NL8102168A - THEOPHYLLINE TABLET WITH CONTINUOUS RELEASE; METHOD FOR MAINTAINING A THERAPEUTICALLY EFFECTIVE BLOOD SERUM CONCENTRATION OF THEOPHYLLINE FOR AN EXTENDED TREATMENT PERIOD. - Google Patents

Abstract

Non-disintegrating tablets containing at least 95% by weight theophylline having a pair of opposing substantially planar surfaces and a very thin cross-section (i.e. 2.03-3.05 mm) 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

• ί ^ i * VO 1920 *

Sustained-release theophylline tablet; method for maintaining a therapeutically effective blood serum concentration of theophylline over an extended treatment period.

A number of sustained-release theophylline products have been described in the literature and are currently commercially available.

There are two types, hard gelatin capsules and tablets. The hard gelatin capsule products contain a collection of small granules formed from an edible core such as a non-pariel pellet coated with alternating active agent layers and an insoluble sustained release lipid material. Techniques have been developed for the production of granules with different drug release rates. To use the different amounts of IQ granules with different release rates in a single capsule, a composite release rate of the desired duration and size can be obtained. This prior art is not relevant to the present invention, but is important as a background. Typical examples are U.S. Pat. No. 3,080,294 and U.S. Pat. No. 3,782,993.

Controlled-release tablets have been prepared by tabletting pellet sets of the type described above or by preparing granules and coating the individual granules with delayed release coatings at different release rates.

US Patent 3,344,029 is representative of this type of sustained-release product. Sustained-release tablets comprising a fat matrix or other insoluble matrix in which the slow-release drug is embedded are also known. Typical examples for this type are U.S. Pat. Nos. 3,402,240, 3,062,720 and 3,456,049.

Tablets and capsules of these types have the drawback that relatively large amounts of carriers or excipients are required to process the release rate. For medicines that are in high 8102 168 * '* I-i: ~ i. - 2 - I: 4 l i; "Doses and administered at frequent intervals, such as theophylline, require a relatively large tablet or capsule, or require multiple tablets or capsules for a single dose.

U.S. Patent 3,279,995 relates to; 5 'on a formed pellet with a bi-concave flanged configuration • which remains intact during dissolution and provides a substantially uniform surface during dissolution period. Although this principle is involved in the present invention, it does not apply to the complicated form described therein.

Since a preferred embodiment of the invention is a molded tablet containing almost exclusively theophylline, commercially available controlled-release theophylline products have been investigated, as well as the literature, to determine whether a theophylline tablet containing previously Nig contains materials such as carriers or excipients, has been described or is currently used. Presently available sustained-release theophylline tablets and capsules have been found to contain from 17 to 52% by weight of active substance and are therefore markedly different from the preferred products of the invention. The inventors do not know of a previous description of tableting theophylline by compression without carriers or excipients.

The invention provides a new controlled-release theophylline tablet, and a method for maintaining therapeutically effective theophylline blood concentrations in patients undergoing theophylline therapy by oral administration of the tablet at intervals of up to 12 hours over an extended treatment period. The tablet is non-disintegrating in nature, so cladding only takes place from the surface and in a preferred embodiment the tablet contains more than 95% by weight of theophylline.

Theophylline (1,3-dimethylxanthine) has acquired a role as a bronchodilator and has other therapeutic effects. The drug is quickly absorbed from the gastrointestinal tract and easily undergoes metabolism and elimination from the blood. The rate of disappearance varies considerably between individuals:. Therefore, patients who are on the usually recommended dosing regimen of 4 times a day using conventional dosing forms ....... 8102 168 - - 3 - * 4 immediate release dosing regimens may exhibit large variations between the maximum and minimum values of the theophylline concentrations in their blood, which are translated into fluctuations in therapeutic success and in the occurrence of side effects.

