Note: Descriptions are shown in the official language in which they were submitted.
Description of the Prior Art
A number of sustainet release theophylline products ha
been descr~bed in the literature ant are presently commercially
available. They are of two types, hard gelatin capsules, and tal
The hart gelatin capsule products conta~n an aggregation of tiny
beadlets which are constituted of an edible core such as a non-p;
pellet which is coated with alternating layers of active ingredi
and an insoluble delayed release lipid substance. Techniques ha~
been developet for manufacturing beadlets having ~arious drug re:
rates. By employing ~arious proportions of beadlees ha~ing diff
release rates in a single capsule, a composite release rate of
~'
S '~ t~ J ~'~
.,, ; '` ~ ,
- ~165241
-- desired duration and magnitude can be obtained. This prior art is
not relevant to the present invention, but is of interest as back-
ground. It is typified by U.S. Patent No. 3,080,294 patented March 5,
1963 by Shephard. and V.S. Patent No. 3,782,993 patented January ~,
1974 by Rothgang, et al.,
Controlled release tablets have been prepared by tableting
aggregates of beadlets of the foregoing type, or by preparing a
granulation and coating the individual granules with delayed release
coatings of varying release rates. U.S. Patent No. 3,344,029 patented
September 26, 1967 by Berger is representative of this type of
sustained release product. Sustained release tablets comprising a
fatty or other insoluble matrix in which the drug substance is
embedded for slow release are also known. Typical of this type are
Cain, et al., U.S. Patent No. 3,402,240 (September 1968), Costello,
U.S. Patent No. 3,062,720 (November 1962), and Hotko, et al., U.S.
Patent No. 3,456,049 (July 1969).
Tablets and capsules of these types have the disatvantage
of requiring rather large amounts of carriers or excipients to effect
the release rate. For drugs atministered in high tosage amounts and
at frequent intervals such as theophylline, a rather large tablet or
capsule is necessary, or multiple tablets or capsules for a single
tose are required.
U.S. Patent No. 3,279,995 patented October 18, 1966 by
A. F. Reld refers to a shaped pellet having a bi-concave flanged
configuration which remains intact during tissolution and affords a
substantially uniform surface area throughout the dissolution period.
While thls principal is involved with the present invention, the
intricate shape referred to by Reid is not.
1165Z41
~~ Since a preferred embodiment of ~ne present invention is a
shaped tablet comprised almost exclusively of theophylline, applicants
have surveyed commercially available controlled release theophylline
products, and the literature to ascertain whether any theophylline
tablet has been previously described or is in current use which
contains lietle in the way of carriers or excipients. They ha~e
found that presently available sustained release theophylline tablets
and capsules contain from 17% to 52% by weight of active ingredient
and are, thus, clearlv distinguished from the preferred products of
the present invention. Applicants are unaware of any previous descrip-
tion of the tableting of theophylline by compression without carriers
or excipients.
Field of the Invention
.~
The present invention provides a new controlled release
theophylline tablet, and the method of maintaining therapeutically
effective theophylline blood concentrations in patients undergoing
theophylline therapy by oral adminlstration of the tablet at intervals
of up to 12 hours turing an extendet trestment periot. The tablet is
non-tisintegrating in nature so that tissolution takes place solely
from the surface ant in a preferret form contains in excess of 95% by
weight of theophylline.
Theophylline (1,3-dimethylxanthine) has an established role
as a bronchodilator and has other therapeutic actions. The drug is
rapidly absorbet from the gastrointestinal tract and is readily
metabolizet ant eliminatet from the blood. The rate of clearance
varies considerably among individuals. Consequently, patients on the
uQually recommented four times a tay dosage regimen using conventional
1165241
immediate release dosage forms, may exhibit wide variations between
the maximal values and the minimal values of theophylline concentrations
in their blood which translate into fluctuations in therapeutic
beneit as well as incidence of side effects.
Aside from its effects on smooth muscle, theophylline
causes stimulation of the central nervous system to produce nervousness
and seizures, acts on the kidney to produce diuresis, stimu1ates the
cardiac muscle to increase both rate and force of contraction, and
dilates blood vessels. These actions are generally considered to be
responsible for the side effects which may include headache, dizziness,
nervousness, nausea? and vomiting, and for some patients militate
against use of the drug unless the dosage amount is carefully adjusted.
