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A paradigm shift in enteric coating: Achieving rapid release in the proximal small intestine of man
Journal of Controlled Release 147 (2010) 242–245
Contents lists available at ScienceDirect
Journal of Controlled Release j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j c o n r e l
A paradigm shift in enteric coating: Achieving rapid release in the proximal small intestine of man Fang Liu 1, Abdul W. Basit ⁎ Department of Pharmaceutics, The School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1N 1AX, UK
a r t i c l e
i n f o
Article history: Received 19 March 2010 Accepted 14 July 2010 Available online 22 July 2010 Keywords: pH-sensitive polymers Methacrylic acid ethyl acrylate copolymer Enteric coatings Enteric polymers Gastric resistance Gamma scintigraphy Gastrointestinal transit
a b s t r a c t The in vivo performance of a novel enteric double-coating technology designed to accelerate release in the proximal small intestine of humans was investigated. Tablet cores were coated with a double layer formulation consisting of an inner layer of EUDRAGIT® L 30 D-55 neutralised to pH 6.0 in the presence of 10% citric acid, and an outer layer of standard EUDRAGIT® L 30 D-55. A conventional single coating of EUDRAGIT® L 30 D-55 was also applied to tablets for comparison purposes, with the identical coating formulation and thickness (5 mg/cm2) as the outer layer of the double coating. Eight fasted volunteers received the double-coated and single-coated tablets in a two-way crossover study. The formulations were radiolabelled and followed by gamma scintigraphy; the disintegration times and positions were recorded. After leaving the stomach, tablets coated with the single-coating formulation showed a significant time delay before disintegration occurred in the mid to distal small intestine, with a mean disintegration time of 66 ± 22 min post gastric emptying. The double-coated tablets disintegrated earlier at 28 ± 6 min post gastric emptying with consistent disintegration in the proximal small intestine. The accelerated in vivo disintegration of the double-coating system can overcome the limitations of conventional enteric coatings. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Enteric coatings are widely applied to solid dosage forms to retard drug release in the stomach and allow release in the small intestine. There are three main reasons for using such dosage forms: (i) to prevent the degradation of active substances in the acidic environment of the stomach, (ii) to protect the stomach from irritant actives and, (iii) to target actives to specific sites in the intestine for the treatment of local diseases [1]. The most commonly used enteric coatings employ pHdependent polymers which contain carboxylic groups. These remain un-ionized in the low pH environment of the stomach, and become ionized in the higher pH conditions of the small intestine, thus allowing the dissolution of the coating and drug release. It is a common misconception that enteric-coated products designed to release in the proximal small intestine disintegrate rapidly after emptying from the stomach [2]. In vivo such products can take up to 2 h to disintegrate in the human small intestine [3–9]. Drug release will then occur in the distal small intestine and cause a delayed response to medication and potentially reduce the bioavailability of those drugs with an absorption window in the upper small intestine. Hence, there is a clear need to achieve rapid drug release from entericcoated products in the proximal small intestine. ⁎ Corresponding author. Tel./fax: + 44 20 7753 5865. E-mail address: [email protected] (A.W. Basit). 1 Present address: The School of Pharmacy, University of Hertfordshire, Hatfield, AL10 9AB, UK. 0168-3659/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2010.07.105
Recently, a new concept was introduced to accelerate the dissolution of enteric coatings for drug delivery to the upper small intestine [10,11] and the ileo-caecal junction for colonic delivery [12]. The system designed to release in the proximal small intestine consists of a double coating based on methacrylic acid copolymer EUDRAGIT® L 30 D-55 (dissolves at pH N 5.5). The double coating comprises an inner layer of partially neutralised enteric polymer and organic acid and an outer layer of standard enteric coating. This is then applied to solid dosage forms. With this concept substantially accelerated coating dissolution was demonstrated, along with rapid drug release in simulated upper small intestine conditions in vitro. The rapid dissolution of the system was attributed to the increased ionic strength and buffer capacity of its inner layer and the migration of water soluble components from the inner to the outer coat [11]. The combination of these effects meant that the coating was effectively being dissolved from its inner and outer surfaces. The objective of the present study was to assess the in vivo performance of this novel double-coating concept in man. The technique of gamma scintigraphy was employed to determine the disintegration time and position of tablets coated with the double-coating system and a conventional single coating based on EUDRAGIT® L 30 D-55. 2. Materials and methods 2.1. Materials EUDRAGIT® L 30 D-55 was donated by Evonik Röhm GmbH, Darmstadt, Germany. Citric acid was purchased from Sigma-Aldrich Co.
