Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~ 6
The Boots Company Limited
Pharmaceutical Compositions
This invention relates to pharmaceu~tical compositions
in tablet form in which sustained release of a -therapeu-tic
agen-t is obtained. The invention is particularly suitable
for tablets containing anti-inflammatory agen-ts such as
5 acetylsalicylic acid (hereinafter referred to as ~SA),
indomethacin, fenoprofen, naproxen, ibuprofen and flurbiprofen
which are used for example in the treatment of rheuma~toid
and osteoarthritis. In the treatment of these diseases it
is necessary for therapeu-tic agents to be given for long
10 periods. I-t is known that the use of aspirin in long term
therapy can give rise to undesired side effects and many
attempts have been made to reduce these sîde ef~ec~ts.
It is an object of the presen-t invention to provide
pharmaceutical compositions in tablet form which, on oral
administration, provide delayed disintegration of the
table-t, provide prolonged dissolution times for the active
therapeutic agent and provide sustained blood levels of
the active therapeutic agent in -the pa-tient. It has been
found that these objects can be met according to the present
invention by controlling the rela-tive amounts of the thera-
peutic agent , a release-controlllng agent and an
erosion-promoting agent.
The present inven-tion provides a sustained-release
pharmaceutical composition in table-t form comprising an
effec-tive amount of an orally-active -therapeu-tic agent,0.~
to 1.6% by weight of a release con-trolling agent and 1.0 -to
'~ ~
.
-
616
-- 2 --
7.5% by weigh-t of an erosion promo-ting agent, the relative
amounts of the components being sucll that a cri-ticality
factor calculated according to equation I
CF = ~
wherein CF is the criticality factor, CA is the amount of
therapeutic agent per tablet in milligrams divided by the
amount of release controlling agent per -tablet in milli-
grams and CS is the amoun-t of erosion promoting agent per
tablet in milligrams divided by the amount of release con-
trolling agent per table-t in milligrams, lies in the range
20 to 450.
All percentages are expressed by weight as percentages
of -the to-tal weigh-t of the table-t. The preferred amount
of release controlling agent lies in the range 1.15 to 1.6%
..` by weight and the preferred range of erosion promoting
agent lies in the range 2 to 5% by weight.
The criticality factor conveniently is in excess of
50 and preferably lies in the range 80 to 330 and more
preferably in the range 210 to 330.
The preferred release-controlling agent is cellulose
~0 acetate phthalate. Other suitable release-controlling
agents include cellulose acetate derivatives disclosed in
~iatt USP 2,196,768, shellac, zein, acrylic resins, ethyl-
cellulose, hydroxypropylme-thylcellulose phthala-te, sandarac
and modified shellac.
The preferred erosion-promoting agent is corn starch.
Other suitable erosion-promoting agents include, rice starch,
potato starch and other equivalent vege-table starches,
modified starch and starch derivatives, cellulose deriva-
tives and modified cellulose or deriva-tives, e.g., me-thyl-
cellulose, sodium carboxymethylcellulose, alginic acid and
alginates, ben-toni-te, veagum, cross-linked polyvinylpyrroli-
- done, ion-eYchange resins, and gums, e.g., agar, guar.
ASA table-ts convenlently con-tain 650 to 800 mg of
ASA per table-t, abou-t 5.0 to abou-t 13.6 mg per tablet
~5 of release-corltrolling agent and about 13.4 to about 63.8 mg
~ 3~L~46~j .
3 --
of erosion-promoting agent per table-t.
Other anti-inflammatory therapeu-tic agents may be
utilised in the pharmaceutical compositions of the present
invention. For example tablets may be prepared containing
400 to 600 mg of ibuprofen per tablet or 100 to 300 mg of
- flurbipro~en per -tablet.
The pharmaceutical compositions of the present inven-
tion may also contain inert fillers or diluents, flow aids
or tableting aids.
