Note: Descriptions are shown in the official language in which they were submitted.
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SUSTAINED RELEASE PEIAR~l~CEUTICAL CO~POS ITIONS
This invention relates to sustained release pharmaceutical
compositions.
We have surprisingly found that a solid oral sustained
release formulation may be produced from the readily
available and widely approved exci~ients microcrystalline
cellulose and hydroxypropyl methylcellulose.
The invention accordingly provides in one aspect a sustained
release pharmaceutical composition comprising a pharmacolo-
gically active agent in admixture with a) microcrystallinecellulose and b) hydroxypropyl methylcellulose wherein the
weight ratio of a) to b) is at least 1 to 1, with the
proviso that when the active agent is other than acetylsali-
cylic acid in free form or salt form, the active agent is
also in admixture with pregelatinized starch.
In an other aspect the invention provides a process for the
production of a sustained release pharmaceutical composition
which comprises mixing a pharmacologically active agent and
a) microcrystalline cellulose and b) hydroxypropyl methyl-
cellulose wherein the weight ratio of a) to b) is at least1 to 1, with the proviso that when the active agent is other
than acetylsalicylic acid in free form or salt form, the
active agent is also in admixture with pregelatinized
starch.
A wide variety of pharmacologically active agents (herein-
after "agents") may be used. These may include water-
soluble or water-insoluble compounds. The agents may be
moisture sensitive or not. The dosage of agent may vary
between wide limits.
-la- 1 3 ~ ?~119
representative active agents include analgesics, anti-
pyretics, anti-inflammatories, anti-histamines, anti-hyper-
tensives, vasodilators, transquillizers, anti-depressants,
neuroleptics, vasoconstrictors, anti-convulsants, anti-
asth~atics, etc.
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The invention is exemplified hereinafter by reference
to acetylsalicylic acid (hereinafter ASA) but it is to
be understood that it is applicable to any active agent.
The ASA is preferably in the form of the free acidO
Alternatively it may be in the form of a salt, e.g. a
sodium or calcium saltO The ASA is preferably in the form
of fine crystals e.g. of particle size under 40 mesh, e.g.
5 to 40 meshO
Preferably the mean polymerisation number of the microcry-
stalline cellulose is from about 200 to 2000, preferably
200 to 300O Preferred mean molecular weights are from about
20,000 to about 100,000 e.gO 30,000 to 50,000. Preferably
the mean particle size is from about 5 to about 140 microns.
Preferably the particle sizeufrom 20 to 100 microns, e.g.
to 80 micronsO Conveniently the specific gravity is about
1040 to 10600 Conveniently the microcrystalline cellulose
is obtained by mechanical treatment of glucose-based poly-
saccharides, eOgO native cellulose, optionally with acidic
treatment.
Preferred forms are the AVICEL brand (Registered Trade
Mark of FMC Corporation).
Conveniently the methoxy content of the hydroxypropyl methyl-
cellulose i 5 from about 15 to about 34 per cent by weight,
preferably from about 19 to 30, especially 19 to 24, per
cent by weight. Preferably the hydroxypropyl content is
from about 4 to about 32 per cent by weight, preferably
from 4 to 12 per cent by weightO
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The viscosity of the hydroxypropyl methylcellulose is
conveniently from about 15 to about 50,000 cps (based on a 2
percent by weight aqueous solution at 20 degrees centigrade)
e.g. 4000 to 50,000 cps.
Conveniently the mean molecular weight is from about 20,000 to
200,000, e.g. 90,000 to 130,000.
Preferred forms of hydroxypropyl methylcellulose are those
available under the trade marks of Methocel A, K and E from
the Dow Chemical Company Michigan.
Preferably the weight ratio of microcrystalline cellulose to
hydroxypropyl methylcellulose is from about 10:1 to 1:1, e.g.
3:1 to 1:1, e.g. 3:1 to 2:1.
Preferably the weight ratio of microcrystalline cellulose to
agent is from 1:5 to 1:10, e.g. 1:6 to 1:7.5, especially 1:6.5
to 1:7. Conveniently pregelatinized starch is present.
Conveniently the starch is soluble to an extent of about 5 to
25, e.g. 10 to 20, percent by weight in cold water. Suitably
the pregelatinized starch is made by reacting starch,
preferably corn starch (based on 80 percent amylopectin
moieties and 20 percent amylose moieties) so as to break down
hydrogen bonding between the amylose and amylopectin moieties
therein. Conveniently the product contains from 60 to 85
percent by weight of corn starch, the remainder being free
amylose and amylopectin.