F. Liu, A.W. Basit / Journal of Controlled Release 147 (2010) 242–245
Ltd., Dorset, UK. Triethyl citrate was obtained from Lancaster Synthesis, Lancashire, UK. Talc (fine powder, b15 μm) was purchased from VWR International Ltd, Poole, UK. Prednisolone was purchased from Aventis Pharma., Antony, France. Lactose (Pharmatose) was obtained from Ellis & Everard, Essex, UK. Cross-linked sodium carboxymethylcellulose was donated by FMC International, Cork, Ireland. Polyvinylpyrrolidone 40000 was purchased from VWR International Ltd, Poole, UK. Magnesium stearate was purchased from Sigma-Aldrich Co. Ltd., Dorset, UK. Bone cement (DeTrey® Zinc) was kindly donated by DentsPly GmbH, Germany. 99mTechnetium (Tc)–diethylenediaminepentaacetic acid (DTPA) and 111indium (In)–DTPA were obtained from Amersham (Hammersmith Hospital, London) and were delivered each morning on the day of the study. All other materials were obtained from SigmaAldrich Co. Ltd., Dorset, UK. 2.2. Preparation and coating of tablets Tablet cores (200 mg, 8 mm diameter) were prepared according to the following wet granulation formula: 5% prednisolone, 88.5% lactose, 5% polyvinylpyrrolidone, 0.5% cross-linked sodium carboxymethylcellulose (added intra and extra-granularly, 50:50) and 1% magnesium stearate, using a single punch tableting machine (Manesty, Speke, UK). The tablets were coated with a EUDRAGIT® L 30 D-55 double-coating formulation comprising an inner coat containing 10% citric acid and neutralised to pH 6.0 and an outer layer of standard EUDRAGIT® L 30 D-55. A conventional single-coating formulation of EUDRAGIT® L 30 D-55 was also applied to separate cores for comparison purposes. The technical details relating to both formulations are described in an earlier publication [10]. The coating level for the single coating was 5 mg polymer per cm2 of the tablet surface, as recommended by the polymer supplier to achieve efficient gastric resistance for coated tablets. The same coating level was used for the inner and outer coats of the double-coating system. 2.3. Radiolabelling of coated tablets Due to the lengthy manufacturing procedure and the safety issues of prolonged handling of radioactive sources, the radioactive materials were incorporated in the dosage form after coating. Coated tablets were labelled with 99mTc (single coating) or 111In (double coating) complexed to diethylenetriaminepentaacetic acid (DTPA). A small quantity of lactose was dissolved in the DTPA complex of each radioactive material and left to dry in an oven. A hole of 1 mm diameter was precisely drilled in the middle of the tablet and the radiolabelled lactose was filled into the hole to the required activity; and the hole was sealed with bone cement. In vitro studies of drug release showed that the integrity of the coating was not compromised by the labelling process and the labelled tablets gave identical drug release profiles as unlabelled tablets in simulated gastrointestinal conditions (0.1 M HCl for 2 h and then pH 5.6 phosphate buffer). The labelled tablets had an activity of 3.0 MBq for 99mTc and 0.6 MBq for 111In at the time of administration. 2.4. Subjects and study protocol The approval for the study was obtained from the local ethics committee. The study followed the tenets of the Declaration of Helsinki (1964) and its subsequent revisions. Eight healthy male volunteers (age 24–33 years, height 1.60–1.83 m and weight 64–85 kg) participated in the study. Following an overnight fast, each volunteer received two tablets (one single-coated formulation and one double-coated formulation) simultaneously with 150 mL water. A pair of small markers radiolabelled with 0.5 MBq 99mTc was taped to the abdomen at the most lateral position of the lower costal margin of the volunteers, for use as an anatomical reference marker and for purposes of correcting for the different positions of the volunteers between images. Sequential static anterior images were acquired using a single head gamma camera
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(GE Maxicamera 400 AC) fitted with a medium energy collimator. The energy windows were set at 126–150 keV for 99mTc and 221–274 keV for 111In, permitting the two radioactive sources to be detected simultaneously and visualised on a dual display monitor. Images were acquired over a period of 1 min at approximately 5 min intervals, with volunteers standing in front of the detector. Volunteers were permitted to move away from the camera between imaging but were required to remain in an upright position and not undergo any form of physical exertion. Volunteers continued to fast until the end of the study. The series of acquired images for each volunteer was replayed on a computer and processed using the Nucmed software (MicasX, Farnborough, UK). Analysis of the images and determination of the gastric emptying times, tablet disintegration times (initial and complete) and disintegration positions was performed independently by two investigators one of whom was blinded to the study. Both investigators reached similar interpretations. Since the images were not continuous, the time of the various events were taken as the mean of the two time points either side of the event. 2.5. Statistics The disintegration times post gastric-emptying of the singlecoated and double-coated tablets were compared using a paired Student's t test. Significance was assumed where p b 0.05. 3. Results and discussion The in vivo performance of the EUDRAGIT® L 30 D-55 singlecoated and double-coated tablets is shown in Tables 1 and 2, respectively. Gastric emptying of the tablets was rapid in all volunteers with times in the range of 15–85 min. These data generally agree with the published literature on the gastric emptying times of non-disintegrating monolithic dosage forms administered in the fasted state [13,14]. These dosage forms are treated by the stomach as indigestible solids and are usually swept out of the stomach by the “housekeeper” wave during phase III of the migrating motor complex (MMC) [15]. The time of gastric emptying therefore depends on the arrival time of the dosage form in the stomach in relation to the contractile phase of the MMC. In the present study, the two tablets were administered concurrently and resulted in similar emptying times in most volunteers. However, for some subjects this was not the case which may be explained by tablets residing in different positions in the stomach. If the tablet is present near the pylorus, the intermittent phase II contractions may be sufficient to sweep it out of the stomach. However, if the dosage form is embedded in the folds of the stomach then stronger phase III contractions will be necessary Table 1 Gastric emptying time (min), initial disintegration time post gastric emptying (min), initial disintegration position, complete disintegration time post gastric emptying (min) and complete disintegration position of EUDRAGIT® L 30 D-55 single-coated tablets (PSB = proximal small bowel, MSB = mid small bowel, DSB = distal small bowel, and AC = ascending colon). Initial Initial Subject Gastric emptying disintegration disintegration position time post time gastric emptying
