Note: Descriptions are shown in the official language in which they were submitted.
~ ~549~
This invention relates to enteric coated
acetylsalicylic acid granules. More particularly it
concerns enteric coated acetylsalicylic acid granules of
improved stability.
Acetylsalicylic acid in granular form, and
especially contained in capsules is currently a very
popular dosage form for the administration of this drug.
However, acetylsalicylic acid in this form as in other
forms have presented problems with respect to gastric
tolerance and as a consequence efforts have been made to
overcome this by providing the granules with an enteric
coating. As is well-known in this art enteric coated
acetylsalicylic acid is generally not released in the
stomach but rather is released when it passes into the
intestine thus substantially avoiding the problem of
gastric intolerance in the stomach.
In preparing enteric coated acetylsalicylic acid
granules an unexpected problem was encountered. It was
found that the stability of the acetylsalicylic acid
granules when enteric coated was less than the uncoated
granules. This was unanticipated since it was thought
that the enteric coating of the aspiring granules might
add a greater measure of stability to the granules.
It has now been discovered that the stability of
~5 enteric coated acetylsalicylic acid granules can be
improved by the presence of glutamic acid hydrochloride.
In the preferred form of this invention the enteric
coated acetylsalicylic acid granules are dry blended
with the glutamic acid hydrochloride: this product then
being preferably filled into capsules such as gelatin
capsules.
Various aspects of this invention are as follows:
An article of manufacture enteric coated
A
~ ~8S4~
acetylsalicylic acid granules commingled with a
stabilizing quantity of glutamic acid hydrochloride.
A unit dosage form comprising a gelatin capsule in
which is disposed a dry blended mixture of enteric
coated acetylsalicylic acid and glutamic acid
hydrochloride, said acetylsalicylic acid being present
in said dosage form at a level of from 250 milligrams to
about 650 milligrams per capsule and said glutamic acid
hydrochloride is present in said dosage form at a level
lo of from about 5 milligrams to about 50 milligrams per
capsule.
A unit dosage form comprising a gelatin capsule in
which is disposed a dry blended mixture of enteric
coated acetylsalicylic acid and glutamic acid
hydrochloride, said acetylsalicylic acid being present
in said dosage form at a level of from 325 milligrams to
about 500 milligrams per capsule and said glutamic acid
hydrochloride is present in said dosage form at a level
of from about 10 milligrams to about 30 milligrams per
capsule.
The U.S. patent 4044125 is concerned with the
increase in the hydrolysis of acetylsalicylic acid in a
product which is prepared by commingling d-propoxyphene
hydrochloride with acetylsalicylic acid. The former,
according to the patentee, is a pharmaceutically active
ingredient used in the treatment of pain associated with
trauma. When commingled with acetylsalicylic acid it
increases both the amount and the rate of
acetylsalicylic acid hydrolysis. He found that the
hydrolysis of acetylsalicylic acid can be reduced in
such a product by incorporating in it a hydrochloride of
an amino acid such as glutamic acid hydrochloride. In
accordance with this patent the combination of
:
`` ~.285490
propoxyphene hydrochloride and the amino acid
hydrochloride are granulated. These preformed granules
are then commingled with acetylsalicylic acid. There is
no teaching in this patent of the use of enteric coated
acetylsalicylic acid granules as is characteristic of
the present invention nor any suggestion of the problem
that it is intended to solve.
The quantity of glutamic acid hydrochloride
employed in the present invention is best related to the
total weight of enteric coated acetylsalicylic acid
granules that is utilized. This may vary over a range
but ordinarily the quantity of the glutamic acid
hydrochloride will amount to from about 1% to about 5%
by weight based on the total weight of the enteric
coated acetylsalicylic acid granules used with the
preferred range being from about 2% to about 3% on the
same weight basis.