In addition to its influences on smooth muscles, theophyl-line stimulates the central nervous system causing nervousness and sudden attacks of disease, acts on the kidneys causing diuresis, stimulates the heart muscle increasing both the rate of contraction and the contraction force, and far it dilates the blood vessels. Generally, these actions are believed to be responsible for the side effects, which may include headache, dizziness, nervousness, nausea, and vomiting, and for some patients these actions argue against the use of the drug unless the dosage amount is carefully adjusted.

Serious adverse reactions affecting the cardiovascular and central nervous systems may occur when blood serum concentrations of theophylline exceed 20 µg / cm.

There is a wide individual variation in the pharmacokinetics of theophylline. The elimination half-life of the drug usually ranges from 3 - 13 hours in normal humans. Variation in liver enzymes between individuals may account for the variations in theophylline disappearance rate. Because of this possibility of variation, there is not a single dose that can and should be recommended for postural therapy of all patients.

sometimes monitoring of serum theophyllin levels is necessary to accurately individualize the dose.

It has been found that theophylline in crystalline powder form can be compressed into pharmaceutical tablets without using the conventional pharmaceutical carriers or tableting aids. However, the use of tabletting lubricant in an amount of 0.1 - 0.6% by weight is preferred when continuous machine tableting is performed. The tablets according to the invention have the property that they remain intact during dissolving and thus over a relatively long period of time. ; - 4 - Irritation instead of over a very short period of time, as is usually the case with tablets that disintegrate when exposed to a solvent. By presenting such a non-disintegrating compressed tablet in a configuration, the surface of which changes little during dissolution, a sustained release effect is obtained, such a configuration has a very thin cross-section and substantially flat opposing surfaces with a relatively large surface relative to the surface of the side walls It has also been found that administration of such a tablet allows delivery of a therapeutic dose of 100-500 mg of theophylline over a period of 6-12 hours after ingestion. immediate release of the dose after ingestion as occurs with a disintegrating tablet does not occur, therefore, the invention provides a method for maintaining a relatively high constant blood serum level of theophylline within the therapeutic region in a patient requiring theophylline treatment, which method comprises repeated administration of such a tablet at appropriate intervals for up to 12 hours. The extremes of a minimum and a maximum blood concentration, which are characteristic in the administration of immediate-release theophylline dosage forms, are avoided.

Figures 1 and 2 show respectively. a top view and a side view of a disc-shaped tablet according to the invention, which has a logo marking on the top surface and a linear cut for bisecting the tablet on the bottom surface.

Fig. 3 is a perspective view of a disc-shaped tablet according to the invention without a linear cut or logo.

. Figures 4, 5 and 6 are resp. a top view, a bottom view and an end view of a rectangular tablet according to the invention. Fig. 4 shows the top surface of the tablet with a logo and two linear cuts for dividing the tablet in three. Fig. 5 shows the bottom face of the same tablet with a single line cut for bisecting the beetroot.

8102168 i '", ~" ”- 5 - * 4

Fig. 7 is a perspective view of a similar tablet as shown in Fig. 4 except that no logo is present on the top surface.

The compressed pharmaceutical tablet according to the invention contains at least 95% by weight of theophylline and up to 5% by weight of conventional tablet ingredients, but can consist entirely of theophylline.

In a preferred embodiment, the sustained release tablet of the invention contains 95-99.8 wt.% Theophylline and the rest conventional tablet ingredients, including at least one 10 tableting lubricant in an amount from about 0.1 wt% to about 0.6 wt% .%. In a preferred embodiment, the tablet contains at least 99% and more preferably 99.4 - 99.8% by weight of theophylline and a tableting lubricant, preferably magnesium stearate, in an amount of 0.1 - 0.6% by weight. The most preferred composition is 99.6 wt% theophylline and 0.4 wt% magnesium stearate "with no other ingredients required or desired. Other lubricants such as stearic acid may be used, but their effect on dissolution properties as here described as indicated below.

