DK155976B - PROCEDURE FOR PREPARING A TABLE WITH LONG-TERM RELEASE EFFECT - Google Patents

Description

in

DK 155976 B

The present invention relates to a process for the preparation of a long-release release theophyl1 in tablet which remains intact during the dissolution period.

Theophylline (1,3-dimethylxanthine) plays a recognized role as a bronchodilator and has other therapeutic effects. The drug is rapidly absorbed from the gastrointestinal system and is easily metabolized and eliminated from the blood. The clearance rate varies considerably depending on the individual. Accordingly, patients in the usually recommended four times a day therapy using conventional immediate release dosage forms may exhibit wide variations between maximal value and minimal value for theophylline concentrations in their blood, which cause therapeutic fluctuations as well. yield as the occurrence of side effects.

Apart from the effects on the smooth muscle, theophylline causes stimulation of the central nervous system, causing nervousness and seizures, affecting the kidney to cause diuresis, stimulating the cardiac muscle to increase both contraction rate and strength, and dilates blood vessels. These effects are generally thought to be responsible for side effects which may include headache, dizziness, nervousness, nausea and vomiting, and for some patients speak against the use of the drug, unless the dose is carefully adjusted.

Serious side effects involving the cardiovascular and central nervous system may occur when blood serum concentrations of theophylline exceed 200 µg / ml. There is considerable individual variation in the theophylline pharmacokinetics. The elimination half-life of the drug usually ranges from 3 to 13 hours in normal human subjects. Variation in liver enzymes between individuals may be due to the variations in clearance rate of theophylline. Because of this variability, no single dose is recommended for maintenance therapy for all patients, and measurement of serum theophylli n mirrors is sometimes necessary to accurately individualize the dose.

A number of sustained release theophylline products 35 have been described in the literature and are currently commercially available. They are of two types, hard gelatin capsules and tablets. The hard gelatin capsule products contain an aggregation of very small beads, which consists of an edible core, such as pellets of different dimensions

DK 155976 B

2 and coated with alternating layers of active ingredient and an insoluble lipoidal agent with delayed release effect. Techniques have been developed to produce small beads at different drug release rates. By using different sizes of beads with different release rates in a single capsule, a release rate composed of the desired duration and order of magnitude can be obtained. This prior art is not relevant to the present invention but is of interest as a background. U.S.A. U.S. Patent No. 3,080,294 of March 5, 1963 to Shephard and U.S.A.

10 Patent No. 3,782,993 of January 1, 1974, Rothgang, et al., Are typical examples thereof.

Controlled release effect tablets have been prepared by tableting aggregates of the above type or by preparing a granule and coating the individual delayed release coating coats and varying release rates. U.S.A. Patent No. 3,344,029 of September 26, 1967, Berger, is representative of this type of product with long-lasting release effect. Also known are sustained-release tablets consisting of a fatty or other insoluble matrix, wherein the drug is enclosed for slow release. U.S.A. U.S. Patent No. 3,402,240 (September 1968), Cain, et al., U.S.A. U.S. Patent No. 3,062,720 (November 1962) to Costello and U.S.A. patent specification no.

3,456,049 (July 1969), Hotko, et al., Are typical of this type.

Tablets and capsules of these types have the disadvantage that they require rather large amounts of carriers or excipients to achieve desired release rates. For drugs that are administered at high doses and at frequent intervals, such as theophylline, a fairly large tablet or capsule is required, or multiple tablets or capsules are required for a single dose.

30 U.S.A. U.S. Patent No. 3,279,995 of October 18, 1966, A.F. Reid, discloses a pill configuration with a bi concave, flanged configuration that remains intact during dissolution and presents a substantially similar surface throughout the dissolution period.

Commercially available controlled release theophylline products are known in the form of theophylline tablets or capsules containing from 17 to 52% by weight of active ingredient. No prior description of theophylline tabletting is known by compression without carriers or excipients.

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The process of the invention is characterized by preparing a tablet mass of 95 to 99.8% by weight of finely divided theophylline and the rest conventional pharmaceutical tablet ingredients which do not include disintegrants or large amounts of components readily dissolved in water or gastrointestinal fluids. and forming the tablet mass into a tablet having two substantially planar facing faces joined by side faces, the total area of the planar opposing faces being large relative to the area of the side faces, and the tablet having a thickness of about 10 2 to approx. 3 mm. The tablet is by nature 10 non-disintegrating, so that dissolution takes place exclusively from the surface.