Preferably the weight ratio of pregelatinized starch to
hydroxypropyl methylcellulose is from about 1:1 to about 1:5,
e.g. to about 1:2.
;'
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Naturally other excipients may be present. These excipients
may be those conventionally used in pharmaceutical formula-
tions, such as anti-frictional agents, e.g. lubricants
such as stearic acid or magnesium stearate, and 91idants
such as silicon dioxide, anti-adherents/soluble fillers such
as lactose, flavouring agents and colourants.
Conveniently the weight ratio of agent to all other excipients
present is from about 0O2 1 to about 0.4: 1, e.g. from about
2: 1 to 4: 1. Conveniently the hydroxypropyl methylcellulose
content is from about 5 to 10 per cent of the total weight, e.g.
6 to 9 per cent, especially 6.5 or 8.5 per cent.
The pharmaceutical composition is preferably in solid form.
Prefera61y it is in~a unit dose form. Conveniently it is in
the form of a tablet.
Conveniently the amount of ASA per unit dose is from 300
to 400 mg or 600 to 700 mg.Such pharmaceutical compositions
may be produced by techniques well known in the art.
Tablets are preferably compressed to a hardness of from about
8 to 12 kiloponds (based on the Heberlein method).
The bioavailability of the compositions of the invention may be
determined in conventional manner.
In a typical trial ASA pharmaceutical compositions of the invention
are administered at 7 am, 3 pm, 11 pm or 7 am and 7 pm.
Immediate release ASA compositions are administered at 7 am,
11 am, 3 pm, 7 pm and 11 pm, as reference formulations.
Free and total salicylic acid (SA) may be measured in conven-
tional manner by HPLC (essentially that of Hamson et al,
J.Pharm.Sci`. (1980) 69 1268).
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Free SA detection method
Heparinized blood samples are collected. Plasma is sepa-
rated within 15 minutes of drawing blood, divided into 2 por-
tions and placed in polypropylene tubes sealed with colour-
coded polypropylene plugs.
0.5 ml Samples are acidified with 1 drop of concentrated
phosphoric acid for a few minutes, and extracted with toluene/
ethyl acetate (50:50). TH~ extracts are analysed using re-
verse phase HPLC with UV detection at 305 mm using 3,4-
dimethoxy-beinzoic acid as internal standard. The method gives
a minimum quantifiable level of 0.1 microgram per milli-
litre of free SA.
Total SA detection method
Total SA is determined from urine as salicylic acid. Each
1 ml urine sample was mixed with 1 ml of concentrated hydro-
chloric acid, sealed and heated for 16 hours at 98C. The
sample is allowed to cool. 1 ml acetonitrile is added con-
taining the internal standard. The samples are subjected to
HPLC analysis and the SA detected by ultra-violet spectroscopy
at 313 mm.
The bioavailability trials are preferably continued for at
leas-t eight days. Further details are apparent from the trials
described hereinafter. The measured mean salicylate concen-
trations show an unexpectedly high availability of free
salicylate in the blood from the pharmaceutical compositions
of the invention, especially at anti-inflammatory therapeutic
levels.
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The trials as described hereinafter show the non-linearity
of ASA kinetics since the 0-8 hour AUC for free salicylate
for a dose of 3.9 gram ASA (1300 mg ASA given 3 times a day
in Trial A) at a dose of 3.9 9 ASA is disproportionately
higher than that for 2O6 gram ASA ( 1300 mg given twice a day
in Trial B). The urine excretion data show that for doses
of 206 9 ASA and 3O9 9 ASA the cumulation excretion of total
SA is similar and independent of dose.
These results suggest that at high doses of ASA at which
an anti-inflammatory effect occurs there is a constant satu-
ration of metabolic pathways (as indicated by the dose-in-
dependent cumulative urinary excretion values). We have found
that the plasma concentration of free SA increases dispro-
portionately to the dose at high doses of ASA. We believe
that this may be due to a combination of the effect of
clearance of the unbound ASA and the ratio of protein-bound
SA to unbound SA in plasma. When metabolism is saturable
clearance should decrease but when protein binding is saturated
clearance increases. Therefore the steady state concentration
of free SA may depend on the magnitude of each of these two
effects.