The tablets according to the invention have the property that they do not disintegrate when exposed to a dissolution medium such as water or liquids in the gastrointestinal tract. They therefore remain intact during the dissolution period, and the dissolution rate is directly proportional to the surface area of a tablet at any time during the dissolution period. This leads to a relatively continuous dissolution of the drug when a tablet form is selected, which changes little in total surface area when the tablet dissolves. The surface of a sphere changes e.g. proportional to the square of the beam, and therefore exhibits the greatest surface change of all tablet shapes during dissolution. Therefore, spherical or ovoid shapes approximating the spherical shape are undesirable for the present purposes.

The simplest and preferred form of the tablet according to the invention has a thin cross-section between relatively large and almost parallel and flat opposing surfaces 8102168. 1 Γ ............-. - .......

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j ι so that the surface area of the surfaces is large compared to f the surface area of the side walls. The minimum tablet thickness, taking into account the ease of manufacture and durability, the total surface area and ease of swallowing, is approximately 2 mm. Empirical '5. it has been determined that the maximum thickness for such a tablet is about 3 mm for delivery of a dose of theophylline of 100-100 mg at a rate that maintains a blood level of 10-20: 3 µg / cm on repeated administration. A 500 mg tablet in the form of a 3 mm thick disc has a diameter of approximately 13.5 mm. Thinner tablets have a larger diameter. This is partly the reason why a 300 mg tablet size is preferred, because smaller widths and lengths, dictated by the tablet thickness restrictions, are possible. A tablet thicker than 3 mm can exhibit a dissolution rate of 15 which changes excessively as dissolution progresses. Also, the dissolution rate of a thicker tablet may be slower than required to achieve 100% bioavailability. A thin dimension between substantially parallel and planar surfaces in combination with a non-disintegrating nature characterize the tablets according to the invention. The preferred tablet thickness is 2.3-2.8 mm.

Although the preferred embodiment is a thin tablet consisting essentially entirely of theophylline as indicated above, it is nevertheless possible to practice the invention with compositions containing slightly lower amounts of theophylline in combination with conventional tablet ingredients. The additional ingredients are chosen to obtain a tablet that remains intact during the dissolution period, and therefore those materials that cause tablet disintegration, such as corn starch, 300 or resins or gums that swell on contact with water, should be avoided. Also, those ingredients which quickly dissolve in water or liquids in the gastrointestinal system are undesirable when they are in. large amounts are used because when exposed to it. dissolution medium wells will be formed in the tablet surface leading to an increased dissolution rate. Excipients that can be used ------------ 81 0 2 1 6 8 ................. - - - 7 - * 1 il usable are glucose, sucrose, lactose, mannitol and sodium chloride. Insoluble excipients in selected amounts, such as calcium phosphate, can also be used.

For a tablet containing 95% or more theophylline, the tablet hardness does not appear to be relevant for the dissolution properties as long as the tablet does not disintegrate during dissolution. Therefore, any tablet hardness suitable for handling, manufacturing, storage and intake can be used in a range of about 8-22 SCU. When using excipients and other tablet ingredients as mentioned above in larger amounts, the tablet hardness can exert an effect on the dissolution rate.

Ingredients for inclusion in a tablet according to the invention are chosen empirically by measuring the dissolution properties of experimental batches of theophylline tablets containing the different ingredients in the desired amounts, and then stepwise modifying the ingredient ingredient by ingredient until the desired dissolution properties are obtained. have been reached. This empirical approach to selecting tablet ingredients is explained more fully below.

In the final analysis, a tablet composition is selected based on the bioavailability of the theophylline contained therein and its blood plasma concentration, resulting from repeated administration of a uniform dose at 6-12 hour intervals, preferably the latter between -25 pauses. The target values are absorption of 90% or more of the theophylline contained in an Individual tablet within 24 hours of ingestion, and repeated administration at 6-12 hour intervals maintaining a blood serum concentration of theophylline within the therapeutic range. For bronchodilator use, the accepted therapeutic blood serum concentration range is about 3-10-20 µg / cm. Suitably sized doses within the range of from about 100 to about 500 mg of theophylline per dose are used for bronchodilator use at a dosing interval of about 12 hours with optionally set to a shorter interval to process the desired blood serum concentration.

8102 168; - 8 -.