Complete Complete disintegration disintegration position time post gastric emptying
1 2 3 4 5 6 7 8 Mean SD
73 56 86 79 82 129 162 97 96 32
61 20 15 65 43 24 38 32 37 18
51 45 53 69 49 91 106 61 66 22
MSB PSB MSB DSB MSB DSB DSB MSB
MSB MSB DSB DSB DSB DSB AC DSB
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F. Liu, A.W. Basit / Journal of Controlled Release 147 (2010) 242–245
Table 2 Gastric emptying time (min), initial disintegration time post gastric emptying (min), initial disintegration position, complete disintegration time post gastric emptying (min) and complete disintegration position of EUDRAGIT® L 30 D-55 double-coated tablets (PSB = proximal small bowel and MSB = mid small bowel). Subject Gastric Initial Initial emptying disintegration disintegration time time post position gastric emptying
Complete Complete disintegration disintegration time post position gastric emptying
1 2 3 4 5 6 7 8 Mean SD
35 22 52 45 38 49 55 28 41 12
34 20 22 65 43 15 38 85 40 24
26 22 35 29 28 33 34 20 28 6
PSB PSB PSB PSB PSB MSB PSB PSB
PSB PSB MSB PSB PSB MSB MSB PSB
to propel it out of the stomach. Similar emptying phenomena have been reported in a previous study by our group [16]. On leaving the stomach, the conventional EUDRAGIT® L 30 D-55 single-coated tablets started to disintegrate after a mean time of 66 ± 22 min and disintegration was complete after 96 ± 32 min (Table 1). This agrees with the reported disintegration times for EUDRAGIT® L 30 D-55 coated dosage forms in humans. For example, Cole et al. reported an initial disintegration time of 60 ± 54 min post gastric emptying for EUDRAGIT® L 30 D-55 coated HPMC capsules [7]. Another study reported an initial disintegration time of 89 ± 19 min for tablets coated with the organic solvent based formulation of the same polymer — EUDRAGIT® L 100-55 [17]. The EUDRAGIT® L 30 D-55 double-coated tablets disintegrated significantly earlier after gastric emptying compared to the single-coated tablets (p b 0.05) (Table 2 and Fig. 1). The mean initial disintegration time was 28±6 min and complete disintegration occurred after 41 ± 12 min. This expedited tablet disintegration can be explained by the rapid and unique coat dissolution process of the double-coating system. In contrast to the single-coating which dissolves gradually from its outer surface in contact with intestinal fluid, the outer layer of the double coating can dissolve from both its inner and outer surfaces. As aforementioned, the inner coat is partially neutralised and more readily dissolves than the outer coat. Once the intestinal fluid starts to penetrate through the outer coat, the neutralised inner coat dissolves rapidly. This produces a fluid and dynamic internal environment of high buffer capacity and ionic strength due to the presence of organic acid, citric acid in this case, in the inner layer. The high buffer capacity and ionic strength of the inner coat assists the outer coat, which is immediately adjacent to the dissolved inner layer, to dissolve from its inner surface. Meanwhile, the outer surface also undergoes dissolution. This unique coat dissolution
mechanism of the double-coating system has been illustrated in vitro in a previous study using Scanning Electron Microspcopy/Energy Dispersive X-ray Detection (SEM/EDX) and Confocal Laser Scanning Microscopy [11] and confirmed here in vivo. Tablets coated with the conventional EUDRAGIT® L 30 D-55 single-coating formulation disintegrated primarily in the mid to distal small intestine. In one volunteer, tablet disintegration was complete in the ascending colon. In contrast, disintegration commenced in the proximal small intestine for the double-coated tablets and was complete in the proximal to mid small intestine. It is noteworthy that tablet disintegration started earlier for the double coating compared to the single coating in all volunteers as illustrated in Fig. 1. The onset time of tablet disintegration for the single-coated tablets was also highly variable (range 45 – 106 min) after gastric emptying, whereas a more consistent initial disintegration time was observed for the double-coated tablets (range 20–35 min). This high degree of variability in the in vivo disintegration of conventional enteric-coated products is common [3–9] and can be attributed to the inter-subject variability in small intestinal pH, transit and fluid volume [2,18]. The accelerated coat dissolution of the double coating technology overcomes these physiological variations and improves the consistency of disintegration in the gastrointestinal tract. It is notable that the rupture of the double-coated tablets was initiated in the small intestine with no sign of disintegration in the stomach, indicating the technology is robust to gastric conditions. It should be appreciated that the present study was performed in fasted volunteers, all of whom had relatively short gastric retention times. However, we have subjected the tablets to in vitro gastric-resistance tests in pH 1.2 HCl for 12 h, and observed no physical changes in the formulation or drug release (data not shown). This can be attributed to the low acid permeability of the EUDRAGIT® L 30 D-55 outer coat. The double coated tablets should therefore be gastro-resistant in cases of prolonged stomach retention, such as in the fed state. However, further in vivo studies would be necessary to confirm this point. The delayed intestinal disintegration of conventional entericcoated dosage forms has undesired clinical implications, including ineffective drug therapy, decreased bioavailability for drugs with an absorption window in the proximal small intestine and delayed onset of action [19–23]. The appreciation of such issues has led to the development of alternative strategies, for example immediate release buffered tablets for oral proton-pump inhibitors, to improve clinical performance [24]. However, the antacid buffering agent used in this formulation can cause stomach irritation and influence the absorption of other medications taken at the same time. The novel double-coating approach presented in this paper provides rapid disintegration in the human small intestine and can be manufactured using conventional coating technology. It is, therefore, a promising strategy to overcome the limitations of conventional enteric coatings.
