`
`Exhibit 1005
`
`J. N. C. Healey, Gastrointestinal Transit
`and Release of Mesalazine Tablets in
`Patients with Inflammatory Bowel Disease,
`25 SCAND J. GASTROENTEROLOGY 47 (Supp.
`127 1990) (“Healey”)
`
`

`
`Gastrointestinal Transit and Release of Mesalazine
`Tablets in Patients with Inflammatory Bowel Disease
`
`J. N. C. HEALEY
`Smith Kline & French Laboratories Ltd., Welwyn Garden City, Hertfordshire,
`England
`
`Healey JNC. Gastrointestinal transit and release of mesalazine tablets in patients
`with inflammatory bowel disease. Scand J Gastroenterol 1990, 25(suppl 172), 47-51
`Gastrointestinal transit and release of a delayed-release, enteric-coated tablet of
`mesalazine (Claversal@) were studied in 13 patients with Crohn’s disease and ulcer-
`ative colitis. The tablets disintegrated a mean of 3.2 h after leaving the stomach,
`resulting in drug dispersion in the distal small intestine or proximal colon. Tablet
`disintegration closely correlated with onset of drug absorption. Peak mean con-
`centrations of mesalazine and its main metabolite, Ac-SASA, were 0.5 pg/ml and
`1.0 pg/ml, respectively, and occurred 3 to 4 h after gastric emptying. The plasma
`levels correlated with scintigraph images of tablet disintegration. It is concluded that
`the tablets effectively deliver mesalazine to the terminal ileum and proximal colon
`in patients with inflammatory bowel disease.
`Key words: Colitis; delayed-release tablets; Crohn’s disease; inflammatory bowel
`disease; mesalazine
`John N. C. Healey, Ph. D., Smith Kline & French Laboratories Ltd. ~ Welwyn Garden
`City, Hertfordshire AL7 IEY, England
`
`The effectiveness of mesalazine in the treatment
`of
`inflammatory bowel disease is attributed
`mainly to a topical action on the intestinal
`mucosa. Because mesalazine is readily absorbed
`from
`the small intestine, metabolized, and
`excreted in the urine, a delayed-release tablet
`preparation has been developed to prevent
`release until the drug has reached the terminal
`ileum and colon. This preparation (Claversal?
`available in some countries as MesasalB) has been
`commercially available in West Germany since
`1985 and is currently awaiting regulatory approval
`in other countries.
`The tablets contain 250 mg of mesalazine and
`are coated with the enteric-coating polymer,
`methacrylic acid copolymer, type A (Eudragit L).
`This pH-sensitive polymer is resistant to gastric
`conditions but soluble above pH 6.0 in the intes-
`tine. The tablet core contains buffers and disin-
`tegrants to promote rapid, fine dispersion of
`mesalazine once the coating eventually ruptures.
`
`A relatively thick polymer coating is applied to
`the tablets to delay any release of the drug until
`they reach the terminal ileum and proximal colon.
`Studies have been undertaken to investigate
`the tablets in
`the gastrointestinal transit of
`patients with Crohn’s disease and ulcerative colitis
`and to determine the site of release of the mesa-
`lazine by gamma scintigraphy. Blood samples
`were also taken during the studies to enable drug
`plasma levels to be related to the scintigraphic
`information and to examine the extent of drug
`absorption.
`
`METHODS
`Patients
`The studies were carried out at Queen’s Medi-
`cal Centre, Nottingham, England (1). Thirteen
`patients with quiescent
`inflammatory bowel
`disease-seven with Crohn’s disease and six with
`studied (Table I). Two of
`ulcerative colitis-were
`
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`
`48
`
`J . N. C. Healey
`
`~~
`
`~~
`
`Table I. Background information on the 13 patients with inflammatory bowel disease
`Years since
`Age
`Diagnosis and
`diagnosis
`(years)
`surgical treatment
`Crohn’s disease
`3
`24
`Crohn’s disease
`21
`55
`17
`Crohn’s disease
`1.5
`Crohn’s disease
`47
`6
`69
`Crohn’s disease
`13
`Ulcerative colitis
`45
`10
`46
`8
`Ulcerative colitis
`8
`Ulcerative colitis
`63
`29
`Ulcerative colitis
`0.8
`Ulcerative colitis
`4
`50
`Crohn’s disease
`53
`14
`Right hemicolectomy
`Crohn’s disease
`Right hemicolectomy
`Ulcerative colitis
`Total colectomy
`
`Patient
`no.
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`
`12
`13
`
`Sex
`M
`M
`F
`F
`F
`M
`M
`M
`F
`F
`M
`M
`
`M
`
`54
`
`54
`
`13
`13
`
`the patients with Crohn’s disease had undergone
`right hemicolectomy and one with ulcerative col-
`itis a total colectomy.