Serious adverse reactions which involve the cardiovascular
system ant the central nervous system may occur when blood serum
lS concentrations of theophylline exceed 20 mcg/ml. There is a wide
lntividual variation in the pharmokinetics of theophylline. Elimination
half-tife of the drug commonly ranges from 3 to 13 hours in normal
human sub~ects. Variation in hepatic enzymes between individuals mav
tccount for the variations in theophylline clearance rate. Because
of this variability, there 19 no single dosage that can be recommended
for malntenance therapy of all patlents, ant monitoring of serum
theophylline levels is sometimes necessary to accurately individualize
the tose.
Summary of the Invention
It has been fount that theophylline in crystalline pulverulent
form can be compresset into pharmaceutical tablets without the use of
conventional pharmaceutical carriers or tableting aids. A tableting
- ~6S24~
lubricane in an amount of from 0.1% to 0.6~ by weight is, however,
preferred when a continuous tableting machine run is conducted. The
tablets of the present invention have the characteristic of remaining
intact durlng dissolution and of thus dissolving over a rather
prolonged period of time rather than in a very short period as is
usual with tablets that disintegrate on exposure to a dissolvin~
medium. By presentation of such a non-disintcgrating compressed
tablet in a configuration whose surface area changes little during
dissolution, a sustained release effect is obtained. One such
configuration is very thin in cross section and has substantially
planar opposing faces large in area relative to the area of the edge
walls. It has also been found that with administration of such a
tablet delivery of a therapeutic dose of from 100 to 500 mg of theophylline
during a period of from 6 to 12 hours following ingestion is possible.
Dumping or i ediate release of the dose following ingestion as
occurs with a tisintegrating tablet does not occur. The present
invention thus provides a process for sustaining a relatively constant
bloot serum level of theophylline within the therapeutic range in a
patlent requiring theophylline treatment which process involves
repeatet administration of such a tablet at suitable intervals of up
to 12 hrs. The extremes of minimal ant maximal blood concentration
characterized by the atministratlon of immediate release theophylline
dosage forms is ~voidet.
Brief Description of the Drawings
Figs. 1 ant 2 illustrate respectively a top view and a
side view of a disc shaped tablet of the present invention having a
1~6SZ41
-- logo marking on the top face and a score line for bisecting the
tablet on the bottom face.
Fig. 3 is a perspective view of a tisc shaped tablet of the
present invention having no score line or logo.
S Figs. 4, 5 and 6 are, respectively, a top view, a bottom view,
and an end view of a rectangular tablet of the present invention.
Fig. 4 illustrates the top face of the tablet having a logo and two
score lines for trisecting of the tablet. Fig. S illustrates the
lowerface of the same tablet having a single score line for bisecting.
Fig. 7 is a perspective view of a tablet similar to that
illustrated in Fig. 4 except that no logo is present on the top face.
Detailet Description of the Invention
The compressed pharmaceutical tablet of the present invention
contalns at least 95% by weight of theophylline and up to 5% by weight
of conventional tableting ingredients, but it may consist entirely of
theophylline. In one preferred form the sustained release tablet of
the present invention contains from 95% to 99.8% by weight of theophylline
and the remainter conventional tableting ingredients including at least
a tableting lubrlcant ln an amount of from about 0.1% up to about
0.6% by welght. $n a preferred form, the tablet contalns at least
99% ant more preferably from 99.4% to 99.8% by weight of theophylline
ant a tableting lubricant, preferably magnesium stearate i~ an amount
of 0.1~ to 0.6% by weight. The most preferred composition is 99.6%
by welght of theophylline ant 0.4% by welght of magnesium stearate
with no other ingretlents being necessary or tesirable. Other lubricants
such as stearic acit may be employet, but the effect thereof on
tis~olution characteristics as disclosed herein must be evaluated as
~hown below.
