CA1165241A - Sustained release theophylline tablet having reduced bulk - Google Patents

Abstract

SUSTAINED RELEASE THEOPHYLLINE
TABLET HAVING REDUCED BULK
Abstract of the Disclosure Non-disintegrating theophylline tablets having a pair of opposing substantially planar surfaces and a very thin cross-section have a high bioavailability on ingestion and a relatively steady release rate permitting a 12 hr. dosing interval for maintenance of non-toxic therapeutic blood theophylline concentrations. Excipients or tableting aids are not required, but trace amounts of a tableting lubricant are preferably included to facilitate continuous large scale production.

Description

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.

~~ 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 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 .

, 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.

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.

.~ .

. ~, . . .

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 .

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 .' 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.

. . . .

~_~
.
,~ 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 ,:' - 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 ..~

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 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 , 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.

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 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.

....
.

C~
U U ~U
~ "
5 ~- u ~ ~ u C .. o o o ~ o o o t~ o o o o o o o ~ z ^ z z ~ z z ^ ^ æ ~ z z z z z I z ~u E~
Y Z Z Z
CC ~ ~
U U
¢ ~, ~
U~ ~J Q~ G~
a~
~ CJ r 'Z ~ OO~OOO OOOO~OOO~O
¢ ~ æ z ~ ~i z z z ~ z z z z cJ z z z u z C~
E~ ~ ~ ' Z Z
t,q ~
C C
C ~ oooooooooooooooo o J-~ ooooooooooooooooI o U ~ ~ ~ u~
X C ¢
. ~ eC~ la~
Ll ~ Ul o ~ U~ o o U~ ~ o o o o U~ o o U~ ~ o C ~ ~ C~ ~ ~ C~l ~ ~ ~ ~ ~ ~ ~ C~l C~l ~ ~ ~ ~ C`~ ~s ~o ~
~ C ::
e o ~ a~
~e cl ~ c ~ ¢ ~ c ~ ¢ c _~ ~ C 1~ q C 6 tll o) ,,. ¢
~: u~ 80

4 o o ~ ~ ~ o u~
o~ol .............. , ... ~.
æ~ ~ ~ 0 ~ ~ ~ 0 0 ~ 0 ~ 0 ~ ~ ~ 0 ~ ~ ~ Z
~ cl~o o ~ ~ ~~ ~ ~ ~ o ~o cn ~ 8 ~
2-- ¢ ~

5 E
~ ~ X ~ O ~ X

~ o ....

i5Z41 ` 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 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.

,, ., _ o a~
X ,~
E u~
-- ~ +1 ~ ~1 ,~
E E r~ r` ,-1 o ~ ~o I X ~ r~ ,; ~ ~
-- + I + I
~ ~E
.~ ~ E I~ ~ ~ c~
U~ C-- I~ CO
~E ' x + I ,-~ +
E o~
t~ ~G u~
~ uE ' ,~ +
u 0~, _ +1 ~0 ~n ~:,~
~ e ~ ~
e u 0 ~ u~ o E u ~a~D U3 ~
~0 ~ ~ , I ,_, ,~
_l O ~
,-1 0~ _~ o~ o ~ u:q ~ a~ o O'~ ~ ~ ,-~
S~
E~ CJ

O ~ E r-l `D ~ o ; ~ p ~u~ +l -~ +l ~0, ~ a Ul 0 , C U c ~ 3 C ~ ~ ~ oC o 3 a~
0 3 ~ ~ ` ~O C ~ ~,1 u O 1~~ 0 ~ O ~ U C
~ rPC ~ C S aU~ O ~ U ~U Uc ~O CJ U C C ~ C~

e~ 0 C ,~ o) Cl U C
o l ~ O
E~ U ~ 5 r-l C r~
* ~~ E, ~ 8 E tJ E
1- 0 U~ ~ ,-1 ~ 0 0 _~

o) ~: a su 0 ~ ~ ~ e ~ l~ ~ u ~~ t~ a~ r~ C
r-lo ~ ~ ~ x c ~t ~ ~ ~o ~o c u ~ ~ ~
~:O ~ ~ 0 5 E u z tn ~ ~ e 5 C ~Ea 1~ 5 ~ I I I I ~ I
a X ~ 0 x c x X
P4 ~ 0 5 ~3 e ~e u o u~

1~6SZ4~`
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.