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A preferred configuration contains 300 mg of theophylline in a rectangular shaped tablet with two and three divisions to obtain two or three equally sized subunits. This is unique in that a single tablet can thus provide dosage units of 100, 150, 200 or 300 mg of theophylline or multiples thereof, making adjustment of the dosage size easy. His character of sustained release becomes! > not changed by administration in the role of subunits one third or one-half of the original tablet size, and it gives a continuous continuous theophylline blood serum concentration 3 in the generally recommended therapeutic range of 10 - 20 µg / cm when administered in an appropriate amount according to a schedule twice a day (every 12. hours).

The invention also provides a method of maintaining a therapeutically effective blood serum concentration of theophylline by repeated oral administration of the above-described tablet to a patient requiring theophylline therapy over an extended treatment period. The required therapeutically effective blood serum concentration is first determined by consulting practice regarding the pending disease condition. For bronchodilator use, 10 - 20 µg / cm is generally considered to be a therapeutically effective blood concentration, but for some patients a therapeutic effect is achieved in the range of 5 - 3 µg / cm theophylline.

Experimental methods are available to determine the rate of disappearance of theophylline and plasma half-lives with respect to theophylline for individuals. Methods are also available to calculate the size of the required dosage unit to obtain a given theophylline blood concentration in the patient from the disappearance rate and the plasma half-lives. The half-life of theophylline in the blood serum varies between individuals, with documentation covering a wide range. Representative values are shown in the following table.

8102168 - 9 - * *

Representative theophylline serum half-lives half-life (hours) mean area adults 5 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 usually takes place over an extended period of 3 or 4 days to several weeks or months depending on the patient's condition. In some cases in the treatment of asthma, administration is started at the appearance of symptoms and then continued for 3 or 4 days after the symptoms disappear. In other cases, the dosing may take place on a seasonal basis over a period of weeks or months, when the exacerbation of symptoms is common.

In the tablet according to the invention, the average starting dose for children under 9 years of age is 100 mg theophylline for el-2Q every 12 hours, i.e. 1/3 part of an incised 300 mg tablet.

For children aged 9-12 years, the average starting dose for the theophylline tablet according to the invention is 150 mg theophylline for every 12 hours. For adolescents 12-16 years of age, the average dose is 200 mg for every 12 hours, and for adults 300 mg theophyllin-25 ne for every 12 hours. For patients exhibiting rapid theophylline metabolism, e.g. children aged 6-16 years or smokers, the dosing interval may be shortened, e.g. up to 8 hours. The optimal dose size and amount can usually be determined by observing the therapeutic results achieved, and the side effects observed, or blood serum analyzes on theophylline can be performed.

Theophylline therapy of the invention using the unique sustained-release tablet provided by the invention differs from therapy with conventional immediate-release theophylline tablets according to 8102 168 i -! -: -------

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Prior art due to the fact that the required dosage / interval is usually doubled over an extended treatment period. This is of great practical importance since the normal regimen for immediate-release tablets is every 6 hours; 5; action required, which represents an inconvenience and a brake on the patient's cooperation. The regimen provided by the invention allows dosing at 12 hour intervals, which is not only a convenience but also an important tool in obtaining patient cooperation.

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

A granulate was prepared by treating 300 g of anhydrous theophylline 3 with 45 cm of water in a mixer, followed by drying at 60 ° C in a forced air oven until the moisture content was less than 1%. The granulate was then comminuted and mixed with 1.2 g of magnesium stearate. The resulting mixture was suitable for tabletting on a conventional tabletting machine to a tab hardness within the range of about 7-9 SCU. The above described charge decreases 1000 tablets of 300 mg or 600 tablets of 500 mg.

Tablet composition B, 95.4% theophylline, 4% tableting aids, 0.6% magnesium stearate.

A granulate was prepared from a dry mixture of 500 g of anhydrous theophylline and 10 g of hydroxypropylmethylcellulose (15 cps), 3 with an aqueous solution of 10 g of povidone, USP, in about 75 cm Z5; water. The granulate was then dried at 60 ° C in a forced air oven until the water content was less than 1%. The dried granulate was crushed and then mixed with 3 g of magnesium stearate. This mixed composition was then compressed in a conventional tabletting press, yielding tablets having a hardness of 8-22 SCU.

