J. Biomater. Sci. Polymer Edn, Vol. 7, No. 1, pp. 39-48 (1995)
`VSP 1995.
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`Polymer-coated gelatin capsules as oral delivery devices
`and their gastrointestinal tract behaviour in humans
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`R. NARAYANI and K. PANDURANGA RAO*
`Biomaterials Department, Central Leather Research Institute, Adyar, Madras 600 020, India
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`Received 22 April 1994; accepted 28 June 1994
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`Abstract—In oral delivery of protein and peptide drugs there is a great need for suitable devices for
`delivering the therapeutic agent-incorporated microspheresselectively in the intestine. It is essential that
`the drug-loaded multiple unit carrier system should be protected from the harsh environment of the
`stomach and deliver the carrier system in the large intestine where drug action or absorption is desired.
`Gelatin capsules were coated with various concentrations of sodium alginate and cross-linked with
`appropiate concentrations of calcium chloride and tested in vitro for resistance to gastric and intestinal
`medium. Gelatin capsules coated with 20% w/v of the polymer which gave the most promising result in
`vitro were evaluated in human volunteers for their in vivo gastro intestinal tract behaviour. The
`radiographical studies show that while the uncoated gelatin capsules disintegrated in the stomach within
`15 min ofingestion, the alginate coated gelatin capsules remained intact as long as they wereretained in
`the stomach (upto 3 h) and then migrated to the ileocecal region of the intestine and disintegrated.
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`Key words: Gelatin capsules; intestine; microspheres; polymer coat; sodium alginate.
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`INTRODUCTION
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`Microencapsulation of drugs for oral administration has been employedto disguise
`the unpleasant taste of drugs, eliminate gastrointestinal irritation, and sustain drug
`release [1,2]. System design for oral delivery of drugs has undergone major
`metamorphosis from enteric coated single unit systems such astablets to zero order
`multiple unit delivery systemslike pellets, granules, and microspheres. Overthelast
`few years instances of the therapeutic failure of enteric coated single unit systems
`has been reported [3, 4,5]. The microparticulate dosage forms are becoming an
`increasingly popular method for providing controlled drug release in the gastro-
`intestinal (GI) tract because they possess certain advantages over the corresponding
`single unit preparations. They spread out more uniformly in the GI tract and have
`relatively reproducible upper GI transit times, minimizetherisk of localirritation,
`and dose dumping when comparedto tablets and pellets in chronic therapy [6-8].
`Even though microspheres with favourable controlled release properties may be
`developed, the extent of absorption of the released drug is dependent on the GI
`transit time of the dosage form. It has been reported that gastric emptying is a con-
`trolling factor in GI transit of the oral dosage forms [9]. In fasted subjects, single
`unit formulations and pellets have been reported to have gastric residence times of
`about 1 h, whereas in the fed state the gastric residence time for single unit prepar-
`ations increased from 10to 12h andin case of multiple unit dosage forms from 3 to
`4h[10]. The transit time generally varies from 3 to 6h from mouth to cecum. The
`gastric emptying time of drug delivery systems is usually within 1-2h in the fasted
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`*To whomthe correspondence should be addressed.
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`40
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`R. Narayarni and K. Panduranga Rao
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`state. However in the fed state, the rate of gastric emptying is dependent on the
`properties of the meal and will vary with different meals. The enteric coated multiple
`unit delivery system such as microspheres may be administered enclosed in a gelatin
`capsule. However, the gelatin capsule will rapidly disintegrate in the gastric environ-
`ment releasing the numerous multiparticulate delivery systems containing the active
`substance in the stomach. It was recently reported that the gastric emptying of most
`of the granules released from a compressed matrix occurred 3-4h following
`administration [11]. This would lead to widespread dispersion and slow accumula-
`tion of the multiparticulate units in the stomach.
`The exposure of multiparticulate systems such as microspheres containing the
`bioactive substance, especially acid and protease sensitive protein-based drugs to the
`gastric environment, will result in the inactivation and proteolytic degradation of the
`therapeutic agent. Hence the administration of drug-loaded gelatin microspheres
`enclosed in gelatin capsulesis of little or no use in therapies where the drug should
`transit to the stomach andreach the intestine for therapeutic action or absorption.
