J. Biomater. Sci. Polymer Edn, Vol. 7, No. 1, pp. 39-48 (1995)
`© VSP 1995.
`
`Polymer-coated gelatin capsules as oral delivery devices
`as oral
`devices
`delivery
`Polymer-coated
`capsules
`gelatin
`and their gastrointestinal tract behaviour in humans
`in humans
`tract
`behaviour
`and
`their
`gastrointestinal
`
`RAO*
`and K. PANDURANGA
`R. NARAYANI
`R. NARAYANI and K. PANDURANGA RAO*
`Biomaterials Department, Central Leather Research Institute, Adyar, Madras 600 020, India
`Biomaterials Department, Central Leather Research Institute, Adyar, Madras 600 020, India
`Received 22 April 1994; accepted 28 June 1994
`Received 22 April 1994; accepted 28 June 1994
`Abstract-In oral delivery of protein and peptide drugs there is a great need for suitable devices for
`Abstract—In oral delivery of protein and peptide drugs there is a great need for suitable devices for
`delivering the therapeutic agent-incorporated microspheres selectively in the intestine. It is essential that
`delivering the therapeutic agent-incorporated microspheres selectively in the intestine. It is essential that
`the drug-loaded multiple unit carrier system should be protected from the harsh environment of the
`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.
`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
`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
`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
`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
`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
`radiographical studies show that while the uncoated gelatin capsules disintegrated in the stomach within
`15m in of ingestion, the alginate coated gelatin capsules remained intact as long as they were retained in
`15 min of ingestion, the alginate coated gelatin capsules remained intact as long as they were retained in
`the stomach (up to 3 h) and then migrated to the ileocecal region of the intestine and disintegrated.
`the stomach (up to 3 h) and then migrated to the ileocecal region of the intestine and disintegrated.
`Key words: Gelatin capsules; intestine; microspheres;p olymer coat; sodium alginate.
`Key words: Gelatin capsules; intestine; microspheres; polymer coat; sodium alginate.
`
`INTRODUCTION
`INTRODUCTION
`
`of drugs for oral administration
`has been employed
`to disguise
`Microencapsulation
`Microencapsulation of drugs for oral administration has been employed to disguise
`taste of drugs, eliminate gastrointestinal
`and sustain drug
`the unpleasant
`irritation,
`the unpleasant taste of drugs, eliminate gastrointestinal irritation, and sustain drug
`for oral delivery of drugs has undergone major
`release
`[1,2]. System design
`release [1, 2]. System design for oral delivery of drugs has undergone major
`to zero order
`from enteric coated single unit systems such as tablets
`metamorphosis
`metamorphosis from enteric coated single unit systems such as tablets to zero order
`multiple unit delivery systems like pellets, granules, and microspheres. Over the last
`multiple unit delivery systems like pellets, granules, and microspheres. Over the last
`failure of enteric coated single unit systems
`few years instances of the therapeutic
`few years instances of the therapeutic failure of enteric coated single unit systems
`an
`[3, 4, 5]. The microparticulate
`forms are becoming
`has been reported
`dosage
`has been reported [3, 4, 5]. The microparticulate dosage forms are becoming an
`drug release
`in the gastro-
`increasingly popular method
`for providing controlled
`increasingly popular method for providing controlled drug release in the gastro-
`(GI) tract because
`they possess certain advantages over the corresponding
`intestinal
`intestinal (GI) tract because they possess certain advantages over the corresponding
`in the GI tract and have
`They spread out more uniformly
`single unit preparations.
`single unit preparations. They spread out more uniformly in the GI tract and have
`times, minimize
`the risk of local irritation,
`upper GI transit
`relatively reproducible
`relatively reproducible upper GI transit times, minimize the risk of local irritation,
`to tablets and pellets in chronic
`and dose dumping when compared
`therapy
`[6-8].
`and dose dumping when compared to tablets and pellets in chronic therapy [6-8].
`controlled
`release properties may be
`Even though microspheres with favourable
`Even though microspheres with favourable controlled release properties may be
`on the GI
`of the released drug
`is dependent
`the extent of absorption
`developed,
`developed, the extent of absorption of the released drug is dependent on the GI
`is a con-
`time of the dosage form. It has been reported
`that gastric emptying
`transit
`transit time of the dosage form. It has been reported that gastric emptying is a con-
`in GI transit of the oral dosage forms [9]. In fasted subjects,
`factor
`trolling
`single
`trolling factor in GI transit of the oral dosage forms [9]. In fasted subjects, single
`times of
`and pellets have been reported
`to have gastric residence
`unit formulations
`unit formulations and pellets have been reported to have gastric residence times of
`in the fed state the gastric residence
`time for single unit prepar-
`about 1 h, whereas
`about 1 h, whereas in the fed state the gastric residence time for single unit prepar-
`from 10 to 12 h and in case of multiple unit dosage forms from 3 to
`ations
`increased
`ations increased from 10 to 12 h and in case of multiple unit dosage forms from 3 to
`to cecum. The
`time generally varies from 3 to 6 h from mouth
`4 h [10]. The transit
`4 h [10]. The transit time generally varies from 3 to 6 h from mouth to cecum. The
`time of drug delivery systems is usually within 1-2 h in the fasted
`gastric emptying time of drug delivery systems is usually within 1-2 h in the fasted
`gastric emptying
`
`* To whom the correspondence should be addressed.
`
`MYLAN EXHIBIT - 1007
`Mylan Pharmaceuticals, Inc. v. Bausch Health Ireland, Ltd. - IPR2022-00722
`
`

