International Journal of Pharmaceutics 231 (2002) 83–95
`
`www.elsevier.com/locate/ijpharm
`
`Enteric coated HPMC capsules designed to achieve
`intestinal targeting
`
`Ewart T. Cole a,*, Robert A. Scott a, Alyson L. Connor b, Ian R. Wilding b,
`Hans-U. Petereit c, Carsten Schminke c, Thomas Beckert c, Dominique Cade´ a
`a Capsugel Di6ision of Pfizer Inc., Fabrikmattenweg 2, CH-4144 Arlesheim, Basel, Switzerland
`b Pharmaceutical Profiles Ltd, Mere Way, Ruddington Fields, Ruddington, Nottingham NG11 6JS, UK
`c Roehm GmbH & Co. KG, Kirschenallee, DE-64293 Darmstadt, Germany
`
`Received 4 June 2001; received in revised form 20 August 2001; accepted 29 August 2001
`
`Abstract
`
`The enteric coating of HPMC capsules containing paracetamol was investigated. Two enteric polymers, Eudragit®
`L 30 D-55 and Eudragit® FS 30 D were studied, which are designed to achieve enteric properties and colonic release,
`respectively. The capsules were coated in an Accela Cota 10, and, as shown by optical microscopy, resulted in
`capsules with a uniform coating. Scanning electron microscopy of the surface of the capsules illustrate that, in
`contrast to gelatin, HPMC has a rough surface, which provides for good adhesion to the coating. Dissolution studies
`demonstrated that capsules coated with Eudragit® L 30 D-55 were gastro resistant for 2 h at pH 1.2 and capsules
`coated with Eudragit® FS 30 D were resistant for a further 1 h at pH 6.8. The product visualisation technique of
`gamma scintigraphy was used to establish the in vivo disintegration properties of capsules coated with 8 mg cm − 2
`Eudragit® L 30 D-55 and 6 mg cm − 2 Eudragit® FS 30 D. For HPMC units coated with Eudragit® L 30 D-55,
`complete disintegration occurred predominately in the small bowel in an average time of 2.4 h post dose. For HPMC
`capsules coated with Eudragit® FS 30 D, complete disintegration did not occur until the distal small intestine and
`proximal colon in an average time of 6.9 h post dose. © 2002 Elsevier Science B.V. All rights reserved.
`
`Keywords: Hydroxypropylmethylcellulose capsule; Enteric coating; Eudragit®; Scintigraphic evaluation
`
`1. Introduction
`
`Enteric coated products are designed to remain
`intact in the stomach and then to release the
`active substance in the upper intestine. The rea-
`
`* Corresponding author. Tel.:+41-61-705-5111; fax: +41-
`61-705-5118.
`E-mail address: ewart.cole@pfizer.com (E.T. Cole).
`
`sons for using enteric coated preparations are well
`documented (Wilding, 2000).
`The polymers commonly used to achieve enteric
`properties are anionic polymethacrylates (copoly-
`merisate of methacrylic acid and either methyl-
`(Eudragit®),
`methacrylate
`or
`ethyl
`acrylate
`cellulose based polymers, e.g. cellulose acetate
`phthalate (Aquateric®) or polyvinyl derivatives,
`e.g. polyvinyl acetate phthalate (Coateric®).
`
`0378-5173/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved.
`PII: S 0 3 7 8 - 5 1 7 3 ( 0 1 ) 0 0 8 7 1 - 7
`
`