The enteric coated acetylsalicylic acid granules
contained in the compositions of this invention need not
be of any special character. Any of a variety of
enteric coated acetylsalicylic acid granules known to
those skilled in this art may be used for the present
purposes. The material used to form the enteric coating
on the acetylsalicylic acid granules will ordinarily be
a film forming polymer that is essentially insoluble in
the gastric juices. These may be exemplified by such
film forming polymers as polyvinyl acetate phthalate
(PVAP), ethyl cellulose, cellulose acetate phthalate,
hydroxypropyl methylcellulose phthalate, copolymers of
methacrylic acid and acrylic acid esters. These
polymers are well-known in the chemical arts and are
available commercially. In this connection attention is
invited to the following citations:
.,~
~.Z854~0
(1) Polyvinyl Acetate Phthalate (PVAP); Colorcon,
Inc. of West Point PA Technical Data
Publication entitled "Polyvinyl Acetate
Phthalate (PVAP); Enteric Polymer Tablet
Sealant".
(2) Cellulose Acetate Phthalate; Eastman Products
Publication No. 2FD-lOOC, entitled "Eastman
C-A-P Cellulose Acetate Phthalate ~SP".
(3) Ethyl Cellulose; Hercules, Inc. Publication
entitled "Ethyl Cellulose, Properties and
Uses".
(4) Copolymers of methacrylic acid and acrylic
acid esters: Rohm Pharma, Technical
Applications Pamphlet (Information LD-ll/E)
entitled "EUDRAGIT L30D, Applications in the
Production of Pharmaceutical Preparations".
(5) Hydroxypropyl methylcellulose phthalate;
Shinestsu Chemical, of Japan, Technical
Bulletin of HDMCP, Appendix II.
The amount of film forming enteric coating
materials that will be contained on the acetylsalicylic
acid granules in accordance with the present invention
will generally be within the range commonly found on
suoh enteric coated acetylsalicylic acid granules that
are known in this art. This will usually be in the
range of from about 6% to about 12% by weight of enteric
coating based on the total weight of the acetylsalicylic
acid granules with the preferred range being from about
8% to about 10% on the same weight basis.
The enteric coated acetylsalicylic acid granules
used for the present purpose will usually be prepared by
coating acetylsalicylic acid granules with an enteric
coating solution containing the polymeric film forming
enteric coating material. The solvent for this solution
.
. - , ' , .
.,: . . . . .
- . ~
1~8549~)
may be any of a variety of solvents such as methylene
chloride, methyl alcohol, isopropyl alcohol, acetone,
triethyle acetate, ethyl alcohol, individually or in
combination. However, the sol~ent of choice will
usually be water.
In addition to the polymer film forming enteric
coating material the enteric coating solution may also
contain other adjuvants to facilitate the granulation
process or to improve the character of the enteric
coated granules. By way of illustration invention may
be made of antiagglomerating agents (e.g. talcum
powder); plasticizers (e.g. acetylated monoglycerides,
diethyl phthalate, propylene glycol, polyethylene
glycol); surfactants (e.g. TweensTM & SpansTM);
antifoaming agents (e.g. Medical Antifoam, AF Emulsion);
anti-tack agents (mineral oil, stearic acid).
In preparing the enteric coated acetylsalicylic
acid granules employed in the present invention the
coating solution will generally first be prepared. This
will usually comprise an aqueous medium in which the
film forming enteric polymer and adjuvant, if any, will
be dispersed. The quantity of enteric polymer that will
be contained in this dispersion will usually be from
about 5% to about 10% by weight based on the total
weight of the composition. The enteric polymer aqueous
dispersion is then sprayed onto the acetylsalicylic acid
granules which are preferably preheated, and the coated
granules are then dried. The weight ratio of coating
dispersion to acetylsalicylic acid granules utilized in
this process will generally be in the range of from
about 12:88 to about 10:90.