The tablets of the present invention preferably have
a hardness on the Schleuniger scale of 6.5to 18Kp.However
it has been shown that satisfactory release character-
istics can be obtained with tablets of varying hardness.
This facilitates the large scale production of the tablets
because any variation in hardness produced by the tableting
machinery does not cause a significan-t change in the release
` characteris-t,ics. `
The compositions of the present invention may be prepared
by dissolving the release-controlling agent in a suitable
organic solvent such as lower-aliphatic alcohols such as
methanol, iso-propanol) or n-propanol, ace-tone and lower-
aliphatic ketones such as methyl ethyl ketone, chloroform~
carbon tetrachloride, ethyl ace-tate and non-chlorinated
hydrocarbons or in a solvent mixture such as methylene
chloride and denatured alcohol [1:1(v/v)].
The therapeutic agent, in powder form ~
is intimately mixed with the erosion-promoting agen-t,
preferably corn starch and -t~.e solution of the release-
controlling agent, preferably of cellulose acetate phthalate,is added -to the mixing powders in a steady s-tream. Mixing
is continued -to form a wet granular mass. The wet mass is
dried to remove residual organic solvent, leaving the
release-conlrolling agent in intimate con-tact with the
par-ticles of the therapeu-tic agent and erosion-promoting
agen-t. The granular mass is reduced to a sui-table granule
si~e by forcing the ma-ter;ial through a
screen and the dry granules are blended to ensure homogeneity
~V9~66
-- 4 --
before being compressed into tablets using a conventional
rotary or single station -tablet press. The table-ts ma~
then be printed directly using conventional tablet
printing equipment and materials to identify the product.
Tablet identification may also be made by debossing the
finished product during compression.
The invention is,illustrated by the following Examples
which are not to be construed as limiting. The Examples
have reference to the accompanying drawings in which:-
FIG. 1 is a graphical illus-tration of the results of
the test described in Example 7 showing mean serum levels of
~SA over the first eight hours of a 24-hour study in
each of two subjects receiving two 650 mg table-ts as a
single 1300 mg dose of ASA , the tablets being in
accordance with this inven-tion (unbroken and broken lines),
as compared with a single 650 mg tab]et, also in accord
' .' with the,inven-tion (alternate'dot and 'dash line)~ :
FIG. 2 is a graphlcal illus-t:ration of -the results of
the test described in Example ~ showing mean serum levels of
salicylic acid over a 120-hour period involving mul-tiple
oral doses (nine doses-each 2 x 650 mg - 12 hours apart
over a 96-hour period) of ASA table-ts in accordance
with this invention in eight subjects, the blood samples
being taken at the hours indicated5
FIG. 3 is a graphical illustration of the results of
the test set forth in Example 8 and described ~or FIG. 2
showing serum levels of ASA,
FIG. 4 is a graphical representation of the two com-
partmen-t model used to produce -the simulated zero-order
absorption curves shown in Figures 5 and 6~
FIG, 5 is a graphical illustration of the resul-ts of
a comparison between a simula-ted compu-ter curve for zero
order absorption of ASA (solid line) and the actual
values from blood samples taken on Day 1 of -trea-tmen-t for
subject 1 (dot;ted line) from Example 8, and
FIG. 6 is a ~raphica] illus-tration of -the resul-ts of
a comparison between -the theoretica] value for zero order
absorp-tion of ASA (solid line) in a second suhject and
6~
the actual ~alues from blood samples taken on Day 1 of
treatment for subject 2 (do-tted line) from Example 8.
Example 1
Cellulose acetate phthalate (67.3 g) was added slowly
to the vortex of a mixture of ethanol (denatured, 625 ml)
and methylene chloride (175 ml) produced b~r a high speed
stirrer. Stirring was continued until solution was
achieved.