`

`84
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`E.T. Cole et al. /International Journal of Pharmaceutics 231 (2002) 83–95
`
`Colon targeting products are also designed to
`remain intact in the stomach but in addition
`intended to release the active substance further
`along the gastrointestinal (GI) tract, e.g. at the
`ileo–caecal junction or in the colon (Ashford and
`Fell, 1994). The site specific delivery of drugs to
`the colon has implications in a number of thera-
`peutic areas (Leopold, 1999).
`As previously mentioned, site specific delivery
`into the upper intestine has been achieved for
`many years by the use of pH-sensitive coatings
`(Healey, 1989). By applying a thicker coating
`and/or raising the threshold pH at which dissolu-
`tion of the coating begins, colon specific delivery
`using enteric polymers has been achieved (Hardy
`et al., 1987a). Tablets containing mesalazine and
`coated with Eudragit® S 100, which dissolves
`above pH 7, are marketed in a number of coun-
`tries (Asacol®, GlaxoSmithKline, UK) (Dew et
`al., 1983). Mesalazine tablets coated with Eu-
`dragit® L100, which dissolves above pH 6, are
`also commercially available (Claversal® and Salo-
`falk®) (Hardy et al., 1987b).
`The majority of the enteric and colon delivery
`systems are based on coated tablets or pellets
`which are filled into conventional hard gelatin
`capsules. However, during the early stages of drug
`development some new chemical entities (NCE’s)
`present a challenge in testing for efficacy due to
`instability in gastric fluids or because of irritation
`in the GI tract. The limited amount of drug
`substance available during the early stage often
`precludes the development of a coated pellet or
`tablet formulation. Since the coating process is
`independent of the capsule contents, there are
`clear advantages resulting from the ability to coat
`a capsule. Thus, the oral pharmacological and/or
`therapeutic efficacy of the NCE can be deter-
`mined without resorting to extensive formulation
`development studies which are expensive, time
`consuming and, in many instances, impossible at
`this point in the development of the NCE. Addi-
`tionally, the capsule provides the possibility to
`deliver liquid or semi-solid formulations to the
`small or large intestine.
`The most commonly used material for manu-
`facturing capsules is gelatin. Although it is possi-
`ble to coat hard gelatin capsules (Murthy et al.,
`
`1986; Thoma and Bechtold, 1992) the process is at
`best very sensitive, especially if an aqueous coat-
`ing system is used, and can lead to shell embrittle-
`ment and poor adhesion of the coat to the smooth
`gelatin surface. A pre-coating can reduce interac-
`tions between the gelatin and the enteric polymer
`but is time consuming and complicated.
`A colonic drug delivery system, based on a
`starch injection moulded capsule, has been de-
`scribed (Watts, 1995). This system has all the
`advantages of a capsule described above but suf-
`fers from the disadvantage of requiring a specially
`designed capsule filling and sealing machine, thus
`narrowing
`the field of
`application of
`the
`technology.
`HPMC capsules have been available commer-
`cially, mainly to the dietary supplement industry
`as a vegetarian alternative to gelatin, for approxi-
`mately 10 years (Ogura et al., 1998). As HPMC is
`often used as a pre-coating material for enteric
`coated tablets, it may be expected that the appli-
`cation of enteric type polymers to a capsule made
`from HPMC would result in ‘good polymer to
`polymer’ adhesion and compatibility.
`imaging
`Gamma scintigraphy is an elegant
`technique which allows the intestinal performance
`of pharmaceutical formulations to be visualized
`(Wilding et al., 2001; Nick, 1996). Over the last 20
`years, the approach has become the technique of
`choice for probing the complex interaction of
`drug preparations/formulations with the heteroge-
`neous environment of the human gut (Wilding
`and Newman, 1998).
`In this paper, we describe the manufacture of
`two different Eudragit® coated HPMC capsules
`and their in vitro/in vivo performance.
`
`2. Materials and methods
`
`2.1. Coating materials
`
`Two commercially available aqueous methacry-
`late coating dispersions (Roehm GmbH, Darm-
`stadt, Germany) were used in this
`study.
`Eudragit® L 30 D-55 (Methacrylic Acid Copoly-
`mer Dispersion, NF), designed to achieve enteric
`properties, is a copolymer of methacrylic acid and
`
`