The pharmaceutical compositions of the invention have a longer
elimination half life (e.g. greater than 9 hours) than that
of immediate release ASA pharmaceutical compositions. In the
case of immediate release ASA compositions large peak-to-trough
ratios of free SA may occur which may provide periods of in-
creased metabolism of SA resulting in lower steady state levels.
The pharmaceutical compositions of the invention on the other
hand provide therapeutic concentrations of SA at lower daily
doses than immediate release ASA pharmaceutical compositions.
and have less GI-irritating potential.
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7 100-6970
The pharmaceutical compositions of the invention may be
administered for all indications that ASA is indicated for~
in particular pains of rheumatism, arthritis, lumbago,
neuralgia, neuritis, sciatica and bursitis (anti-inflammatory
indications)~ fever and cerebral ischemic attacks.
~or anti-inflammatory indications a dose of about 600 to
1300, e.g. 650 to 1300 mg, ASA every 8 to 12 hours is satis-
factory~ Daily doses contemplated are from about 2.6 to
about 3.9 9. Analgesic and anti-pyretic indicated doses
are from about 300 to about 700 mg, e.g. 325 to 650 mg. For
rheumatic fever daily doses of 100 mg ASA/kg body weight
may be given in divided doses every 8 to 12 hours to counter-
act pain, swelling and fever. For cerebral ischemic attacks
an indicated dose is 650 mg every 12 hours.
In another aspect the present invention provides an oral solid
pharmaceutical composition comprising at least 300 mg acetyl-
salicylic acid in sustained release form and capable of providing in the
steady state on administration of an acetylsalicylic acid daily
dose of 2.6 9 in divided doses 2 or 3 times a day a si~nifi-
cantly higher blood plasma free salicylic acid concentration
than that obtained on administration of immediate release acetylsali-
cylic acid tablets given at the same daily dose in divided doses every
4 hours.
Conveniently the pharmaceutical composition contains 300 to
700 mg ASA and has dissolution rate at 37 C in water of from
15 to 40 per cent in 1 hour and not less than 70 9O/ at 8 hours.
Prefera~ly in 1 hour from 20 to 35 per cent is released.
Conveniently at 8 hours from 70 to 90 per cent eOg. 80 to
90 per cent is releasedO
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The following examples illustrate the invention.
In the Examples:
Microcrystalline cellulose has a molecular weight of from
30,000 to 50,000: ~mean particle size 30-100 microns; specific
gravity 1055; tap volume 0.30 to 0.80~ The material used was
the brand Avicel PH 102 (Registered Trade Mark) available
from FMC Corporation, Marcus Hook, USA. It complies with
specifications given for microcrystalline cellulose in
USP/National Formulary XXI.
Hydroxypropyl methylcellulose 2208 has a number average
molecular weight of 120,000; viscosity approx. 15,000 cps:
a 19-24 per cent hy weight methoxyl content and a 4-12 per
cent by weight hydroxypropyl content. Used was brand Methocel
K15M Premuim (Registered Trade Mark) available from Dow
Chemical Company Michigan USA. It complies with specifications
given for hydroxypropyl methylcellulose 2208 in USP XXI.
Pregelatinized Starch is a modified corn starch and comprises
5 per cent amylose, 15 per cent amylopectin and 80 per cent
unmodified corn starch. It is partially cold water soluble.
The material used was the brand Starch 1500 (Registered Trade
Mark) available from Colorcon Inc., West Point, Pennsylvania.
USA. It complies with the specifications given for pregela-
tinized starch in USP / National Formulary XXI.
Colloidal silicon dioxide was the brand Cab-0-Sil (Registered
Trade Mark) available from Cabot Corporation, Boston, Mass.USA.
It complies with the specifications given in USP/~National
Formulary XXI.
The ASA used are 40 mesh crystals. The immediate release for-
mulation used as reference in the bioavailability trials was
brand Bayer Aspirin (Registered Trade Mark).