ASA (4.375 kg, 40 mesh/inch crystal, USP) and
corn starch (0.2255 kg, USP) were deaggregated through a
40 mesh/inch screen into -the bowl of a Hobart*mixer. The
dry powders were mixed for five minutes at speed 1. The
cellulose acetate phthalate solution was added to the
mixing powders over a thirty-second period, wi-th mixing at
speed 1. Further mixing for four minutes at speed 2 was
, , "carried,out to,promote, gr,anulation. ,, ,, ,, . ,~
' The wet granular mass was discharged onto s~ainIess
steel trays and air dried until it could be forced through
a 20 mesh/inch screen. The screened granulate was further
air dried to remove residual sol~ent. The granules were
weighed, blended by tumbling, and compressed on a con-
ventional rotary tablet press using half-inch flat bevelled
edge tooling to produce tablets containing 650 mg of ASA
with a hardness of 8 to 10 Kp (Schleuniger~.
Example 2
Cellulose acetate phthalate (750 g) was added slowly
to the vortex of a mixture of methylene chloride (3750 ml)
and ethanol C3750 ml). Stirring was continued until
solution was achieved~
ASA (60 kg, 80 mesh per inch powder, USP) and corn
starch (3.0 kg, USP~ were placed in the bowl of a Littleford~
MGT 400 mixer. The dry powders were mixed using the impeller
at speed 1 for two minutes. The cellulose acetate ph-thalate
solution was poured in a stead~ s-tream onto the powders
mixing at impeller speed 1 and chopper speed 1. Following
addition of the solution, mixing was con-tinued at impeller
and chopper speed 2 until a ~SUi table granular mass was
obtained. The wet granular mass was spread on stainless
* Trade Mark
66
-- 6 --
steel trays and dried in a forced convection oven a-t a
temperature not greater than 120F. The dry granular mass
was processed through a Jackson Crockat~ granulator
carrying a stainless steel screen of 16 mesh/inch. The
5 dried sized granules were blended in a drum blender ~or
five minutes, and compressed on a conventional rotary
tablet press using capsule shaped tooling to give tablets
containing 800 mg of ASA wi-th a hardness of 8 to 11 Kp
(Schleuniger).
10 Examples 3 to 6
Four batches of tablets having the compositions set
out in Table I were prepared as described in Example 1.
The disintegration time in a buffer at pH 7.5 was determined
by the procedure described in the United States Pharma~
15 copoeia XX page 958 but omitting the discs and the release
properties were determined in a bu~fer at pH 7.5 by the
procedure described in the Unitëd -States Pharmacopoeia.XX
.. . . . . .
page 959 but using a modified version of the apparatus
described as Apparatus 1 in which a propeller is mounted
20 on the shaft above the basket. The results of ~ese tests
are set out in Table 1 which also shows the results
obtained using conventional ASA tablets (Example A)
and tablets (Examples B and C) in which the criticality
factor is greater than required by the present invention.
The dissolution data for Examples 4 and 6 was obtained using
a further batch of tablets prepared in the same manner as
those used for the disintegration experiments.
* Trade Mark
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-- 8 --
The release properties of ~table-ts prepared in accord-
ance with Example 5 were de-termined in another ex~eriment
and the results shown below ob-tained.
~ . . ... _
Time of Acetylsalicylic acid dissolved
sample(hr) (%)
_ . . .~ ,
0~5 23.8
1 34.8
2 61.3
_ ___ 82.4
These results, when plotted as a graph of time
1--- ~ I versus percent acetylsalicylic acid dissolved
I -l give a straight line indicative of zero order
release. Linear regression analysis of the da-ta gives a
correlation coefficient of 0.999, compared to a straigh-t
line value of 1,0.
The dissolution of the tablets of ~xample 3 and of a
further batch prepared according to Example 6 were assessed
in a method involving a pH change. The method was according
to the United Sta-tes Pharmacopoeia XX page 959 using the
modification described above. The resul-ts are shown in
Table 2.
Table 2
... . .