`

`40
`40
`
`R. Narayarni and K. Panduranga Rao
`
`in the fed state,
`state. However
`the rate of gastric emptying
`is dependent on the
`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
`properties of the meal and will vary with different meals. The enteric coated multiple
`unit delivery system such as microspheres may be administered
`in a gelatin
`enclosed
`unit delivery system such as microspheres may be administered enclosed in a gelatin
`the gelatin capsule will rapidly disintegrate
`in the gastric environ-
`capsule. However,
`capsule. However, the gelatin capsule will rapidly disintegrate in the gastric environ-
`ment releasing
`the numerous multiparticulate
`the active
`ment releasing the numerous multiparticulate delivery systems containing the active
`delivery systems containing
`in the stomach.
`substance
`It was recently reported
`that the gastric emptying of most
`substance in the stomach. It was recently reported that the gastric emptying of most
`of
`released
`the granules
`from a compressed matrix occurred
`3-4 h following
`of the granules released from a compressed matrix occurred 3-4 h following
`administration
`[ 11 ] . This would
`lead to widespread dispersion and slow accumula-
`administration [11]. This would lead to widespread dispersion and slow accumula-
`units in the stomach.
`tion of the multiparticulate
`tion of the multiparticulate units in the stomach.
`The exposure of multiparticulate
`systems such as microspheres
`the
`The exposure of multiparticulate systems such as microspheres containing the
`containing
`bioactive substance, especially acid and protease sensitive protein-based
`drugs to 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
`gastric environment, will result in the inactivation and proteolytic degradation of the
`the administration
`agent. Hence
`of drug-loaded
`therapeutic agent. Hence the administration of drug-loaded gelatin microspheres
`therapeutic
`gelatin microspheres
`in gelatin capsules
`is of little or no use in therapies where the drug should
`enclosed
`enclosed in gelatin capsules is of little or no use in therapies where the drug should
`transit
`to the stomach and reach the intestine
`for therapeutic
`action or absorption.
`transit to the stomach and reach the intestine for therapeutic action or absorption.
`towards
`The present study was directed
`the development
`of enteric capsules
`for
`The present study was directed towards the development of enteric capsules for
`active proteins and peptides
`dumping microspheres containing therapeutically active proteins and peptides (for
`dumping microspheres
`containing
`therapeutically
`(for
`that are well absorbed
`in the intestine but need
`insulin) or other drugs,
`example, insulin) or other drugs, that are well absorbed in the intestine but need
`example,
`selectively in the intestine. Sodium alginate which is
`protection against degradation, selectively in the intestine. Sodium alginate which is
`protection against degradation,
`a natural, biodegradable
`polysaccharide was chosen for coating the gelatin capsules.
`a natural, biodegradable polysaccharide was chosen for coating the gelatin capsules.
`The gelatin capsules coated with this pH-sensitive
`biopolymer will pass through
`The gelatin capsules coated with this pH-sensitive biopolymer will pass through
`the stomach unaffected
`in the
`by the acidity of the gastric
`juice and disintegrate
`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
`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-
`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
`coated gelatin capsules for the oral delivery has been demonstrated using human
`volunteers.
`volunteers.
`
`MATERIALSA ND METHODS
`MATERIALS AND METHODS
`Barium
`sodium alginate
`calcium
`Barium sulphate (Ranbaxy, India), sodium alginate (Riedel, Germany), calcium
`sulphate
`(Ranbaxy,
`India),
`(Riedel, Germany),
`chloride (BDH, England), and gelatin capsules ('0' size, hard) (Shibi Capsules Ltd.,
`chloride (BDH, England), and gelatin capsules (`O' size, hard) (Shibi Capsules Ltd.,
`India) were used as received. All other reagents used were of analytical grade.
`India) were used as received. All other reagents used were of analytical grade.
`
`Polymeric coating of gelatin capsules
`Polymeric
`coating of gelatin capsules
`The gelatin capsules were coated with sodium alginate and cross-linked by dropping
`The gelatin capsules were coated with sodium alginate and cross-linked by dropping
`in a solution of calcium chloride
`time 3 min). The coated capsules were
`in a solution of calcium chloride (contact time 3 min). The coated capsules were
`(contact
`quickly air dried. They were then coated and cross-linked with various concentra-
`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
`tions of sodium alginate and calcium chloride. After in vitro disintegration tests
`were performed
`on the gelatin capsules coated with various concentrations
`of the
`were performed on the gelatin capsules coated with various concentrations of the
`in humans.
`the most promising was selected for evaluation
`polymer, the most promising was selected for evaluation in humans.
`polymer,
`
`In vitro disintegration
`test of uncoated and coated gelatin capsules
`In vitro disintegration test of uncoated and coated gelatin capsules
`tests were carried out to determine
`the behaviour of sodium alginate-
`Disintegration tests were carried out to determine the behaviour of sodium alginate-
`Disintegration
`coated and -uncoated gelatin capsules in simulated gastric fluid (0.1 N HCI, pH 1.2)
`coated and -uncoated gelatin 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
`and simulated intestinal fluid (0.01 M phosphate buffer, pH 7.4) at 37°C. The
`times were evaluated as the time taken
`to rupture
`the coating. The
`disintegration
`disintegration times were evaluated as the time taken to rupture the coating. The
`behaviour of uncoated and coated gelatin capsules in simulated gastric and intestinal
`behaviour of uncoated and coated gelatin capsules in simulated gastric and intestinal
`media was also studied by taking optical photographs
`at stipulated
`time intervals.
`media was also studied by taking optical photographs at stipulated time intervals.
`
`