4. Conclusions
Fig. 1. The initial disintegration times of the EUDRAGIT® L 30 D-55 single-coated and double-coated tablets in human volunteers.
The novel double-coating concept in enteric coating demonstrated improved in vivo performance compared to a conventional single enteric coating. The double coating consists of a neutralised inner layer with organic acid and an outer layer of standard enteric coating, utilising EUDRAGIT® L 30 D-55 as a model enteric polymer. Tablets coated with the conventional single enteric coating disintegrated in the mid to distal small intestine with a significant time delay after gastric emptying. In contrast, the double-coated tablets disintegrated significantly earlier after leaving the stomach and exhibited more consistent disintegration in the proximal small intestine. This expedited in vivo disintegration can be beneficial for drugs with an absorption window in the proximal small intestine or actives requiring a rapid onset of action.
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References [1] G.A. Agyilirah, G.S. Banker, Polymers for enteric coating and applications, in: P.J. Tarcha (Ed.), Polymers for Controlled Drug Delivery, CRC Press, Baca Raton, 1991, pp. 39–66. [2] E.L. McConnell, H.M. Fadda, A.W. Basit, Gut instincts: explorations in intestinal physiology and drug delivery, Int. J. Pharm. 364 (2008) 213–226. [3] D. Catteau, C. Barthelemy, M. Deveaux, H. Robert, F. Trublin, X. Marchandise, H.V. Drunen, Contribution of scintigraphy to verify the reliability of different preparation processes for enteric coated capsules, Eur. J. Drug Metab. Pharmacokinet. 19 (1994) 91–98. [4] C.J. Kenyon, E.T. Cole, I.R. Wilding, The effect of food on the in vivo behaviour of enteric coated starch capsules, Int. J. Pharm. 112 (1994) 207–213. [5] C. Bogentoft, M. Alpsten, G. Ekenved, Absorption of acetylsalicylic acid from enteric-coated tablets in relation to gastric emptying and in-vivo disintegration, J. Pharm. Pharmacol. 36 (1984) 350–351. [6] I.R. Wilding, J.G. Hardy, R.A. Sparrow, S.S. Davis, P.B. Daly, J.R. English, In vivo evaluation of enteric-coated naproxen tablets using gamma scintigraphy, Pharm. Res. 9 (1992) 1436–1441. [7] E.T. Cole, R.A. Scott, A.L. Connor, I.R. Wilding, H.-U. Petereit, C. Schminke, T. Beckert, D. Cade, Enteric coated HPMC capsules designed to achieve intestinal targeting, Int. J. Pharm. 231 (2002) 83–95. [8] J.P. Ebel, M. Jay, R.M. Beihn, An in vitro/in vivo correlation for the disintegration and onset of drug release from enteric-coated pellets, Pharm. Res. 10 (1993) 233–238. [9] I.R. Wilding, S.S. Davis, R.A. Sparrow, K.J. Smith, K.A. Sinclair, A.T. Smith, The evaluation of an enteric-coated naproxen tablet formulation using gamma scintigraphy, Eur. J. Pharm. Biopharm. 39 (1993) 144–147. [10] F. Liu, R. Lizio, C. Meier, H.-U. Petereit, P. Blakey, A.W. Basit, A novel concept in enteric coating: a double-coating system providing rapid drug release in the proximal small intestine, J. Control Release 133 (2009) 119–124. [11] F. Liu, R. Lizio, U.U. Schneider, H.-U.P. Petereit, Blakey, A.W. Basit, SEM/EDX and confocal microscopy analysis of novel and conventional enteric coated systems, Int. J. Pharm. 369 (2009) 72–78.