- 1~6SZ41
~ The tablets of the present invention have the chnracteristic
of being non-disintegrating on exposure to a dissolving medium such
as water or gastrointestinal fluids. That is, they remain intact
turing the dissolution period, and the dissolution rate is directly
proportional to tlle surface area of the tablet at any given time
during the dissolution period. This results in a relatively steady
dissolution of the drug when a tablet shape is selected which changes
little in total surface area as the tablet dissolves. The area of a
sphere, for instance, changes in proportion to the square of the
radius, and therefore exhibits the greatest change in area of any
tablet shape during dissolution. Thus, spherical or ovoid shapes
approaching the spherical are undesirable for present purposes.
The simplest and preferred form of the present tablet is
thin in cross section between relatively large and substantially
parallel and planar opposing faces such that the area of the faces is
large in comparison to the area of the edge walls. The minimal
tablet thickness considering convenience of manufacture ant durability,
total surface area, and ease of swallowing, is about 0.08 inches. It
has been determined empirically that the maxlmum thickness for such
tablet is aboùt 0.12 inches for delivery of a tose of theophylline of
from 100 mg to 500 mg at a rate to sustain a blood level of from
10-20 mcglml on repeated administration. A 500 mg tablet in the form
of a disc having a thickness of 0.12 inches has a diameter of about
17/32 inch. Thinner tablets have a greater diameter. This, in part,
is the reason why a 300 mg tablet ~ize is preferred since smaller
witths ant lengths tictatet by the constraints on tablet thickness
are possible. A tablet thicker than 0.12 inch may exhibit a dissolution
1165Z4~
"; rate which chan~es excessively as dissolution progresses. Also, the
tissolution rate of a thicker tablet may be less than required to
provide lOOX bioavailability. A thin dimension between substantially
parallel ant planar faces in combination wieh a non-disintegrating
nature characterizes the tablets of the present invention. The
preferred tablet thickness is 0.09 to 0.11 inches.
While the preferred embodiment is a thin tablet compriset
almost wholly of theophylline as indicated above, it is nevertheless
possible to practice the invention with compositions containing
somewhat lower proportions of theophylline in combination with
conventional tablet ingredients. The additional ingredients are
seIected to provide a tablet that remains intact turing thq disso-
lution period, ant thus those materials which cause tablet dlsinte-
gration such as corn starch or resins or gums which swell an contact
wlth water are to be avoided. Also, those ingretients which rapidly
tissolve in water or gastrointestinal fluids are undesirable when
us-t in high proportion since pltting of the tablet surface will
occur on exposure to the tissolution medium resulting in an increased
rate of tlssolution. Exclpients of possible utillty are glucoqe,
gucro~e, lactoge, ~annitol, ant sotiuw chlorlte. ~nsoluble excipients
ln selectet amounts such as calcium phosphate ~ay also be employet.
For a tablet which contains 95Z or more of theophylline,
tablet hartness toes not appear to be relevant to the tlssolution
-characteristics 80 long as the tablet toes not tisintegrate while
dlg~olvlng. Accortlngly, any tablet hartness convenlent with respect
to hantllng, manufacture, storage, ant lngestion in the range of
about 8 to 22 SCU is applicable. When uslng exclpients ar.t other
- 8 -
.
,
116SZ41
eablet ingredients as referred to above in higher proportion ta~lct
hardness may have an effect on the dissolution rate.
Ingredients for inclusion in a tablet according to the
present invention are selected empirically by measurlng the disso-
S lution characteristics of experimental batches of theophyllinetablets containing the various ingredients in the desired proportions,
and then modifying the composition ingredient-by-ingredient in step-
wise fashion until the desired dissolution characteristics are
achieved. Thi~ empirical approach to selecting tablet ingredients is
described ~ore fully hereinafter.
In the final analysis, a tablet composition is chosen on
the basis of the bioavailability of the theophylline contained
therein ant the blood plasma concentration thereof resulting on
repeated atministration of a uniform dose at intervals of from 6 to
12 hours, preferably the latter. The target values are absorption of
90% or more of the theophylline contained in an individual tablet
within 24 hours following ingestion, and on repeated dosing at
intervals of 6 to 12 hours maintenance of a blood serum concentration
of theophylline within the therapeutic range. For bronchodilator use
the acceptet therapeutic bloot serum concentration ran8e i5 about 10
to 20 mcg/ml. Doses of sultable size within the range of from about
100 mg to about 500 mg of theophylline per dose are employed for
bronchotilator use on a dosage interval of about 12 hours with atjust-
ment to a shorter interval, if necessary, to affort the desired blood
serum concentration.