The charge gave 1000 500 mg tablets or a larger number of smaller tablets,

In vitro dissolution method.

The dissolution test method II as described in USP XIX, 4th Sup-35 plement, is suitable for measuring the dissolution properties of 81 0 2 1 6 8 ~ '.................. ..

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tabs manufactured according to the invention. Briefly, the method involves placing an individual tablet in 900 on water at 37 ° C in a 1 dm dissolution kettle equipped with a paddle type agitator operated at 50 rpm. Fractions of the dissolution medium are removed intermittently, filtered and spectrophotometrically analyzed for dissolved theophylline using a wavelength of 268 nm, and a standard reference curve established by measuring the absorbance of solutions of pure theophylline at different concentrations, may have been measured in the same manner as the test solution.

Biological availability.

One open. single dose, crossover clinical study with 12 normal volunteers was used to determine the bioavailability of various tablets prepared according to the invention. A commercially available immediate-release theophylline product served as a reference. 12 non-smoking male volunteers were selected using the following criteria as grounds for exclusion from the study: 20 a. Abnormal hematology, urinalysis, or blood chemistry for treatment.

b. systolic blood pressure greater than 150 mm Hg and / or diastolic blood pressure greater than 100 mm Hg.

c. history with serious physical or mental illness.

25 d. evidence for gastrointestinal ailments (i.e. peptic ulcer or duodenal ulcer. colitis, recurrent diarrhea), e. history of hepatitis or liver dysfunction.

f. diabetes mellitus g. thyroid disease 30 h. history of seizures i. intake of medication in the 7 days before the test period, and / or medication containing xanthine during the 15 days prior to the test period, j. intake of xanthine-containing nutrients (coffee, tea, chocolate, cola drinks) for 24 hours before the test day.

8102168 j: "; - 12 - ί

Subjects fasted from bed the night before the test day until after the 4 hour blood sample was taken. A light meal without coffee, tea, chocolate, cola drinks, butter or cream was consumed after the 4 'sample, and again between! 5 10 hours and 12 hours of sample collections. The participants reported at the test unit for 6 hours after noon pp the day before the test day I. to remain internal for the next 32 hours.

; A single dose of one of the test tablets was administered to a subject 3 with 100 cm of water 8 hours before noon of the test period. A crossover test period with the immediate-release theophylline reference standard was used for each subject. Test periods were separated by 1 week periods.

3

Blood samples of sufficient volume to deliver 5 cm of plasma were collected immediately prior to drug administration and at a .15 quart, a half, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 and Drawn 24 hours after that. Plasmas were analyzed for theophylline using the high pressure liquid chromatographic method of Weddele and Mason, J. Pharm. Sci., 1976, 65: 865. A plot of the plastheophylline concentration versus time was plotted. The areas below the curves extrapolated to infinity were determined by a standard mathematical method, and used to calculate the percent bioavailability by comparing the area below the curve of a test tablet with the area for the reference standard with immediate 25 issue.

In vitro solution and bioavailability were determined according to the method described above for four disc-shaped tablets and one rectangular tablet with the compositions shown in the table below, while the results are also listed in the table. The dissolution data for a second similar rectangular tablet are also shown in the table.

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Tablet 051 with a thickness of 3.8 mm, but otherwise complying with the invention, bMek to have a bioavailability of 76% of that of a conventional immediate release tablet. Modification of the composition of this tablet 5 by incorporation of a small amount of hydroxypropylmethylcellulose as a tablet disintegrant, and povidone as a granulation ingredient as shown in Table 111 resulted in a bioavailability! 86%. Each of the tablets 181, 191 and 201 had the same composition, but different tablet shapes and thicknesses, as indicated in the table. Each showed a bioavailability of more than 90%. These tablets and tablet 202 are preferred embodiments of the invention.

