MULTIPARTICULATE EXTENDED-RELEASE COMPOSITION OF MESALAMINE
Field of the Invention -
g The present invention relates to a multiparticulate extended-release pharmaceutical
composition of mesalamine, and a process for the preparation thereof.
Background of the Invention
Mesalamine, 5-aminosalicylic acid, belongs to the class of anti-inflammatory agents and is
used for the treatment of mild to moderate active ulcerative colitis.
Mesalamine is commercially available in various dosage forms such as ASACOLB
(Mesalamine 200mg and 400mg delayed-release tablets; Procter and Gamble, USA), ASACOL~
HD (Mesalamine 800mg delayed-release tablets; Procter and Gamble, USA), APRISO@
(Mesalamine 375mg extended-release capsules; Salix Pharms), PENTASAB (Mesalamine 400mg
extended-release capsules; Shire, USA) and LIALDAB (Mesalamine 1.2g delayed-release tablets;
Shire, USA) for oral administration. It is also commercially available for rectal administration as an
aqueous suspension or as suppositories. APRIso@ is once-daily dosage form x of mesalamine
available for maintenance of remission in adult patients with ulcerative colitis.
U.S. Patent No. 6,551,620 discloses an oral pharmaceutical pellet formulation having
controlled release profile, comprising a core and an enteric coating, wherein the active ingredient 5-
amino-salicylic acid is present in the core in a non-gel forming polymer matrix, the matrix-forming
polymer making up at least 1% by weight of core.
U.S. Publication No. 200710071 820 discloses a delayed-release pharmaceutical formulation
comprising a drug and a disruption agent and further comprising a regulatory membrane coating on
the core formed from a mixture of a water-soluble gel-forming polymer and a water-insoluble filmforming
polymer.
European Patent Application No. 629,398 discloses a controlled release pharmaceutical
preparation comprising a core containing a medicinal compound and an enteric coating over the
core, wherein the core contains a medicinal compound and an organic acid, is film coated by
aqueous coating of water-insoluble and slightly water permeable acrylic polymer having a
trimethylammonioethyl group.
Summary of the Invention
The present invention provides an alternative multiparticulate extended-release
pharmaceutical composition of mesalamine, which has a dissolution profile comparable to ~ ~ r i s o @ .
Detailed Description of the Invention
An aspect of the present invention provides a multiparticulate extended-release
pharmaceutical composition of mesalamine, comprising a) an inert core, b) an active ingredient
layer comprising mesalamine and other pharmaceutically acceptable excipients, c) an inner coating
layer comprising a water-insoluble cellulose derivative, and d) an outer coating layer comprising an
enteric polymer.
The term "mesalamine" as used herein is intended to include isomers, polymorphs, solvates
and hydrates of mesalamine.
Mesalamine may exist in any polymorphic form such as crystalline or amorphous.
The microparticulate composition is contained in a dosage form e.g. hard gelatin capsule or
a sachet, or is formed into tablets by compression. Multiparticulates can be designed to provide
extended-release, delayed-release, pulsatile or bi-phasic release, or even site-specific release of the
drugs.
The term "pharmaceutically acceptable excipients" as used herein includes diluents,
disintegrants, lubricants, glidants, anti-oxidants, plasticizers and opacifiers.
The term "inert core" as used herein includes sugar spheres (non-pareil seeds) or
microcrystalline cellulose beads (CelphereB). Size of the inert core ranges from about 500 pm to
about 850pm.
- I he dug coated core is further coated with two coating layers i.e. an inner coat and an outer
coat. The inner coating comprises a water-insoluble cellulose derivative. Examples of waterinsoluble
cellulose derivatives include ethylcellulose.
Ethylcellulose is a hydrophobic film coating agent used in pharmaceutical preparations to
modify the release of drugs. Commercially available grades of ethyl cellulose like EthocelTM
standard premium with different viscosities can be used. Ethylcellulose films may be modified to
alter their solubility, by the addition of hypromellose or a plasticizer. The concentration of
ethylcellulose may vary from 2%w/w to 5% w/w by weight of the total composition.
Hypromellose in ethyl cellulose layer modifies the characteristics of the ethyl cellulose
layer. It is also known as "Hydroxypropylmethylcellulose" or "HPMC" and is available in various
grades e.g. K4M, K15M and K35M, based on their viscosities.
The target weight gain after inner coating may vary between 5% w/w to 10% w/w by
weight of uncoated composition.
The outer coating layer comprises an enteric polymer that prevents the release of drug in
acidic condition and releases the drug in alkaline environment. Examples of enteric polymers
include cellulose acetate phthalate, hydroxypropylmethylcellulose acetate phthalate, polyvinyl
acetate phthalate, hydroxypropyl phthalate, hydroxypropylmethylcellulose phthalate (HPMC
phthalate), hydroxypropylmethylcellulose acetate succinate, methacrylic acid /methyl methacrylate
copolymers e.g. Type A (EudragitN L 100, ~ u d r a ~ iLt @12 .5), Type B (EudragitN S 100, EudragitN
S 12.5) or mixtures thereof.