A preferred conflguratlon contains 300 mg of theophylline
in a rectangularly shapet tablet having bisect and trisect scores to
provide 2 or 3 subunits of equal size. This i~ unique in that a
11~;5~41
single tablet can thus provide dosage units of 100, 150, 200 or
300 mg of theophylline or multiples thereof for convenience in
dosage size ad~ustment. Its sustained release character is not
altered by administration as subunits of lt3, or 1/2 the original
tablet size, and it provides a steady state theophylline blood serum
concentration in the generally recommended therapeutic range o f 10 to
20 mcg/ml when administered in suitable amount on a twice-a-day
schedule (every 12 hours).
Further Detailed Description of the Invention
The present invention also provides a method for maintaining
a therapeutically effective blood serum concentration of theophylline
by repeated oral administration of the foregoing tablet to a patient
requirlng theophylline therapy during an extended treatment period.
The requiret therapeutically effective blood serum concentration is
flrst ascertained by reference to the practice in the art with respect
to the partlcular disease condition being treated. For bronchodilator
use a therapeutically effective bloot concentration ls generally
reBarted a~ 10-2~ mcg/ml, but for some patlents a therapeutic effect
ls achleved wlthln the range of 5-10 mcg/ml of theophylllne.
Experlmental methots are avallable for teterminlng the rate
of theophylline clearance and the plasma half-life values relative to
theophylline for lndlvidual sub~ects. Methods are also available to
calculate the size of the dosage unit required to establish a given
theophylline bloot concentration in the patlent from the rate of
clearance and plasma half-llfe values. The half-life of theophylline
in the blood serum varies among individuals with a wide range having
been documented. Representative values are shown ln the following
table.
-- 10 --
116S~4~
Representative Theophylline Serum l~alf-Lives
Half-Life tHours)
Mean Range
Atults
non-smokers 8.7 6.1-12.8
smokers 5 5 4 0_ 7 7
congestive heart failure 22.9 3.1-82.0
Children (6-16 years~ 3.7 1.4- 7.9
Therapy with theophylline ordinarily takes place over an
extended period of from three or four days up to several weeks or
months depending upon the patient's condition. In some instances in
ehe treatment of asthma, administration is commenced on the appearance
of symptoms and then continued for three or four days after symptoms
disappear. In others, dosage mav be on a seasonal basis for a period
of weeks or months when the exacerbation of symptoms is com~on.
With the tablet of the present invention the average
initial dose for children under 9 years of age is 100 mg of theophvlline
every 12 hours, e.g. one trisectional portion of a scored 300 mg
tablet. For chiltren of ages 9 to 12 years the average initial tose
with the theophylline tablet of the present invention is 150 mg of
theophylline every 12 hours. For adolescents of ages 12-16 years
the average dose is 200 mg every 12 hours, ant for adults 300 mg of
theophylllne every 12 hours. For those patlents who are rapid
theophylline metabolizers, such as children of 6-16 years or smokers,
the tosage interval may be retucet, for instance to 8 hours. The
optimal dosage size and amount can ortinarily be teterminet by
observation of the therapeutic results achieved, ant the site effects
encounteret, or bloot seru~ analyses for theophylline may be mate.
.~ .
-- 11 --
. ~, . . .
1:1`6SZ41
Theophylline therapy according to the present invention
employing the unique sustained release tablet provided thereby is
distinguished from therapy wlth conventlonal lmmediate release
theophylline tablets of the prior art by the fact that the required
dosage interval during an extended treatment period is usually
doubled. This is of great practical benefit because the normal
regimen with immediate release tablets requires treatment every six
hours which is an inconvenience and impediment to patient compliance.
The regimen provided by the present invention permits dosage at
12 hour intervals which not only is a convenience but also an important
aid to achieving patient compliance.
Description of Specific Embodiments
Tablet Composition A. Th_ophylline 99.6%, Magnesium Stearate
0.4%.- A granulation i9 prepared by treatlng 300 g of anhydrous
theophylline with 45 mlof water in a mixer followed by drying in a
forced air oven at 60C until the moisture content is less than 1~.
