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Scandinavian Journal of Gastroenterology

ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20

Pharmaceutic Development: Mesalazine

H. P. Osterwald

To cite this article: H. P. Osterwald (1990) Pharmaceutic Development: Mesalazine,


Scandinavian Journal of Gastroenterology, 25:sup172, 43-46

To link to this article: http://dx.doi.org/10.3109/00365529009091909

Published online: 08 Jul 2009.

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Download by: [Deakin University Library] Date: 07 January 2016, At: 10:16
Pharmaceutic Development: Mesalazine
H. P. OSTERWALD
Smith Kline Dauelsberg GmbH, Gottingen, FRG

Osterwald HP. Pharmaceutic development: mesalazine. Scand J Gastroenterol 1990,


25(suppl 172). 43-46
Sulfasalazine is composed of mesalazine and sulfapyridine linked by an azo bond. It
has been shown that the clinical activity of sulfasalazine in the treatment of inflam-
matory bowel disease is derived from the mesalazine moiety, whereas most of the
side effects are associated with the sulfapyridine component. To avoid the side effects
associated with sulfapyridine. researchers have developed dosage forms that deliver
mesalazine to the site of inflammation. The preparations were developed by com-
bining two mesalazine molecules, by joining mesalazine with a carrier molecule
Downloaded by [Deakin University Library] at 10:16 07 January 2016

that has a low side-effect profile. and by formulating controlled and slow-release
mesalazine products. Claversal@is a controlled-release product that contains 250 mg
or 500 mg of mesalazine plus buffered adjuvants in a tablet core surrounded by a
special acrylic polymer. The polymer coating starts to dissolve at pH 6.0, and, as a
result, mesalazine is reliably released in the distal small bowel and colon. Thus this
product can be useful in the treatment of patients with ulcerative colitis and Crohn’s
disease.
Key words: Azo-bond drugs; controlled-release drugs; pharmacokinetics; mesalazine
suppositories; mesalazine tablets
Hermann P. Osierwald. Ph. D., Srniih KIine Dauelsberg GmbH, Postfach 3333. 3400
Gotiingen, FRG

Sulfasalazine is composed of sulfapyridine and it is rapidly absorbed in the proximal intestine,


mesalazine (5-aminosalicylic acid) joined by an little unprotected mesalazine administered orally
azo bond. Sulfasalazine has been used for more is likely to reach the distal small bowel and colon
than 40 years in the treatment of patients with (which are the most commonly desired target
inflammatory bowel disease, but it has only areas in patients with inflammatory bowel
recently been discovered that mesalazine is the disease) (2). To enable mesalazine to reach these
pharmacologically active moiety. It appears that sites, several oral formulations have been devel-
sulfasalazine acts as a pro-drug and sulfapyridine oped which ensure that therapeutic quantities of
as a carrier molecule to deliver mesalazine to its mesalazine are released in the terminal ileum or
proposed site of action. In addition, sulfapyridine colon. or both. These new products use two basic
seems to cause most of the observed side effects methods to facilitate drug delivery: 1) linking
of sulfasalazine. Consequently, researchers have mesalazine to itself or to a carrier moiety that has
focused on the development of mesalazine prod- a lower side-effect profile than that of sulfa-
ucts that are as effective as sulfasalazine but pyridine, and 2) developing controlled or slow-
devoid of the adverse reactions caused by sul- release preparations of mesalazine that reduce
fapyridine (1). proximal absorption. The release of mesalazine
from these various preparations depends on the
transit time, the bacterial environment (for azo-
ORAL DOSE FORMULATIONS
bond pro-drugs), and the local pH (for some
It is generally agreed that mesalazine acts locally slow-release preparations).
to produce its anti-inflammatory effect, but since Examples of new azo-bond drugs include olsa-
44 H . P. Osierwald

HO
HOOC

-@ N= N a NHSO, @ Sulfapyridine Sulfasalazine

NaOOC COONa

Olsalazine

NaOOC 0

4-Aminobenzoyl- lpsalazide

0
NaOOC

HO @N = N aId - NH CH, CH, COON^ 4-Aminobenzoyl-


p-alanine
Balsalazide
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NaOOC -
Sulfanilamido- Poly-5-ASA
ethylenepolymer
U n

Fig. I . Structural formulae of new azo-bond drugs.

lazine, a combination of two molecules of mesa- arations, two basic pharmaceutic technologies
lazine ( 2 ); ispalazide and balsalazide, which have have been used. One method is to formulate slow-
mesalazine linked to 4-aminobenzoyl glycine nad release mesalazine tablets that contain micro-
4-aminobenzoyl @-alanine, respectively (3); and granules of 5-aminosalicylic acid that are indi-
poly-5-ASA, a combination of mesalazine and a vidually coated with ethyl cellulose varying in
nonabsorbable polymer (4) (Fig. 1). It should be thickness (Pentasa@). With this formulation,
noted that azo-bond drugs have several limi- mesalazine is dispensed slowly throughout the
tations. For example, release of mesalazine from entire gut ( 2 , 5 , 6 ) .
such drugs requires enzymatic cleavage by bac- Another method is to use pH-dependent poly-
terial azo-reductase and is therefore restricted to mer coatings of specified thickness that dissolve
the large bowel. If the intestinal transit time is during transit through the gut and release
increased, the amount of active drug will be mesalazine to target areas in the intestine. The
substantially decreased and the efficacy of azo- specific location of drug release will depend on
bond drugs may be reduced in patients with more the type and thickness of the polymer coating.
active disease or severe diarrhea. Finally, exten- Examples of various acrylic polymers that can be
sive studies are required of the pharmacology used in enteric-coated tablets are shown in Fig. 2
and toxicology of the parent drug of these new (7). In selecting an appropriate coating, it must
azo-bond preparations, including the carrier be remembered that these films typically consist
molecules and their metabolites. of long-chain polymers with ionizable carboxyl
To eliminate the need for bacterial cleavage groups. In the low-pH environment of the gastric
of azo-bond mesalazine, controlled- and slow- fluid, the acid groups are not ionized and there-
release dosage forms have been developed. These fore are poorly soluble in water. As the pH
preparations do not require a carrier molecule increases distally in the gastrointestinal tract
(which might have its own pharmacologic and (Table I), the acid groups become increasingly
toxicologic properties) or rely on bacterial action ionized (as defined by the Henderson-
for the release of the active substance. Hasselbalch equation) and are more soluble (8).
With regard to controlled- or slow-release prep- One controlled-release formulation uses a
Pharmaceuric Deoelopmenr: Mesalazine 45