`

`Gelatin capsules for oral drug delivery
`
`41
`41
`
`study of uncoated and coated gelatin capsules
`In vivo radiographical
`In vivo radiographical study of uncoated and coated gelatin capsules
`The gelatin capsules were packed with about 250 mg of barium sulphate and then
`The gelatin 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
`coated with sodium alginate for in vivo tests. Uncoated gelatin capsules packed with
`the same amount of barium sulphate served as controls. The study was carried out
`the same amount of barium sulphate served as controls. The study was carried out
`(age group 30-35 years) and free from any detectable
`in healthy male volunteers
`in healthy male volunteers (age group 30-35 years) and free from any detectable
`disorders. The subjects having fasted overnight were administered
`gastrointestinal disorders. The subjects having fasted overnight were administered
`gastrointestinal
`three coated capsules along with 100 ml water. Similarly three uncoated gelatin cap-
`three coated capsules along with 100 ml water. Similarly three uncoated gelatin cap-
`subject. X-rays were taken after regular
`to another
`time
`sules were administered
`sules were administered to another subject. X-rays were taken after regular time
`in the GI tract of
`to study the behaviour of uncoated and coated capsules
`intervals
`intervals to study the behaviour of uncoated and coated capsules in the GI tract of
`the human subjects.
`the human subjects.
`
`RESULTS AND DISCUSSION
`RESULTS AND DISCUSSION
`studies
`In vitro disintegration
`In vitro disintegration studies
`For the purpose of dumping multiple unit delivery system of gelatin microspheres
`For the purpose of dumping multiple unit delivery system of gelatin microspheres
`in the intestine,
`the gelatin capsules were coated and cross-linked with
`selectively in the intestine, the gelatin capsules were coated and cross-linked with
`selectively
`of sodium alginate and calcium chloride. Even though some
`various concentrations
`various concentrations of sodium alginate and calcium chloride. Even though some
`have been carried out
`in the preparation
`of microspheres
`investigations have been carried out in the preparation of microspheres using
`investigations
`using
`this biopolymer
`has not been used as a pH-
`sodium alginate
`for drug delivery,
`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
`sensitive polymer for coating capsules for targeted drug delivery, when compared to
`[12]. In an attempt
`to use this natural bio-
`such as Eudragit
`synthetic polymers such as Eudragit [12]. In an attempt to use this natural bio-
`synthetic polymers
`compatible and biodegradable
`polymer, sodium alginate was selected for coating the
`compatible and biodegradable polymer, sodium alginate was selected for coating the
`gelatin capsules. The ultimate aim of the study was to utilize the system for loading
`gelatin capsules. The ultimate aim of the study was to utilize the system for loading
`them with drug-containing microspheres
`for colon-targeted
`them with drug-containing microspheres for colon-targeted delivery.
`delivery.
`
`In vitro disintegration
`of uncoated and coated gelatin capsules
`In vitro disintegration of uncoated and coated gelatin capsules
`Figure 1 shows the uncoated and alginate-coated
`gelatin capsules. The results of the
`Figure 1 shows the uncoated and alginate-coated gelatin capsules. The results of the
`tests of capsules coated and cross-linked with various concentrations
`disintegration tests of capsules coated and cross-linked with various concentrations
`disintegration
`of sodium alginate and calcium chloride are presented
`in Fig. 2. The data given are
`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 average of the disintegration times of six capsules evaluated at pHs 1.2 and 7.4.
`the uncoated
`show
`that
`The optical photographs
`The optical photographs show that the uncoated gelatin capsules disintegrated
`gelatin capsules disintegrated
`
`Figure 1. Optical photograph of uncoated and polymer coated gelatin capsules.
`Figure 1. Optical photograph of uncoated and polymer coated gelatin capsules.
`
`

