Note: Descriptions are shown in the official language in which they were submitted.
CA 02263703 1999-02-26
A PROCESS FOR PRODUCING
ENTERIC COATED PANCREATIN GRANULES
FIEND OF THE INVENTION
The present invention relates to a process for producing enteric-coated
pancreatin
granules which are stable at acidic pHs and for their tabletting.
BACKGROUND OF THE INVENTION
Pancreatin is a digestive enzyme isolated from the pancreases of mammals, such
as cows and pigs, having amylase, protease and lipase activities. It is known
that
pancreatin can treat cystic fibrosis, pancreatitis, pancreoprivic syndrome and
similar
conditions. The pancreatic enzymes, produced from the pancreas, are released
into the
duodenum, the pH of which is close to neutral or slightly alkaline. Under
these pH
conditions, the released pancreatic enzymes are active and digestion of the
food by the
enzymes proceeds normally in the upper segment of the small intestine.
However, when
pancreatin is administered exogenously to the patient in need of the treatment
for
pancreatin malfunction, the gastric conditions in the stomach, namely the
presence of
acid and pepsin, will irreversibly render the enzymes inactive. Under the
acidic
conditions the enzymes exhibit 10% to 40% of their normal activity. The acidic
pH
especially influences lipase activity. Therefore, orally administered enzymes
must be
protected against inactivation due to gastric acid so that they remain intact
during their
transit through the stomach into the duodenum.
The best way to protect the enzymes is through application of an enteric
coating.
Two techniques can be used to apply an enteric coating. The first technique,
which is
well known, involves mixing the pancreatin with an appropriate adjuvant,
tabletting the
resulting mixture, and applying an enteric coating to the tablets thus
obtained. The
pancreatin is often used in combination with other digestive enzymes, rather
than as a
single ingredient. As such, even those among the additional digestive enzymes
working
in the stomach may be coated and thereby they do not exhibit their benefits
sufficiently
in the stomach. The other technique is disclosed in U.S. Pat. Nos. 5,260,074
and
5,302,400. It consists of blending pancreatin with the appropriate adjuvant,
binder, and
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organic solvent, granulating the blend, compacting the granulates into
spherical particles,
drying the spherical particles, and applying an enteric coating to the dried
particles.
Specifically, the pancreatin is mixed with the appropriate binder, stabilizer,
disintegrant,
and organic solvents disclosed in U. S. Pat. No. 4,079,125, followed by
granulation of the
resulting mixture. The granules thus obtained are molded into beads by
Marumerizer
compaction and the resulting beads are coated. Alternatively, the pancreatin
powder is
mixed with a lubricant, and the resulting mixture is compacted into spherical
plates using
roller compaction, concave compaction or convex compaction. The plates thus
obtained
are ground, sieved, and coated without organic solvents. This technique is not
advantageous as the activity of the enzyme is decreased by the solvent used
during
granulation and by the heat generated during compaction. The technique is also
inefficient because it includes many steps. When the enteric coated granules
are tableted,
they must be stable against tabletting pressure and must be minute. As such,
because the
tableting pressure dissipates, the enteric coated granules can be molded
without
becoming brittle. However, the prior techniques cannot produce minute and
uniform
granules, and consequently do not result in enteric coated granules stable
under acidic
conditions and for tabletting.
Therefore, although pancreatin is advantageous when it is used as a complex
preparation, i.e., tablet wherein gastric enteric compartments are formed by
naked
tabletting or gastric coating, there is still a need to develop enteric coated
granules stable
against tabletting pressure when used singly. We have achieved an improved
enteric
coating technique ensuring intact activity of the pancreatin in the gastric
environment,
rapid dissolution of the enteric coated granule in the intestine and stability
of the coated
granule against tabletting pressure.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for producing enteric
coated pancreatin granules which comprises spraying the pancreatin powder with
a
coating solution at a high speed while floating the pancreatin powder at low
temperature
to obtain fine coated pancreatin granules, if necessary, again spraying the
resulting fine
granules with another coating solution, identical to or different from the
first coating
solution, at a high speed while floating the fine granules at low temperature
to produce
the coated pancreatin granules.
