyant Layers The compositions of the buoyant layer of the FPRT for floating testing were shown in Table 1. All powdered excipients were mixed for 5 min using a mortar and pestle to form a homogenous directly compressible powder mix. When the system was immersed in a 0.1 M HCl solution at 378C, it sank at once in the solution and formed swollen tablet with a density much lower than 1 g/mL. The reaction was due to carbon dioxide generated by neutralization in the buoyant layer with the 0.1 M HCl solution. These systems (Tab. 1, F2, F3, F6, F7, F8) were found to float completely within 1 min and remained floating over a period of 12 h. The onset time of F1 floating was about 2–3 min because of no sodium bicarbonate including the buoyant layers. Table 1. The Composition of the Buoyant Layers for Floating Testing, Expressed as mg per Tablet No.
Figure 2. In vitro release profiles of Ver from the pulsatile release tablet (PRT) coated with 240-mg different kinds of HPMC in 0.1 M HCl. DOI 10.1002/jps
Carbopol1 934P Methocel1 K4M NaHCO3
F1
F2
F3
F4
F5
F6
F7
F8
50 40 0
50 40 10
40 40 20
30 30 40
25 20 5
40 50 10
20 70 10
70 20 10
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The duration time of F4 remaining floating was no more than 3 h because of too large amount of sodium bicarbonate including the buoyant layers. The formulation of F5 sank at once in the 0.1 M HCl solution and was not found to floating within 12 h, thus showing floating ability depending on the bulk density of a dosage form. It is worth mentioning here that sodium bicarbonate, in addition to imparting buoyancy to the novel formulation, provides the initial alkaline microenvironment for polymers to gel.33 Moreover, the release of CO2 helps to accelerate the hydration of the floating layer, which is essential for the formation of a bioadhesive hydrogel.34 This provides an additional mechanism (‘bioadhesion’) for retaining the dosage form in the stomach, apart from floatation.
Floating and Pulsatile Release Tablet (FPRT) The FPRT was manufactured as described above and consisted of the buoyant layer F2 (Tab. 2) combined with a PRT containing 40 mg Ver compression-coated with 260-mg Methocel1 E15. The FPRT coated with 260-mg HPMC E15 was 4.1 0.1 h, which was considered suitable lag time for Ver preventing the time-related occurrence of ischemic. The buoyant layer, prepared by 40mg Methocel1 K4M, 50-mg Carbopol1 934P and 10-mg sodium bicarbonate, provided buoyancy to increase the retention of the oral dosage form in the stomach. Since an orally administered FPRT comes into contact with gastro-intestinal fluids of different pH, it was important to investigate the lag time of FPRT in different media. The release pattern
Figure 4. In vitro release profiles of Ver from the floating–pulsatile release tablet (FPRT) coated with 260-mg Methocel1 E15 in different media.
and lag time (Fig. 4) are quite similar in 0.1 M HCl, pH 7.4 PBS and purified water. This could be attributed to pH-independent properties of coating layers with Methocel1 E15. The floating behavior of FPRT in different media was also investigated. In 0.1 M HCl, carbon dioxide generated in the buoyant layer was easily liberated by the acidity of the acidic environment and entrapped in the gellified hydrocolloid. As expected, the longer onset time of floating (5 min) was observed in purified water and pH 7.4 PBS than in 0.1 M HCl (<1 min). However, in all three media the FPRT could remain floating over a period of 12 h. These results indicated that lag times and floating duration of the FPRT appeared to be pH-independent.
Gamma-Scintigraphic Study Six healthy males took part in the study. Figure 5 shows the series of gamma-scintigraphic images
Table 2. Floating Ability of Various Formulation of Buoyant Granules of the Floating–Pulsatile Release Tablet (FPRT)
Formulation F1 F2 F3 F4 F5 F6 F7 F8
Floating Onset Time (min)a
Floating Duration (h)b
Integrity
2–3 <1 <1 <1 —c <1 <1 <1
>12 >12 >12 <3 —c >12 >12 >12
Intact Intact Intact Broken Intact Intact Intact Intact
a The floating onset time (time period between placing FPRT in the medium and buoyancy begining). b Floating duration of FPRT. c Not occured.