`

`42
`42
`
`R. Narayarni and K. Panduranga Rao
`
`Concentration of calcium c Nor ido
`
`V. W1 .1/1
`
`3
`
`5
`
`7
`
`10
`
`17
`
`22
`
`24
`
`500r
`
`400 -
`
`3 00 -
`
`200 -
`
`100 -
`
`Disintegration time {min)
`
`3
`
`5
`
`10
`
`20
`
`200
`
`Content rati on
`
`} sodium alginate W/ V 1
`
`Fl
`
` pH 1-2
`
`P H 74
`
`0-20 V4W/V } double coat
`
`Figure 2. Effect of sodium alginate polymeric coating on the in vitro disintegration of gelatin capsules.
`Figure 2. Effect of sodium alginate polymeric coating on the in vitro disintegration of gelatin capsules.
`
`within 10 min in simulated gastric fluid and within 20 min in simulated
`intestinal
`within 10 min in simulated gastric fluid and within 20 min in simulated intestinal
`fluid (Figs 3 and 4). Whereas coating of gelatin capsules with alginate increased
`their
`fluid (Figs 3 and 4). Whereas coating of gelatin capsules with alginate increased their
`the data of the in vitro disintegration
`resistance
`to gastric medium,
`study indicated
`resistance to gastric medium, the data of the in vitro disintegration study indicated
`that
`the resistance of the capsules
`increased with an increasing
`to gastric medium
`that the resistance of the capsules to gastric medium increased with an increasing
`coated with 2007o alginate
`concentration
`of alginate
`(Fig. 2). Gelatin
`concentration of alginate (Fig. 2). Gelatin capsules coated with 20% alginate
`capsules
`in 0.1 N HCI for up to 8 h, and following a change
`(double coat) were intact
`to
`(double coat) were intact in 0.1 N HCl for up to 8 h, and following a change to
`0.01 M phosphate buffer, pH 7.4, the disintegration
`of the same capsule occurred
`0.01 M phosphate buffer, pH 7.4, the disintegration of the same capsule occurred
`after 15 min (Figs 5 and 6).
`after 15 min (Figs 5 and 6).
`
`in humans
`In vivo radiographical
`studies of uncoated- and coated-gelatin
`In vivo radiographical studies of uncoated- and coated-gelatin capsules in humans
`capsules
`
`in the GI tract was
`The behaviour of uncoated and polymer coated gelatin capsules
`The behaviour of uncoated and polymer coated gelatin capsules in the GI tract was
`studied by administering
`the coated capsules to human volunteers and taking X-rays
`studied by administering the coated capsules to human volunteers and taking X-rays
`time
`the behaviour
`of uncoated-
`and
`at stipulated
`intervals. Figure 7 illustrates
`at stipulated time intervals. Figure 7 illustrates the behaviour of uncoated- and
`in the human GI tract.
`coated-gelatin capsules in the human GI tract.
`coated-gelatin
`capsules
`Figure 8 a-c illustrates
`behaviour of uncoated gelatin capsules
`the gastrointestinal