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In another aspect, the present invention provides a process for producing
pancreatin tablets that comprises spraying the pancreatin powder with a
coating solution
at a high speed while floating the pancreatin powder at low temperature to
obtain fine
coated pancreatin granules, if necessary, again spraying the resulting fine
granules with
another coating solution, identical to or different from the first coating
solution, at a high
speed to produce the coated pancreatin granules, mixing, based on the total
weight of the
tablets, from 5% to 80% of the resulting coated granules with a
pharmaceutically
acceptable adjuvant, and tabletting the resulting mixture.
DETAILED DESCRIPTION OF THE INVENTION
The coating base for this invention includes corn protein extract, sodium
alginate,
alginic acid, methacrylic acid-ethyl methacrylate copolymer, shellac, carbopol
(carbomer~, carboxyvinyl-polymer), hydroxypropylmethylcellulosephthalate,
hydroxy-
propylmethylcellulose acetate succinate, hydroxypropylmethyl acetate
succinate,
carboxymethylcellulose, cellulose acetate phthalate, hydroxypropylcellulose,
ethyl-
cellulose, methylcellulose, polyvinyl acetate phthalate, soybean protein,
wheat protein,
chitin, chitinic acid, agar, carrageenan, pectin, guar gum, locust bean gum,
xanthan gum,
gellan gum, arabic gum, and medium chain fatty acid of 6 to 12 carbons. These
can be
used singly or as a mixture of two or more. The coating base can be used in
amounts of
from 1 % to 250% based on the total weight of the pancreatin used, preferably
from 50%
to 180% by weight.
The plasticizer used for the coating of the present invention includes
polyethylene
glycol, glycerin fatty acid ester, sorbitan fatty acid ester, propylene
glycol, glycerin,
triethyl citrate, triacetin, cetyl alcohol, and stearyl alcohol. These can be
used as singly
or as a mixture of two or more. The plasticizer can be used in amounts of from
1 % to
50% based on the total weight of the pancreatin used, preferably from 5% to
30% by
weight.
If the coating base and plasticizer are used in ratios other than those given
above,
disintegration of the coated granule is delayed or the coating becomes
unstable in the
gastric fluid. Consequently, the pancreatin either does not act rapidly or its
activity
decreases.
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The solvent for the coating solution of the present invention includes water,
alcohol, acetone, acetonitrile,methylene chloride, ether, hexane,
chloroform,1,4-dioxane,
tetrahydrofuran, dimethyl sulfoxide, ethyl acetate, methyl acetate, or a
mixture thereof.
Many fluid beds or similar devices can be used for coating. The fluid bed SFC-
MINI (Freund Co., Japan) was used for this invention. The temperature of
influx air
ranges from 35°C to 70°C. The temperature of the granules must
be at least 25°C during
the whole procedure in order to prevent aggregation and crumbling of the
granules. It is
preferable to adjust the temperature of the granules within a range of 25
°C to 60°C during
the procedure because the enzyme titer can reduce at temperatures in excess of
60°C.
The following examples illustrate the composition and process forthe
preparation
of enteric coated pancreatin granules in accordance with the present
invention, without
limiting the scope thereof.
EXAMPLES
Example 1
The First Coating
Seed Pancreatin powder 300 g
Coating Solution HPMC 2208 15 g
Water I 300 ml
Polyethyleneglycol 6000 ~ 2 g
The Second Coatine
Seed The first fine coated granule 300 g
Coating Solution ~ Eudragit~ L 30D ( 1,320 ml
(water dispersive) (400 g as solid powder)
Water ~ 500 ml
I I Propyleneglycol I 40 g
(A) Preparation of the first fine coated granules
While the pancreatin powder was floated in the fluid bed (SFC-MINI), it was
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sprayed with the above first coating solution. The product in the fluid bed
was adjusted
to a temperature of from 25°C to 60°C.
(B) Preparation of the second coated granules
While the first fine coated granules were floated in the fluid bed, they were
sprayed with the above second coating solution comprising Euragit~ L 30D and a
plasticizer. The granules in the fluid bed did not depart from a temperature
range of 25 °C
to 60°C. As the second coating base, Kollicoat MAE 30 DP can be used
instead.