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Figure 5. Gamma-scintigraphic images showing the movement of the floating– pulsatile release tablet (FPRT) and the non-floating and non-pulsatile release tablet (NRT) for volunteer 1 at selected time-points when the two tablets were administered simultaneously to the volunteer, 4 h after dinner and then supine 8 h following the dose, with 200 mL of water: (a) image at 6 min after administered showing FPRT and NRT with the intact tracer-containing core somewhere in the stomach, (b) image at 1.5 h after administered showing NRT had left the stomach and FPRT remain in the stomach, (c) image at 3.0 h after administered showing FPRT was found to still remain in the stomach, hotspots of radioactivity was not found to break-up, (d) image at 4.5 h after administered showing hotspots of radioactivity broke up, indicated the disintegration of the tracer-containing core from the FPRT with the spread in the stomach.
that were obtained for volunteer 1 when the FPRT and NRT were swallowed with 200 mL of water containing 99mTc, outlining the gastrointestinal tract. Within the series, the position of the two tablets in the stomach of the volunteer and the passage through to the intestine could clearly be seen. The red areas, indicating greater radioactivity, depicted the FPRT or NRT. The images and anatomical visualizations shown in Figure 5 were representative of all the volunteers. Figure 5 shows distinct areas of radioactivity with both stomach and intestinal areas highlighted. Gastric emptying was deemed complete when either two successive images of minimal radioactivity were collected or by noting the last time that two units were seen in the stomach and DOI 10.1002/jps
the next frame that clearly showed that one or both units had left the stomach.35 The window of time in all cases between the two points was 30 min, and therefore, the measure of gastric emptying was complete within a time error of 15 min. The gastric emptying times of NRT for volunteer 1 were reflected by Figure 5b and c for the current study. The lag time of FPRT was defined as the time at which all the radio labeled tablet dissipated in the GI tract and no signs of a distinct ‘‘core’’ remained. Scintigraphic images from the study showed that when the unit released in the stomach there was a marked increase in dispersion of the marker.36 Through the images taken at 30-min intervals by a gamma-camera the gastrointestinal transit JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 1, JANUARY 2008
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Table 3. The Onset Times to Gastric Emptying and the Pulsatile Release Time Obtained From the Series of Gamma-Scintigraphic Images for Six Volunteers Gastric Retention Timea (h) Subjects 1 2 3 4 5 6 Mean SD
Pulsatile Release Timeb(h)
Anatomical Position of Disintegration
NRTc
FPRTd
NRTc
FPRTd
FPRTd
1.5 1.0 1.0 0.5 1.5 2.5 1.3 0.7
>4.5 >4.0 >4.5 4.5 >4.0 >4.5
—e — — — — —
4.5 4.0 4.5 5.0 4.0 4.5 4.4 0.4
Stomach Stomach Stomach Small intestine Stomach Stomach
a
The time to the onset of gastric emptying, determined as the time that showed hotspots of radioactivity leaving the stomach and entering the small intestine. b The time of hotspots of radioactivity breaking-up, determined by spreading of radiolabel in the GI tract contents. c The radio-labeled floating and pulsatile release tablet. d The radio-labeled non-floating and non-pulsatile release tablet. e Not occured.
of the dosage forms was followed and the site and time of their break-up were assessed. The lag time of FPRT for volunteer 1 was reflected by Figure 5d for the current study. In all studies the two tablets (FPRT and NRT) remained as two distinct the signs with a distinct ‘‘core’’ whilst in the gastrointestinal tract before the pulsatile release occurred. But once the pulsatile release of FPRT occurred, all the radiolabeled tablets dissipated in the GI tract and no signs of a distinct ‘‘core’’ remained. Such observations were expected, as NRT, compression coated with Ethocel1 45cp instead of Methocel1 E15, could not release the intact tracer within the core at any time. So we were able to distinguish between FPRT and NRT by visualization of the spreading of the marker. A summary of the results showing the onset times to gastric emptying time and the lag time were obtained for the six volunteers taking part in the study and were shown in Table 3. Overall, Table 3 showed that the FPRT used in the study could be retained in the stomach for extended periods in the half-fed state (4 h after dinner). The gastric retention of the FPRT tablet was observed in six volunteers who took part in the study. When compared with the time to onset of emptying of the NRT tablet, the residence time of the FPRT tablet was found to increase in excess of 4 h. In addition to the times recorded for the onset of gastric emptying, the lag time from the FPRT tablet was also noted. The analysis of gamma-scintigraphic images for the volunteers showed that in vivo lag time values (4.4 0.4 h on JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 1, JANUARY 2008
average) of FPRT were found to be the relatively low variability and be consistent with the corresponding in vitro lag time (4.1 0.1 h).
Pharmacokinetic Study Figure 6 displayed the average plasma levels of Ver obtained following the oral administration of the FPRT tablet and the core tablet. In Table 4 the relevant pharmacokinetic parameters were collected. Also the in vivo behavior of the Methocel1 E15-coated tablet with the buoyant layer appeared quite different from that exhibited by the core tablet. The FPRT gave rise to a delayed appearance of model drugs in plasma. The AUC values of the FPRT tablet (4105 1318.94 ng h/
Figure 6. Mean Ver plasma concentration versus time after a single oral administration the core tablet and the floating–pulsatile release tablet coated with 260-mg Methocel1 E15 (FPRT) (80 mg) in 8 Beagle dogs. Bars represent standard deviation. DOI 10.1002/jps
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Table 4. Pharmacokinetic Data of Eight Beagle Dogs Relevant to the Core Tablet (RRT) and the Floating and Pulsatile Release Tablet (FPRT) Subject No.