`The study was approved by the hospital ethical
`committee, and each patient provided written
`informed consent before
`taking part. The
`administration of the radioactive substances was
`authorized by the U.K. Department of Health
`and Social Security; the effective radiation dose
`equivalent to each patient was 0.3 mSv.
`
`Procedure
`Each tablet contained 250 mg of mesalazine
`and was radiolabelled with 1 MBq of indium-
`111-labelled resin powder. The radiolabel was
`incorporated into the mesalazine granules before
`compression into tablets and subsequent coating
`with the polymer.
`One tablet was given to each patient after a
`light breakfast and was taken with 100 ml of water
`containing 3 MBq of
`technetium-99m-labelled
`diethylenetriaminepentaacetic acid to outline the
`anatomy of the stomach and intestine and to
`facilitate identification of the tablet location.
`Images of indium and technetium were obtained
`simultaneously by gamma camera but recorded
`separately by computer for subsequent analysis.
`The patients remained moderately active during
`the study and were imaged standing. Twenty or
`more pairs of isotope images were obtained over
`
`the first 12 h for each patient, and a further image
`pair was recorded at 24 h.
`The tablets were administered at 0945 h, and
`the patients were provided with a full cooked
`lunch at 1315 h and an evening meal at 1800 h.
`Venous blood samples were taken at hourly inter-
`vals for 11 h with additional specimens at 5.5,
`6.5, 7.5, and 23 h after dosing. The plasma was
`analysed for mesalazine and acetyl-5-amino-
`salicylic acid by high-performance liquid chroma-
`tography.
`
`RESULTS AND DISCUSSION
`Tablet location and the point of tablet dispersion
`were readily determined (Fig. 1). The first images
`recorded immediately after dosing showed all tab-
`lets to be in the stomach. The median time for
`gastric emptying of the tablets was 2.9 h (Table
`11), with a range of from 0.8 h to more than 11 h.
`None of the tablets dispersed in the stomach. The
`average gastric emptying time for the tablet was
`the same as that found in an earlier study of
`healthy subjects dosed after a similar meal (2). In
`that study it was also shown that emptying times
`of less than 1 h could be expected for tablets
`administered to patients with an empty stomach.
`Accurate
`tablet disintegration
`times were
`obtained for 11 of the patients, and distintegration
`was always quickly followed by dispersion of the
`
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`
`Delayed-Release Mesalazine
`
`49
`
`u 1.01
`
`Lc I
`
`2.0 b.
`
`4-5 hours
`
`50 hours
`
`... .. I ._ 27
`
`Time [hours)
`
`7.0 hours
`
`Time (hours)
`
`Time lhoursl
`
`24 hours
`I I hours
`Fig. 1 . Gastrointestinal transit of the tablet in a patient with ulcerative colitis (Patient 7). showing tablet dispersion
`in the terminal ileum, and plasma mesalazine levels (0) and Ac-5-ASA levels (0) (concentrations in pg/ml).
`(Adapted from Hardy et al. ( I ) . with permission.)
`
`tracer. On average, the tablets disintegrated 3.2 h
`after leaving the stomach, resulting in drug disper-
`sion in the distal small intestine or proximal colon,
`except in one of the surgically treated patients
`with a right hemicolectomy, in whom dispersed
`preparation was first detected in the transverse
`colon.
`The polymer used for tablet coating, Eudragit
`L. is soluble only at pH 6.0 and above. The tablets
`were therefore resistant to gastric conditions, and
`the coating would only begin to dissolve as the
`tablets entered the small intestine. The site of
`
`disintegration then mainly depends on the rate
`of intestinal transit and the amount of polymer
`coating present, a relatively thick coating having
`been defined for this application.
`Transit rates through the colon are slower than
`through the small intestine, and are slower for
`fine, dispersed particles than for large non-
`disintegrating units (3). The dispersed tablets
`were thus observed to move slowly through the
`proximal colon and tended to be retained
`throughout the full course of the study, in some
`instances even after defaecation 20 h after dosing.
`
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`

`
`50
`
`J. N. C. Healey
`
`Table 11. Transit and disintegration times of the tablets in patients with inflammatory bowel disease
`
`Patient
`no.
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`1 1
`12
`13
`Median
`
`Gastric
`emptying
`(h)
`
`Small-intestinal
`transit
`(h)
`
`Disintegration time
`(hours after leaving
`stomach)
`
`7.7
`11.0
`1.3
`2.3
`>11.0
`2.9
`2.3
`2.3
`2.3
`3.7
`4.2
`3.9
`0.8
`2.9
`
`3.3
`
`5.4
`1.2
`
`2.1
`4.5
`3.9
`6.6
`3.1
`3.1
`1.2
`
`3.9*
`
`1.8
`
`3.5
`6.0
`
`3.5
`2.5
`3.4
`3.7
`2.6
`2.3
`3.9
`2.2
`3.2
`
`Adapted from Hardy et al. (I). with permission.