Example 2
The First Coating
Seed Pancreatin powder 300 g
Coating Solution Sodium alginate 3 g
Water 300 ml
Glycerin 3 g
The Second Coating
Seed The first fine coated granule 300 g
Coating Solution Zein-DP~ (corn protein extract) 150 g
Shellac 30 g
80% ethanol 1,200 ml
Propylene glycol 6 g
Glycerin 12 g
The first and second coated granules were prepared in the same manner as
described in Example 1, but using the above ingredients.
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Example 3
The First Coating
Seed Pancreatin powder 300 g
Coating Solution HPMC 2910 10 g
Water 200 ml
Glycerin 2 g
The Second Coating
Seed The first fine coated granule 300 g
Coating Solution HPMCP 400 g
80% ethanol 4,000 ml
Glycerin fatty acid ester 30 g
The first and second coated granules were prepared in the same manner as
described in Example 1, but using the above ingredients. HPC can be used
instead as the
first coating base.
Example 4
The First Coating
Seed Pancreatin powder 300 g
Coating Solution HPC 10 g
Water 200 ml
Glycerin 4 g
The Second Coating
Seed The first fine coated granule 300 g
Coating Solution Polyvinylacetatephthalate 450 g
Water 4,000 ml
Propylene glycol 10 g
The first and second coated granules were prepared in the same manner as
described in Example 1, but using the above ingredients.
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Example 5
Seed Pancreatin powder 300 g
Coating Solution HPMCP 400 g
80% ethanol 4,000 ml
Glycerine fatty acid ester 30 g
The pancreatin was mono-layer coated in the same manner as described in
Example 1, but using the above ingredients.
Example 6
Seed Pancreatin powder 300 g
Coating Solution Eudragit~ L 30D 1,485 ml
(450 g as solid powder)
Water 300 ml
Triethyl citrate 30 g
The pancreatin was mono-layer coated in the same manner as described in
Example 1, but using the above ingredients. If desired, Kollicoat 30 DP can be
used
instead of the above coating base. The preparation of the mono-layer coated
granule by
increasing the spray rate can prevent reduction of the enzyme titer by the
coating
solution.
Experimental Example 1
The particle size distribution of the coated granules prepared by Examples 1
through 8 was determined. The results are indicated in Table 1 below.
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Table 1. The Particle Size Distribution (%) of the Coated Pancreatin Granule
Mesh Size
(mm)
20 (0.84) 30 (0.59) 40 (0.42) 50 (0.297)
Example 1 7.4 50.5 38.6 3.5
Example 2 9.5 47.6 34.4 8.5
Example 3 9.3 45.8 37.3 7.6
Example 4 11.7 44.1 40.0 4.2
Example 5 4.8 52.2 38.6 4.4
Example 6 9.0 54.7 30.5 5.8
It can be seen from Table 1 that particles of 30 to 40 meshes account for at
least
80% of the coated granules. The results indicate that the coated granules
prepared by the
present invention are uniform.
Experimental Example 2
The coated pancreatin granules prepared by the above Examples 1 to 6 were
measured on the activities of lipase, amylase and protease by the pancreatin
assay
described in the European Pharmacopoeia. The activities were compared to those
of the
raw pancreatin as control. The results are indicated in Table 2 below.
Table 2
The amount Enzyme activity
of (U/mg)
pancreatin
in
the coated Lipase Amylase Protease
granule(%)
Raw material 73.1 80.5 6.1
Example 38.4 28.3 31.5 2.4
1
Example 59.1 43.3 47.0 3.6
2
Example 39.5 28.9 32.0 2.4
3
Example 37.7 27.4 30.9 2.3
4
Example 41.1 30.3 33.8 2.6
5
Example 38.5 28.2 31.3 2.3
6
_g_
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It can be seen from Table 2 that the enzyme titer of the coated pancreatin
prepared
by the above Examples 1 to 6 is almost consistent with that of the raw
pancreatin as
control in which the coating base and plasticizer were excluded. The results
indicate that
the enzyme titer of the pancreatin does not decrease during coating.