Polymethactylate Copolymers Table 11. In vitro dissolution of the 250-mg mesalazine


(ClaversaP) tablet

pH of
dissolution Time Percentage
media (min) released
MA= Methacrylic MMA=Methyl EA = Ethyl 1.2 120 0
Acid Methacrylate Acrylate
<5 .O 120 0
Type Molecular Ratio Solubility 6.0 60 0
EudragitL30D MA-EA 1:l pH > 5.5 90 <5
Eudragit L 100 MA-MMA 1:l pH > 6.0 6.4 30 0
Eudragit S MA-MMA 1:2 pH>7.0
60 <25
6.8 15 0
C.llulor Derlvatlv.. 30 < 10
60 >95
1
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CH20R'

Claversal@(250 mg and 500 mg) (Claversal will


be available in some countries as MesasaP) con-
tains a tablet core of mesalazine and a buffer
agent that is coated with a specific thickness of an
Solubility acrylic polymer that starts to dissolve at pH 6.0.
Type ~. ~ -~
Cellulose acetate phthalate pH > 6.0 This formulation results in a release pattern that
Hydroxypropyl methylcellulose phthalate pH > 5.0/5.5
Carboxymethyl ethylcellulose pH > 5.0/5.516.0 targets mesalazine to the distal small bowel and
Fig. 2. Polymers used for enteric coatings.
colon; thus the product can be used to treat both
ulcerative colitis and Crohn's disease. The
inclusion of a buffer in the tablet ensures a rapid
Eudragit@-Scoating that dissolves in the intestine and fine dispersion of active drug. The reliable
from pH 7.0 upwards (AsacoP). Although this disintegration and dispersion of Claversal has
particular tablet may reliably reach the colon, it is been demonstrated in vivo by Hardy et al. (10).
unlikely to deliver mesalazine to the small bowel. The in vitro dissolution behavior of Claversal is
Consequently, it should have limited efficacy in shown in Table 11.
Crohn's disease when the small bowel is involved.
In addition, in patients who have a rapid gas-
RECTAL DOSE FORMULATIONS
trointestinal transit time, this formulation may
fail to release the drug completely (6,9). To treat specifically inflammatory bowel disease

Table I . pH in gastrointestinal (GI) tract


Transit time
of tablets
>4 mm diameter
Part of the Length Diameter pH of
GI tract (cm) (cm) chyme Min. Max.

Mouth 10 Approx. 7 0 . 2 min 0.3 min


Esophagus 25 2.5 Approx. 7 2 min 20 min
Stomach 2s 15 1-3 30 min 480 min
Duodenum 25-30 5 5.54.5 6h 8h
Jejunum 300 5 6-7.4 6h 8h
Ileum 300 2.5-5 6-8 6h 8h
Colon 12G-150 5 7.0-7.5 9h 20h
Rectum 12-20 2.5 Approx. 7
46 H. P . Osterwald

localized in the distal colon or rectum and to 2. Klotz U, et al. Pharmacology and pharmacokinetics
minimize systemic drug exposure, Claversal sup- of 5-aminosalicylicacid. Dig Dis Sci 1987, 32, 46s
3. Chan RP, et al. Studies of two novel sulfasalazine
positories (250 mg, 500 mg, and 1000 mg) have analogs. Dig Dis Sci 1983,23, 609
been developed. This commercially available 4. Brown JP, et al. A polymeric drug for treatment of
dosage form has been shown to be effective in the inflammatory bowel disease. J Med Chem 1983,26,
1300
treatment of proctosigmoiditis (left-side colitis) 5. Rasmussen SW, et al. 5-ASA in a slow release
and proctitis. preparation: Bioavailability, plasma level and
Currently in development are Claversal liquid excretion in humans. Gastroenterology 1982, 83,
1062
(2g/30ml and 4g/60ml) and foam enemas. 6. Martin F, et al. Oral 5-ASA preparations in treat-
These enema formulations are packaged in con- ment of inflammatory bowel-diiease. Dig Dis Sci
1987. 32. 57s
venient, easy-to-use containers and are more 7. Osterwald HP. Properties of film-formers and their
stable than other available mesalazine enema use in aqueous systems. Pharm Res 1985, 1, 14
Downloaded by [Deakin University Library] at 10:16 07 January 2016

products. 8. Chambliss WG. The forgotten dosage form: enteric


coated tablets. Pharm Techno1 1983, 7, 124
9. Dew MJ, et al. An oral preparation to release drug
in the human colon. Br J Clin Pharmacol 1982, 14,
REFERENCES 405
10. Hardy JG, et al. Evaluation of an enteric-coated
1. Bondesen S. et al. 5-aminosalicyclic acid in the delayed-release 5-aminosalicylic acid tablet in
treatment of inflammatory bowel disease. Acta Med patients with inflammatory bowel disease. Aliment
Scand 1987. 221. 227 Pharmacol Ther 1987, 1, 273

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