DE3117756A1 - "THEOPHYLLIN TABLET" - Google Patents

Description

PATENT LAWYERS J. REITSTÖTTER W. KINZEBACH

PROP. DR. DR. DIPL. ING. DR. PHIL. DIPL. CHBM.

W. BUNTE (ΐ9βθ-ΐθ7β) K. P. HÖLLER

DR. INO. DR. RISR. NAT. DIPL. CHBM.

TBLBFONl (OSO) 87 00 88 TBLBXl 0210308 Ι8ΛΒ D.

aa, sooo monchbn -to VNR 104 523

Munich, May 5, 1981 M / 22 112

BRISTOL-MYERS COMPANY 345, Park Avenue

New York, N.Y. 10022 U.S.A.

Theophylline tablet

POSTAL ADDRESS! POSTP ¹ ACH 7ΘΟ, D- 80OO MUNICH

3 Π 7756

Μ / 22 112

Some sustained release theophylline products are described in the literature and are currently commercially available. There are two types, hard gelatin capsules and tablets. The hard gelatin capsules contain a collection of tiny pearls / consisting of an edible core / like a "non-pariel" pellet with alternating layers an active ingredient and an insoluble lipid sustained release substance. There were too Process techniques developed for the production of beads with various drug release rates. By Using different proportions of pearls with different release rates in one capsule can be a Overall release rate of desired duration and size can be obtained. The prior art is for the present application not relevant, but can be used for comparison; See U.S. Patent 3,080,294 and U.S. Patent 3,782,993.

Controlled release tablets were made by tabletting aggregates of the above-described pearls, or by producing granules and coating them

of the individual granules with coatings of different Release rate received; See US Pat. No. 3,344,029. Delayed release tablets are also known which have a Have fat or otherwise insoluble matrix in which the pharmaceutical agent is incorporated. Typical examples U.S. Patent No. 3,402,240, U.S. Patent No. 3,062,720 and U.S. Patent No. 3,456,049 refer to these.

M / 22 112

Tablets and capsules of this type have the disadvantage that they require relatively large amounts of carriers and auxiliaries, to effect the delayed release. For drugs that are administered in high doses and at frequent intervals Like theophylline, a fairly large tablet or capsule is required, or it must be for a single one Dosage several capsules or tablets can be administered.

U.S. Patent 3,279,995 relates to a bi-concave shaped pellet that remains compact during dissolution and has a substantially uniform surface throughout the entire dissolution period.

As a preferred tablet according to the invention almost exclusively formed from theophylline, sustained release theophylline products have become commercially available searched and the literature was also monitored to ensure that any theophylline tablets were prescribed or are in use which contain only small amounts of carriers or auxiliaries. It was found that the Currently commercially available TheophyHin tablets and sustained release capsules about 17% to about 52% by weight contain active ingredient and are thus clearly different from the products according to the invention.

The present invention provides a new controlled release theophylline tablet and method to maintain therapeutically effective theophillink concentrations in the blood in patients taking theophylline tablets orally for a prolonged period of treatment administered at intervals of up to 12 hours.

M / 22 112

This table does not disintegrate, so that only its dissolution takes place from the surface and, according to a preferred embodiment, contains more than 95% by weight of theophylline.

[Theophylline (1,3-dimethylxanthine) has been shown to be Bronchodilator recognized and has other pharmaceuticals Effects. The drug is rapidly absorbed from the gastrointestinal tract, easily metabolized, and from the blood eliminated. The clearance rate varies greatly from person to person. Consequently, patients can whom the usual four times a day using the usual, immediately the active ingredient free *, Seating .. tablets prescribed, large variations between the maximum and minimum theophylline blood concentrations exhibit, which can lead to different therapeutic effects and also to side effects.

Apart from its effect on the smooth muscles Theophylline causes central nervous system stimulation, causing nervousness and seizures may affect the kidneys causing diuresis to occur It can stimulate the heart muscle, increasing both the speed and the strength of the contractions is affected and it dilates the blood vessels. These influences are generally used for the side effects such as headache, dizziness, nervousness, and nausea Vomiting blamed and / that some patients are reluctant to use the drug when the dosage level is exceeded is not set carefully.

Serious side effects can occur in the cardiovascular system or in the central nervous system if the blood serum concentrations of theophylline exceed 20 μg / ml.

M / 22 112

There are wide individual vafiations in the pharmakinetics of theophylline. In healthy people, the drug elimination half-life is generally 3 to 13 hours. Different hepatic enzymes in individuals may be responsible for these variations in the theopyhlline clareance rate. Because of these differences, no single dose can be recommended for a Aufrechterhaitungstherapie in all patients, and sometimes a monitoring serum theophylline levels is necessary to dose individually exactly einzu- ^one place.