`* Data from surgically treated patients 11. 12, and 13 are excluded from median.
`
`There was a close correlation between the
`detection of tablet disintegration and the onset of
`drug absorption ( r = 0.988, p < 0.001) (Fig. 2).
`The peak mean concentrations in plasma of mesa-
`lazine and its main metabolite, Ac-5-ASA, were
`(5.1 pM),
`0.5 pg/ml
`(3.3 pM) and 1.0 pg/ml
`respectively, and occurred 3 to 4 h after the tablet
`had emptied from the stomach (Fig. 3). Mesa-
`lazine is rapidly converted to the acetyl derivative,
`and plasma mesalazine subsequently decreased
`
`with a half-life of 1.7 h. The plasma con-
`centrations and clearance rates are comparable
`to those reported by Klotz et al. (4) in patients
`with inflammatory bowel disease given a similar
`enteric-coated tablet preparation.
`The patients' individual plasma mesalazine and
`Ac-5-ASA concentrations correlated with the
`scintigraphic data throughout
`the 24 h. The
`plasma concentrations of Patient 7, for example,
`are shown in Fig. 1, with the corresponding
`
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`
`O L
`0
`
`I
`I
`I
`2
`6
`4
`( h o u r s )
`Tablet dispersion time
`Fig. 2. Relationship between tablet dispersion and drug absorption (r = 0.988,
`p < 0,001). (Reprinted, with permission, from Hardy et al. (l).)
`
`I
`8
`
`I
`10
`
`

`
`Delayed-Release Mesalazine
`
`51
`
`available to exert a topical action on the intestinal
`mucosa.
`In conclusion, we have demonstrated that
`mesalazine is effectively delivered from the
`coated tablet to the terminal ileum and proximal
`colon
`in patients with
`inflammatory bowel
`disease.
`
`REFERENCES
`1 . Hardy JG, Healey JNC, Reynolds JR. Evaluation
`of an enteric-coated delayed-release 5-aminosalicylic
`acid tablet in patients with inflammatory bowel
`disease. Aliment Pharmacol Ther 1987. 1. 273-280
`2. Hardy JG, et al. Gastrointestinal transit of an enteric-
`coated delayed-release 5-aminosalicylic acid tablet.
`Aliment Pharmacol Ther 1987, 1, 209-216
`3. Hardy JG, Wilson CG, Wood E. Drug delivery to
`the proximal colon. J Pharm Pharmacol 1985, 37.
`874-877
`4. Klotz U, et al. A new slow-release form of 5-amino-
`salicylic acid for the oral treatment of inflammatory
`bowel disease. Drug Res 1985, 35, 636639
`5. Myers B, et al. Metabolism and urinary excretion
`of 5-aminosalicylic acid in healthy volunteers when
`given intravenously or released for absorption at
`different sites in the gastrointestinal tract. Gut 1987,
`28. 196200
`
`CLINICAL INTERPRETATION
`S. Hanauer
`The Claversal tablet does not release its active
`ingredient in the stomach, nor is the majority of
`it released in the small intestine. Release of the
`active ingredient is delayed until the pH rises
`above 6. Thus the drug is reliably released in the
`terminal ileum and is available throughout the
`colon. Of course, the availability of the drug will
`depend on the intestinal pH of the individual
`patient and, less so, on the transit time.
`
`1.4-
`
`-- 1.2 -
`
`E
`
`0
`
`6
`4
`2
`(hours)
`Time affer gastric emptylng
`Fig. 3. Plasma concentrations of mesalazine (0) and
`Ac-5-ASA (A) (mean 2 1 SEM). (Reprinted, with per-
`mission, from Hardy et al. (I).)
`
`8
`
`images. The observation of tablet disintegration
`at 5.0 h after dosing corresponds with the first
`the two substances in plasma,
`detection of
`although both were at concentrations below the
`level of quantification of 0.02 Fg/ml. Plasma
`mesalazine concentrations then increased to a
`maximum of 0.54 pg/ml at 6.0 h. The scintigraph
`images show that the dispersed mesalazine then
`moves mainly from the small intestine into the
`caecum and ascending colon by 7.0 h, and this
`coincides with a rapid fall in plasma mesalazine
`levels. Drug absorption was relatively slow in all
`patients once the preparation had entered the
`colon.
`Mesalazine absorption from the coated tablets
`was much lower than that found from uncoated
`tablets ( 5 ) ; this indicates that a significant part of
`the drug remains in the intestinal lumen and is
`
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