`

`E.T. Cole et al. /International Journal of Pharmaceutics 231 (2002) 83–95
`
`85
`
`ethyl acrylate and dissolves at a pH of 5.5. Eu-
`dragit® FS 30 D is a 30% dispersion of a copoly-
`mer of methacrylic acid, methyl acrylate and
`methylmethacrylate. Due to the free carboxylic
`acid group the polymer dissolves at pH 7 or
`above making it particularly suitable for delivery
`into the colon (Gupta et al., 2001).
`Excipients used for the coating dispersions were
`triethyl citrate, NF (Morflex Inc., Greensboro,
`NC, USA) as a plasticizer, Polysorbate 80 (Tween
`80 V, ICI Espana, SA, Barcelona, Spain) as an
`emulsifier and Mono and Di Glycerides, NF
`(Imwitor 900, Hu¨ls AG, Witten Germany) as a
`glidant. The composition of the coating disper-
`sions and their method of preparation are given in
`Table 1.
`In order to increase the flexibility and the adhe-
`sion of the enteric coating from methacrylic acid
`copolymer dispersion, the amount of plasticizer
`was adjusted to 20%, based on the polymer. Talc
`was not added as an anti sticking agent so as to
`avoid any discoloration of the capsule surface.
`Due to the lower glass transition temperature of
`the polymer in Eudragit® FS 30 D, a glidant was
`needed to reduce the tackiness. Thus 8%, calcu-
`
`lated on the polymer, of Mono and Di Glycerides
`(glyceryl monostearate) was added, using polysor-
`bate 80 as a co-emulsifier. Furthermore, in con-
`trast
`to talc, GMS does not
`increase
`the
`brittleness of coatings due to its physico chemical
`properties. The solid concentration of the spray
`liquids was adjusted to 15%, in order to achieve as
`uniform a coating as possible.
`
`2.2. Capsule filling and coating
`
`Size 0 capsules (Capsugel Division of Pfizer Inc)
`of surface area 5.0 cm2, made from hydrox-
`ypropyl methylcellulose without colouring agent,
`were filled by hand with 380 mg paracetamol
`(Rhodia France) into which had been mixed 10
`mg natural abundance samarium oxide. The cap-
`sules were sealed with the LEMS™ process (Cole,
`2000) using a modified sealing fluid.
`Capsule coating was carried out in an Accela
`Cota 10 (BWI Manesty) with a batch size of 5 kg.
`For each trial the pan was loaded with 4.936 kg
`size 1 HPMC capsules filled with 250 mg of a
`paracetamol formulation and 130 size 0 capsules.
`This size difference enabled the capsules contain-
`
`Table 1
`Composition and preparation of the coating dispersions used to coat HPMC capsules
`
`Enteric coating
`(Eudragit® L 30 D-55)
`
`Colonic coating (Eudragit® FS 30 D)
`
`Eudragit® Dispersion
`Triethyl citrate
`Glyceryl
`Monostearate
`Tween 80 (33%
`aqueous solution)
`Water
`
`Dispersion preparation
`
`2287.5 g=686.2 g polymer
`137.2 g
`–
`
`2287.5 g=686.2 g polymer
`34.3 g
`54.9 g
`
`–
`
`65.9 g
`
`3065.2 g
`5489.9 g=823.5 g total
`solids
`
`2873.5 g
`5316.1 g=797.4 g total solids
`
`TEC added to water and
`homogenised
`Added to Eudragit® under
`stirring
`
`Tween 80 added to water and heated to 63 °C with stirring
`
`GMS added and stirred for 10 min. and resulting suspensions allowed
`to cool to below 40 °C
`TEC added
`Added to Eudragit® under stirring
`
`