It has now been found that theophylline is compressed in crystalline powder form into pharmaceutical tablets without the use of conventional carriers or tabletting aids. Preferably one uses however, a tabletting lubricant in an amount of 0.1-0.6% by weight when a tabletting machine is continuous should be operated. The tablets according to the invention have the property that they are during dissolution stay compact and therefore dissolve relatively slowly compared to tablets, which disintegrate when they are Be exposed to the solution medium. By providing such a non-disintegrating compressed tablet, whose surface changes only slightly during dissolution, a delayed release effect is achieved. One of these embodiments has a very minor one Cross-section and essentially flat, opposite surfaces large in relation to the narrow sides. It has also been found that upon administration of such a tablet, the release of a therapeutic dose of 1QQ mg to 500 mg theophylline is possible within a period of 6 to 12 hours after ingestion. Dumping or an immediate release of the dose after ingestion, as occurs with disintegrating tablets, does not occur. The present invention thus enables

M / 22 112

maintaining a relatively constant blood serum level of theophylline within the therapeutic range in a patient in need of theophylline treatment. Such a tablet is used at suitable intervals administered repeatedly for up to 12 hours. The extremes of minimum and maximum blood concentrations, like them thus occur in the administration of dosage forms which immediately release the theophylline dose avoided.

M / 22 112

The compressed pharmaceutical tablets of the invention contain at least 95% by weight theophylline and up to 5% by weight conventional tableting additives, they can however, consist entirely of theophylline. According to a preferred embodiment, the invention contains Delayed release tablet 95% to 99.8% by weight theophylline and the remainder consists of conventional tableting ingredients, containing at least one tabletting lubricant in an amount of about 0.1% up to about 0.6% by weight In a preferred embodiment, the tablet contains at least 99% and preferably 99.4 to 99.8% by weight Theophylline and a tabletting lubricant, preferably magnesium stearate, in an amount of 0.1 to 0.6% by weight. The most preferred composition contains 99.6% by weight theophylline and 0.4% by weight magnesium stearate, with none further components are necessary or desirable. Other lubricants such as stearic acid can also be used however, their influence on the disintegration properties must be examined as described below. The tablets according to the invention have the property that they do not disintegrate when they are exposed to a dissolving medium, such as water or gastrointestinal juices. This means that they remain compact throughout the dissolution time and the dissolution speed is directly proportional to the surface area of the tablet at any given time during the dissolution process. This gives a relatively uniform dissolution of the drug if one chooses a tablet form which changes its surface only slightly during the dissolution time. The area of a sphere for example changes in proportion to the square of the radius, and therefore has of all tablet shapes the largest change in surface during dissolution. So spherical or oval, ball-like shapes are according to the invention not suitable.

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Μ / 22 112 - ^ -

The simplest and most preferred tablet form has one thin cross-section between relatively wide and substantially parallel and flat, opposite one another Areas, so that the extension of the surface is large in relation to the narrow sides. The minimum tablet thickness amounts to what the possibilities of manufacture and durability, the entire surface and a light weight As for swallowing, about 2mm. It has been empirically determined that the maximum thickness of such a tablet is about 3 mm and is designed to deliver a dose of theophylline of 100 to 500 mg at a rate that with repeated administration a blood level of 10-20 μg / ml is obtained. One 500 mg tablet in The shape of a disk 3 mm thick is about 13.5 mm (17/32 inch) in diameter. Thinner tablets have a larger diameter. This is in part why a 300 mg tablet size is preferred since smaller widths and lengths are possible in terms of tablet thickness regulations. A tablet that is thicker than 0.3 mm may have a rate of dissolution that increases with Resolution changed greatly. The dissolution rate of a thicker tablet may also be slower than it is necessary for 100% bioavailability. A small dimension between substantially parallel and flat surfaces in combination with the fact that the tablet does not disintegrate characterizes the invention Tablets. The preferred tablet thickness is 2.28 to 2.8 mm.

Although a thin tablet is preferred which consists almost entirely of theophylline, according to the invention also tablets with a slightly lower theophy11ine content in Combination with conventional tabletting agents can be produced. The additional ingredients will be like this selected that a tablet is obtained during the

M / 22 112

Disintegration time remains compact, and materials which cause tablet disintegration, such as corn starch or Resins or rubber, which swell on contact with water, are to be avoided. Also those components which quickly in water or gastrointestinal juices dissolve are undesirable if they are ingested in large quantities, as this would cause depressions in the Tablet surface form when exposed to the dissolving medium are exposed, and thus the dissolution rate is increased. Possible carrier materials that can be used are glucose, sucrose, lactose, mannitol and sodium chloride. Insoluble Carriers in selected amounts such as calcium phosphate can can also be used.