`Figure 8 a-c illustrates the gastrointestinal behaviour of uncoated gelatin capsules
`in human
`in
`that all the three capsules were
`intact
`subjects. Figure 8a shows
`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
`the stomach of the subject after 5 min of ingestion. Figure 8b, c show the X-ray
`
`

`

`Gelatin capsules for oral drug delivery
`
`43
`43
`
`Figure 3. Photograph of the disintegration of uncoated gelatin capsule in simulated gastric fluid (0.1 N
`HCI, pH 1.2) after 10 min.
`
`Figure 4. Photograph of uncoated gelatin capsule in simulated intestinal fluid (0.01 M phosphate buffer,
`Figure 4. Photograph of uncoated gelatin capsule in simulated intestinal fluid (0.01 M phosphate buffer,
`pH 7.4) after 20 min.
`pH 7.4) after 20 min.
`
`w
`
`Figure 5. Photograph of alginate-coated gelatin capsule (20% w/v) in simulated gastric fluid (0.01 N
`Figure 5. Photograph of alginate-coated gelatin capsule (20% w/v) in simulated gastric fluid (0.01 N
`HCI, pH 1.2) after 8 h.
`HC1, pH 1.2) after 8 h.
`
`

`

`44
`44
`
`R. Narayarni and K. Panduranga Rao
`
`Figure 6. Photograph of alginate-coatedg elatin capsule (20% w/v) in simulated intestinal fluid (0.01 M
`Figure 6. Photograph of alginate-coated gelatin capsule (20'o w/v) in simulated intestinal fluid (0.01 M
`phosphate buffer pH 7.4) after 15 min.
`phosphate buffer pH 7.4) after 15 min.
`
`a
`
`it
`co
`
`•
`
`Figure 7. In vitro behaviour of uncoated and polymer coated gelatin capsules in the gastro intestinal
`Figure 7. In vitro behaviour of uncoated and polymer coated gelatin capsules in the gastro intestinal
`tract of the human subjects: (a) uncoated capsules holding the microspheres in the stomach 5 min after
`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 15m in of ingestion and
`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
`the microspheres are scattered in the stomach and exposed to acid and enzymes; (c) polymer coated
`gelatin capsules are intact in the stomach 1 h after ingestion; (d) polymer coated capsules are intact after
`gelatin capsules are intact in the stomach 1 h after ingestion; (d) polymer coated capsules are intact after
`2 h and pass into the intestine; (e) the disintegration of the polymer coated capsules in the ileocecal region
`2 h and pass into the intestine; (e) the disintegration of the polymer coated capsules in the ileocecal region
`after 3 h and the microspheres are scattered in the intestine; and (f) the disintegration of all capsules after
`after 3 h and the microspheres are scattered in the intestine; and (f) the disintegration of all capsules after
`4 h in the ileocecal region.
`4 h in the ileocecal region.
`
`