`

`86
`
`E.T. Cole et al. /International Journal of Pharmaceutics 231 (2002) 83–95
`
`Table 2
`Operating parameters used to coat HPMC capsules with Eu-
`dragit® L 30 D-55 and Eudragit® FS 30 D
`
`Parameter
`
`Value
`
`Spray gun
`Nozzle diameter
`Speed of rotation
`Atomising pressure
`Inlet air volume
`Inlet air temperature
`Outlet air temperature
`Temperature of capsule bed
`Spray rate
`
`Spraying time
`Drying conditions
`
`BWI Manesty
`1 mm
`12 rpm
`1.3 bar
`9 m3 min−1
`35 °C
`25–30 °C
`25–27 °C
`4.2 g min−1 kg−1 per
`capsules
`263 min
`5 min at 30 °C
`
`ing samarium oxide to be sampled from the bulk
`capsules. At various time intervals, during capsule
`coating, samples were taken corresponding to a
`theoretical coating thickness of 6, 8 and 10 mg
`cm− 2. At the end of the coating process the
`capsules had received 12 mg cm− 2 of polymer
`substance. The operating parameters used during
`the coating process are provided in Table 2. As
`the mechanical properties of hydrophilic polymers
`are influenced by the residual moisture, any dry-
`ing by pre-heating or high process temperatures
`must be avoided. Due to the low minimum film-
`forming temperatures of the coating dispersions,
`the temperature of the capsules could be kept
`between 25 and 27 °C during spraying. By using
`such mild process conditions any drying of the
`capsule shells or spray drying of the atomised mist
`can be avoided. After the coating process the
`capsules were dried on trays for 2 h at 30 °C.
`
`2.3. In 6itro dissolution studies
`
`To select the appropriate coating thickness for
`the capsules to be evaluated in the in vivo scinti-
`graphic studies dissolution testing on the size 0
`capsules was undertaken using USP Apparatus 2
`at 50 rpm, in 900 ml of medium at 37 °C with a
`wire sinker. Due to the small number of capsules
`available only limited in vitro testing was possible.
`For the enteric capsules 2 h of exposure in 0.1
`N hydrochloric acid (pH 1.2) was followed by
`
`testing in 0.05 M phosphate buffer of pH 6.8. The
`colonic capsules were tested for 2 h at pH 1.2,
`followed by 1 h at pH 6.8 and finally in phosphate
`buffer of pH 7.4. Paracetamol concentrations
`were determined by UV spectrophotometry at a
`wavelength of 300 nm.
`
`2.4. Scanning electron microscopy (SEM)
`
`surface properties of
`the
`To characterise
`HPMC capsules the SEM (Jeol JSM 35) tech-
`nique was used. As a comparison, the surface of a
`gelatin capsule was also examined. In an attempt
`to characterise the interface between HPMC and
`the coat a coated capsule was cleaved. The sample
`was prepared as a mechanically cleaved cross-
`section.
`
`2.5. Optical microscopy
`
`Low Resolution optical microscopy (Nikon
`Labophot 2A) was used to document the unifor-
`mity of film thickness on the domed area of an
`HPMC capsule and also on the junction where
`the cap and body meet. The capsule cross-section
`was prepared by encapsulating the whole capsule
`in a slow-setting resin which was allowed to set
`for 24 h. The sample was then cut with a diamond
`saw and ground and polished to achieve the de-
`sired longitudinal cross-section.
`
`2.6. In 6i6o e6aluation
`
`The product visualisation technique of gamma
`scintigraphy was used to establish the in vivo
`disintegration properties of the coated HPMC
`capsules in a group of eight healthy volunteers.
`The objectives of
`the scintigraphic evaluation
`were to establish both the intestinal site and time
`of initial/complete capsule disintegration follow-
`ing fasted dosing.
`This was a two way randomized crossover
`study in eight healthy male or non-pregnant fe-
`male volunteers. All subjects received either the
`Eudragit® L 30 D-55 or Eudragit® FS 30 D
`coated HPMC capsules in randomized order after
`an overnight fast. The Clinical Protocol for the
`study was approved by the Quorn Research Re-
`
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`