In the method according to the invention, a theophylline tablet with long-lasting release effect is obtained, but without the disadvantage mentioned above.

Theophylline in crystalline powdered form can be compressed into pharmaceutical tablets without the use of conventional pharmaceutical carriers or tableting aids. However, a tableting lubricant in an amount of from 0.1 to 0.6% by weight is preferred when a continuous tableting machine is used. The tablets prepared according to the present invention are characterized in that they remain intact during dissolution and thus dissolve over a rather extended period of time, rather than over a very short period, as is usual with tablets. which disintegrates when exposed to a dissolving medium. By providing such a non-disintegrating compressed tablet in a configuration whose surface area is only slightly altered during dissolution, a long-lasting release effect is achieved. Such a configuration is very thin in cross-section and has substantially planar opposite faces, the area of which is large relative to the area of the side surfaces. It has been found that with administration of such a tablet, obtaining a therapeutic dose of from 100 to 500 mg of theophylline over a period of from 6 to 12 hours after ingestion is possible. Immediate release of the dose after ingestion, as occurs with a disintegrating tablet, does not occur. Thus, the present invention provides for the possibility of maintaining a relatively constant blood serum level of theophylline within the therapeutic range of a patient in need of theophylline treatment by repeated administration of such a tablet at appropriate intervals of up to 12 hours. The extreme minimal and maximum blood concentrations characteristic of the theophylline administration

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4 immediate release dosage forms are avoided.

The invention will now be described in more detail with reference to the accompanying drawings, in which

Figures 1 and 2 show a top, and 5 side view, respectively, of a disc shaped tablet made in accordance with the present invention with a logo embossed on the top surface and a love line for halving the tablet on the bottom surface,

Figure 3 is a perspective view of a disc-shaped tablet made in accordance with the present invention without a notch line or logo,

Figures 4, 5 and 6 show a top, bottom and end view, respectively, of a rectangular tablet made in accordance with the present invention. Figure 4 illustrates the top surface of the tablet with a logo and two cut lines for tripleting the tablet. Figure 5 illustrates the bottom surface of the same tablet with a single notch line for halving the tablet.

Figure 7 shows a perspective view of a tablet similar to that shown in Figure 4, except that there is no logo on the top surface.

The compressed pharmaceutical tablet prepared in accordance with the present invention contains at least 95% by weight of theophylline and up to 5% by weight of conventional tableting agents, but 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 remainder conventional tableting agents including at least one tableting lubricant in an amount of from 0.1 to approx. 0.6% by weight. In a preferred form, the tablet contains at least 99, and more preferably from 99.4 to 99.8% by weight of theophylline and a tableting lubricant, preferably 30 magnesium stearate, in an amount of 0.1 to 0.6% by weight. The most preferred composition is 99.6% by weight of theophylline and 0.4% by weight of magnesium stearate, with no other ingredients being necessary or desirable. Other lubricants, such as stearic acid, may be used, but the effect thereof on the dissolution characteristics described herein must be assessed as shown below.

The tablets prepared according to the present invention are characterized in that they are non-disintegrating when exposed to a dissolving medium such as water or gastrointestinal fluids. It will

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5 say that they remain intact during the dissolution period and the dissolution rate is directly proportional to the surface area of the tablet at any given time during the dissolution period. This results in a relatively regular solution of the drug when selecting a tablet form whose surface area is only slightly changed as the tablet dissolves. For example, the area of a sphere changes relative to the square of radius and therefore exhibits the largest change in area of any tablet form during resolution. Therefore, spherical or oval shapes approaching the spherical shape are undesirable for present purposes.

The simplest and preferred form of the present tablet has a thin cross-section between relatively large and substantially parallel and planar opposite surfaces, so that the surface area is large relative to the surface area area. The minimum tablet thickness, when taken into account for convenient preparation and duration, the total surface area, and the ease with which it is sucked, is approx. 2 mm (0.08 inches). It has been empirically determined that the maximum thickness of such a tablet is approx. 3 mm (0.12 inches) to deliver a dose of theophylline of 100 to 500 mg at a rate that maintains a blood level of 20-10 to 20 µg / ml upon repeated administration. A 500 mg tablet of the form of a disc and with a thickness of approx. 3 mm (0.12 inches) has a diameter of approx. 13.5 mm (17/32 inches). Thinner tablets have a larger diameter. This is partly the reason why a 300 mg tablet size is preferred, since smaller widths and lengths dictated by the forced tablet thickness are possible. A tablet thicker than approx. 3 mm (0.12 inches), may exhibit a rapidly changing resolution rate as resolution progresses. Likewise, the dissolution rate of a thicker tablet may be less than that required to provide 100% bioavailability. A thin dimension between substantially parallel and planar surfaces in combination with a non-disintegrating nature characterizes the tablets in question. The preferred tablet thickness is 2.3 to 2.8 mm (0.09 to 0.11 inches).