In the case of a tablet containing 95% or more theophylline, the tablet hardness does not appear to have any effect on the dissolution properties as long as the tablet does not disintegrate during the dissolution process. Accordingly, everyone can Tablet hardness useful in handling, manufacturing, storage and ingestion, in a range from 8 to 22 SCU can be used. If carriers and other tablet components are used as described above in larger proportions, the hardness of the tablet can have an influence on the rate of dissolution.

Components for inclusion in a tablet according to the invention are selected empirically by looking at the decay properties of test quantities of theophylline tablets, which contain the various components in the desired quantities, measures, then, gradually changing the composition component by component until the desired dissolution properties are achieved are achieved. The empirical way of selecting tablet ingredients is described in more detail below.

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M / 22 112

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The final analysis is a tablet composition chosen, depending on the bioavailability of the theophylline it contains and its concentration in the blood plasma after repeated administration of a constant dose at intervals of 6 to 12 hours, preferably 12 hours. The goal is to absorb 90% or more of that contained in a single tablet Theophylline within 24 hours of ingestion, and with repeated dosing at intervals of 6 to 12 Hours to maintain serum theophylline concentrations within the therapeutic range. For bronchodilator use, the recommended therapeutic blood serum concentration is between about 10 to 20 µg / ml. Dosages of appropriate size in the range of about 100 mg to about 500 mg theophylline per dose is for bronchodilator use at dosing intervals of about 12 hours, if necessary, shortening the dosing intervals to the desired one Obtain blood serum concentration.

A preferred embodiment contains 300 mg of theophylline in a rectangular tablet with two or three notches in order to obtain two or three equally sized parts. This is unique in that a single tablet thus dosage units of 100, 150, 200 or 300 mg of theophylline, or multiples thereof, resulting "karinr ~ w ~ ± e" is ^r in the selection of dose level is desired. The delayed release property is not changed by the administration of 1/3 or 1/2 of the original tablet size and a balanced theophylline blood serum concentration in the generally recommended therapeutic range of 10 to 20 μg / ml is obtained when given an appropriate amount twice daily administered (every 12 hours).

M / 22 112 - K

By repeated oral administration of the above-described tablet over a prolonged treatment period to a patient in need of theophylline therapy, therapeutically effective blood level concentrations of theophylline can also be maintained. The required therapeutic blood serum concentration is first determined according to the applicable methods, with regard to the specific disease and the condition to be treated. For bronchodilator use of a therapeutically effective blood concentration in general, the _reaction requires from 10 to 20 ug / ml, being achieved in some patients already in the range of 5 to 10 ug / ml theophylline therapeutic effects.

There are experimental procedures in place that can be used to determine the theophylline clearance rate and the plasma half-life regarding theophylline in ■ individual patients. Methods are also known for calculating the dose level required to achieve a specific theophylline blood concentration in the patient based on the clearance rate and plasma half-lives. The half-life of theophylline in blood serum is very different in individual patients, although of a wide range is reported. Representative values are summarized in the table below.

Representative theophylline serum half-lives

Half-life , 7 6, area 8th average , 5 4, 7th adult , 9 3, 1 - 0 Non-smoker 8th 0 - Smoker 5 1 - stroke 22nd - 12, - 7, - 82.

Children (6 to 16 years) 3.7 1.4-7.9

M / 22 112 - '"'"

Theophylline therapy generally lasts longer, starting from 3 to 4 days up to several weeks or longer Months, depending on the patient's condition. Sometimes, in the treatment of asthma, the administration is used when it occurs started by symptoms and then continued for three or four days after the symptoms subsided. In other In cases, the dosage may vary depending on the season and last a few weeks or months if it worsens symptoms are common.

In the case of the tablet according to the invention, the average starting dose for children under 9 years of age is 100 mg theophylline every 12 hours, e.g. one third of a notched 300 mg tablet. In children between the ages of 9 and 12 years, the average starting dose with the tablet according to the invention can be 150 mg theophylline all 12 hours. For adolescents between the ages of 12 and 16, the average dose can be 200 mg every 12 hours and for adults 300 mg theophylline every 12 hours. Those patients taking theophylline metabolize rapidly, such as children from 6 to 16 years of age or Smokers can receive theophylline at shorter intervals, for example up to 8 hours. The optimal one Dosage size and amount can usually be determined by observing the therapeutic results achieved and the occurred side effects, or carries out blood serum analyzes for theophylline.