`E.T. Cole et al. /International Journal of Pharmaceutics 231 (2002) 83–95
`
`87
`
`view Committee and all volunteers provided writ-
`ten Informed Consent to participate in the study.
`Neutron activation methods can be used to
`radiolabel dosage forms for scintigraphic studies.
`These techniques require the addition of a stable
`non-radioactive isotope within a formulation;
`subsequent irradiation in a neutron source con-
`verts the isotope into a gamma emitting radionu-
`clide (Digenis and Sandefer, 1991; Kenyon et al.,
`1995). In order to validate this technique, the
`irradiation process must be shown to have no
`significant effect on the formulation,
`i.e.
`the
`preparation must behave in a similar manner both
`prior to and following the irradiation procedure.
`Coated capsules were irradiated for 4.5 min in a
`neutron flux of 1012 n cm − 2 s− 1. In vitro dissolu-
`tion tests showed that the neutron activation pro-
`cess did not adversely affect the performance of
`the dosage form.
`The volunteers arrived at the study site having
`fasted from midnight. Anterior anatomical mark-
`ers containing 0.1 MBq 99mTc were taped to the
`skin, where the mid-clavicular line meets the right
`costal margin so that they lay in approximately
`the same transverse plane as the pylorus. Each
`subject received a single preparation radiolabelled
`with 1 MBq 153Sm on each of two occasions. The
`preparations were administered at approximately
`08.00. Subjects remained fasted until 4 h post-
`dose at which time a standard lunch was pro-
`vided. An evening meal was also provided at 9 h
`post-dose.
`Anterior scintigraphic images were recorded at
`frequent intervals for 12 h post-dose, using a
`gamma camera (General Electric Maxicamera)
`with a 40 cm field of view and fitted with a low
`energy parallel hole collimator.
`Images were
`recorded at approximately 10 min intervals until 8
`h post-dose and at approximately 20 min intervals
`until 12 h post-dose. The times provided for the
`transit and disintegration properties of the two
`enteric coated formulations are the mid-point val-
`ues of the two images either side of the intestinal
`event. Return visits were made to the clinical unit
`at 24 h post-dose to allow the acquisition of a
`further scintigraphic image. Acquired images were
`initially of 50 s duration. The volunteers remained
`moderately active throughout the study period
`
`images were acquired with the subjects
`and all
`standing in front of the gamma camera.
`
`3. Results and discussion
`
`3.1. Microscopy of uncoated and coated capsules
`
`Coatings on gelatin capsules often suffer from
`insufficient adhesion between the shell and the
`coating. Thus previous workers in the area of
`enteric coating have found it necessary to pre-coat
`gelatin capsules with, for instance, a cellulose
`derivative, either to promote adhesion of poly-
`mers to the capsule shell (Murthy et al., 1986) or
`to improve gastro-resistance (Plaizier-Vercammen
`et al., 1992). A procedure recommended for coat-
`ing gelatin capsules (Roehm Technical Brochure,
`1994) also involved pre-coating with Eudragit® L
`30 D-55 plasticized with glycerol to improve adhe-
`sion and storage stability. When the capsule itself
`is made of a cellulose derivative it would be
`expected, based on the experience with enteric
`coating of tablets with a pre-coating of HPMC,
`that a pre-coating step could be eliminated.
`Gelatin capsules have a very glossy surface due
`to the fact that the amount of regular reflection
`from the surface is high and the amount of diffuse
`reflection is low. In contrast, HPMC capsules
`have a visually matt
`surface with a greater
`amount of diffuse reflection, suggesting a more
`irregular surface. SEM’s of the surface of HPMC
`and gelatin capsules are shown in Fig. 1 where
`this difference is clearly visible. During the coat-
`ing process the temperature of the capsule bed
`reaches 25–27 °C. At this temperature HPMC is
`soluble and will start to dissolve in the aqueous
`based film providing a strongly adhesive surface.
`Gelatin, on the other hand, is only slightly soluble
`at this temperature and its surface characteristics
`will remain virtually unchanged. Fig. 2 shows a
`SEM of the cross-section of a cleaved surface
`through a capsule coated with 10 mg cm− 2 Eu-
`dragit FS 30 D. The contours of the coating
`material are seen to follow the irregular surface of
`the HPMC capsule. During the cleaving process it
`was observed that the strength of the interface
`was superior to that of either the substrate or the
`
`