Although the preferred embodiment is a thin tablet consisting almost exclusively of theophylline as described above, it is nonetheless possible to utilize the invention in formulations containing somewhat lower amounts of theophylline in combination with conventional tablet ingredients. The additional ingredients are selected to provide a tablet that remains intact during dissolution.

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Thus, materials which cause tablet incorporation, such as corn starch or resins or gums which swell upon contact with water, should be avoided. Likewise, ingredients which dissolve rapidly in water or gastrointestinal fluids are undesirable when used in large quantities as pitting will occur in the tablet surface upon exposure to the dissolution medium, which will result in an increased dissolution rate. Excipients of possible utility are glucose, sucrose, lactose, mannitol and sodium chloride. Insoluble excipients in selected amounts, such as calcium phosphate, may also be used.

For a tablet containing 95% or more theophylline, the tablet hardness does not appear to be relevant to its dissolution characteristics as long as the tablet does not disintegrate during dissolution. Accordingly, any tablet hardness which is convenient when taken into account in handling, manufacturing, storage and nutritional intake is in the range of approx. 8 to 22 SCU, usable. When excipients and other tablet ingredients, as described above, are used on a larger scale, tablet hardness can affect the dissolution rate.

The ingredients to be included in the present tablet are empirically selected by measuring the dissolution characteristics of experimental portions of theophylline tablets containing the various ingredients in the desired ratios and then modifying the composition, ingredient by ingredient in incremental manner until the desired dissolution characteristics are achieved. This empirical method for selecting tablet ingredients is described in more detail below.

In the final analysis, a tablet composition is selected based on the bioavailability of the theophylline contained therein and the blood plasma concentration resulting from repeated administration 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 theophylline contained in an individual tablet within 24 hours of ingestion, and, at repeated dosing at intervals of 6 to 12 hours, maintaining a blood serum concentration of theophylline within the therapeutic range. When used as a bronchodilator, the accepted therapeutic blood serum concentration range is approx. 10 to 20 µg / ml. Doses of suitable size are used within the range of approx. 100 mg to approx.

500 mg theophylline per dose when used as a bronchodilator at a dose range of approx. 12 hours of adaptation to a shorter interval,

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7 if necessary, to obtain the desired blood serum concentration.

A preferred embodiment contains 300 mg of theophylline in a rectangular shaped tablet with half-slit and three-part slits to provide 2 or 3 smaller units of equal size. This 5 is unique in that as a single tablet can thus provide dosage units of 100, 150, 200 or 300 mg of theophylline or multiples thereof for convenient dose size adjustment. Its sustained release character is not altered by administration as smaller units of 1/3 or 1/2 of the original tablet size, and it provides a stable 10-stage of theophylline blood serum concentration in the commonly recommended therapeutic range of 10 to 20 µg / ml when administered. administered in appropriate amount by a twice daily regimen (every 12 hours).

The present invention also provides a method for maintaining a therapeutically effective blood serum concentration of theophylline by repeated oral administration of the above tablet to a patient in need of theophylline therapy for an extended treatment period. The required therapeutically effective blood serum concentration is first determined taking into account previous practice with respect to the particular disease state being treated. When used as bronchodilator 20, the therapeutically effective blood concentration is usually 10-20 µg / ml, but for some patients a therapeutic effect is obtained in the range of 5-10 µg / ml theophylline.

Experimental methods have been provided to determine the rate of theophylline clearance and plasma half-life values of theophylline for individual subjects. Methods are also provided for calculating the size of the dosage unit required to provide a given theophylline blood concentration in the patient from the clearance rate and plasma half-life values. The half-life of theophylline in blood serum varies from individual to individual, as a wide range has been documented. Representative values are shown in the following table.