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[12] F. Liu, P. Moreno, A.W. Basit, A novel double-coating approach for improved pHtriggered delivery to the ileo-colonic region of the gastrointestinal tract, Eur. J. Pharm. Biopharm. 74 (2010) 311–315. [13] R. Khosla, S.S. Davis, Gastric emptying and small and large bowel transit of nondisintegrating tablets in fasted subjects, Int. J. Pharm. 52 (1989) 1–10. [14] H.M. Fadda, E.L. McConnell, M.D. Short, A.W. Basit, Meal-induced acceleration of tablet transit through the human small intestine, Pharm. Res. 26 (2009) 356–360. [15] S.S. Davis, F. Norring-Christensen, R. Khosla, L.C. Feely, Gastric emptying of large single unite dosage forms, J. Pharm. Pharmacol. 40 (1988) 205–207. [16] V.C. Ibekwe, F. Liu, H.M. Fadda, M.K. Khela, D.F. Evans, G.E. Parsons, A.W. Basit, An investigation into the in vivo performance variability of pH responsive polymers for ileo-colonic drug delivery using gamma scintigraphy in humans, J. Pharm. Sci. 95 (2006) 2760–2766. [17] K.P. Steed, G. Hooper, P. Ventura, R. Musa, I.R. Wilding, The in vivo behaviour of a colonic delivery system: a pilot study in man, Int. J. Pharm. 112 (1994) 199–206. [18] V.C. Ibekwe, H.M. Fadda, E.L. McConnell, M.K. Khela, D.F. Evans, A.W. Basit, Interplay between intestinal pH, transit time and feed status on the in vivo performance of pH responsive ileo-colonic release systems, Pharm. Res. 25 (2008) 1828–1835. [19] B.D. Damle, S. Kaul, D. Behr, C. Knupp, Bioequivalence of two formulations of didanosine, encapsulated enteric-coated beads and buffered tablet, in healthy volunteers and HIV-infected subjects, J. Clin. Pharmacol. 42 (2002) 791–797. [20] L. Guarner, R. Rodriguez, F. Guarner, J.-R. Malagelada, Fate of oral enzymes in pancreatic insufficiency, Gut 34 (1993) 708–712. [21] U. Gundert-Remy, R. Hildebrandt, A. Stiehl, E. Weber, G. Zurcher, M.D. Prada, Intestinal absorption of levodopa in man, Eur. J. Clin. Pharmacol. 25 (1983) 69–72. [22] F. Marotta, S.J.D. O'Keefe, I.N. Marks, A. Girdwood, G. Young, Pancreatic enzyme replacement therapy. Importance of gastric acid secretion, H2-antagonists, and enteric coating, Dig. Dis. Sci. 34 (1989) 456–461. [23] P.J. Robinson, A.L. Smith, P.D. Sly, Duodenal pH in cystic fibrosis and its relationship to fat malabsorption, Dig. Dis. Sci. 35 (1990) 1299–1304. [24] D. Castell, Review of immediate-release omeprazole for the treatment of gastric acid-related disorders, Expert Opin. Pharmacother. 6 (2005) 2501–2510.
Contents lists available at ScienceDirect
Journal of Controlled Release j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j c o n r e l
A paradigm shift in enteric coating: Achieving rapid release in the proximal small intestine of man Fang Liu 1, Abdul W. Basit ⁎ Department of Pharmaceutics, The School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1N 1AX, UK
a r t i c l e
i n f o
Article history: Received 19 March 2010 Accepted 14 July 2010 Available online 22 July 2010 Keywords: pH-sensitive polymers Methacrylic acid ethyl acrylate copolymer Enteric coatings Enteric polymers Gastric resistance Gamma scintigraphy Gastrointestinal transit
a b s t r a c t The in vivo performance of a novel enteric double-coating technology designed to accelerate release in the proximal small intestine of humans was investigated. Tablet cores were coated with a double layer formulation consisting of an inner layer of EUDRAGIT® L 30 D-55 neutralised to pH 6.0 in the presence of 10% citric acid, and an outer layer of standard EUDRAGIT® L 30 D-55. A conventional single coating of EUDRAGIT® L 30 D-55 was also applied to tablets for comparison purposes, with the identical coating formulation and thickness (5 mg/cm2) as the outer layer of the double coating. Eight fasted volunteers received the double-coated and single-coated tablets in a two-way crossover study. The formulations were radiolabelled and followed by gamma scintigraphy; the disintegration times and positions were recorded. After leaving the stomach, tablets coated with the single-coating formulation showed a significant time delay before disintegration occurred in the mid to distal small intestine, with a mean disintegration time of 66 ± 22 min post gastric emptying. The double-coated tablets disintegrated earlier at 28 ± 6 min post gastric emptying with consistent disintegration in the proximal small intestine. The accelerated in vivo disintegration of the double-coating system can overcome the limitations of conventional enteric coatings. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Enteric coatings are widely applied to solid dosage forms to retard drug release in the stomach and allow release in the small intestine. There are three main reasons for using such dosage forms: (i) to prevent the degradation of active substances in the acidic environment of the stomach, (ii) to protect the stomach from irritant actives and, (iii) to target actives to specific sites in the intestine for the treatment of local diseases [1]. The most commonly used enteric coatings employ pHdependent polymers which contain carboxylic groups. These remain un-ionized in the low pH environment of the stomach, and become ionized in the higher pH conditions of the small intestine, thus allowing the dissolution of the coating and drug release. It is a common misconception that enteric-coated products designed to release in the proximal small intestine disintegrate rapidly after emptying from the stomach [2]. In vivo such products can take up to 2 h to disintegrate in the human small intestine [3–9]. Drug release will then occur in the distal small intestine and cause a delayed response to medication and potentially reduce the bioavailability of those drugs with an absorption window in the upper small intestine. Hence, there is a clear need to achieve rapid drug release from entericcoated products in the proximal small intestine. ⁎ Corresponding author. Tel./fax: + 44 20 7753 5865. E-mail address: [email protected] (A.W. Basit). 1 Present address: The School of Pharmacy, University of Hertfordshire, Hatfield, AL10 9AB, UK. 0168-3659/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2010.07.105