`

`88
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`E.T. Cole et al. /International Journal of Pharmaceutics 231 (2002) 83–95
`
`coating material. It is suggested that the high
`strength of the bond between HPMC and the film
`is a combination of the irregular surface and the
`tackiness of the partially dissolved surface.
`
`In contrast to tablets, capsules are of much
`lower density, which could result in capsules stick-
`ing together to give a non-uniform coating. Fig. 3
`shows a cross-section through a domed end of an
`
`Fig. 1. Scanning electron micrographs of the surface of HPMC and gelatin capsules.
`
`

`

`E.T. Cole et al. /International Journal of Pharmaceutics 231 (2002) 83–95
`
`89
`
`Fig. 2. Scanning electron micrograph of the cross-section of a cleaved surface through an HPMC capsule coated with 10 mg cm − 2
`Eudragit® FS 30 D.
`
`HPMC capsule coated with 10 mg cm− 2 Eudragit®
`L 30 D-55 and a longitudinal cross-section of a
`capsule coated with 6 mg cm− 2 Eudragit® L 30
`D-55. These micrographs confirm that a uniform
`coating thickness around the curved surface of the
`capsule as well as along the flat surface was
`achieved. No pores or cracks can be observed, due
`to the well controlled coating process. In addition,
`the critical area of overlap between the cap and
`body of the capsule is covered with polymer ensur-
`ing gastric integrity.
`During the coating process no significant loss of
`coating material was observed as was demonstrated
`by good agreement between the actual and theoret-
`ical weight of the coated capsules. This is confirma-
`tion of the excellent compatibility between the
`HPMC capsule and the anionic methacrylate dis-
`persions.
`
`3.2. In 6itro dissolution
`
`The dissolution profiles from the capsules coated
`with Eudragit® L 30 D-55 and Eudragit® FS 30 D
`are shown in Fig. 4. No paracetamol was released
`
`over 2 h at pH 1.2 from the capsules coated with
`6 and 8 mg cm− 2 Eudragit® L 30 D-55. At pH 6.8
`release of paracetamol was rapid, with very little
`difference between the two coating thicknesses. In
`order to ensure in vivo gastric integrity, the cap-
`sules coated with 8 mg cm− 2 Eudragit® L 30 D-55
`were selected for evaluation in the scintigraphic
`study.
`No release of paracetamol was detected at pH 1.2
`over 2 h or at pH 6.8 over the subsequent 1-h period
`for the capsules coated with Eudragit® FS 30 D. At
`pH 7.4 the capsules coated with 6, 8 and 10 mg
`cm− 2 all opened rapidly and release of paracetamol
`commenced. Incomplete release of paracetamol
`was due to the inclusion of drug by pockets of
`polymer which did not dissolve under the gentle
`conditions of the dissolution test. It was considered
`that the minimum coating to achieve a 3 h in vitro
`lag time (2 h at 1.2 and 1 h at 6.8) would be suitable
`to achieve in vivo capsule opening either in the
`terminal
`ileum or colon; therefore, the capsule
`formulation coated with 6 mg cm− 2 of Eudragit®
`FS 30 D was selected for in vivo evaluation.
`
`

`

`90
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`E.T. Cole et al. /International Journal of Pharmaceutics 231 (2002) 83–95
`
`Tablets coated with a monolayer of enteric
`polymer will show small amounts of drug release,
`usually around 1–2% per h, when tested at a pH
`
`below that of the solubility of the polymer due to
`diffusion through the film. At these pH values no
`release of paracetamol was detected from either
`
`Fig. 3. Optical micrographs of HPMC capsules coated with Eudragit® L 30 D-55. (Top) Cross-section of domed end of capsule
`coated with 10 mg cm − 2 Eudragit® L30 D-55. (Bottom) Longitudinal cross-section through a capsule coated with 6 mg cm − 2
`Eudragit® L30 D-55.
`
`