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8

Representative of theophyl1 in the serum halfway paths

Half-life (hours)

Average Area

Adults 5 Non-smokers 8.7 6.1-12.8

Smokers 5.5 4.0- 7.7

Congestive heart disease 22.9 3.1-82.0 Children (6-16 years) 3.7 1.4- 7.9 10 Treatment with theophylline usually takes place over a prolonged period of three or four days. for several weeks or months depending on the patient's condition. In some cases of asthma treatment, administration begins when symptoms appear, and then continues for three or four days after the 15 symptoms disappear. In other cases, dosing may be based on the time of year for a period of weeks or months when symptoms of acute exacerbation are common.

With the tablet prepared according to the present invention, the average dose for children under 9 years of age is 100 mg of theo-20 phyllin every 12 hours, ie. one-third portion of a 300 mg slotted tablet. For children aged 9 to 12 years, the average starting dose of theophylline tablet of the present invention is 150 mg of theophylline every 12 hours. For young people aged 12 to 16 years, the average dose is 200 mg every 12 hours, and for 25 adults 300 mg theophylline every 12 hours. For those patients who metabolize theophylline rapidly, such as children aged 6-16 years or smokers, the dose range may be reduced, e.g. for 8 hours. The optimal dose size and amount can usually be determined by observing the obtained therapeutic results or side effects, or blood serum analyzes for theophylline can be performed.

Theophylline treatment of the present invention utilizing the unique sustained release tablet produced according to the invention differs from treatment with conventional prior art immediate release theophylline tablets in that the required dose range over an extended treatment period is usually doubled. This is of great practical value because the normal therapy with instant release tablets requires treatment every 6 hours, which is inconvenient and a barrier to

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9 the patient's willingness to cooperate. The therapy made possible by the present invention allows dosing at 12 hour intervals, which is not only a convenience but also an important aid in achieving the patient's willingness to cooperate.

5

Description of Specific Embodiments

Tablet composition A. theophylline 99.6%, magnesium stearate 0.4%.

A granulate is prepared by treating 300 g of anhydrous theophylline with 45 ml of water in a mixer followed by drying in an oven with air circulation at 60 ° C until the moisture content is less than 1%. The granulate is then comminuted and mixed with 1.2 g of magnesium stearate. The resulting mixture is suitable for tabletting on a conventional tableting machine for a tablet hardness in the range of about 7 15 to 9 SCU. Said portion provides one thousand 300 mg tablets or six hundred 500 mg tablets.

Tablet Composition B. 95.4% Theophylline. 4% tablet aid.

0.6% magnesium stearate.

A granulate is prepared from a dry mixture of 500 g of anhydrous theophylline and 10 g of hydroxypropylmethyl cellul ose (15 cps) with an aqueous solution of 10 g of povidone, USP, for approx. 75 ml of water. The granulate is then dried in an oven with air circulation at 60 ° C until the water content is less than 1%. The dried granules are comminuted and then mixed with magnesium stearate, 3 g. This mixed composition is then compressed into a conventional tablet press to form tablets having a hardness of from 8 to 22 SCU. The portion provides a thousand 500 mg tablets or a larger number of smaller tablets.

30 In Vitro-QD Solution Method.

The one in the U.S.P. XIX, Supplement 4, described "Dissolution Test Method II", is well suited for measuring the dissolution characteristics of the tablets of the present invention. Briefly, the method is that an individual tablet is placed in 900 ml of water at 37 ° C in a 1 35 liter boiler equipped with a bucket-type stirrer, which is operated at 50 rpm. Portions of the solvent medium are removed at intervals, filtered and analyzed spectrophotometrically for dissolved theophylline using a wavelength of 268 nm and a standard reference curve produced by measuring the absorption of pure theophylline solutions of different concentration measured by the same method as the sample solution.

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10

Bioavailability! Iahed.

An open, single-dose cross-over clinical trial using 12 normal volunteers was used to determine the bioavailability of various tablets prepared according to the present invention. A commercially available immediate release theophylline product served as a reference. Twelve male non-smoker volunteers were selected, using the criteria below to exclude the study.

a. Abnormal hematology, urine analysis or blood chemistry for which treatment is being treated; b. Systolic blood pressure greater than 150 mm Hg and / or a di astole in so-called blood pressure greater than 100 mm Hg, c. Medical history comprising serious physical or mental illness, d Evidence of gastrointestinal disease (ie, peptic or duodenal ulcer, colitis, recurrent diarrhea), e. History of hepatitis or liver dysfunction, 20 f. Diabetes mellitus, g. Thyroid disorder, h. History of seizures, i. drug for 7 days prior to trial and / or a xanthine-containing drug for 15 days prior to 25 trial, j. Intake of xanthine-containing foods (coffee, tea, chocolate, cola) for 24 hours prior to the test day.