`The present study was directed towards the developmentof enteric capsules for
`dumping microspheres containing therapeutically active proteins and peptides (for
`example, insulin) or other drugs, that are well absorbed in the intestine but need
`protection against degradation, selectively in the intestine. Sodium alginate whichis
`a natural, biodegradable polysaccharide was chosen for coating the gelatin capsules.
`The gelatin capsules coated with this pH-sensitive biopolymer will pass through
`the stomach unaffected by the acidity of the gastric juice and disintegrate in the
`intestinal fluid where it can dump the microspheres. The microspheres will then
`provide controlled release of the drug in the intestine. The viability of the polymer-
`coated gelatin capsules for the oral delivery has been demonstrated using human
`volunteers.
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`MATERIALS AND METHODS
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`Barium sulphate (Ranbaxy, India), sodium alginate (Riedel, Germany), calcium
`chloride (BDH, England), and gelatin capsules (‘0’ size, hard) (Shibi Capsules Ltd.,
`India) were used as received. All other reagents used were of analytical grade.
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`Polymeric coating of gelatin capsules
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`The gelatin capsules were coated with sodium alginate and cross-linked by dropping
`in a solution of calcium chloride (contact time 3 min). The coated capsules were
`quickly air dried. They were then coated and cross-linked with various concentra-
`tions of sodium alginate and calcium chloride. After in vitro disintegration tests
`were performed on the gelatin capsules coated with various concentrations of the
`polymer, the most promising was selected for evaluation in humans.
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`In vitro disintegration test of uncoated and coated gelatin capsules
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`Disintegration tests were carried out to determine the behaviour of sodium alginate-
`coated and -uncoatedgelatin capsules in simulated gastric fluid (0.1 N HCl, pH 1.2)
`and simulated intestinal fluid (0.01 M phosphate buffer, pH 7.4) at 37°C. The
`disintegration times were evaluated as the time taken to rupture the coating. The
`behaviour of uncoated and coated gelatin capsules in simulated gastric andintestinal
`media was also studied by taking optical photographs at stipulated time intervals.
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`Gelatin capsules for oral drug delivery
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`In vivo radiographical study of uncoated and coated gelatin capsules
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`Thegelatin capsules were packed with about 250 mg of barium sulphate and then
`coated with sodium alginate for in vivo tests. Uncoated gelatin capsules packed with
`the same amountof barium sulphate served as controls. The study wascarried out
`in healthy male volunteers (age group 30-35 years) and free from any detectable
`gastrointestinal disorders. The subjects having fasted overnight were administered
`three coated capsules along with 100 ml] water. Similarly three uncoated gelatin cap-
`sules were administered to another subject. X-rays were taken after regular time
`intervals to study the behaviour of uncoated and coated capsules in the GItract of
`the humansubjects.
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`RESULTS AND DISCUSSION
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`In vitro disintegration studies
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`For the purpose of dumping multiple unit delivery system of gelatin microspheres
`selectively in the intestine, the gelatin capsules were coated and cross-linked with
`various concentrations of sodium alginate and calcium chloride. Even though some
`investigations have been carried out
`in the preparation of microspheres using
`sodium alginate for drug delivery, this biopolymer has not been used as a pH-
`sensitive polymer for coating capsules for targeted drug delivery, when compared to
`synthetic polymers such as Eudragit [12]. In an attempt to use this natural bio-
`compatible and biodegradable polymer, sodium alginate wasselected for coating the
`gelatin capsules. The ultimate aim of the study wasto utilize the system for loading
`them with drug-containing microspheres for colon-targeted delivery.
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`In vitro disintegration of uncoated and coated gelatin capsules
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`Figure 1 shows the uncoated and alginate-coated gelatin capsules. The results of the
`disintegration tests of capsules coated and cross-linked with various concentrations
`of sodium alginate and calcium chloride are presented in Fig. 2. The data given are
`the average of the disintegration times of six capsules evaluated at pHs 1.2 and 7.4.