Time Initial mg ASA released Cumula-tive % of Theory
(hrs) pH by end of time amount ASA ASA released
__ __ relea sed(mg)
Ex.6 Ex.~ Ex.6 Ex.3 Ex.6 Ex.
_ . . ... _ ... ___
0-1/2 1.250 46 5o 46 7.7 7.1
0-1 1.272 60 72 60 11.1 9.2
1-3 4.4125 96 197 156 3.3 24.0
3o 3-6.5 7.5410 425 607581 93.4 89.~
The level of chemlcal degradation which occurs on storage
with tablets according to the presen-t inven-tion is less
than tha-t occur~ing with conventional ASA formulations.
AcetylsalicyliG acid degrades to sa]icylic acid, and this
reaction is promo1ved by elevated tcmpera-ture. The reactiGn
66
g - .
occurs readily and has led to the adoption by -the United
States Pharmacopoeia of an upper limit for the level of
free salicylic acid (FSA) in ASA tablets at 0.3%.
Tablets prepared according to Examples 1 and 5 were
assayed for free salicylic acid (FSA) after storage under
extreme conditions. The results are shown in Table 3.
Table 3
ExampleTime ~torage Level
of FSA %
1 0.04
3 months 40C 0.12
O _ o.o6
6 months 40C 0.14
37C/75% 0.22
relative
humidity
,. ~ ... -.. ,. . ~ . .. . ... - . ... , , . . i,.. .....
: . .. . .
It is widely known that, under similar conditions of
storage, the limiting level of FSA, viz., 0.3%, would be
exceeded by conventional ASA formulations.
Tablets prepared in accordance with Examples l~, 5 and 6
20 subjected to a drop test in a Roche~friabilator. After lOO
drops a weight loss of between 0.12 and 0.46 percent by
weight was observed. When the test was extended to give
75Q drops the edges of the tablets became worn but the tablets
did not break up. A commercial sustained release aspirin
25 tablet showed a weight of 0.85% after lOO drops and were
severely worn after 750 drops.
ExamPle 7. Serum Levels After a Sin~le Oral Dose
Tablets containing 650 mg of AS~ : were produced
according to the method of Example 1. One human volunteer
30 was ~iven a single oral dose of 650 mg while two other
- individuals received a single dose of 1300 mg (two 650 mg
tablets). Blood samples were taken from each subject via
an indwelling catheter from a vein in the forearm. The
samples were collected in a chilled vacutainer tube a-t the
35 following times:prior to dosing and at 15, 30, 45 and 60
minutes; 1.5, 2.0, 2.5, 3.0, 4.0, 8.0, 12.0, 16.0, and 24
~* Trade Mark
66
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. . .. . . .
hours pos-t dose. The blood samples were analyzed for
plasma salicylic acid and acetylsalicylic acid using high
pressure liquid chromatography, Table 4 and FIG. 1 show
the resul-ts of -these measurements. In figure l -the results
5 for subject l are shown as an unbroken line, those of subject
2 as an al-ternate dot and dash line and those of subject 3 as
a broken line. The x axis represents the time in hours and
the y axis the plasma concentration of ASA in micrograms/ml.
Table 4
10 Pl~
._ ~ .. . _
Subjeet No 1 2 3
Dose1300 mg 650 mg 1300 mg
mcg/ml mcg/ml mcg/ml
.. _ .~ _ ._ _ _
15 Study Time(hrs) ASA SA ASA S~ ASA SA
. _ __ . __ _ . _ _
0 0.1 O. l 0.1 0~1 0.1 0.1
t ~ 0.1 0.38 0.1 0.1 0.1 0.2
0.1 0.93 0.'1 0.1 0.46 0.99
~ 0.43 1.58 0.'1 0.28 0.49 1.81
1 0.41 2.18 0.'19 0.67 0.53 2.26
1.5 0,37 3.19 0,35 1.53 0.71 3.24
2.0 o .59 ~ .30 0,30 2.45 0.61 4.07
2.5 0,61 5.55 0.25 3.08 0.51 4.99
3.0 Ø46 5,70 0.35 3.29 0.89 6.01
4. o 0.68 8.89 0.38 4.27 0.97 ~ o o 70
8.0 0.39 17.00 0.18 5.47 0.20 11.30
12.0 0.1 17.90 0.1 3.72 0.26 19.30
I 16.0 0.1 8.87 0.1 3.83 0.20 14.00
24.0 0.1 0.36 0.1 2.96 0.17 9.24
`l 30
l~ The serum levels of aeetylsalieylic acid were shown -to
`! peak, in all -three subjects, four hours af-ter drug inges-tion.