Experimental Example 3
From the coated granules prepared by Examples 1 to 6, two were selected
depending on mesh size and compressed to obtain tablets. The dissolution test
on the
obtained tablets was carried out to determine the effect of the tableting
pressure on
various mesh size coated granules. Microcrystalline cellulose was used as an
adjuvant
and the amount of the coated granules was 50% by weight of the tablet. Each
800 ml of
artificially prepared gastric fluids of pH 2.0 and pH 3.0 was stirred at 100
rpm in
Dissolution Test Instrument 1 for 60 minutes. This was transferred to
artificially prepared
enteric fluid (phosphate buffer, pH 6.0) and was stirred at 100 rpm in
Dissolution Test
Instrument 2 for 30 minutes. The specimens taken in the proper quantity was
tested on
lipase activity. The results are indicated in Table below 3.
Table 3
Artificially Artificially
produced produced
gastric gastric
fluid fluid
of pH of pH
2.0 3.0
Lipase ToleranceLipase Tolerance
activity (%) activity (%)
(U/mg) (U/mg)
20-30 mesh23.8 84.1 26.1 92.2
E
l
1
xamp
e
30-40 mesh24.7 87.3 27.4 96.8
20-30 mesh15.0 34.6 18.5 42.7
E
l
2
xamp
e
30-40 mesh18.0 41.6 19.1 44.1
20-30 mesh24.1 83.4 26.5 91.7
E
l
3
xamp
e
30-40 mesh25.0 86.5 27.5 95.2
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20-30 mesh23.2 84.7 24.5 89.4
E
l
4
xamp 30-40 mesh24.5 89.4 26.2 95.6
e
20-30 mesh24.9 82.2 27.2 89.8
E
l
5 xamp 30-40 mesh26.5 87.5 28.7 94.7
e
20-30 mesh22.8 80.9 25.1 89.0
E
l
6
xamp 30-40 mesh24.8 87.9 26.8 95.0
e
The results of Table 3 indicate that the enteric coated pancreatin granule
sufficiently serves as a protective barrier under acidic conditions depending
on the mesh
size of the granule.
The coating layer of the enteric coated pancreatin granule of the present
invention
was not broken by the tableting pressure. The acid tolerance test revealed
that the larger
the coated granule, the more the enzyme titer is reduced. This means that as
the smaller
coated granule is more able to dissipate or adsorb the tableting pressure, its
coating layer
is not broken.
Experimental Example 4
The coated pancreatin granules were compressed using the microcrystalline
cellulose as an adjuvant. The dissolution test on the resulting tablet was
carried out to
decide the effect of the adjuvant on the tablet. The coated pancreatin
granules of 30 to 40
mesh were used in amounts of 25%, 50%, 75% and 90% by weight based on the
tablet.
The absolute amounts of the coated pancreatin granules in the tablets were
same. The
results are indicated in Table 4 below.
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Table 4
Artificiallyproduced Artificiallyproduced
gastric d of pH gastric of pH 3.0
flui 2.0 fluid
The amount Lipase ToleranceLipase Tolerance
of the coatedactivity (%) activity (%)
pancreatin (U/mg) (U/mg)
granule
(%)
25 26.1 92.2 27.9 98.6
50 24.7 87.3 27.4 96.8
l
1
Examp 75 21.2 74.9 24.4 86.2
e
90 18.3 64.7 21.0 74.2
25 20.4 47.1 21.3 49.2
50 18.0 41.6 19.1 44.1
l
2
Examp 75 14.2 32.8 16.7 38.6
e
90 10.5 24.2 13.5 31.2
25 26.8 92.7 28.2 97.6
50 25.0 86.5 27.5 95.2
l
3
Examp 75 22.7 78.5 25.1 86.9
e
90 19.4 67.1 21.0 72.7
25 26.0 94.9 27.0 98.5
50 24.5 89.4 26.2 95.6
l
4
Examp 75 21.7 79.2 23.9 87.2
e
90 19.2 70.1 20.7 75.5
25 28.6 94.4 29.3 96.7
50 26.5 87.5 28.7 94.7
l
E
5
xamp 75 23.2 76.6 26.4 87.1
e
90 20.0 66.0 23.1 76.2
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25 26.9 95.4 27.9 98.9
SO 24.8 87.9 26.8 95.0
E
l
6
xamp 75 21.5 76.2 24.0 85.1
e
90 18.7 66.3 21.2 75.2
The results of Table 4 indicate that when the adjuvant in the tablet is used
in too
small amounts, it cannot serve as a buffer against the tabletting pressure and
the coating
layer can be easily broken.
15
25
35
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