`

`E.T. Cole et al. /International Journal of Pharmaceutics 231 (2002) 83–95
`
`91
`
`Fig. 4. Dissolution of paracetamol from HPMC capsules coated with Eudragit® L 30 D-55 and Eudragit® FS 30 D. N=3.
`
`capsule system demonstrating that the HPMC
`capsule provides a system of low permeability and
`a good barrier to drug diffusion at the pH, where
`protection is required.
`As can be seen from Fig. 4 variation in coating
`levels had little influence on the dissolution profi-
`les of paracetamol confirming the robustness of
`the formulation and the good compatibility be-
`tween HPMC and the polymethacrylate films.
`
`3.3. Human product 6isualisation
`
`Time-lapse photography of intestinal perfor-
`mance was assessed by obtaining scintigraphic
`images at frequent intervals for approximately 12
`h post-dose. Analysis of the images provided de-
`tailed information on the GI transit and in vivo
`disintegration of the Eudragit® L 30 D-55 (Table
`3) and Eudragit® FS 30 D (Table 4) coated
`capsules.
`The major factor influencing the gastric emp-
`tying of oral dosage forms is whether they are
`
`administered with or without food. In the fasted
`state, stomach residence time is predominantly
`controlled by the frequency of
`the phase III
`housekeeper wave, which occurs approximately
`every 2 h. Therefore, not surprisingly, gastric
`emptying of the capsules occurred within this time
`interval for the majority of subjects.
`Both capsule types remained intact in the stom-
`ach which confirmed the gastro-resistant proper-
`ties of the Eudragit® L 30 D-55 and Eudragit® FS
`30 D polymers. In addition, the interaction of the
`polymer and underlying capsule substrate was
`strong in vivo, providing excellent evidence of
`enteric protection for the coated units.
`Following gastric emptying, the site and time of
`disintegration were strongly correlated with the
`choice of Eudragit® polymer. For the HPMC
`units coated with Eudragit® L 30 D-55, complete
`disintegration occurred in the small bowel (Fig. 5)
`in all but one subject confirming that once gastric
`emptying has occurred, the capsule disintegrates
`relatively rapidly within the small intestine.
`
`