`

`Gelatin capsules for oral drug delivery
`
`45
`45
`
`(a)
`
`S
`
`{L1
`
`Figure 8. X-ray photograph of uncoated gelatin capsules in the GI tract of human subject after: (a)
`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 of ingestion.
`5 min; (b) 15 min; and (c) 30 min of ingestion.
`
`of the stomach after 15 and 30 min. It can be clearly observed
`that all
`photographs of the stomach after 15 and 30 min. It can be clearly observed that all
`photographs
`and dissolved within 15 min in the
`the three uncoated gelatin capsules disintegrated
`the three uncoated gelatin capsules disintegrated and dissolved within 15 min in the
`stomach.
`stomach.
`Figure 9 illustrates
`the behaviour of alginate coated gelatin capsules
`(20Vo w/v,
`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
`double coat) in the GI tract of human subjects at various time intervals. Figure 9a
`shows the coated gelatin capsules in the stomach after 15 min of ingestion. Figure 9b
`shows the coated gelatin capsules in the stomach after 15 min of ingestion. Figure 9b
`fashion
`in stomach,
`shows that the three capsules have spread out in a triangular
`shows that the three capsules have spread out in a triangular fashion in stomach,
`after 30 min, and Fig. 9c and d are the first and second hour X-ray photographs
`of
`after 30 min, and Fig. 9c and d are the first and second hour X-ray photographs of
`the GI tract. From the figures it can be seen that all the coated capsules were intact
`the GI tract. From the figures it can be seen that all the coated capsules were intact
`in the stomach even after 2 h of ingestion. The third hour X-ray photograph
`shows
`in the stomach even after 2 h of ingestion. The third hour X-ray photograph shows
`in the stomach and was intact whereas
`the
`that one of the capsules was retained
`that one of the capsules was retained in the stomach and was intact whereas the
`to the ileocecal
`other
`region of the intestine and had
`two capsules had migrated
`other two capsules had migrated to the ileocecal region of the intestine and had
`
`

`

`46
`46
`
`R. Narayarni and K. Panduranga Rao
`
`(c)
`
`(d)
`
`(e)
`
`(f
`
`Figure 9. X-ray photograph of alginate-coatedg elatin capsules (20% w/v) in the GI tract of human
`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) 1 h; (d) 2 h; (e) 3 h; and (f) 4 h of ingestion.
`subject after: (a) 15 min; (b) 30 min; (c) 1 h; (d) 2 h; (e) 3 h; and (f) 4 h of ingestion.
`
`