`The optical photographs show that the uncoated gelatin capsules disintegrated
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`Figure 1. Optical photograph of uncoated and polymercoated gelatin capsules.
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`42
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`R. Narayarni and K. Panduranga Rao
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`Contettratien of calcium chloride
`(4 Wi¥)
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`Concentration of
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`sodium alginate (A W/¥)
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`Co) pH te
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`D-ZO(% WY) double coat
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`Figure 2. Effect of sodium alginate polymeric coating on the in vitro disintegration of gelatin capsules.
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`within 10 min in simulated gastric fluid and within 20 min in simulated intestinal
`fluid (Figs 3 and 4). Whereascoating of gelatin capsules with alginate increased their
`resistance to gastric medium, the data of the in vitro disintegration study indicated
`that the resistance of the capsules to gastric medium increased with an increasing
`concentration of alginate (Fig. 2). Gelatin capsules coated with 20% alginate
`(double coat) were intact in 0.1 N HCl for up to 8h, and following a change to
`0.01 M phosphatebuffer, pH 7.4, the disintegration of the same capsule occurred
`after 15 min (Figs 5 and 6).
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`In vivo radiographical studies of uncoated- and coated-gelatin capsules in humans
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`The behaviour of uncoated and polymercoated gelatin capsules in the GI tract was
`studied by administering the coated capsules to human volunteers and taking X-rays
`at stipulated time intervals. Figure 7 illustrates the behaviour of uncoated- and
`coated-gelatin capsules in the human GItract.
`Figure 8 a-c illustrates the gastrointestinal behaviour of uncoated gelatin capsules
`in human subjects. Figure 8a shows that all
`the three capsules were intact in
`the stomach of the subject after 5 min of ingestion. Figure 8b, c show the X-ray
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`PH 7.4) after 20 min.
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`Figure 3. Photograph of the disintegration of uncoated gelatin capsule in simulated gastric fluid (0.1.V
`HCI, pH 1.2) after 10min.
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`Figure 4. Photograph of uncoated gelatin capsule in simulated intestinal fluid (0.01 M phosphatebuffer,
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`Figure 5. Photograph of alginate-coated gelatin capsule (20% w/v) in simulated gastric fluid (0.01 N
`HCl, pH 1.2) after 8h.
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`R. Narayarni and K. Panduranga Rao
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`Figure 6. Photographof alginate-coated gelatin capsule (20% w/v) in simulatedintestinal fluid (0.01 M
`phosphate buffer pH 7.4) after 15 min.
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`Figure 7. Jn vitro behaviour of uncoated and polymercoated gelatin capsules in the gastrointestinal
`tract of the human subjects: (a) uncoated capsules holding the microspheres in the stomach 5 min after
`ingestion; (b) uncoated capsules holding the microspheres disintegrated within 15 min of ingestion and
`the microspheres are scattered in the stomach and exposed to acid and enzymes; (c) polymer coated
`gelatin capsulesare intact in the stomach 1 h after ingestion; (d) polymer coated capsulesare intact after
`2h andpassinto the intestine; (e) the disintegration of the polymer coated capsulesin the ileocecal region
`after 3 h and the microspheresare scattered in the intestine; and(f) the disintegration ofall capsules after
`4h in theileocecal region.
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`(a)
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`Gelatin capsules for oral drug delivery
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`Figure 8. X-ray photograph of uncoated gelatin capsules in the GI tract of human subject after: (a)
`5 min; (b) 15 min; and (c) 30 min ofingestion.
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`photographsof the stomach after 15 and 30 min. It can be clearly observed thatall
`the three uncoated gelatin capsules disintegrated and dissolved within 15 min in the
`stomach.