Lag Time (h)
tmax (h)
The core tablet 1 0.02 2.0 2 0.11 2.0 3 0.17 1.5 4 0.04 2.0 5 0.18 1.5 6 0.19 1.0 7 0.14 1.5 8 0.21 1.0 Mean 0.13 1.6 SD 0.07 0.4 CV (%) 52.26 26.7 The floating and pulsatile release tablet 1 4.5 8.0 2 5.0 8.0 3 5.0 8.0 4 5.0 8.0 5 5.0 8.5 6 5.0 8.5 7 4.5 8.0 8 4.5 8.0 Mean 4.8 8.1 SD 0.3 0.2 CV (%) 5.4 2.9
mL) were lower than that of the core tablet (4630.48 1930.48 ng h/mL) since the peak plasma levels of the FPRT tablet (542.87 98.60 ng/mL) were very similar with that of the core tablet (546.28 147.68 ng/mL). With the FPRT configuration evaluated in this study it was possible that the sluggish stirring provided by the stomach could not cause the coated tablet complete dissolution and might limit dispersion of the core. In addition, it was interesting to underline that the lag time values in vivo (4.8 0.3 h) were similar with that in vitro (4.1 0.1 h) and this preliminary result might represent a suitable basis for the development of in vitro–in vivo correlations. Also in the case of FPRT formulations, good correlations were found between the pharmacokinetic result and gamma-scintigraphic evaluation. Finally, the average lag time of FPRT was of 4.8 0.3 h and the relatively low variability of this parameter pointed out the reproducibility of the in vivo performances of the system. Dressman reported that while the gastric pH in dogs and humans is very similar in the fasted state, the initial postprandial pH peak that occurs consistently in humans appears to be absent in DOI 10.1002/jps
Cmax (ng/mL)
AUC0<1 (ng h/mL)
667.45 566.72 502.58 350.92 819.80 399.61 512.43 550.75 546.28 147.68 27.03
5316.55 6598.12 4315.50 3358.86 8193.33 2795.84 3065.73 3397.43 4630.17 1930.48 41.69
527.50 493.66 547.89 748.47 438.06 544.93 446.48 596.00 542.87 98.60 18.16
5744.92 5863.53 3444.14 2597.57 3971.84 2477.84 3709.55 5034.88 4105.53 1318.94 32.13
dogs.37 Akimoto et al., reported that the gastric pH in fasting dogs fluctuated from 2.7 to 8.3, with a mean 6.8, which is higher than that in humans.38 As far as the pH values of in-vivo conditions, the values of pH in beagle dog or human stomach is still controversial. But the fact that in vivo lag time values of beagle dogs (4.8 0.3 h, Pharmacokinetic study) and volunteers (4.4 0.4 h, gamma-scintigraphic evaluation) are comparable to the corresponding in vitro lag times (4.1 0.1 h, dissolution profile) in this study, might partly be explained by the pH-independent lag times and floating duration of the FPRT.
CONCLUSIONS The FPRT containing the buoyant material, such as Methocel1 K4M, Carbopol1 934P and NaHCO3, achieved a satisfactory buoyant force in vitro, whereas the floating onset time was less than 1 min and the floating duration was more than 12 h. The pulsatile releasing mechanism of FPRT is based on the exploitation of the peculiar interaction between hydrophilic polymeric JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 1, JANUARY 2008
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coating and the aqueous gastrointestinal fluids. The in vitro release profiles of Ver from FPRT prepared using Methocel1 E15 as retarding polymer are characterized by a predetermined lag phase, the duration of which depends on the kind and amount of the polymeric layer applied on the cores. The developed system offers a simple and novel technique for pulse release of drugs in stomach or upper part of small intestine. Both the pharmacokinetic and gamma-scintigraphic data point out the capability of the system of prolonged residence of the tablets in the stomach and releasing drugs after a programmed lag time. From the results obtained we highlighted the following important points: the FPRT we prepared could achieve a rapid release after lag time in vivo, with the relatively low variability, which was consistent with the corresponding that in vitro.
ACKNOWLEDGMENTS Authors wish to acknowledge the National Natural Science Foundation of China (NSFC) (No. 30070898) and the Shanghai Science and Technology Commission (SSTC) for financial support.
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