Recently, a new concept was introduced to accelerate the dissolution of enteric coatings for drug delivery to the upper small intestine [10,11] and the ileo-caecal junction for colonic delivery [12]. The system designed to release in the proximal small intestine consists of a double coating based on methacrylic acid copolymer EUDRAGIT® L 30 D-55 (dissolves at pH N 5.5). The double coating comprises an inner layer of partially neutralised enteric polymer and organic acid and an outer layer of standard enteric coating. This is then applied to solid dosage forms. With this concept substantially accelerated coating dissolution was demonstrated, along with rapid drug release in simulated upper small intestine conditions in vitro. The rapid dissolution of the system was attributed to the increased ionic strength and buffer capacity of its inner layer and the migration of water soluble components from the inner to the outer coat [11]. The combination of these effects meant that the coating was effectively being dissolved from its inner and outer surfaces. The objective of the present study was to assess the in vivo performance of this novel double-coating concept in man. The technique of gamma scintigraphy was employed to determine the disintegration time and position of tablets coated with the double-coating system and a conventional single coating based on EUDRAGIT® L 30 D-55. 2. Materials and methods 2.1. Materials EUDRAGIT® L 30 D-55 was donated by Evonik Röhm GmbH, Darmstadt, Germany. Citric acid was purchased from Sigma-Aldrich Co.
F. Liu, A.W. Basit / Journal of Controlled Release 147 (2010) 242–245
Ltd., Dorset, UK. Triethyl citrate was obtained from Lancaster Synthesis, Lancashire, UK. Talc (fine powder, b15 μm) was purchased from VWR International Ltd, Poole, UK. Prednisolone was purchased from Aventis Pharma., Antony, France. Lactose (Pharmatose) was obtained from Ellis & Everard, Essex, UK. Cross-linked sodium carboxymethylcellulose was donated by FMC International, Cork, Ireland. Polyvinylpyrrolidone 40000 was purchased from VWR International Ltd, Poole, UK. Magnesium stearate was purchased from Sigma-Aldrich Co. Ltd., Dorset, UK. Bone cement (DeTrey® Zinc) was kindly donated by DentsPly GmbH, Germany. 99mTechnetium (Tc)–diethylenediaminepentaacetic acid (DTPA) and 111indium (In)–DTPA were obtained from Amersham (Hammersmith Hospital, London) and were delivered each morning on the day of the study. All other materials were obtained from SigmaAldrich Co. Ltd., Dorset, UK. 2.2. Preparation and coating of tablets Tablet cores (200 mg, 8 mm diameter) were prepared according to the following wet granulation formula: 5% prednisolone, 88.5% lactose, 5% polyvinylpyrrolidone, 0.5% cross-linked sodium carboxymethylcellulose (added intra and extra-granularly, 50:50) and 1% magnesium stearate, using a single punch tableting machine (Manesty, Speke, UK). The tablets were coated with a EUDRAGIT® L 30 D-55 double-coating formulation comprising an inner coat containing 10% citric acid and neutralised to pH 6.0 and an outer layer of standard EUDRAGIT® L 30 D-55. A conventional single-coating formulation of EUDRAGIT® L 30 D-55 was also applied to separate cores for comparison purposes. The technical details relating to both formulations are described in an earlier publication [10]. The coating level for the single coating was 5 mg polymer per cm2 of the tablet surface, as recommended by the polymer supplier to achieve efficient gastric resistance for coated tablets. The same coating level was used for the inner and outer coats of the double-coating system. 2.3. Radiolabelling of coated tablets Due to the lengthy manufacturing procedure and the safety issues of prolonged handling of radioactive sources, the radioactive materials were incorporated in the dosage form after coating. Coated tablets were labelled with 99mTc (single coating) or 111In (double coating) complexed to diethylenetriaminepentaacetic acid (DTPA). A small quantity of lactose was dissolved in the DTPA complex of each radioactive material and left to dry in an oven. A hole of 1 mm diameter was precisely drilled in the middle of the tablet and the radiolabelled lactose was filled into the hole to the required activity; and the hole was sealed with bone cement. In vitro studies of drug release showed that the integrity of the coating was not compromised by the labelling process and the labelled tablets gave identical drug release profiles as unlabelled tablets in simulated gastrointestinal conditions (0.1 M HCl for 2 h and then pH 5.6 phosphate buffer). The labelled tablets had an activity of 3.0 MBq for 99mTc and 0.6 MBq for 111In at the time of administration. 2.4. Subjects and study protocol The approval for the study was obtained from the local ethics committee. The study followed the tenets of the Declaration of Helsinki (1964) and its subsequent revisions. Eight healthy male volunteers (age 24–33 years, height 1.60–1.83 m and weight 64–85 kg) participated in the study. Following an overnight fast, each volunteer received two tablets (one single-coated formulation and one double-coated formulation) simultaneously with 150 mL water. A pair of small markers radiolabelled with 0.5 MBq 99mTc was taped to the abdomen at the most lateral position of the lower costal margin of the volunteers, for use as an anatomical reference marker and for purposes of correcting for the different positions of the volunteers between images. Sequential static anterior images were acquired using a single head gamma camera