M / 22 112

The theophylline therapy of the invention using the new sustained release tablets is different abstain from therapy with conventional theophylline tablets with immediate release of the active ingredient after Prior art in that the required dosage interval during a longer treatment period in general is doubled. This is of great practical use because of the conventional treatment with tablets with immediate release of active ingredients one treatment all 6 hours is necessary, which is a disadvantage and is more uncomfortable for the patient. In the inventive Mode of administration, the doses can be administered at 12 hour intervals, which is not only more convenient but also more tolerable for the patient.

Description of specific embodiments

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

Granules are produced by treating 300 g of anhydrous theophylline in a mixer with 45 ml of water and then drying in a drying cabinet with air circulation at 60 ^° C. until the moisture content is less than 1%. The granules are then crushed and mixed with 1.2 g of magnesium stearate. The mixture obtained can be processed into tablets with a hardness of about 7 to 9 SCU on a conventional tableting device. The above approach gives one thousand 300 mg tablets or six hundred 500 mg tablets.

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Μ / 22 112 - 'ttf - ·

Tablet composition B, 95.4% theophylline, 4% tabletting aid, 0.6% magnesium stearate

Granules are prepared from a dry mixture of 500 g of anhydrous theophylline and 10 g of hydroxypropylmethylcellulose (15 cP) with an aqueous solution of 10 g of povidone, USP, in about 75 ml of water. This is then dried in a drying cabinet with air circulation at 60 ^° C. until the water content is less than 1%. The dried granules are crushed and then mixed with 3 g of magnesium stearate. This blended composition is then compressed in a conventional tablet press to obtain tablets with a hardness of 8 to 22 SCU. The batch results in a thousand tablets of 500 mg or a larger amount of smaller tablets.

In vitro dissolution method

The dissolution test procedure II according to USP XIX, 4th supplement, is suitable for measuring the dissolution properties of the tablets produced according to the invention. In this procedure a single tablet is placed in 900 ml of water at 37 ° C. in a 1 liter dissolving container with a paddle stirrer he who works at 50 rpM is equipped. Aliquots of the dissolution medium are removed at intervals, filtered and examined spectrophotometrically for dissolved theophylline, based on a wavelength of 268 nm and compared with a standard control curve obtained by measuring the absorbance of solutions of pure theophylline was obtained in various concentrations, using the same procedure for these measurements as for Test solution applied.

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M / 22 112 - \} f-

Bio availability

An open, single-dose clinical cross-test was performed on 12 healthy volunteers. around the bioavailability of various produced according to the invention To determine tablets. A commercial theophyllium product with immediate drug release was used as a comparison used. Twelve voluntary male non-smokers were selected, the following criteria being grounds for exclusion from the investigation were:

a) Abnormal hematology, urinalysis or chemical Blood values before treatment,

b) systolic blood pressure higher than 150 mmHg and / or diastolic blood pressure higher than 100 mmHg,

c) previous severe physical or mental illnesses,

d) Occurrence of gastrointestinal diseases (e.g. peptic or duodenal ulcer, colitis, repeated diarrhea),

e) previous hepatitis or liver dysfunction,

f) diabetes mellitus,

g) thyroid diseases,
h) previous seizures,

i) taking any medication 7 days before

Test period and / or xanthine-containing drugs 15 days before the test period,

j) Consumption of xanthine-containing foods (coffee, tea, chocolate, cola drinks) 24 hours before the day of the experiment.

The test subjects are not allowed to eat anything from the time they go to bed on the evening before the day of the experiment until after taking the blood sample, which takes place 4 hours after administration. After taking this sample, a light meal is made given without coffee, tea, chocolate, cola drinks, butter or cream, as well as between samples at 10 a.m. and 12 p.m. The test participants arrived at 6 p.m. the evening before the test and stayed during the

M / 22 112 - \ y -20

the following 32 hours in the house.

A test person was given a single dose of the test tablets with 100 ml of water at 8 a.m. For each subject was given a "cross-over" trial period with the theophylline drug with immediate release of the active ingredient used. There was a week between the trial periods. Blood samples so extensive that 5 ml of plasma could / were obtained immediately before administration and 1/4, 1/2, 1, 2, 3, 4, 5, 6, 7, 8, 10, Taken 12, 16 and 24 hours after administration. The plasma samples were obtained by the high pressure liquid chromatography method von Weddele and Mason, J. Pharm. Sci., 1976, 65: 865 for theophylline. It became a Plot of theophylline concentration versus time. The areas under the extrapolated to infinity Curves were determined using standard mathematical methods and used to calculate the percentage bioavailability by comparing the area under the curve for a test tablet with that of a tablet with immediate Drug release used as the standard.