Levels did not return to 0.1 mierogram/milliliter un-til
after eigh-t hours. This finding is to be compared -to the
35 established half l:ife (t=1/2) of twen-ty minutes for serum
acetylsalicylic acid following administra-tion of a standard
650 mg table~.
:,
46~
- 11 ~
rUm 1eVe1S :fG110Win~ dOSe5
ASA tablets prepared according -to -the me-thod o~ Example 1
were administered orally to eight heal-thy volunteers in
doses of 1300 mg (two 650 mg tablets) twice-a-day at 0800
and 2000 hours ~or nine consecutive doses~ the last dose
being given on the 96th hour, to determine -the steady-state
pharmacodynamics of the ASA tablet formula-tion o~ this
invention. Blood samples were taken from the subjec-ts at
predetermined time intervals during the course o~ the study.
The blood samples were analyzed by high performance liquid
chromatography for levels of salicy~ic acid and ace-t~lsali-
cylic acid. Individual blood levels of salicylic acid and
acetylsalicylic acid found on Day five of the study are
shown in Tables 5 and 6. Graphical representation of the
mean blood levels for salicylic acid and acetylsalicylic
' acid for the entire study are shown in FIGS 2 and 3, res-
'' pectively. In these figures the figures on the x axis rep-
~''~ resen-t the time in hours and the figures on the y axis
~ ' represent -the SA and ASA le~els in the blood in micrograms/ml.
~ .~, .. ,.,.. ~ , .. .. .. . . . . . , - -. .
Example'9. Comparison o~ AS~ absorption with a_theoret-
ical zero order curve
To demonstrate that the in vivo absorption charac-teristics
of aspirin table-ts prepared according to the present
invention are generally zero-order, results from subjects
1 and 2 of Example 8 were compared to -the predic-ted results
~5 calculated by a computer. The computer calculations were
, ,~ased,on a two com~artment model with first order metabolism.
The model is shown diagrammatically in Figure 4. The model
assume5 that the total dose D is absorbed at a constant rate
ko over a period of time T. At the end o~ the time T all the
dose will have bee~ absorbed. The model also assumes that
60% o~ the ASA'passes the liver 2 unhydrolysed be~ore passing
into a central compartment 3 which has an apparen-t volume
o~ distribution of 6.3 li~tres. The acetylsalicylic acid may
pass reversibly from the cen-tral compartment 3 to body tissue
~ho~1 as 4) or may be removed irreversibly as me-tabolites
(shown diagrammatically as 5). The rate constants used in the
model and shown in Figure L~ were taken from Rowland and Xiegelman
J. Pharm. SC L. VO1 _57 page 1313 (1~6~).
.
- 12 -
The -time T required for the en-tire dose -to be absorbed
will limit the ex-tent to which multiple doses overlap one
another. In Figure 5 the results obtained from Subject No. 1
of Example 8 (do-tted line) are compared wi-th the compu-ter
generated curve (solid line) produced when T was given -the
value of 16 hours. The results obtained from Subject No. 2
of Example 8 (dotted line) are shown in Figure 6 and are
compared with the computer generated curve (solid line)
produced when T was given the value of six hours. In
Figures 5 and 6 the figures on -the x axis represen-t the time
in hours and the figures on the y axis represent the ASA
levels in the blood in micrograms/ml.