According to one embodiment of this aspect, there is provided a multiparticulate extendedrelease
pharmaceutical composition of mesalamine, comprising a) an inert core, b) an active
ingredient layer comprising mesalamine and one or more pharmaceutically acceptable excipients,
c) an inner coating layer comprising ethylcellulose, and d) an outer coating layer comprising an
enteric polymer.
According to one embodiment of this aspect, the multiparticulate extended- release
pharmaceutical composition further comprises multiparticulate immediate-release composition,
wherein the multiparticulate immediate-release composition comprises a) an inert core, b) an active
ingredient layer and one or more pharmaceutically acceptable excipients, and c) an outer coating
layer comprising an enteric polymer. The ratio of multiparticulate extended-release composition to
multiparticulate immediate-release composition is from 60:40 to 90: 10.
According to another embodiment of this aspect, there is provided a process for the
preparation of a multiparticulate extended -release pharmaceutical composition of mesalamine,
comprising the steps of:
a) dissolving/dispersing mesalamine and one or more pharmaceutically acceptable excipients
in a solvent;
b) spraying the dispersion/solution obtained from step a) onto an inert core;
c) dissolving/dispersing water -insoluble cellulose derivative and one or more
pharmaceutically acceptable excipients in a solvent;
d) spraying the dispersion/solution obtained from step c) onto mesalamine core of step b);
e) preparing a dispersion~solutiono f enteric polymer along with one or more pharmaceutically
acceptable excipients;
f) spraying the dispersion of step e) onto beads of step d); and
g) lubricating the bead obtained from step f) and filling into suitable sized capsules or
compressing into tablets.
Suitable diluents are selected from the group comprising calcium carbonate, calcium
phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose,
silicified microcrystalline cellulose, cellulose powdered, magnesium oxide, dextrates, dextrins,
dextrose, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, pregelatinized starch,
sucrose, sugar compressible, sugar confectioners or mixtures thereof.
Suitable disintegrants are selected from the group comprising sodium starch glycolate,
pregelatinized starch, powdered cellulose, crospovidone, croscarmellose sodium, colloidal silicon
dioxide, microcrystalline cellulose, sodium carboxymethylcellulose, dried corn starch or mixtures
thereof.
Suitable lubricants and glidants are selected from the group comprising stearic acid,
magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, glyceryl
monostearate, glyceryl palmitostearate, hydrogenated vegetable oil, mineral oil, silicon dioxide,
sodium lauryl sulfate, talc, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax,
white beeswax or mixtures thereof.
Suitable anti-oxidants are selected from the group comprising butylated hydroxyanisole,
propyl gallate, butylated hydroxytoluene (BHT), ascorbic acid, ascorbyl palmitate, alpha-
,
tocopherol, biflavonoids or mixtures thereof.
The target weight gain after enteric coating ranges between 10% to 20% by weight of
uncoated composition.
The coating composition may further comprise pharmaceutically acceptable excipients such
as plasticizers and opacifiers. Examples of plasticizers include acetylated triacetin, triethyl citrate,
tributyl citrate, glycerol tributyrate, diacetylated monoglyceride, polyethylene glycols, propylene
glycol, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, diethyl oxalate, diethyl phthalate,
diethyl maleate, diethyl fumarate, dibutyl succinate, diethylmalonate, dioctyl phthalate, dibutyl
sebacate or mixtures thereof.
Suitable opacifiers are selected from the group comprising titanium dioxide, talc, calcium
carbonate, behenic acid, cetyl alcohol or mixtures thereof.
Suitable solvents that can be used for dispersing/dissolving coating polymer or mesalamine
are selected from the group consisting of water, ethanol, methanol, ammonium hydroxide,
isopropyl alcohol or mixtures thereof.
The following examples are representative of the invention, but are not to be construed as
limiting the scope of the claims.
EXAMPLES
Example -1
Batch -A
Manufacturing Process:
Ingredient
Drug layering
1) Non-pareil seeds were charged in Wurster fluidized bed dryer.
mglcap
2) Hydroxypropylmethylcellulose was dispersed in isopropyl alcohol to form a dispersion.
3) Mesalamine, talc and colloidal silicon dioxide were dispersed in the dispersion of step 2).
4) The dispersion obtained from step 3) was sprayed onto non-pareil seeds of step 1).
ER coat
Drug Layering
5) Hydroxypropylmethylcellulose was dissolved in water.
6) Ethylcellulose and Diacetylated monoglycerides were added to solution of step 5).
7) The solution obtained from step 6) was sprayed onto beads of mesalamine core to obtain ER
Non-pareil seeds
Mesalamine
Hydroxypropylmethylcellulose E5
Talc
Colloidal silicon dioxide
Purified water
Isopropyl alcohol
coated beads.
DR coat
8) ~ u d r a g iLt ~l 0 0 was dispersed in purified water.
220.00
375.00
20.00
5.00
3.00
q.s.
q.s.
9) The dispersion of step 8) was neutralized with ammonium hydroxide.