In vitro dissolution and bioavailability were determined by the procedures described above for four disc-shaped Tablets and a rectangular tablet with the compositions shown in the table below certainly. The results are also included in the table below. The values for a second, similar one rectangular tablet are also listed in the table.

Together Theophylline In Vitro resolution and Bioavailability 2.0 (%) Hours 6.0 Bioavailability 3 settlement Shortage Tablets Tablets resolution 50 4.0 - (% in 24 hours) to
IO tablet A. 500 mg thickness (mm) diameter
(mm) 0.5 1.0 55 80 93 76 k
to No. A. 300 mg 3.810 11,906 15th 28 57 83 94 106 051 A. 300 mg 2.616 11.113 - 32 73 86 - 93 181 A. 300 mg 2.210 11,906 - 33 74 95 - 96 191 A. 300 mg 2.540 * 30th 45 75 94 _ - 201 B. 500 mg 2.540 + 24 43 95 86 202 3.810 11,906 25th 45 111

Rectangular shape, length 16.76 mm, width 5.84 mm, split in two on the narrow sides
Parts and notched on the opposing surfaces for division into three parts;

Rectangular shape, length 16.25 mm, width 6.35 mm, on one flat surface for dividing
in two parts and on the opposite flat surface to divide into three parts
notched.

m / 22 112

The tablet 051 with a thickness of 3/81 mm, but which otherwise corresponds to the invention, has a bioavailability of 76%, which is that of a conventional tablet with immediate Drug release corresponds. A change in the composition of this tablet by adding one small amount of hydroxypropyl methylcellulose as a tablet disintegrant and povidone as a granulating agent, how this happened to tablet 111 indicates bioavailability of 86%. All three tablets 181, 191 and 201 had the same composition but different shapes and sizes j Thicknesses as shown in the table. Each of these tablets had a bioavailability greater than 90%. These tablets and tablet 202 represent preferred embodiments of the invention.

It is important and surprising to note that the j tablet 201, a rectangular tablet, is juxtaposed with one another lying notches for dividing into two parts on the narrow sides and opposing notches for Divide into three parts on the flat surfaces, in vitro essentially the same rate of dissolution has, as indicated in the table above, regardless of whether the intact tablet, the tablet with notch to divide into two parts or a tablet divided into 3 parts is used for the measurements. In the US-PS 4,215,104 are described rectangular tablets, the on different surfaces for the optional dividing of Hand notched in two or three parts, but it does not describe that such a design also is suitable for a controlled drug release tablet. Under the conditions of the present invention

has the division of a theophylline tablet from 100 to 500 mg into three or two sections if the tablet has substantially flat surfaces and a thickness of 2 to 3 mm, practically no influence on the dissolution rate.

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Reference is made to the full disclosure of the aforementioned U.S. Patent 4,215,104 and related U.S. Patent 4,258,027 taken.

Screening of tablet components

Tablets were prepared as described above for Composition A, but with different amounts of magnesium stearate and 250 mg of anhydrous theophylline. The tablets were disc-shaped, with a diameter of 10.32 mm and a thickness of 2.54 mm. The in vitro dissolution rate was determined for each as described above. The results obtained are summarized in the table below.

Effect of Magnesium Stearate on Dissolution

Magnesium-
stearate
(Wt%) 0.5 h 1 h % solved
2 h 3 h 93.7 4 h 5 h 6 h without 28.4 51.5 82.2 86.1 95.3 - - 0.3 22.2 41.1 70.1 80.1 93.8 94.5 95.8 0.4 20.0 36.4 62.3 75.2 89.9 95.7 97.0 0.5 20.0 34.4 58.9 54.3 84.7 91.4 94.9 0.8 14.7 25.0 41.6 64.4 71.8 78.9

It is evident that increasing levels of magnesium stearate slow down the rate of dissolution of the tablet. Although those achieved in the above tablets Dissolution rates, with the exception of the 0.8 wt% magnesium stearate tablet, were acceptable, the range of 0.3% to 0.5% magnesium stearate was chosen as preferred, and most preferably 0.4%.

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The procedure described above for determining the effect of magnesium stearate on dissolution properties The tablet received can also be used for screening others

Tablet components are used which are to be included in the tablets according to the invention.

Those components are selected which have a

Tablet with the following dissolution criteria

(% dissolved) using the above test gives:

0.5 h up to 35%; 1.0 h 30 to 54%; 2h 55-89% and 4 h 83 - 100%.