There is reasonable agreement between the experimental
and theoretical curves thus demonstrating that, in vivo
there is a close approximation to zero order absorption
wi-th ASA -tablets prepared according to the present invention
.,, . .,.. . . , . ,., . ,.. , . , ,. . ,... . ., , ~ . ..
Tnblo 5
Sallcyllc Acld L~vnls on Day Flve, mcgrml
. .
SubTlmr, thrs) Post Dosr,
No. 0 O.S I 2 4 6 8 10 12 16 24
.
1 9.37 9.98 10.0510,9313,3B18.3315,0312.7310.418.31 1.58
2 63.85 68.23 73.98 77.~2 72,08 89,96 75.93 79.æ ~35.07 75.0~ 43.32
3 80.3 18.5783.4190.3187.8294.4785.6774.2764.8437.83 9.91
4 72.48 68.~8 62.69 62.63 67.49 67.4~ 60.0~ 49.41 52.85 40,1g 16.87
5 38.37 32.39 31.42 30.;8 28.39 34.27 33.51 34.42 35.16 31.37 12.16
6 22.8524.8125.2628.8028.0930.2229.6130.,54 36.95 15.36 ?.70
7 11,98 14.53 15.98 20.90 ?4.47 33.42 35.19 35.47 34.07 10.35 0.40
8 10.5512.0413.9816.5718.6124.0119.5215.9315.5813.78 3.59
Mean3û.73 38.6739.fiO42.2642.54 49.0244.3141.5040.62 29.03 11.31
iSEM10.4510.1010.3410.6410.0910.749.308.70 8.97 7.93 5.01
Table 6
Acetylsallcyllc Acld Lcvels on Day Flve, mc~rml
.. . , . . . .. . ~ .. , , .. . . ...... . ... . .. ..
S~lbTlme ~hrs) Post Dose
No. 0 0.5 1 2 4 6 8 10 12 16 24
1 0.15 0.39 0.430.470.49 0.310.3~10,460.220.18 0.09
~0 2 0~81 1.07 1.970.760.47 0.320.2~0.470.280.16 0.09
3 0.79 0.76 0.75 0.66 0.40 0.28 0.05 0.05 0.05 0.05 0.10
4 1.08 0.65 O.B80.650.95 0.630.430.260.430.26 0.09
5 0.74 0.59 0.~9 0.55 0.32 0.89 0.43 0.24 0.25 0.23 O.la
5 0.23 0.80 0.620.890.35 0.310.430.460.2~0.16 0.09
7 0.15 0.41 0.500.540.75 0,280.300.37 û.l90.08 0.09
8 0.65 0.65 0.86 0.~0 0.62 0.43 0.33 0.19 0.13 0.16 0.09
Mo~l~0.58 0.67 0~810.670.54 -0.430.320,310.230.16 0.10
~S~:M 0.12 0.08 0.180.510.08 0.0~ b.o40.540.0~0.02 0.01
,...... ' . , .
-- 2 2 --
~4(~466
- 14 -
Example 10
Cellulose acetate phthalate (50 g) was added slowly to a
rapidly stirred mixture of ethanol (6?0 ml) and methylene
chloride. Stirring was continued until a solution was
obtained. This solution was added to a mixture of ibuprofen,
2-(4-isobutylphenyl)-~ropionic acid, (2.5 kg), dicalcium
phosphate dihydrate sold under the trade name Emcompress *
(0.75 kg) and corn starch (0.155 kg) which had been
thoroughly mixed. The wet granular mass was air-dried on
stainless steel trays, passed through a 14 mesh/inch screen
and dried further to remove all solvent.
A quantity of dried granule of about 0.05 kg was with-
drawn from the bulk and blended with a colloidal silicon
dioxide sold under the trade name Aerosil*200 (0.5% based
on total weight of granules). This preblend was then mixed
: with the bu~k of the~granules ~or ten min~tës;
The blended granules were obtained in a yield of 98.4%.