The subjects fasted from bedtime the night before the test day and until the 4 hour blood test was taken. A light meal without coffee, tea, chocolate, 30 cola drinks, butter or cream is eaten after the 4 hour sample and again between the collection of the 10 and 12 hour samples. Participants appeared at the test site before 1 p.m. 18:00 on the day before the trial day and they stayed there for the next 32 hours.

A single dose of one of the test tablets is administered to the person 35 together with 100 ml of water at 8.00 during the trial period. For each person, a cross-over trial with a standard theophylline instant reference was used. The trial periods are separated by periods of one week. Blood samples of sufficient volume to deliver

DK 155976 B

Aliquot of 5 ml plasma was taken immediately before drug administration and 1/4, 1/2, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 and 24 hours thereafter. The plasma portions were analyzed for theophylline by the high pressure liquid chromatography method of Weddele and Mason, J. Pharm. Sci., 1976 5 65: 865. A graph of the plasma theophylline concentration was prepared over time. Areas under the curves extrapolated to infinity were determined by a standard mathematical method and used to calculate the percentage bioavailability by comparing the area under the curve of a sample tablet with the area of a standard instantaneous reference reference.

In vitro

In vitro solution and bi oti 1 viability were determined according to the above methods for four disc-shaped tablets and one rectangular tablet with the compositions shown in the following table, where the results are shown. Resolution data for another similar rectangular tablet are also shown in the table.

12 DK1S5976B

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DK 155976B

Tablet 051 with a thickness of 0.381 cm, but otherwise in accordance with the present invention, was found to possess a bioavailability of 76% of that of a conventional instant release tablet. Modification of the composition of this tablet 5 by adding a small amount of hydroxypropylmethyl cellulose as tablet disintegrant and povidone as granulating agent as shown in tablet 111 resulted in a bioavailability of 86%. Each of the tablets 181, 191 and 201 had the same composition but different tablet shapes and thicknesses as shown in the table. Each of them exhibited a bioavailability of more than 90%. These tablets and tablet 202 are preferred embodiments of the present invention.

It is significant and surprising to note that tablet 201, which is a rectangular tablet with opposite side splits on the side surfaces and opposite three-part splits on the planar surfaces, showed essentially the same in vitro dissolution rate as indicated in the above table, although the measurement used the intact tablet, the halved tablet or the triplicate tablet. Although Patent Application No. 024,139 of March 26, 1979, now U.S.A. U.S. Patent No. 4,215,104 of July 29, 1980, discloses rectangular slots on different sides for 20 optional halves or triplets by manual splitting, there is no indication in this patent that such a design would be suitable for a controlled tablet. release effect. However, within the narrow scope of the present invention, tripling or halving a theophylline tablet containing from 100 to 500 mg thereof and 25 having substantially planar surfaces and a thickness of 0.203 to 0.305 cm has no practical effect on the dissolution rate. Reference is now made to all of the above application No. 024,139 and related application No. 121,615 of February 14, 1980, now U.S.A. U.S. Patent No. 4,258,027 of March 24, 1981.

30

Screening of tablet ingredients.

Tablets were prepared as described above for Composition A, but containing varying amounts of magnesium stearate and 250 mg of anhydrous theophylline. The tablets were disc-shaped, 1,032 cm in diameter 35 and 0.254 cm thick. The in vitro dissolution values for each were determined as described above and the results obtained are shown in the following table.

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14

Effect of magnesium stearate on solution

Magnesium Percent dissolved stearate 5 (wt%) 0.5 hour 1 hour 2 hours 3 hours 4 hours 5 hours 6 hours

Nothing 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 10 0.8 14.7 25.0 41, 6 54.3 64.4 71.8 78.9

It is obvious that increasing the amount of magnesium stearate delays the dissolution of the tablet. While the dissolution rates obtained for the above tablets 15 were acceptable, except for those containing 0.8% by weight of magnesium stearate, the preferred content of magnesium stearate was in the range of 0.3% to 0.5% and the most preferred amount of 0.4%. .