The granulation is then comminuted ant blendet with 1.2 g of magnesium
8tearate. The resulting blend is suitable for tableting on a conventional
tableting machine to a tablet hardness withln the range of from about
20 7 to 9 SCU. The foregoing batch provites one thousand 300 mg tablets
or slx hundred 500 mg tablets.
Tablet Composition B. 95.4% Theophylline, 4% Tableting Aids.
0.6% Ma~nesium Stearate.- A granulation is prepared from a drv blend
of 500 g of anhydrous theophylline ant 10 g of hydroxypropyl methyl-
cellulose (15 cps), with an aqueous solution Oe 10 g povltone, USP,
ln approximately 75 ml of water. The granulation ls then drled in a
- 12 -
.
4i
forcet air oven at 60C until the water content is less than l~.
The dried gsanulation is comminuted, and then blended with magnesium
stearate, 3 g. This blended composltion is then compresset in a
conventional tableting press to provide tablets having a hardness of
from 8 to 2~ SCU. The batch provides one thousand 500 mg tablets or
a greater number of smaller tablets.
In Vitro Dissolution Method.- Dissolution Test Method II
as described in U.S.P. XIX, 4th Supplement, is convenient for the
measurement of the dissolution characteristics of tablets made
according to the present invention. Briefly, the method involves
placing an individual tablet in 900 ml of water at 37C in a
l liter dissolution kettle bearing a paddle type agitator which is
operated at 50 rpm. Aliquots of the dissolution medium are removed
at intervals, filtered, and analy~ed spectrophotometrically for
dissolved theophylline using a wave length of 268 nm, and a standard
reference curve prepared by measurement of the absorption of solutions
of pure theophylline having various concentrations measured in the
same ashion as the test solution.
Bioavailability.- An open, slngle tose, cross-over clinical
stuty employing 12 normal volunteers was employed to determine the
bioavailability of varlous tablets prepared according to the present
lnventlon. A commerclally available immediate release theophylline
product served as reference. Twelve non-smoking male volunteers were
selectet using the following criteria as grounts for exclusion from
the stuty.
a. Abnormal pre-treatment hematology, urinalysis, or
blood chemistrles
.'
- 13 -
ll6æ4l
- b. Systolic blood pressure greater than 150 mmHg and/or a
diastolic blood pressure greater than 100 mmH~
c. History of severe physical or mental disease
d. Evidence of gastrointestinal disease (l.e., peptic or
duodenal ulcer, colitis, recurrent diarrhea)
e. History of hepatitis or liver dysfunction
f. Diabetes mellitus
g. Thyroid disease
h. History of seizures
i. Ingestion of any medication for 7 days prior to the
test period, and/or a xanthine containing medication
for 15 days prior to the test period
j. Ingestion of xanthine-containing foods (coffee, tea,
chocolate, cola beverages) for 24 hours prior to the
test day
Subjects fasted from bedtime of the night prior to the test day until
after the 4 hr blood sample hat been withdrawn. A light meal
without coffee, tea, chocolate, cola beverages, butter or cream was
eaten after the 4 hr 8ample, and again between the lO hr and 12 hr
~ample collections. Participants presented to the testing unit prior
to 6:00 p.m. on the day before the test tay for domiciling over the
next 32 hours.
A single dose of one of the test tablets was atminlsteret
to the sub~ect with lO0 ml of water at 8:00 a.m. of the test period.
2S For each subject a crossover test periot wlth the immediate release
theophylline reference standard was employed. Test periods were
separatet by periods of one week. Blood samples of sufficient
~ 14 _
~165Z4~
volume to deliver 5 ml of plasma were drawn immediately prior to
drug administration and at 1/4, 1/2, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12,
16, and 24 hours thereafter. Plasmas were analyzed for theophylline
by the high pressure liquid chromatographic method of Weddele and
S Mason, J. Pharm. Sci., 1976 65:865. A graph was prepared of plasma
theophylline concentration versus time. Areas under the curves
extrapolated to infinitv were deter~inet by a standard mathematical
mechod, and were used to calculate percentage bioavailability by
comparison of the area under the curve for a test tablet with that of
the immediate release reference standard.
In vitro tissolution and bioavailabilities were determined
according to the foregoing methods for four disc-shaped tablets and
one rectangular tablet having the compositions shown in the following
table where the results are arranged. Dissolution data for a second
similar rectangular tablet are also shown in the table.