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(GE Maxicamera 400 AC) fitted with a medium energy collimator. The energy windows were set at 126–150 keV for 99mTc and 221–274 keV for 111In, permitting the two radioactive sources to be detected simultaneously and visualised on a dual display monitor. Images were acquired over a period of 1 min at approximately 5 min intervals, with volunteers standing in front of the detector. Volunteers were permitted to move away from the camera between imaging but were required to remain in an upright position and not undergo any form of physical exertion. Volunteers continued to fast until the end of the study. The series of acquired images for each volunteer was replayed on a computer and processed using the Nucmed software (MicasX, Farnborough, UK). Analysis of the images and determination of the gastric emptying times, tablet disintegration times (initial and complete) and disintegration positions was performed independently by two investigators one of whom was blinded to the study. Both investigators reached similar interpretations. Since the images were not continuous, the time of the various events were taken as the mean of the two time points either side of the event. 2.5. Statistics The disintegration times post gastric-emptying of the singlecoated and double-coated tablets were compared using a paired Student's t test. Significance was assumed where p b 0.05. 3. Results and discussion The in vivo performance of the EUDRAGIT® L 30 D-55 singlecoated and double-coated tablets is shown in Tables 1 and 2, respectively. Gastric emptying of the tablets was rapid in all volunteers with times in the range of 15–85 min. These data generally agree with the published literature on the gastric emptying times of non-disintegrating monolithic dosage forms administered in the fasted state [13,14]. These dosage forms are treated by the stomach as indigestible solids and are usually swept out of the stomach by the “housekeeper” wave during phase III of the migrating motor complex (MMC) [15]. The time of gastric emptying therefore depends on the arrival time of the dosage form in the stomach in relation to the contractile phase of the MMC. In the present study, the two tablets were administered concurrently and resulted in similar emptying times in most volunteers. However, for some subjects this was not the case which may be explained by tablets residing in different positions in the stomach. If the tablet is present near the pylorus, the intermittent phase II contractions may be sufficient to sweep it out of the stomach. However, if the dosage form is embedded in the folds of the stomach then stronger phase III contractions will be necessary Table 1 Gastric emptying time (min), initial disintegration time post gastric emptying (min), initial disintegration position, complete disintegration time post gastric emptying (min) and complete disintegration position of EUDRAGIT® L 30 D-55 single-coated tablets (PSB = proximal small bowel, MSB = mid small bowel, DSB = distal small bowel, and AC = ascending colon). Initial Initial Subject Gastric emptying disintegration disintegration position time post time gastric emptying
Complete Complete disintegration disintegration position time post gastric emptying
1 2 3 4 5 6 7 8 Mean SD
73 56 86 79 82 129 162 97 96 32
61 20 15 65 43 24 38 32 37 18
51 45 53 69 49 91 106 61 66 22
MSB PSB MSB DSB MSB DSB DSB MSB
MSB MSB DSB DSB DSB DSB AC DSB
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Table 2 Gastric emptying time (min), initial disintegration time post gastric emptying (min), initial disintegration position, complete disintegration time post gastric emptying (min) and complete disintegration position of EUDRAGIT® L 30 D-55 double-coated tablets (PSB = proximal small bowel and MSB = mid small bowel). Subject Gastric Initial Initial emptying disintegration disintegration time time post position gastric emptying
Complete Complete disintegration disintegration time post position gastric emptying
1 2 3 4 5 6 7 8 Mean SD
35 22 52 45 38 49 55 28 41 12
34 20 22 65 43 15 38 85 40 24
26 22 35 29 28 33 34 20 28 6
PSB PSB PSB PSB PSB MSB PSB PSB
PSB PSB MSB PSB PSB MSB MSB PSB