The above method for evaluating the effect of magnesium stearate on the dissolution characteristics of the resulting tablet may be used in screening other tablet ingredients which may be desirable to include in a tablet of the present invention. Such ingredients are selected which provide a tablet according to the following dissolution criteria (percent dissolved) using the test described above: 0.5 hours up to 40%, 1.0 hours 30-60%, 2 hours 55- 89% and 4 hours 83-100%. Preferred resolution criteria are: 0.5 hours up to 40%, 1.0 hours 35-60%, 2 hours at least 60% and 4 hours at least 85%.

Further description of specific embodiments

A portion 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 above 4 hour target value, 83-100%. A number of these tablets are comminuted through a suitable mill.

Two portions of the milled powdered tablets were then diluted with theophylline, which contained no additional magnesium stearate as a lubricant, in a ratio of 1 parts by weight of milled powdered tablets to

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15 1 or 2 parts by weight of theophylline without lubricant. These mixtures provided rectangular tablets when compressed as described above containing 0.2 and 0.13% by weight of magnesium stearate, respectively. A portion of the ground tablets without added theophylline 5 was also tabulated. The dissolution properties of these three portions of tablets were then determined according to the above method with the following results.

Solution of 300 mg theophylline tablets with low magnesium stearate content

Solution,% dissolved (average 6 tablets) 0.5 1.0 2.0 3.0 4.0

Original tablets1 20.9 35.6 56.4 15 79.9

Formed and re-compressed tablets1 19.0 30.4 46.9 - 68.7

Formed, diluted 1: 1 and compressed tablets2 23.4 39.8 63.1 91.5

Ground, diluted 1: 2 and compressed tablets3 28.9 50.7 78.6 96.1 25 102.5 1 0.4% magnesium stearate 2 0.2% magnesium stearate 3 0.13% magnesium stearate.

30

The results show that re-tableting of undiluted milled tablets slowed the dissolution rate. Dilution of milled tablets with theophylline without lubricant followed by re-tableting increased the dissolution rate. The milled, diluted and compressed tablets containing 0.13 and 0.2% by weight of magnesium stearate are well within the above-mentioned target solution limits.

16

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Biotilqænaeliqhed. study of multiple doses

Tablets of the present invention with controlled release effect (designated product B in this study) of composition and form similar to tablet No. 202 disclosed in the first of the previous 5 tables were compared for their bioavailability in multiple dosing with a commercial theophylline tablet with immediate liberation (designated product A in this study). The study of multiple doses was performed over two periods, with random crossovers, with known designations, using 18 normal voluntary test subjects. Each subject was evaluated with a physical examination, medical history, complete blood chemistry (including white cell differential count and standard drug analysis-12), and urine analysis.

Only such subjects who met the following criteria were accepted for the trial.

15 a. Non-smokers of male between 21 and 40 years.

b. Excellent medical condition with regard to medical history, physical examination and the tests described above.

c. No past or current drug or alcohol abuse.

20 d. Plasma theophylline clearance greater than or equal to 2.7 liters / hour, and plasma half-life less than or equal to 9 hours as determined in the initial test dose phase of the study as described below.

e. Weight between 63.5 and 90.8 kg and within ± 10% of the normal weight corresponding to 25 heights.

f. No theophylline-containing drug should be taken for 15 days prior to the study, and no other drug of any kind for 7 days prior to the study.

Thirty doses were individualized to each individual in an initial test dose phase, during which the clearance rate and half-life of theophyll into the plasma were determined after a single dose. A single oral 400 mg dose of product A was taken approx. pm. 8 am after a 12 hour fast. The drug is swallowed with 100 ml of water and no 35 chocolate, tea, coffee, coca-cola - or other caffeine-containing foods or drinks are allowed for 24 hours before and 24 hours after the test dose. The subjects fasted for 2 hours after the test dose, and 5 ml of blood samples were taken immediately before the test dose was swallowed and 0.5, 1, 2, 3, 4, 5, 7, 9, 12 and 24 17

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hours after the test dose. PIasma-theophylli n mirrors were measured from each of these samples and data from them were used to determine the clearance rates and plasma half-life values. Then, the appropriate test dose for each subject was calculated to provide a mean average plasma concentration of 13 µg / ml and a peak plasma concentration of 15 µg / ml. The table below provides clinical information on each of the 18 participants, including the dose size determined for use in the multiple-dose phase of the study and a note on adverse drug effects observed.