3 .S 2 ~ O q
Further specifications for the above products are available
in Manufacturer's brochures and in Lexikon der Hilfsstoffe
by H.P.Fiedler. Second Edition 1981~ Editio Cantor~Aulen-
dorf, WOGermanyO
All other ingredients used meet the specifications laid down
by the USP XXIo
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EXAMPLE 1: 325 m~ ASA tablets
__.___ ____ _ _____
mg/tahlet
ASA 325.000
Microcrystalline cellulose 47.500
Hydroxypropyl methylcellulose 27.625
Pregelatinized Starch 22.100
Stearic Acid 2.125
Colloidal Silicon Dioxide 0.650
A charge to make up 1 million tablets is made up as follows:-
The above quantities are multipled by 1 million,e.g. 325 kgacetylsalicylic acid are used. 50 kg of acetylsalicylic acid
are mixed with the silicon dioxide. The remaining acetylsali-
cylic acid, hydroxypropyl methylcellulose, silicon dioxide/
acetylsalicylic acid mixture, microcrystalline cellulose and
pregelatinized starch are introduced in an alternating fashion
into a 30 cubic feet twin shell blender. Mixing is effected for
15 minutes. 40 kg of the mixture is removed. The remaining
mixture is passed through a 20 mesh (aperture size 1.00 mm ;
wire diameter 0.63 mm) stainless steel screen on an oscilla-
ting granulator~ The 40 kg unscreened mixture and the stearic
acid are mixed for 5 minutes, screened through a 20 mesh stain-
less steel screen as described above with an oscillating granu-
lator, and mixed ~ith the previously screened mixture. Mixing
is effected.for 15 minutes using a tumbling action to produce
a granulate. The granulate is then tabletted on a rotary tablet
press. Tablet weight 425 mg. Thickness 4.68 - 4.85 mm. Hardness
8-12 Kiloponds (Heberlein method).
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Dissolution release data (average of 6 tablets) in water at
37C:
Per cent release of ASA
Lot 1 Lot 2
1 hour 23.1 30.3
2 hour 39.4 45.4
3 hour 51.2 57.0
4 hour 61.4 65.9
6 hour 72.5 76.5
8 hour 80.7 &6.6
12 hour 87.1 93.6
EXAMPLE 2: 650 m~ ASA tablets
In analogous manner to that disclosed in Example 1 are pro-
duced tahlets each containing:
mg/tablet
ASA 650.000
Microcrystalline cellulose 95.000
Hydroxypropyl methylcellulose55.25
Pregelatinized Starch 44.20
Stearic Acid 4.25
Colloidal Silicon Dioxide 1.30
The batch size is for 500,000 tablets. The resultant tablets
have a weight each of 850 mg and thi-ckness 6.25 to 6.40 mm.
~issolution release date (average of 6 tablets) in water at
37~C:-
Per cent release of ASA
Lot 1 Lot 2
1 hour 21.5 26.8
2 hour 34.4 39.9
3 hour 44.2 49.8
4 hour 53-4 57-7
6 hour 66.1 69.0
8 hour 75.7 77.1
12 hour 86.9 85.7
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Trial A:
Steady State Bioavailability of 1300 mg ASA according to
the i~nvention administered 3 times a day
The pharmaceutical composition of the invention described
in example 2 (650 mg ASA tablet) was administered at a
dose of 2 tablets to 12 healthy male volunteers at 7 am,
3 pm and 11 pm on days 1 to 8 and at 7 am on day 9. The
total daily dose was 3.9 9 ASA.
An immediate release formulation was given at a dose of
325 mg tablets every 4 hours from 7 am to 11 pm on days 1
to 8 and at 7 am and 11 am on day 9. The total daily dose
was 3~25 9 ASA.
Each subject received the two formulations in a 9 day study
session according to a random sequence. The wash-out period
at the end of the study session was 6 days.
Blood samples were obtained on day 8 at 7 am (pre-dose) and
11 am (pre-dose) and on day 9 at 7 am (pre-dose) and 1, 2,
3, 4 (pre-dose in the case of the immediate release formu-
lation), 5, 6, 8, 10 and 12 hours following drug administra-
tion at 7 am.
Statistical evaluation for both formulation on days 8 and 9
indicated that both were at the steady state for
the day 9 bioavailability study.