7
ER coat
Ethylcellulose
Diacetylated monoglycerides
Hydroxypropylmethylcellulose E5
Purified water
DR coat
~ u d r a g iLt ~ 10 0
24.05
1.06
21.50
q.s.
30.00
Triethyl citrate 15.00
Ammonium hydroxide
30.00
Total 744.1 1
I
10) Triethyl citrate and talc were added to dispersion of step 9) and stirred.
ORIGINAL
1 1) The polymeric dispersion from step 10) was sprayed onto ER coated beads of step 7).
Batch -B
Manufacturing Process:
Drug layering
1) Non-pareil seeds were charged in Glatt.
2) Hydroxypropylmethylcellulose was dispersed in isopropyl alcohol to form a dispersion.
3) Mesalamine, talc and colloidal silicon dioxide were dispersed in the dispersion of step 2).
4) The dispersion obtained from step 3) was sprayed onto non-pareil seeds of step 1).
DR coat
5) ~udra~iLt@ 100 was dispersed in purified water.
6) The dispersion of step 5) was neutralized with ammonium hydroxide.
7) Triethyl citrate and talc were added to dispersion of step 6) and stirred.
8) The polymeric dispersion from step 7) was sprayed onto beads of mesalamine core of step 4).
Beads obtained from Batch-A and Batch-B were filled into suitable sized hard gelatin capsules in
the ratio of 85 : 1 5.
Dissolution Study ORIGINAL
Table 1 shows the comparison of dissolution profiles of the formulations of examples 1 vis-a-vis
~ ~ r i s o 'T. he dissolution was performed for 2 hours in 750 ml of O.1N HC1 at 100 rpm using the
basket method followed by 1000 ml of pH 6.8 phosphate buffer at 100 rpm using the basket
method. The samples were analyzed using HPLC method as described in USP (USP 29, Page
1352). As seen from the results, there is no difference in the dissolution of the composition of
example 1 and ~ ~ r i s o @ .
Table 1. Dissolution profile at pH 6.8 phosphate buffer11000 ml/lOO rpm
Time point (hrs)
0.5
1
2
4
7
9
Example 1
30
40
5 1
8 0
89
90
AprisoB
26
4 1
60
83
96
101
ORIGIN A\-
WE CLAIM:
1. A multiparticulate extended-release pharmaceutical composition of mesalamine, comprising
a) an inert core, b) an active ingredient layer and one or more pharmaceutically acceptable
excipients, c) an inner coating layer comprising a water-insoluble cellulose derivative, and
d) an outer coating layer comprising an enteric polymer.
2. The pharmaceutical composition according to claim 1, wherein the water-insoluble cellulose
derivative is ethylcellulose.
3. The pharmaceutical composition according to claim 1, wherein the enteric polymer is
selected from the group consisting of cellulose acetate phthalate, hydroxypropyl
methylcellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl phthalate,
hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate
and methacrylic acid /methyl methacrylate copolymers or mixtures thereof.
4. The pharmaceutical composition according to claim 1, wherein the inert core is selected
from the group consisting of non-pareil seeds or microcrystalline cellulose beads.
5. The pharmaceutical composition according to claims 1, wherein the size of inert core is in
the range from about 500 pm to about 850pm.
6. The pharmaceutical composition according to claim 1, is a tablet, hard gelatin capsule or a
sachet.
7. The pharmaceutical composition according to claim 1, wherein the pharmaceutically
acceptable excipients are selected from the group consisting of diluents, disintegrants,
lubricants, glidants, plasticizers and opacifiers.
8. The pharmaceutical composition according to claim 1, wherein the pharmaceutical
composition further comprises multiparticulate immediate-release composition.
9. The pharmaceutical composition according to claim 1, wherein the rnultiparticulate
immediate-release composition comprises a) an inert core, b) an active ingredient layer and
one or more pharmaceutically acceptable excipients, and c) an outer coating layer
comprising an enteric polymer.
10. The pharmaceutical composition according to claim 9, wherein the ratio of multiparticulate
extended-release composition to multiparticulate immediate-release composition is from 60:
40 to 90: 10.
1 1. The pharmaceutical composition according to claim 10, wherein the ratio of multiparticulate
extended-release composition to multiparticulate immediate-release composition is 85: 15.
12. The pharmaceutical composition accordini to claim 1 wherein the composition is prepared
by a process comprising the steps of:
a) dissolving/dispersing mesalamine and one or more pharmaceutically acceptable
excipients in a solvent;
b) spraying the dispersion/solution obtained from step a) onto an inert core;
c) dissolving/dispersing water-insoluble cellulose derivative and one or more
pharmaceutically acceptable excipients in a solvent;
d) spraying the dispersion/solution obtained from step c) onto beads of mesalamine core of
step b);
e) preparing a dispersion/solution of enteric polymer along with one or more
pharmaceutically acceptable excipients;
f) spraying the dispersion of step e) onto beads of step d); and
g) lubricating the bead obtained from step f) and filling into suitable sized capsules or
compressing into tablets.