In preparing the final products of this invention
the enteric coated acetylsalicylic acid granules are
lZ85490
mixed with glutamic acid hydrochloride this mixing
preferably being accomplished by dry blending the
enteric coated granules with the glutamic acid
hydrochloride. In optional forms of this invention
certain adjuvants may also be employed to aid in the
blending operation or to improve the product
characteristics. By way of example mention may be made
of lubricants (e.g. zinc stearate), antiagglomerating
agents (e.g. sodium lauryl sulfate).
It is generally anticipated that acetylsalicylic
acid will be the essentially sole pharmaceutically
active ingredient of the products of this invention.
However, other pharmaceutically active ingredients may
also be included without departing from its essential
character.
In a preferred procedure a mix containing the
glutamic acid hydrochloride and the adjuvants that may
facilitate the preparation of the final products (e.g.
lubricants, antiagglomerating agents) is first prepared
and then properly sized by passing it through screens of
appropriate mesh size. This, together with the
acetylsalicylic acid granules prepared as described
above will be dry mixed within an appropriate blender.
For this purpose, for example a Twin Shell or Conical
blender may be employed.
The particle sizes of the enteric coated
acetylsalicylic acid granules and the glutamic acid
hydrochloride that will comprise the products of this
invention may vary somewhat. This to some extent will
depend upon the dosage form that the product may take.
In a preferred form of the present invention the
acetylsalicylic acid granules and the glutamic acid
hydrochloride component will be contained in capsules
:
, .~ .
: . . ~' . ' - -' '
' ' '' , . ' ' ' "' ' '~ ' `' ' '
,-. ,
- .
~2~35~90
and particularly gelatin capsules they may be swallowed
conveniently. In this case the particle size of the
acetylsalicylic acid granules will be such as to pass
through a screen of from about 16 mesh to about 40 mesh.
The glutamic acid hydrochloride similarly will have a
particle size such that it will pass through a screen of
from about 30 mesh to about 40 mesh.
It is a feature of the present invention to provide
a unit dosage form containing enteric coated
acetylsalicylic acid granules commingled with a
stabilizing amount of glutamic acid hydrochloride. A
particularly useful unit dosage form is one in which
these materials are contained in an edible capsule and
preferably a gelatin capsule. The quantity of
acetylsalicylic acid which will be contained in each
capsule will vary with the dose of acetylsalicylic acid
that is to be given and or the number of capsules which
are to be administered. Generally, each capsule will
contain from about 250 milligrams to about 650
milligrams of acetylsalicylic acid with the preferred
range being from about 325 milligrams to about 500
milligrams per capsules.
The quantity of glutamic acid hydrochloride that
will be used will be enough to stabilize the quantity of
enteric coated acetylsalicylic acid granules contained
in each capsule. This will usually be in the range of
from about 5 milligrams to about 50 milligrams of
glutamic acid hydrochloride per capsule with the
preferred range being from about 10 milligrams to about
30 milligrams per capsule.
The enteric coating materials contained in each
capsule is most conveniently expressed on a dry basis.
This will usually amount to from about 5 milligrams to
~ ~R54~0
about 20 milligrams per capsule and preferably from
about 7 milligrams to about 12 milligrams.
The following Examples are given to further
illustrate this invention. It i~ to be understood,
however, that thQ invention i8 not li~ited thereto.
~.
R~. #2324
Acid G~Dles
326.633 1. Aan~ ~ lic ~ a~ 91.213
A~K~AN-'16/40 gn~
~ 99.5% A~q Sp~.)
qM
24~497~ 2. Eu~ Ir30D (30%~w ~i~d 6.841
4.354 3. T~lcum P~br, ~ 5251 ~XD)1.216
2.450 4. Tr~*hyl citx~te F.C.C. 0.684
(Citroflex-2~ (Pfizer Inc.)