Preferred resolution parameters are: 0.5 h up to 40%;

1.0 h 35 to 60%, 2 h at least 60% and 4 h at least

Further description of specific embodiments

Containing a batch of tablets prepared as described for Tablet Composition A above Theophylline 99.6%, magnesium stearate 0.4% had a slightly slower dissolution rate of 79.9% after the 4 hour interval compared to the one given above Value from 83 to 100% after 4 hours. A number of these tablets were crushed in a suitable mill. Then two portions of the ground, powdery tablets were diluted with theophylline, which no additional Magnesium stearate contained as a lubricant, in a ratio of 1 part by weight of ground powder '' Tablets containing 1 or 2 parts by weight of theophylline not provided with lubricant. From these mixtures rectangular tablets were obtained when they were compressed as described above, which contained 0.2 or 0.13% by weight Contained magnesium stearate. It was also part of the milled tablets without additional theophylline tabletted. The dissolution criteria of these three batches of tablets were then determined according to that described above Method determined, the following results were obtained.

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Dissolution of 300 mg theophylline tablets with controlled release, which contain small amounts of magnesium stearate

Resolution,% solved (average 6 tablets)

0.5 1.0 2.0 3.0 4.0 Original tablets 20.9 35.6 56.4 79.9 gerrahJLene and again ₁
compressed tablets 19.0 30.4 46.9 68.7 ground, diluted 1: 1
and recompressed
Tablets ² 23.4 39.8 63.1 91.5 ground, diluted 1: 2
and recompressed
Tablets 28.9 50.7 78.6 96.1 102.5

1) 0.4% magnesium stearate

2) 0.2% magnesium stearate

3) 0.13% magnesium stearate

The results show that re-tableting undiluted ground tablets increases the rate of dissolution delayed. If the ground tablets are diluted with theophylline without lubricant and tabletted again, then becomes the dissolution rate increases. The ground, diluted and recompressed tablets which contain 0.13% and 0.2 wt% magnesium stearate are well within the objectives set above for dissolution.

Bioavailability, multiple dose testing

Controlled drug release tablets of the invention (referred to as product B in this investigation) with the composition and shape of the table in the first table No. 202 tablet is assessed for its bioavailability at multiple doses compared to one commercially available TheophyHin tablet with immediate Drug release (in this investigation product A

3117VbB

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called) compared. This study was carried out as a cross-test in two test periods, with the Preparations were not labeled and 18 healthy volunteers were used. Any volunteer was determined by a medical exam, medical history, complete blood chemistry (including differentiated white blood cell count and standard medical analysis 12) and urinalysis. Only subjects who met the following criteria were accepted:

a) non-smoking male test persons aged 21 to 40 years,

b) in excellent health, what history, medical examination and the experiments described above as far as

c) no previous drug or alcohol abuse,

d) with a plasma theophylline clearance greater than or equal to 2.7 liters / h and a plasma half-life less than or equal 9 hours as determined in the preliminary test dosage phase of the study described below,

e) a weight between 63.5 and 90.7 kg and within a normal weight of + 10% depending on the size,

f) 15 days before the examination, no theophylline-containing was allowed Medication and no other medication was taken 7 days prior to the examination.

The dosage was set individually for each person in a preliminary test dosage phase, with the The rate of clearance and half-life of theophylline in blood plasma after administration of a single dose was determined became. A single oral dose of 400 mg of Product A was taken at 8 a.m. after fasting for about 12 hours. That The drug was taken with 100 ml of water and not chocolate, tea, coffee, Coca-Cola or any other caffeinated

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Food or drinks were allowed 24 hours before and 24 hours after the test dose. The test subjects stayed 2 hours after taking the test dose and 5 ml of blood samples were taken just before taking the test dose and taken 0.5, 1, 2, 3, 4, 5, 7, 9, 12 and 24 hours after the test dose was administered. Every sample became the plasma theophylline levels were determined and these data were used to calculate the clearance rates and the plasma half-lives to determine. From this, the appropriate test dose was then calculated for each test person so that one at equilibrium a plasma concentration of 13 μg / ml and a peak plasma concentration of 15 μg / ml receives. The table below provides clinical data for each of the 18 participants, including those for the Usage in the multi-dose phase of the study regarding dosage level and comments to be used harmful drug side effects.