`Figure 9 illustrates the behaviour of alginate coated gelatin capsules (20% w/v,
`double coat) in the GI tract of human subjects at various time intervals. Figure 9a
`showsthe coated gelatin capsules in the stomach after 15 min of ingestion. Figure 9b
`showsthat the three capsules have spread out in a triangular fashion in stomach,
`after 30 min, and Fig. 9c and d are thefirst and second hour X-ray photographs of
`the GI tract. From the figures it can be seen that all the coated capsules wereintact
`in the stomachevenafter 2 h of ingestion. The third hour X-ray photograph shows
`that one of the capsules wasretained in the stomach and was intact whereas the
`other two capsules had migrated to the ileocecal region of the intestine and had
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`R. Narayarni and K. Panduranga Rao
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`Figure 9. X-ray photograph of alginate-coated gelatin capsules (20% w/v) in the GI tract of human
`subject after: (a) 15 min; (b) 30 min; (c) 1h; (d) 2h; (e) 3h; and (f) 4h of ingestion.
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`_Gast ie. pH
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`intestinal pH
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`copsule
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`Alginate coat
`ronised form
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`Figure 10. Schematic representation of gelatin capsules in different pH conditions of the gastro intestinal
`tract.
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`disintegrated (Fig. 9e). Figure 9f shows the complete disintegration and disappear-
`ance of the two capsules which’ had reachedthe ileocecal region and the remaining
`single capsule had migrated from the stomachtotheintestine andits disintegration
`had alsosetin.
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`From the radiographical studiesit is evident that uncoated gelatin capsules were
`digested in the stomach immediately after ingestion (15 min). It can be observed
`from these X-rays that gelatin capsules by themselves are unsuitable as carriers for
`oral delivery of peptide and protein drugs to the colon. Coating the gelatin capsules
`with a natural polymersuch as alginate and cross-linking with calcium chloride had
`madethem resitant to the gastric environment. The coated capsules were intact as
`long as they wereretained in the stomach (up to 2h), after which they passed into
`the ileum of the small intestine and degradedin the ileocecal region of the intestine,
`dueto the solubility of alginate at alkaline pH. The explanation for the aboveresults
`can be given as follows. As shownin Fig. 10 sodium alginate will be protonated in
`the acid environmentand the coating of the capsule will be intact in the stomach,
`whereasin the alkaline medium ofthe intestine the alginate will exist in the form of
`sodium salt which is water soluble. This, in turn makes the coating of the capsule
`dissolve in the intestine and expose the gelatin capsules to the intestinal fluid which
`resulted in the rupture of the gelatin capsule holding barium sulphatein the ileocecal
`region of the human subject.
`Theresults of this study clearly suggested that alginate-coated gelatin capsules are
`safe candidates as oral delivery devices to carry microspheres containing bioactive
`peptides and proteins and dump them selectively in the large intestine where
`therapeutic action or drug absorption is desired. The polymer-coated gelatin
`capsules will facilitate the routine use of the oral route of drug delivery for protein
`and peptide drugs.
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`REFERENCES
`
`1. A. Kondo, Microcapsule Processing and Technology, Marcel Dekker, New York (1979).
`2. P. B. Deasy, Microencapsulation and related Drug Process. Marcel Dekker, New York (1984).
`3. J. G. Wagner, In: Biopharmaceutics and Relevant Pharmacokinetics p. 158, J. G. Wagner (Ed.).
`Drug Intellegence Publications, Hamilton Press, IL (1971).
`4. D. Y. Graham, New Engl. J. Med. 296, 1314 (1977).
`a
`. M. Marvola, J. Heinamaki, E. Westermark and I. Happonen, Acta Pharm. Fenn. 95, 59 (1986).
`6. Y. Kawashima, H. Niwa, H. Takeuchi, T. Iwamoto and Y. Ito, Proc. Int. Symp Controlled Release
`Bioact Mater. 185-186 (1988).
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`con
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`. R. Bodmier, H. Chen and O.Paeratakul, Pharm. Res. 6, 413 (1989).
`. Y. Kawashima, T. Niwa, H. Takeuchi, T. Hino and Y. Ito, J. Contr. Rel. 16, 279 (1991).
`. S. S. Davis, J. G. Hardy and J. W. Fara, Gut 27, 886 (1986).
`. J. D. Smart and I. W. Kellaway, Jnt. J. Pharm. 53, 79 (1989).
`11.
`J. Heinamaki, Acta Pharm. Fenn. 100, 27 (1991).
`12.
`L. C. Murray and I. G. Tucker, Aust. J. Hosp. Pharm. 20, 235 (1990).
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