- 15 -
. . . .
116SZ41
~_~
.
,~ r ~O ~O ~ ~O
_~ ~ I~ O O~ O~ I X
_~
a
:~ C
~t~ ~ .
_ ~
3 ~t -
l
~o C ^
1 ~ C C
~ _ C~ X oo ~ o ~
_l ~_ . o U~ tJ C
C
,1 x
a U~ O ~ u~ c c-,
o
o U~
O U V U O O
~ e e ~ ~ +
o ~ ~ e u~
0 E~ ~ ~ 33 e
~ " CI o~ oo o 8 u~ o o
~ ~ ~c ~1 o o o o o o O ~ O ~
'v 4~ v e
t~ ~o o
_1 e e e e e 6 ~ I Co~
o~3 o o oO o o o ~ o U
e ~ o
e 0 è o~
U U
, v ~v
;~ Z o ~ ~ o
,:'
-- 16 --
- 116SZ4~
Tablet 051 having a thickness of 0.15 inches but otherwise
conforming to the present invention was found to have a bioavaila-
bility of 76% that of a conventional immediate release tablet.
Modification of the composition of this tablet by inclusion of a
small quantity of hydroxypropyl methylcellulose as a tablet disintegrant
and povidone as a granulation ingredient as shown in tablet 111
resulted in a bioavailability of 86%. Each of tablets 181, 191 and
701 had the same composition but different tablet shapes and thick-
nesses as shown in the table. Each exhibited a bioavailability in
excess of 90~. These tablets and tablet 202 constitute preferred
embodiments of the present invent~on.
It is significant and surprising to note that tablet 201, a
rectangular tablet having opposing bisect scores on the edge walls
and opposing trisect scores on the planar faces, exhibited substantially
the same in vitro dissolution rate as indicated in the foregoing
table whether the intact tablet, the bisectet tablet, or the trisected
tablet was employed for the measurement. While co-pending application
Serlal No. 024,139 filet ~arch 26, 1979 and now U.S. Patent No. 4,215,104
patented July 29, 1980 tiscloses rectangular tablets scored on
tifferent faces for optional bisecting, or trisecting by manual
breaking, there is no suggestion in that patent that such a tesign
woult be suitable for a controlled release tablet. However, wlthin
the narrow constraints of the present invention, trtsecting or bisecting
of a theophylline tablet containing from 100 to 500 mg thereof,
having substantially planar faces, and a thickness of from 0.08 to
0.12 lnches has no practical effect on the dissolution rate. The
entire disclosures of application Serial ~o. 024,139 cited above, and
..~
- 17 -
1165241`
of related application Serial No. 121,615 filed February 14, 1980 and
now U.S. Patent No. 4,258,027 patented March 24, 1981 are of some
interest herein.
Screening of Tablet Ingredients - Tablets were preparet as
.
described above for Composition A but containing varying amounts of
magnesium stearate; and 250 mg of anhydrous theophylline. The tablets
were disc-shaped, 13/32 inches in diameter and 0.10 inches thick. The
in vitro dissolution values for each was determined as described
above, and the results obtained are shown in the following table.
Effect of Magnesium Stearate on Dissolution
Magneslum Percent Dissolved
Stearate
(% b~ wt.) 0 5 hr 1 hr 2 hr 3 hr 4 hr 5 hr 6 hr
None 28.4 51.5 82.2 93.7 95.3
0.3 22.2 41.1 70.1 86.1 93.8 94.5 95.8
0.4 20.0 36.4 62.3 80.1 89.9 95.7 97.0
0.5 20.0 34.4 58.9 75.2 84.7 91.4 94.9
0.8 14.7 25.0 41.6 54.3 64.4 71.8 78.9
It is evident that increasing the proportlon of magnesium
gtearate retards the rate of dissolutlon of the tablet. While the
tls~olutlon rates obtalned for the foregoing tablets except that
contalning 0.8% by weight of magnesium stearate were acceptsble, the
preferret range of 0.3X to 0.5% of magne~lum stearate, ant the most
preferred proportion of 0.4% was selected.