old age size
(cm) Clinical data for 18 test participants 250 . 202 300 500 Disadvantage 2 Effects of the n>
Lkaments _i no Headache, nausea release no « ⁵ K • * ■ α
σ Numi 22nd 193 weight dose 300 200 600 Ld C ^Med: Treatment B »o no no I. : ο 22nd 178 90.0 250 300 500 Treatment a no no 1 22nd 183 75.0 follow * treatment A treatment
qid bid 250 200 500 no nausea headache 2 22nd 186 68.3 AWAY 300 250 600 no no 3 23 183 77.3 BA 300 300 600 Headache no 4th 23 188 72.7 AWAY 250 300 500 Headache Headache 5 25th 185 77.3 BA B interrupted- 250 600 no no 6th 23 175 80.0 BA BA 250 600 no no 7th 22nd 180 68.5 AWAY AWAY 200 400 no Nausea, headache 8th 22nd 170 79.5 BA AWAY 600 - Nausea, headache 9 22nd 188 68.2 AWAY 400 no no 10 25th 183 79.5 AWAY 500 no Headache 11 25th 183 80.5 BA 600 no no 12th 23 188 72.7 BA 600 no Nausea, headache no 13th 22nd 178 77.7 BA 500 no 14th 22nd 168 72.7 A interrupt - no 15th 22nd 175 68.2 AWAY 400 no 16 24 188 65.9 A: commercial tablet with immediate 17th treatment 84.1 B: tablet no 18th treatment *

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The people were then randomly assigned to one of two groups of equal size. One group received product A with the following dosage instructions for days 1 to 4 when taken orally at: 8 a.m., 2 p.m., 8 p.m. and 2 a.m. and at 8:00 am on day 5. Those who took Product B received their medication orally at 8:00 am and 8:00 pm Day 1 to 4 and only at 8 a.m. on the 5th day. No drug was administered on the sixth and seventh days, those days were used to eliminate the previous drugs. Then each participant received the other test product, which as described above every 6 hours or every 12 Hours. All drug doses were swallowed with 100 ml of water. The blood samples were as in shown in the table below. In each case, the 8:00 am, 2:00 pm, and 8:00 pm samples were taken prior to administration of the drug taken.

Blood sample plan

Product tag

a 2 .m. Time of day 1, 1 2 'P- m. 6, 8th 9, 1, 1 2 8th 8th, 9, 10, 2, 8th 8th, 12th 10, 1 2, 4, 6, 8th 8th, 1 1, 1 2 6, 8th 8th, 9, 1, 1 2 8th 6, 8th 8th 9, 10, 2, 4, 8th, 10 10, 1 2, 4, 8th, , 12 1 2, 4, 8th,

! A 3

! 4th

j .5

B 3

I ⁴

I 5

! 6th

j The plasma theophylline concentrations were measured ! Tests determined and the values listed in the table below were calculated.

Multiple dose bioavailability of theophylline from delayed product Release (product B) and tablets with immediate release (product A) under constant conditions

number
Product people

Average daily total dose intervals

(mg) (hours) (h "mg / l) Availability (ug / rnl) ^ g / ml)

co * ^p ss

C *

Max

C * C -C * T * min max min max

(min)

16

16

12th

1050

151

+ _ 26

156 + 30

12.55

13.04

15th ,8th 8.77 + 7, 07 235 , 0 + 2 »6 ± 1.82 1, 97 ± 68 ,8th 15th , 9 10.3 + 5, 61 95 , 4 + 3 , 2 + 2.2 2, 2 + 39 ,1

AUD - area under the plasma concentration curve

CP - mean plasma concentration under constant conditions

C - mean maximum plasma concentration

C. - average minimum plasma concentration min

C -C. - mean plasma concentration "Swing" max min

T - average time to maximum concentration max

M / 22 112

Only the data from 16 people were evaluated, since two of the test persons, one of whom was product A and who had received other product B stopped the experiment because of nausea and headache.

The dosage with the tablets according to the invention with delayed drug release (product B) every 12 hours brought about the same in equilibrium maximum plasma theophylline concentrations such as the 6-hour dosage with the commercially available preparations with immediate Approval (product A). For product B, there was a greater difference between the maximum and minimum plasma concentrations observed, but this difference was not considered so great as to affect clinical efficacy could affect. The areas under the curve for the dependence of the plasma concentration on the time and the maximum theophylline concentrations in blood plasma are not statistically different for each treatment.

The results of this study clearly show that after administration of the product B according to the invention all 12 hours, obtained plasma theophylline concentrations those with product A, a commercially available product with immediate release effect, when administered all 6 hours obtained, were comparable. The plasma theophylline concentrations achieved are in the therapeutic range generally recommended range of 10 to 20 ng / ml. To illustrate this latter point in more detail those with the delayed release agent of the present invention (Product B) after the morning dose on days 4 and 5 (equilibrium) in theophylline concentrations reached at various intervals and measured in the following Table compiled.