0.165 5. Mblk21 anti~oam e~Jion 0.046
(~ ~-)
-- ** 6. Water, dc1lu~e~ and d~s~Uled
(358.099) 100.000
AY
~ ~8~490
P~rt IIs Fin~l b1end for enca~6ulation
362.925 7 Part I abovc (based on ~--aY-90~ ~pirin) 96.851
10.000 8. Glut~ic Acid ~Cl 2.669
TM
1.000 9. Zinc Stcarate (Mallinckrodt) 0.26~
0.800 10. Sodium Lauryl Sulfate 0.213
374.725 100.000
Should ~e stored at tenp. between 5-20C
Evaporate~ during coating process.
Code 0001 is an acceptable alternate.
~ Enteric Coated AcetYlsalicylic Acid Granules
A-pirin (item 1) is enteric coated u-ing solution made from
items 2,3,4,5 ~ 6 using the following procedures
Pre~aration of Coating Solution~
1. $te~ 3 i~ su~pended in water with high shear. Then add
item~ 4 L 5: ~ix well.
2. Slowly add Item 2, mix very gently ~higher shear causes
coagulation of Item 2, whlch cannot be re-dispersed).
Coating Proces~ t
1. ltem 1 i~ placed in fluid bed spray granulator/dryer
(scr-en through #8 ~esh if lumpy). (SWEC0 through 12/40
mesh screen, di ward the fines, use granules left on 40
wreen only.)
2. Granule~ are preheated to about 50-C exhaust temperature
(approx. 2 min.).
~ ~85490
3. Coating olution i5 ~prnyed at about 150 ~ in. with
exhaust air temp. at 40-45-C with no~zle ~ize 1.8 mm.
After co~pletion of the coating, the granules are dried
for 20 ~in. with the inlet temp. reauced to 40-C.
Part II: Final blends for encaP~ulation
l. Mix items 8,9, ~ 10 together, pass it thru a #30 6creen.
2. Add item 7 to Twin Shell Blender; add above blend; mix
well.
Caps~l- f111 on Rotofill or H~K machine usinq Pellet feeding
device
__
Place above (Part II) granules in the hopper of the capsule
filling machine and fill into cap~ules.
Eudragit L-30D iB a copolymer, anionic in character, based on
polymethacrylic acid and acrylic acid est~rs of formula:
+CH 2 - I CH 2
C = O C -O
L H IR1 h
wherein n is a number:
R is H or CH3; and Rl is CH3 or C2H5
~he ratio of the ~ree carboxyl groups to the ester groups in this
polymer is lsl and the mean molecular weight is 250,000.
.
~.~85490
Several enteric coated acetylsalicylic acid
granules each with a different enteric coating materials
were subjected to accelerated stability testing. Each
formulation contained 325 mg acetylsalicylic acid
enteric coated, 10 mg glutamic acid HC1 and 1 mg zinc
stearate. These were identified by the Codes CM 3124-3,
CM 3124-4, CM 3124-5 and 3124-12.
A corresponding set of formulations with the same
coatings but without glutamic acid was also prepared and
10 identified by the Codes CM 3124-6, CM 3124-7, CM 3124-8
and 3124-13.
The compositions of each of the formulations is
given below.
The identity of the enteric coating materials used
to coat acetylsalicylic acid granules in Example 2, 3,
4, 5, A, B, C and D is as follows:
1 - BM Eudragit L30D: (See definition of EUDRAGIT L30D
above)
2 - Eurand America Inc.: Cellulose acetate phthalate;
this is a polymer of glucose in which each glucose
unit contains three hydroxyl groups. About half of
hydroxyl groups are acetylated and about one-forth
are esterified with one or two acid groups of
phthalic acid.
3 - Eli Lilly & Co.: Hydroxypropyl methyl cellulose
phthalate, this is derived from hydroxypropyl
methyl cellulose (NFXIII) by esterification with
phthalic anhydride.
4 - Reumyl: Cellulose Acetate phthalate - same as 2.