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.
,~
, , .

' . .

Claims (23)

WHAT IS CLAIMED IS:

1. A pharmaceutical tablet for the sustained release of a therapeutic dose of theophylline during a dosage interval of up to 12 hours following ingestion comprised of 95% to 99.8% by weight of theophylline, and the remainder conventional pharmaceutical tablet ingredients selected to provide a tablet that remains intact during the dissolution period, said tablet having a pair of substantially planar opposing faces joined by edge walls and a thickness of from 0.08 to 0.12 inches.

2. The pharmaceutical tablet of Claim 1 which when admin-istered to an adult human at consecutive 12 hour intervals affords a continuous blood serum concentration of from 10 mcg/ml to 20 mcg/ml of theophylline during said intervals.

3. The pharmaceutical tablet of Claim 1 containing 100 mg to 500 mg of theophylline.

4. The pharmaceutical tablet of Claim 1 having a thickness of 0.09 to 0.11 inches.

5. The pharmaceutical tablet of Claim 1 containing from 0.2% to 0.6% by weight of magnesium stearate as tableting lubricant.

6. The pharmaceutical tablet of Claim 1 containing 0.3% to 0.5% by weight of magnesium stearate as tableting lubricant.

7. The pharmaceutical tablet of Claim 1 consisting essen-tially of 99.6% by weight of theophylline and 0.4% by weight of magnesium stearate.

8. The pharmaceutical tablet of Claim 7 containing 300 mg of theophylline.

9. The pharmaceutical tablet of Claim l or Claim 8 having a bisect score on one of said planar faces and a pair of trisect scores on the opposing planar face.

10. The pharmaceutical tablet of Claim 9 wherein said edge walls define a rectangle.

11. A pharmaceutical tablet for the maintenance of a thera-peutically effective blood concentration of theophylline during a dosage interval of up to 12 hours following ingestion comprised of at least 95% by weight of theophylline in therepeutically effective amount and the remainder conventional pharmaceutical tablet ingredients selected to provide a tablet at least 83% by weight of which dissolves when contacted with water for a period of about 4 hours without disintegrating said tablet having a pair of substantially planar opposing faces Joined by edge walls and a thickness of from 0.08 to 0.12 inches.

12. The pharmaceutical tablet of Claim 11 containing a bronchodilative effective dose of from about 100 mg to 500 mg of theophylline.

13. The pharmaceutical tablet of Claim 12 which when administered to a human at consecutive intervals of from about 8 to 12 hours maintains a bronchodilative effective blood serum concentration of theophylline during said interval.

14. The pharmaceutical tablet of Claim 13 wherein the blood serum concentration maintained therapy is substantially within the range of from about 10 mcg/ml to 20 mcg/ml.

15. The pharmaceutical tablet of Claim 11 having a thickness of 0.09 to 0.11 inches.

16. The pharmaceutical tablet of Claim 11 containing at least 99% by weight of theophylline and a tableting lubricant.

17. The pharmaceutical tablet of Claim 16 containing from 0.1% to 0.6% by weight of magnesium stearate as tableting lubricant.

18. The pharmaceutical tablet of Claim 16 containing from 0.3% to 0.5% by weight of magnesium stearate as tableting lubricant.

19. The pharmaceutical tablet of Claim 11 consisting essentially of 99.6% by weight of theophylline and 0.4% by weight of magnesium stearate.

20. The pharmaceutical tablet of Claim 11 containing 300 mg of theophylline.

21. The pharmaceutical tablet of Claim 11 or Claim 19 having score lines arranged for both bisecting and trisecting the tablet.

22. The pharmaceutical tablet of Claim 21 having a bisect score line on one of salt planar faces and a pair of trisect score lines on the opposing planar face.

23. The pharmaceutical tablet of Claim 21 wherein said edge walls define a rectangle.