`

`Gelatin capsules for oral drug delivery
`
`47
`47
`
`pH Change]
`
`Gastric pH
`
`Intestinal pH
`
`.-•••••• •
`
`Alginate coot
`aratonated
`
`COOH COOH
`
`Gelatin
`capsule
`
`Alginate coat
`ionised form
`
`CO
`
`Figure 10. Schematic representation of gelatin capsules in different pH conditions of the gastro intestinal
`Figure 10. Schematic representation of gelatin capsules in different pH conditions of the gastro intestinal
`tract.
`tract.
`
`(Fig. 9e). Figure 9f shows the complete disintegration
`and disappear-
`disintegrated (Fig. 9e). Figure 9f shows the complete disintegration and disappear-
`disintegrated
`ance of the two capsules which had
`reached
`the ileocecal region and the remaining
`ance of the two capsules which had reached the ileocecal region and the remaining
`from the stomach
`single capsule had migrated
`to the intestine and its disintegration
`single capsule had migrated from the stomach to the intestine and its disintegration
`had also set in.
`had also set in.
`From the radiographical
`studies it is evident that uncoated gelatin capsules were
`From the radiographical studies it is evident that uncoated gelatin capsules were
`in the stomach
`after
`It can be observed
`digested in the stomach immediately after ingestion (15 min). It can be observed
`digested
`immediately
`ingestion
`(15 min).
`from these X-rays that gelatin capsules by themselves are unsuitable as carriers
`for
`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
`oral delivery of peptide and protein drugs to the colon. Coating the gelatin capsules
`with a natural polymer such as alginate and cross-linking with calcium chloride had
`with a natural polymer such as alginate and cross-linking with calcium chloride had
`made them resitant
`to the gastric environment. The coated capsules were intact as
`made them resitant to the gastric environment. The coated capsules were intact as
`in the stomach
`long as they were retained
`(up to 2 h), after which they passed into
`long as they were retained in the stomach (up to 2 h), after which they passed into
`the ileum of the small intestine and degraded
`in the ileocecal region of the intestine,
`the ileum of the small intestine and degraded in the ileocecal region of the intestine,
`due to the solubility of alginate at alkaline pH. The explanation
`for the above results
`due to the solubility of alginate at alkaline pH. The explanation for the above results
`can be given as follows. As shown in Fig. 10 sodium alginate will be protonated
`in
`can be given as follows. As shown in Fig. 10 sodium alginate will be protonated in
`the acid environment
`and the coating of the capsule will be intact
`in the stomach,
`the acid environment and the coating of the capsule will be intact in the stomach,
`whereas in the alkaline medium of the intestine
`the alginate will exist in the form of
`whereas in the alkaline medium of the intestine the alginate will exist in the form of
`sodium salt which is water soluble. This, in turn makes the coating of the capsule
`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
`dissolve in the intestine and expose the gelatin capsules to the intestinal fluid which
`in the rupture of the gelatin capsule holding barium sulphate
`resulted
`in the ileocecal
`resulted in the rupture of the gelatin capsule holding barium sulphate in the ileocecal
`region of the human subject.
`region of the human subject.
`The results of this study clearly suggested that alginate-coated
`gelatin capsules are
`The results of this study clearly suggested that alginate-coated gelatin capsules are
`safe candidates
`as oral delivery devices to carry microspheres
`containing bioactive
`safe candidates as oral delivery devices to carry microspheres containing bioactive
`and proteins
`and dump
`them
`in the
`intestine where
`peptides and proteins and dump them selectively in the large intestine where
`peptides
`selectively
`large
`action or drug absorption
`is desired. The polymer-coated
`therapeutic action or drug absorption is desired. The polymer-coated gelatin
`therapeutic
`gelatin
`capsules will facilitate
`the routine use of the oral route of drug delivery for protein
`capsules will facilitate the routine use of the oral route of drug delivery for protein
`and peptide drugs.
`and peptide drugs.
`
`REFERENCES
`REFERENCES
`1. A. Kondo, MicrocapsuleP rocessing and Technology, Marcel Dekker, New York (1979).
`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).
`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.).
`3. J. G. Wagner, In: Biopharmaceutics and Relevant Pharmacokinetics p. 158, J. G. Wagner (Ed.).
`Drug IntellegenceP ublications, Hamilton Press, IL (1971).
`Drug Intellegence Publications, Hamilton Press, IL (1971).
`4. D. Y. Graham, New Engl. J. Med. 296, 1314 (1977).
`4. D. Y. Graham, New Engl. J. Med. 296, 1314 (1977).
`5. M. Marvola, J. Heinamaki, E. Westermark and I. Happonen, Acta Pharm. Fenn. 95, 59 (1986).
`5. 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
`6. Y. Kawashima, H. Niwa, H. Takeuchi, T. Iwamoto and Y. Ito, Proc. Int. Symp Controlled Release
`Bioact Mater. 185-186 (1988).
`Bioact Mater. 185-186 (1988).
`
`

`

`48
`48
`
`R. Narayarni and K. Panduranga Rao
`
`7. R. Bodmier, H. Chen and O. Paeratakul, Pharm. Res. 6, 413 (1989).
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