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H. P. Osterwald
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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
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
HO
HOOC
NaOOC COONa
Olsalazine
NaOOC 0
4-Aminobenzoyl- lpsalazide
0
NaOOC
NaOOC -
Sulfanilamido- Poly-5-ASA
ethylenepolymer
U n
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
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'
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
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