The flow properties of the granules assessed by the method
of Carr (Brit. Chem. Eng. 15, 1541-1549, 1970) were found
to be fair to passable.
The granules were compressed on a conventional rotary
tablet press using half-inch flat-bevelled edge tooling to
gi~e tablets containing 400 mg of ibuprofen with a hardness
~rom 8 to 12 kp (Schleuniger).
The CF for this example is 155 and the percent by
weight of release-controlling agent and erosion promoting
agent 1.44 and 4.46, respectively.
Tablets produced from granules prepared as described
above were compressed to different hardness and the
resulting tablets subjected to disintegration tests
(United States Pharmacopoeia XX page 959) in a buffer at
pH 7.5 at 37C.
Hardness Mean disintegration
Kp time (mins)
4.14 >235
.54 >275
10.86 _ -
.; _ .
* Trade Marks
4~
- 1$
A conventional ibuprofen tablet disintegrates in less than
one minute and a sugar coated table-t disintegrates within
five to ten minutes.
n vitro dissolution tests (~ni-ted States Pharmacopoeia
XX page 959) show -that -the tablets of Example 10 (Hardness
10.86 Kp) do cause a sus-tained release of the ibuprofen
when compared to conventional ibuprofen table-ts. Each
ex~eriment was rePeated six times.
~ _ _ . , ~
Amount ibuprofen dissolved (mg.)
_ Conven-tional table-t
Time/ E~. 10 (pH 7.5) (pH 6.8)
mins_ After 3 months Y After 3 months¦
; -initial storage at 40C -initial storage at 40C
. _ _ _ _.
_ _ 277 6~
_ _ 31~ 110
68 63 365 163
100 99 383 248
120 169 163
180 219 217
240 265 274
~ t~ 155 153 8.L~ 41.3
__ . . . _ .,
In -the abo e results t~ is the time taken for 50% of the
ibuprofen to dissolve. The results after three months
storage show that the tablets of the present Example have
good storage stability.
The results for the tablets of Example 10 which had
not been stored give a straight line when the amount of
ibuprofen dissolved is plot-ted against time. Linear
regression analysis on the results gave a correlation
coefficient 0.996 thus indica-ting zero-order dissolution in
30 vitro.
.
3~L6~
- 16 -
Examples 11 and 12
Tablets containing flurbiprofen, (2-(2-fluoro-4-biphenylyl)~
propionic acid, were prepared by adding a solution of
cellulose acetate ph-thalate to a mixture of the active
5 ingredient dicalcium phospha-te dihydrate (sold under the
trade name Emcompress) and corn starch. The wet mass was
air dried, screened and dried further to remove organic
solvent. Magnesium stearate (0.5 % of the total weight
of granules) was added and the granules tableted. The
10 compositions of examples 11 and 12 are given below.
CAP solution Ex,11 Ex.12
_ .
Cellulose acetate phthalate ~ g 8.33 g
Ethanol denatured 60 ml 55 ml
Methylene chloride 60 ml 55 ml
0-ther components
Flurbiprofen ~ 300 ~- - ? g
Emcompress 240 g ~00 g
Corn Starch 18.6 g 17,2 g
We'ght of flurbiprofen 300 mg 100 mg
20 per tablet
Hardness of tablet (Kp) 8.7 ~ 1.2 7.14`~0.54
CF 25 25
% release controlling
agent 1.58 1.58
% erosion promoting agent3.27 3.27
.
6 6
17 -
The mean disintegration -times of the tablets o~
Examples 11 and 12 in a buffer at pH 7.5 were determined
by the me-thod described on page 958 of the Uni-ted States
Pharmacopoeia XX. The results obtained are shown below.
.. ..