`

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`E.T. Cole et al. /International Journal of Pharmaceutics 231 (2002) 83–95
`
`In contrast, the HPMC capsules coated with
`the relatively new polymer, Eudragit® FS 30 D,
`were more resistant to in vivo dissolution with
`complete disintegration occurring lower down
`the GI tract in the mid to distal small intestine
`and proximal colon (Fig. 6). Enteric coatings
`that dissolve at relatively high pH values have
`been used previously to target drug delivery to
`the colon (Watts and Illum, 1997).
`A number of researchers have concluded that
`a change in luminal pH cannot be used reliably
`
`and routinely as a mechanism to deliver drugs
`specifically to the colon (Ashford and Fell,
`1994). However,
`the data from this
`study
`demonstrate that in seven of the eight subjects
`dosed with the FS 30 D coated units, initial and
`complete
`capsule disintegration occurred be-
`tween the mid to distal small intestine and prox-
`imal colon suggesting that the subject’s intestinal
`pH was sufficient to dissolve the coating on this
`formulation and thereby provide for distal intes-
`tinal targeting.
`
`Table 3
`Transit and disintegration of the Eudragit® L 30 D-55 coated HPMC capsules (h)
`
`Subject
`
`Gastric emptying
`
`Colon arrival
`
`Initial disintegration
`
`Complete disintegration
`
`1
`2
`3
`4
`5
`6
`7
`8
`Mean
`S.D.
`n
`
`2.0
`0.2
`0.4
`0.9
`0.8
`0.1
`0.4
`1.5
`0.8
`0.7
`8
`
`–
`–
`–
`–
`2.6
`–
`–
`–
`–
`–
`–
`
`Time
`
`2.8
`1.4
`1.5
`1.3
`1.9
`2.5
`1.3
`2.0
`1.8
`0.6
`8
`
`Site
`
`PSB
`MSB
`MSB
`PSB
`DSB
`PSB
`PSB
`DSB
`
`Time
`
`3.2
`1.9
`1.9
`1.3
`3.2
`3.6
`1.6
`2.5
`2.4
`0.9
`8
`
`Site
`
`MSB
`MSB
`MSB
`PSB
`AC
`DSB
`MSB
`DSB
`
`PSB, proximal small bowel; MSB, mid small bowel; DSB, distal small bowel; AC, ascending colon.
`
`Table 4
`Transit and disintegration of the Eudragit® FS 30 D coated HPMC capsules (h)
`
`Subject
`
`Gastric emptying
`
`Colon arrival
`
`Initial disintegration
`
`Complete disintegration
`
`1
`2
`3
`4
`5
`6
`7
`8
`Mean
`S.D.
`n
`
`2.5
`0.5
`2.3
`0.6
`0.7
`0.3
`2.5
`2.9
`1.5
`1.1
`8
`
`–
`–
`4.0
`4.1
`2.6
`2.8
`-
`4.0
`3.5
`0.8
`5
`
`Time
`
`Site
`
`Time
`
`2.7
`3.6
`3.5
`3.8
`3.0
`3.7
`4.3
`9.0
`4.2
`2.0
`8
`
`PSB
`MSB
`DSB
`DSB
`AC
`AC
`MSB/DSB
`AC
`
`5.0
`5.6
`10.0
`7.0
`6.5
`4.7
`6.0
`10.0
`6.9
`2.1
`8
`
`Site
`
`MSB
`DSB
`AC
`AC
`AC
`HF
`DSB
`AC
`
`PSB, proximal small bowel; MSB, mid small bowel; DSB, distal small bowel; AC, ascending colon; HF, hepatic flexure.
`
`

`

`E.T. Cole et al. /International Journal of Pharmaceutics 231 (2002) 83–95
`
`93
`
`Fig. 5. Time lapse drug delivery from the Eudragit® L 30 D-55 HPMC capsules in subject 7.
`
`4. Conclusion
`
`The investigations described demonstrate that
`the enteric coating of HPMC capsules is an indus-
`trially viable process. The matt surface of the
`capsule provides a good substrate for adhesion of
`the coating material, which results in an all round
`
`uniform film, providing gastric integrity. Scinti-
`graphic techniques demonstrated that in the case of
`Eudragit® L 30 D-55, disintegration of the capsule
`was relatively rapid within the small intestine. The
`capsules coated with Eudragit® FS 30 D, however,
`disintegrated lower down the GI tract towards the
`distal small intestine and proximal colon.
`
`

`

`94
`
`E.T. Cole et al. /International Journal of Pharmaceutics 231 (2002) 83–95
`
`Enteric coated HPMC capsules can thus be
`considered to provide a good container for drugs
`during the early development phase providing the
`possibility of drug release either in the small intes-
`tine or towards the colon.
`
`Acknowledgements
`
`The authors gratefully acknowledge contribu-
`tions from Dr Rod Smith and Jim Scott at P.A.
`Consulting Group, Melbourn, Herts, UK,
`for
`
`Fig. 6. Time lapse drug delivery from the Eudragit® FS 30 D HPMC capsules in subject 7.
`
`

`

`E.T. Cole et al. /International Journal of Pharmaceutics 231 (2002) 83–95
`
`95
`
`providing the SEM’s and OM’s and for helpful
`discussions in interpreting the pictures, Dr Nico-
`las Madit, Dr Xionwei He and Elizabeth
`Groshens from Capsugel R&D Laboratories, Col-
`mar, France, for support in testing of HPMC
`capsules and finally, Wolfgang Weisbrod of
`Roehm for his valuable contribution to the coat-
`ing formulation concept.
`
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