EXAMPLF 2
Enteric Coated Acetylsalicylic Acid Capsules - CM 3124-3
Each Capsule contains:
Enteric coated Acetylsalicylic Acid
(B-M Eudragit L30D) 325 mg
Glutamic Acid Hydrochloride10 mg
Zinc Stearate 1 mg
... .
~ ~5490
EXAMPLE 3
Enteric Coated Acetvlsalicvlic Acid Ca~sules - CM 3124-4
Each Capsule contains:
Enteric Coated Acetylsalicylic Acid
(Eurand America Inc.) 325 mg
Glutamic Acid Hydrochloridelo mg
Zinc Stearate 1 mg
E&~MPLE 4
~nteric Coated Acetylsalicvlic Acid Capsules - CM 3124-5
Each Capsule contains:
Enteric coated Acetylsalicylic Acid
(Eli Lilly & Co.) 325 mg
Glutamic Acid Hydrochloride10 mg
Zinc Stearate 1 mg
EXAMPLE A
Enteric Coated Acetvlsalicvlic Acid CaPsules - CM 3124-6
Same as CM 3124-3, but without Glutamic Acid
Hydrochloride.
EX~MPLE B
Enteric Coated Acetvlsalicylic Acid CaPsules - CM 3124-7
Same as CM 3124-4, but without Glutamic Acid
Hydrochloride.
EXAMPLE C
Enteric Coated Acetvlsalicvlic Acid CaPsules - CM 3124-8
Same as CM 3124-5, but without Glutamic Acid
Hydrochloride.
EXAMPLE 5
Enteric Coated Acetylsalicvlic Acid Ca~sules
- CM 3124-12
Each Capsule contains:
Enteric coated Acetylsalicylic Acid
(from Reumyl 500 mg) 325 mg
Glutamic Acid Hydrochloride10 mg
Zinc Stearate 1 mg
1~'
~ ~S4~0
EXAMPLE D
Enteric Coated AcetvlsalicYlic Acid Capsules
- CM 3124-13
Same as CM 3124-12, but without Glutamic Acid
Hydrochloride.
The result~ of these tests are sunmari&ed in Table I below. The
atability of the various for~ulations are ~ea~ured by the quantity of
~al~cylic acid generated per cap~ule from the hydroly6is of aspirin on
~torage at elevated temperature. The lower the analysis of salicylic
acid per cap the more 6table the product.
TABLE I
A. For~ulation~ with
Glutamic Acid
_ mg/~alicylic acid caps
4 Day~ 60 &/ 10 Days 27 Days
Initial 60t RH~ 50C *~ 50C
3124-3 (Eudragit) 0.6 4.1 1.6 2.5
3124-4 (Eurand)1.4 4.7 2.0 2.6
3124-5 (Lilly)1.7 5.2 2.3 3.3
3124-12 (R~u~yl)1.9 6.0 2.9 4.0
B. Formulation~ without
Glutamic Acid
3 Day~ 60 &/ 10 Days 27 Days
Initial 60t RH 50C 50C
33124-6 (Eudragit) 0.6 33 6.1 19
3124-7 (Eurand)1.3 15 4.0 6.2
3124-B (Lilly)1.8 14 4.1 6.8
3124-13 (Reumyl)1.9 12 4.4 6.3
* Average of two s~parate runs in the Analytical Department
"torture chamber".
*~ Storage in HD/PE non-safety cap containers.
5490
As can be seen from this data the formulation~ with glutamic a~id
were virtually lndi~tingui-hable chemically after 27 day- at SO C and
4 days at 60 C/60% RH The Eudragit formulation was slightly better
than the others and the Reumyl was 61ightly wor-e physically, nll
sample~ wore acceptable after 27 days at 50 C the heat/hu~idity
samples were all moderate to poor
All formulations without glutamic acid demonstrated much worse
chemical and physical stability than the corresponding glutamic acid
formulat$ons However, the Eudragit samples were clearly much worse
than the other three, and it can be ~een that the Eudragit formulation
was improved most by the addition of glutamic acid