10

18 DK 155976B

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The persons were then placed in one of two equal groups according to random principles. A group administered Product A in a pattern chart on days 1 to 4 involving oral ingestion of their drug at 1 p.m.

8 am, 2 pm, 8 pm and 2 pm and 2 pm 8 am on day 5. Those who are administered 5 product B took their drug orally at. 8am and 2pm. 8 pm on days 1 to 4 and only at 3pm. No drug was administered on days 6 and 7, which served to excrete the previous drug, and then each participant switched to the second test product, which was administered like the previous every 6 hours or every 12 hours accordingly. -10 vote thus. All drug doses are swallowed with 100 ml of water. Blood samples were taken as shown in the following table. In each case, 7 p.m. 8, 14 and 20 samples taken before taking medication.

Blood Test Schedule 15

Point in time

Product Day a.m. p.m.

A 3 8, 2 8 4 8, 9, 10, 11, 12 2, 8 20 5 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 5 8, 9, 10, 11, 12 2, 4, 6, 8 25 6 8, 10, 12 2, 4, 6, 8 PIasma theophylline concentrations were determined by analysis, and the results shown in the following table were calculated.

30

DK 155976B

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Only data were used for 16 of the 18 subjects, with two persons, one of whom administered Product A and the other Product B, discontinuing the study due to headache and nausea.

Dosage with the tablet of the present invention with sustained release effect (product B) resulted in approx. the same mean steady state and maximum plasma theophylline concentrations as dosing with the commercially available immediate release drug (product A) at 6 hour intervals. Greater difference was observed between the maximum and the minimum plasma concentration with product B, but this difference was not considered to be large enough to affect clinical performance. The areas below the plasma concentration versus time curves and the maximum theophylline concentrations observed in the blood plasma for each treatment were not statistically different. The results of this study clearly show that product B of the present invention, when administered in a 12 hour dosing regimen, results in plasma theophylline concentrations comparable to those obtained with product A, a commercially available preparation with immediate release effect when administered at 6 hour dosing interval. The plasma theophylline concentrations obtained are within the usually recommended therapeutic range of 10-20 pg / ml. To further illustrate this latter feature, the average theophylline plasma concentration values obtained at the various time intervals after the morning dose on days 4 and 5 (steady-state conditions) with the present sustained release tablet 25 (product B) are shown. in the table below.

DK 155976 B

23

Average Theophilic N Plasma Concentration (and / ml Hours After 8 Dose Dose Day 4 Day 5 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 10 6 14.8 13.9 8 13.2 11.8 10 11.2 10.2 12 9.5 8.6 15 The higher values at 0 time (before 8 p.m. -dose) seems to reflect a daily variation in the body's excretion of theophylline.

Claims (8)

A process for preparing a sustained-release theophylline tablet which remains intact during the dissolution period, characterized in that a 5-tablet mass of 95 to 99.8% by weight of finely divided theophylline and the rest of the conventional pharmaceutical tablet constituents does not include disintegrants. or large amounts of constituents which are readily dissolved in water or gastrointestinal fluids, and form the tablet mass into a tablet having two substantially planar, opposite faces joined by lateral surfaces, of which the total area of the planar opposed faces is large. to the surface of the side surfaces, and the tablet has a thickness of approx. 2 to approx. 3 mm. Process according to claim 1, characterized in that the tablet contains 100 mg to 500 mg theophylline. Method according to claim 1 or 2, characterized in that the tablet has a thickness of approx. 2.3 to approx. 2.8 mm. Process according to claims 1 to 3, characterized in that the tablet contains from 0.2 to 0.6% by weight of magnesium stearate as tablet lubricant. Process according to claim 4, characterized in that the light weight contains 0.3 to 0.5% by weight of magnesium stearate as tablet lubricant. Process according to claims 1 to 5, characterized in that the tablet consists essentially of 99.6% by weight of theophylline and 0.4% by weight of magnesium stearate. Process according to claim 6, characterized in that the tablet contains 300 mg of theophylline. The method according to claim 1, characterized in that the content of theophylline and conventional pharmaceutical tablet ingredients is adjusted such that at least 83% by weight of the tablet is dissolved by contact with water for a period of approx. 4 hours without disintegrating the tablet. 35