Ex.11 Exo12
Mean disintegrationtime >300 >360
(mins)
Residue (%) 3.7 4.9
The dissolution of flurbiprofen over a period of -time from
the tablets of Examples 11 and 12 was assessed using the
apparatus described on page 959 of the United States
Pharmacopoeia XX. A phospha-te buffer at pH 6.8 was used.
The experiment was repeated six times and the mean value
~of the amount of active material released is given below.
.. . ..
15Time(hours) % ~lurbipro~en dissolved
Ex~11 Ex~12
1 9~6 10~6
2 22~5 17~1
3 29~3 24~7
4 34.8 28.8
44~8 35~1
7 56~9 4707
74~0 68~5
~ ...~.. ,.,. ~,,
.
.
11~0~6
- 18 -
! A plot of the percentage of flurbiprofen dissolved
against time for each of these sets of results gave a
straight line indicating that a zero order mechanism is
operating in each case. Application of regression analysis
to the data gives a correlation coe~ficient of 0.993 for
Example 11 and 0.999 for Example 12.
By way of comparison a conventional flurbiprofen
tablet containing ~00 mg of flurbiprofen in the same test
- showed complete dissolution in about one hour.
` 10 The tablet of Example 12 was used in an experiment in
which the plasma level of flurbiprofen in ~our
volunteers was measured after a single dose and
the results are shown in the columns headed A in Table 7.
The results obtained with a conventional 100 mg.
~ flurbiprofen tablet used in a similar experiment with
1~ 15 -the same volunteers are shown in the columns headed B
¦ in Table 7. N.D. indicate~ that no flurbiprofen could be
detected.
:- : Table 7 ~:
. ': ,:. _
Flurbiprofen concentrations in plasma mcg/ml.
(Tlhmes) Volu - ;eer 1 Volun1eer Z Volun teer 3 Volurteer 4
A B A B A B A B
0.5 ND 1.0 ND 6.0 5.6 10.9 0'4 7.8
1 ND 8.7 o~5 11.9 12.1 15.8 o~7 14.0
25 2 0.910.9 1.7 12.1 15.8 11.2 1.4 10.9
3 3.5 9.2 5.6 8.9 11.1 8.0 5.8 7.2
4 4.8 6.4 10.3 6.5 7.7 6.0 5.3 5 5
4.1L~.6 7.3 4.7 5.7 4.8 L~,5 3'7
6 3.4 3.7 5.6 ~.0 4.6 3.7 3.6 3.1
il 30 9 3.8 1.9 2.7 2.1 2.6 2.0 2.7 1.5
12 2.5 1.2 1.6 1.3 1.6 1.4 2.8 1.0
i! 24 0.5 0.2 0~2 0.2 o.3 o~3 o.4 ND
ND ND ND ND O.Z ND 0.2 ND
,i '
, ~ .
:'
,.
66
-- 19 --
Although the foregoing Examples evidencë the appli-
cation of the present inven-tion to various orally-active
therapeutic agents or medicaments to provide controlled-
release tablets thereof, -the inven-tion is not limited to
the tabl~tting of the specific medicaments of the Examples.
In this aspect, -the invention can be varied widely and is
applicable for the controlled-release tabletting of any
orally active medicament, al-though is preferably in the
tabletting of medicaments of an acidic nature, especially
aspirin and nonsteroidal arylalkanoic acid anti-inflammatory
agents, including -their salts, esters, anhydrides, and other
derivatives, as previously disclosed. These compounds are
antipyretics, analgesics, and an-ti-inflammatory agents.
Other representative types of orally active medicaments
which may be incorpora-ted into sustained-release tablets
according to the invention include sedatives, stimulants,
antibiotics? antispasmodics? nutritional agen-ts, hema-tinics,
- anthelmintics, expec-torants, hormones of various -types
including adrenocorticosteroids, androgenic steroids,
es-trogenic s-teroids, progestational steroids, and anabolic
steroids, nonsteroidal coun-terparts of the foregoing,
psychic energi~ers and antiviral agents.
3o