She foregoing method for evaluatlng the 0ffect of magnesium
~tearate on the tlssolution characterlstics of the resultlng tablet
can be applled to the screenlng of other tablet ingredients whlch lt
may be teslred to inclute in a tablet preparet accortlng to the
- 18 -
B
116S24~
present invention. Those ingredients are selected which provide a
tablet conforming to the following dissolution (percent dissolved)
criteria using the test described above: 0.5 hr, up to 35~; 1.0 hr,
30-54%; 2 hr, 55-89~; and 4 hr, 83-100~. Preferred dissolution
criteria are: 0.5 hr, up to 40%; 1.0 hr, 35-60%; 2 hr, at least
6070; and 4 hr, at least 85%.
Further Description of Specific Embodiments
A batch of tablets prepared as described above for Tablet
Composition A, Theophylline 99.6%, Magnesium Stearate 0.4%, was found
to have a slightly slower dissolution rate at the 4-hour interval,
79,9~, relative to the 4-hour target value referred to above, 83-
100%. A number of these tablets were comminuted through an appropriate
mill. Two portions of the ground powdered tablets were then diluted
with theophylline containing no additional magnesium stearate as
lubricant in the proportion of 1 part by weight of ground powdered
tablets to 1 or Z parts by weight of unlubricated theophylline.
These blents producet rectangular tablets when compressed as described
above containlng 0.2 and 0.13% magneslum stearate respectively by
weight. A portion of the ground tablets without added theophylline
wag algo tableted. The dlssolution properties of these three batches
of tablets were then tetermined according to the method referred to
above with the following results.
,~ - 19 -
v
,
116S241
Dissolution of 300 mg Contro~led Release Theophylline
Tablets Containing Low Levels of Magnesium Stearate
Dissolution, % Dissolved (Avg 6 Tabs)
_ 1.0 2.0 3.0~~4.0
Original tabletsl 20.9 35.6 56.4 - 79.9
Ground ~nd recompressed 19.0 30.4 46.9 - 68.7
tablets
Ground, diluted 1:1 ~nd 23.4 39.8 63.1 - 91.5
recompressed tablets
- 10 Ground, diluted 1:2 ~nd 28.9 50.7 ~8.696.1 102.5 recompressed tablets
1) 0.4% magnesium stearate
2) 0.2~ magnesium stearate
3) 0.13% magnesium stearate
The results show that retableting undiluted ground tablets
retarded the dissolution rate. Diluting of the ground tablets with
unlubricated theophylline followed by retableting increased the rate
of dissolution. The ground, diluted and recompressed tablets containing
0.13% and 0.2% by weight of magnesium stearate were well within the
target dissolution limits referret to above.
Bioavailability, Multiple-Dose Study.- Controlled release
tablets of the present invention (designatet Product B for this
study) havlng the composition ant shape of tablet No. 202 referred to
in the fir~t of the foregoing tables were comparet for thelr bio-
avallablllty on multiple tos~ng to an immetiate release commercialtheophylline tablet (designated Protuct A for this study). The
multiple dose study was conducted accorting to a two-periot, randomized
cross-over, open label teslgn ant employet 18 normal volunteers.
Each volunteer was evaluatet wlth a physical examination, medical
histroy, complete bloot chemistry (inclutlng tifferential whlte cell
count ant standart metical analysis-12~ and urinalysis. Only those
volunteers were accepted for the study who conformed to the following
crlterla.
- 20 -
1165~41
a. Non-smoking male subjects ~etween the ages of 21 and
40 years.
b. In excellent health on the basis of history, physical
examination. and the above described tests.
c. No history of trug or alcohol abuse.
d. Plasma theophylline clearance greater than or equal to
2.7 L.lhr. and plasma half-life less than or e~ual
to 9 hrs as determined in the preliminar~ test dose
- phase of the study described below.
e. Weight between 140 and 200 pounds and within 110% of
normal weight for height.
f. No theophylline-containing medication to have been
taken for 15 davs prior to the study and no other
medication of any kind for 7 days prior to the study.