to propel it out of the stomach. Similar emptying phenomena have been reported in a previous study by our group [16]. On leaving the stomach, the conventional EUDRAGIT® L 30 D-55 single-coated tablets started to disintegrate after a mean time of 66 ± 22 min and disintegration was complete after 96 ± 32 min (Table 1). This agrees with the reported disintegration times for EUDRAGIT® L 30 D-55 coated dosage forms in humans. For example, Cole et al. reported an initial disintegration time of 60 ± 54 min post gastric emptying for EUDRAGIT® L 30 D-55 coated HPMC capsules [7]. Another study reported an initial disintegration time of 89 ± 19 min for tablets coated with the organic solvent based formulation of the same polymer — EUDRAGIT® L 100-55 [17]. The EUDRAGIT® L 30 D-55 double-coated tablets disintegrated significantly earlier after gastric emptying compared to the single-coated tablets (p b 0.05) (Table 2 and Fig. 1). The mean initial disintegration time was 28±6 min and complete disintegration occurred after 41 ± 12 min. This expedited tablet disintegration can be explained by the rapid and unique coat dissolution process of the double-coating system. In contrast to the single-coating which dissolves gradually from its outer surface in contact with intestinal fluid, the outer layer of the double coating can dissolve from both its inner and outer surfaces. As aforementioned, the inner coat is partially neutralised and more readily dissolves than the outer coat. Once the intestinal fluid starts to penetrate through the outer coat, the neutralised inner coat dissolves rapidly. This produces a fluid and dynamic internal environment of high buffer capacity and ionic strength due to the presence of organic acid, citric acid in this case, in the inner layer. The high buffer capacity and ionic strength of the inner coat assists the outer coat, which is immediately adjacent to the dissolved inner layer, to dissolve from its inner surface. Meanwhile, the outer surface also undergoes dissolution. This unique coat dissolution
mechanism of the double-coating system has been illustrated in vitro in a previous study using Scanning Electron Microspcopy/Energy Dispersive X-ray Detection (SEM/EDX) and Confocal Laser Scanning Microscopy [11] and confirmed here in vivo. Tablets coated with the conventional EUDRAGIT® L 30 D-55 single-coating formulation disintegrated primarily in the mid to distal small intestine. In one volunteer, tablet disintegration was complete in the ascending colon. In contrast, disintegration commenced in the proximal small intestine for the double-coated tablets and was complete in the proximal to mid small intestine. It is noteworthy that tablet disintegration started earlier for the double coating compared to the single coating in all volunteers as illustrated in Fig. 1. The onset time of tablet disintegration for the single-coated tablets was also highly variable (range 45 – 106 min) after gastric emptying, whereas a more consistent initial disintegration time was observed for the double-coated tablets (range 20–35 min). This high degree of variability in the in vivo disintegration of conventional enteric-coated products is common [3–9] and can be attributed to the inter-subject variability in small intestinal pH, transit and fluid volume [2,18]. The accelerated coat dissolution of the double coating technology overcomes these physiological variations and improves the consistency of disintegration in the gastrointestinal tract. It is notable that the rupture of the double-coated tablets was initiated in the small intestine with no sign of disintegration in the stomach, indicating the technology is robust to gastric conditions. It should be appreciated that the present study was performed in fasted volunteers, all of whom had relatively short gastric retention times. However, we have subjected the tablets to in vitro gastric-resistance tests in pH 1.2 HCl for 12 h, and observed no physical changes in the formulation or drug release (data not shown). This can be attributed to the low acid permeability of the EUDRAGIT® L 30 D-55 outer coat. The double coated tablets should therefore be gastro-resistant in cases of prolonged stomach retention, such as in the fed state. However, further in vivo studies would be necessary to confirm this point. The delayed intestinal disintegration of conventional entericcoated dosage forms has undesired clinical implications, including ineffective drug therapy, decreased bioavailability for drugs with an absorption window in the proximal small intestine and delayed onset of action [19–23]. The appreciation of such issues has led to the development of alternative strategies, for example immediate release buffered tablets for oral proton-pump inhibitors, to improve clinical performance [24]. However, the antacid buffering agent used in this formulation can cause stomach irritation and influence the absorption of other medications taken at the same time. The novel double-coating approach presented in this paper provides rapid disintegration in the human small intestine and can be manufactured using conventional coating technology. It is, therefore, a promising strategy to overcome the limitations of conventional enteric coatings.
4. Conclusions
Fig. 1. The initial disintegration times of the EUDRAGIT® L 30 D-55 single-coated and double-coated tablets in human volunteers.
The novel double-coating concept in enteric coating demonstrated improved in vivo performance compared to a conventional single enteric coating. The double coating consists of a neutralised inner layer with organic acid and an outer layer of standard enteric coating, utilising EUDRAGIT® L 30 D-55 as a model enteric polymer. Tablets coated with the conventional single enteric coating disintegrated in the mid to distal small intestine with a significant time delay after gastric emptying. In contrast, the double-coated tablets disintegrated significantly earlier after leaving the stomach and exhibited more consistent disintegration in the proximal small intestine. This expedited in vivo disintegration can be beneficial for drugs with an absorption window in the proximal small intestine or actives requiring a rapid onset of action.
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