The results obtained for the measurement of free plasma
salicylate in the blood were as follows (REFERENCE = imme-
diate release formulation):-
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Results:
Day 9 (Steady-State)
Mean Plasma Salicylate
Concentrations (mcglmL)
3.9 G/day 3.25 G/day
Sampling Time EXAMPLE 2 REFERENCE
(hour) 2 x 650 mg q8h 2 x 325 mg q4h
0 113.90 + 56.14* 56.29 + 36.90
1.00 117.91 + 56.02* 68.55 + 37.07
2.00 114.17 + 57.27* 72.53 + 31.12
3.00 118.58 + 61.07* 68.54 + 39.81
4O00 117015 + 59.25* 54.49 + 32.29
5.00 115.66 + 58.85* 67.02 + 27.50
6000 111082 + 57.34* 64.28 + 21.55
8.00 94.20 + 57.19* 54.57 + 29.53
10.00 82.82 + 49.36* 41.94 + 26.46
12000 68.11 + 52007* 30.02 + 23.23
* The two formulations differ statistically at the 5
level or greater.
Pharmacokinetic Indices for Salicylate at Steady-State (Day 9)
EXAMPLE 2 REFERENCE
2 x 650 mg q 8 h 2 x 325 m~ q4h
0 - 8 hr AUC (mcg-hrs/mL)902.35 + 456.88* 510,26 + 227.46
max (mcg/mL) 128.00 + 60.54* 83.81 + 33.20
Tmax (hours) 3.08 + 1.51 3.42 + 1.88
t 1/2 (hours) 10.15 + 5.38* 5.00 + Z.37~
el (hours 1)1) o.og + 0.04* 0.17 + 0.09
* Statistically different at the 5~O level or greater.
^ Calculation on numbers after second dose.
1) Elimination constant
Relative 0 - 8 hr AUC (~) 177.26 + 57.61
Relative Cmax (%) 153.18 + 47.92
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Evaluation of results
Statistical evaluation of steady-state plasma salicylate
concentrations usina appropriate statistical tests (paired
t-tests) showed significantly higher plasma concentrations
for the Example 2 formulation at every time point. The in-
crease in plasma free salicylate levels is greater than
predicted even if a 3.9 gram dose of the reference formula-
tion had been administered. Statistical evaluation showed
that the mean 0-8 hours AUC and mean Cmax were significantly
higher for the Example 2 formulation. Adjustment of the mean
0-8 hour AUC to a 3.9 g/dose for each product provides an
estimated relative bioavailability of the Example 2 formula-
tion of the invention of 147 per cent that of the reference
product. The Example 2 formulation of the invention showed a
significantly longer half-life and smaller Kel.
The total salicylate concentration in urine was measured
over 24 hours on day 9. Values obtained for the Example 2
formulation were 1488.42 + 531.08 mg and for the reference
formulation 1265.97 + 572.16 mg. These values are similar.
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1 3s280q
Trial B:
Steady-State Bioavailability of 1300 mg ASA according to
the invention administered twice a day
The Example 2 formulation (650 mg ASA tablet) was admini-
stered at a dose of 2 tablets to 6 healthy male volunteers. 3 of
whom had completed the previous trial A at 7 am and 7 pm
for 8 days with a final dose at 7 am on day 9. The total
daily dose of ASA was 2~6 gOThe protocol was the same as that
discussed above except for the lower dose.
Statistical evaluation on day 8 and day 9 indicated that
the steady state had been achieved by day 9.
The results obtained up to 12 hours after
drug administration are given below:
Day 9 (Steady-State) Mean
Plasma Salicylate Conc. (mcg/mL)
Sampling Time Example 2
(hour) 2 x 650 mg ql2h
0 49.70 + 21.16
1.0 54.82 + 22.75
2.0 58.72 + 22.53
3.0 62.19 + 23.31
4.0 59.90 + 23.18
5.0 55087 + 25.84
6.0 55.18 + 22.04
8.0 47~22 + 24.77
10.0 42.98 + 24.19
12.0 34.72 + 20.09
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1 332~0q
The 0 - 8 hour AUC was calculated as 446 + 182.46 mcg-hours/
ml. Cmax was 64.11 + 21,78 (mcg/ml).
The results indicate that the dose of 2.6 9 ASA gi ven as
a dose of 1 300 mg ASA twice a day in a formulation according
~the invention provides comparable plasma free salicylate
levels to the immediate release formulation at a dose of
3025 9 ASA given as a dose of 650 mg ASA five times a day.
Urine total SA concentrations are also measured over a 24
hour periodO The cumulative total SA was 1322 + 162 mg.
This value is similar to the values found in Trial A.