Dosage was individualized for each sub~ect in a preliminary
test dose phase in which the clearance rate ant half-life of theophylline
ln the blood plasma following a single dose was determined. A single
oral 400 mg dose of Protuct A was taken at about 8:00 a.m. after
fasting for 12 hrs. The metication was swallowet with 100 ml of
water and no chocolate, tea, coffee, coca-cola or other caffiene
containing foot or beverage was permitted for 24 hrs before or
24 hr~ after the test dose. The sub~ects fasted for 2 hrs after the
test tose and 5 ml blood samples were collected ~ust prior to swallowlng
the test dose and 0.5, 1, 2, 3, 4, 5, 7, 9, 12 and 24 hrs after the
test dose. Plasma theophylline levels were measured from each of
these samples and the tata were uset to tetermine the clearance rates
ant the plasma half-life values. The appropriate test dose for each
- 21 -
1165241
subject to provide a mean steady state plasma concentration of
13 mcg/ml and a peak plasma concentration of 15 mcg/ml was then
calculated. The following table contains clinical information for
each of the 18 participants including the dosage s~ze determined for
use in the multiple dose phase of study and a notation as to adverse
drug reactions observed.
- 22 -
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116SZ41
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` The subjects were then assigned to one of two equal sized
groups using a randomization schedule. One group received Product A
on a dosage schedule for days 1 through 4 involving taking their
medication orally at 8:00 a.m., 2:00 p.m., 8:00 p.m. and 2:00 a.m.
and at 8:00 a.m. on day 5. Thosc receiving Product B took their
medication orally at 8:00 a.m. and 8:00 p.m. on days 1 through 4 and
at 8:00 a.m. only on day 5. No medication was administered on days 6
and 7 which served for wash-out of the prior medication, and then
each participant was switched to the other test product which was
administered according to the foregoing every six hour or everv
twelve hour schedule as appropriate. All doses of medication were
swallowed with 100 ml of water. Blood samples were collected as shown
in the following table. In each instance the 8 a.m., 2 p.m., and 8 p.m.
samples were taken prior to medication.
Blood Sample Schedule
Time of Day
Product Day a.m. p.m.
A 3 8, 2 8
4 8, 9, 10, ll, 12 2, 8
8, 9, 10, 11, 12 2, 4, 6, 8
6 8, 12
B 3 8 8
4 8, 9, 10, 11, 12 2, 4, 6, 8
8, 9, 10, 11, 12 2, 4, 6, 8
6 8, 10, 12 2, 4, 6, 8
Plasma theophylline concentratlons were determined by assay
and the results shown in the following table were calculated.
- 24 -
,,
.,
1165Z41
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~E ' x + I ,-~ +
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Data for only 16 of the 18 subjects were employed since two
subjects, one having Product A and the other Product B, tiscontinued
the study because of headache or nausea.
Dosing with the sustained release tablet of the present
invention (Product B) every 12 hours resul~ed in approximately the
same mean sceady state and maximal plasma theophylline concentrations
as did dosing with the commercial immediate release preparation
(Product A) at 6 hr intervals. A greater difference between the
maximal and minimal plasma concentrations was observed with Product B
but this difference was not deemed to be large enough to effect the
clinical performance. The areas under the plasma concentration
versus time curves and the maximal theophylline concentrations
observed in the blood plasma for each treatment were not statistically
tifferent. The results of this study clearly show that when Product B
of the present invention when administered on a 12 hr dosage schedule
results in plasma theophylline concentrations comparable to those
' obtained with Protuct A, a commercial immedlate release preparation
when atmlnisteret on a 6 hr tosage schetule. The plasma theophylline
concentrations achievet are within the generally recommended therapeutlc
range of 10-20 mcg/ml. To further lllustrate this latter point the
mean theophylline plasma concentration values achieved at the various
time Intervals ~ollowing the morning dose on tays 4 and 5 tsteady-
state contitions) with the present sustainet release tablet tProtuct B)
are shown in the following table.
- 26 -
116S24~
Mean Theophylline Plasma Conc. (mcg/ml)
Hours
Following
8 a.m. Dose Day 4 Day 5
0 10.8 10.0
1 11.8 11.5
- 2 13.4 12.9
3 14.8 14.6
- 4 15.6 15.0
6 14.8 13.9
8 13.2 11.8
11.2 10.2
12 9.5 8.6
The higher values at 0 time (before the 8 a.m. dose) appear to
reflect a diurnal variation in the elimination of theophylline by the
body.
,~
, , .
- 27 -
'
. .