Ol I / / OO

M / 22

Mean plasma theophy11ine concentrations

(µg / ml)

Hours after appointment
Delivery at 8 a.m.
In the morning Day 4 Day 5 O 10.8 10.0 1 11.8 11.5 2 13.4 12.9 3 14.8 14.6 4th 15.6 15.0 6th 14.8 13.9 8th 13.2 11.8 10 11.2 10.2 12th 9.5 8.6

The higher values at time 0 (before the 8 a.m. dose) appear to be a diurnal variation in theophylline

I reflect elimination through the body.

j i

ι. j

Claims (23)

M / 22 112 X Claims Delayed release pharmaceutical tablet a therapeutic dose of theophylline via one Dosing period of up to 12 hours after administration, characterized by 95% to 99.8% by weight theophylline and conventional pharmaceutical tablet ingredients selected so that the tablet during the Dissolution time remains compact, with the tablet taking a Has pair of substantially flat, opposite surfaces, which are connected to one another by narrow sides and has a thickness of about 2 to about 3 mm. 2. A pharmaceutical tablet according to claim 1, characterized in that when administered to a Adults continuously maintain a blood serum concentration of at 12-hour intervals 10 ig / ml to 20 ug / ml theophylline yields. 3. A pharmaceutical tablet according to claim 1, containing 100 mg to 500 mg theophylline. 3 Ί17756 Μ / 22 112 - 2 - 4. A pharmaceutical tablet according to claim 1 with a thickness of 2.25 mm to 2.75 mm. 5. A pharmaceutical tablet according to claim 1, containing 0.2% to 0.6% by weight magnesium stearate as a tabletting lubricant. 6. A pharmaceutical tablet according to claim 1, containing 0.3% to 0.5% by weight magnesium stearate as a tabletting lubricant. 7. A pharmaceutical tablet according to claim 1, essentially consisting of 99.6% by weight theophylline and 0.4% by weight magnesium stearate. 8. A pharmaceutical tablet according to claim 7, containing 300 mg theophylline. 9. A pharmaceutical tablet according to claim 1 or claim having a notch which divides into two parts on the one, and two notches that divide into three parts on the other of the opposing flat surfaces. 10. Pharmaceutical tablet according to claim 9, characterized in that that the narrow sides form a rectangle. 11. Pharmaceutical tablet for maintaining a therapeutically effective concentration of theophylline in the blood for a period of up to 12 hours Administration, characterized in that it consists of at least 95% theophylline in a therapeutic effective amount and the remainder is selected from conventional pharmaceutical tablet ingredients so that that one contains a tablet, of which at least M / 22 112 - 3 - 83% by weight dissolve without disintegrating when in contact with water for a period of about 4 hours is brought, this tablet having a pair of substantially flat, opposing surfaces, which are connected to one another by narrow sides, the tablet having a thickness of about 2 to 3 mm Has. 12. A pharmaceutical tablet according to claim 11, containing a bronchodilator-effective dose of about 100 mg up to 500 mg theophylline. 13. A pharmaceutical tablet according to claim 12, which when administered a bronchodilator-effective blood serum concentration on a human at intervals of 8 to 12 hours on theophylline maintains. 14. A pharmaceutical tablet according to claim 13, which has a blood serum concentration of substantially 10 μg / ml to Maintains 20 μg / ml. 15. A pharmaceutical tablet according to claim 11 having a thickness from about 2.25 mm to about 2.75 mm. 16. A pharmaceutical tablet according to claim 11, containing at least 99% by weight of theophylline and a tabletting lubricant. 17. A pharmaceutical tablet according to claim 16, containing about 0.1% to 0.6% by weight of magnesium stearate as Tableting lubricants. 18. A pharmaceutical tablet according to claim 16, containing 0.3% to 0.5% by weight magnesium stearate as a tabletting lubricant. M / 22 112 - 4 - 19. Pharmaceutical tablet according to claim 11, consisting in essentially of 99.6% by weight theophylline and 0.4% by weight Magnesium stearate. 20. A pharmaceutical tablet according to claim 11 containing 300 mg theophylline. 21. Pharmaceutical tablet according to claim 11 or 19, which is provided with notches so that it can be divided into two parts as well as into three parts. 22. A pharmaceutical tablet according to claim 21, which is provided on one of the flat surfaces with a notch so that it can be divided into two parts and on the opposite side a pair of score lines to divide in has three parts. 23. A pharmaceutical tablet according to claim 21, whose Define a rectangle on the narrow sides.