Significantly and surprisingly, tablet 201, a rectangular tablet with opposing, two-part cuts on the side walls and opposite, three-part cuts on the planar surfaces, exhibited substantially the same in vitro dissolution rate as in the table above is indicated, or. now the intact tablet, the two-part tablet or the three-part tablet was used for the measurement. Although in co-pending United States patent application 24,139, now US patent 4,215,104 (July 29, 1980, therefore not in time) discloses rectangular tablets, which are cut in different planes for optionally in two or three parts by breaking with the hand, it is not suggested that such a cartridge would be suitable for a controlled release tablet. However, within the narrow limitations of the invention, dividing a theophylline tablet containing 100-500 mg of theophylline, with substantially planar surfaces, and a thickness of 2-3 mm, into three or two parts has no practical effect on the rate of dissolution . The full contents of the above-mentioned United States patent application 24,139 and of the related United States patent application 121,615, now United States patent 4,258,027 (March 24, 1981, therefore not in time) are hereby incorporated by reference.

Research of ♦ tablet ingredients.

35. Tablets were prepared as described above for 81 0 2 1 6 8 ................ ". - 15 - f - Composition A, which, however, vary in amounts of magnesium: stearate as well as 250 mg theophylline anhydrous The tablets were disc shaped, 10.3 mm in diameter and 2.5 mm thick The in vitro dissolution values for each were determined as described above, and the results obtained are shown in the table below:

Effect of magnesium stearate on dissolution

Magnesium percentage welded stearate (wt%) 0.5 hour 1 hour 2 hours 3 hours 4 hours 5 hours 6 hours 10 _ _ _ _ _ __ _ _ 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 15 0.8 14.7 25.0 41.6 54.3 64.4 71.8 78, 9

It is clear that increasing the magnesium stearate content slows the dissolution rate of the tablet. Although the dissolution rates obtained for the tablets described above were acceptable, except for those containing 0.8% by weight magnesium stearate, the preferred range was 0.3 - 0.5% magnesium stearate, most preferably 0.4%. .

The above-described method of evaluating the influence of magnesium stearate on the dissolution properties of the resulting tablet can be used to examine other tablet ingredients, which it may be desirable to use in a tablet made according to the invention, on to take.

Those ingredients are selected which provide a tablet which meets the following dissolution criteria [percentage dissolved] using the test described above: 0.5 hours to 35%; 30 1 hour 30 - 54%; 2 hours 55 - 89%; and 4 hours 83-100%. The preferred dissolution criteria are from 0.5 hours to 40%; 1 hour 35 -60%; 2 hours at least 60%; and at least 85% for 4 hours.

A batch of tablets prepared as above for tablet composition A, theophylline 99.6%, magnesium stearate 0.4%, has been described as found to have a slightly lower dissolution rate at 8102168 r - ^ ----- "" - 16 - t! 4 hour interval ,. 79.9%, compared to the aforementioned 4 hour target of 83 - 100%. Some of these tablets were crushed with a suitable mill. Two parts of the powdered · | tablets were then diluted with theophylline to give no additional "5; magnesium stearate as a lubricant in an amount of; 1 part by weight of powdered tablets to 1 or 2 parts by weight lubricant-free: theophylline. These mixtures yielded rectangular tablets at compressions as described above, which are 0.2 resp. 0.13% by weight of magnesium stearate. Some of the crushed tablets were also tableted without the addition of theophylline. The dissolution properties of these three batches of tablets were then determined according to the method described above with the following results:

Dissolving 300 mg controlled-release theophylline tablets containing low levels of magnesium stearate

Dissolving, percentage dissolved (average of 6 tablets) 0.5 1.0 2.0 3.0 4.0, - 20 original tablets 20.9 35.6 56.4 - 79.9 ground and compressed again tablets1 19.0 30.4 46.9 - 68.7 ground, diluted 1: 1 and compressed tablets2 23.4 39.8 63.1 - 91.5 25 ground, diluted 1: 2 and compressed tablets3 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-tabletting of undiluted crushed tablets slowed the rate of dissolution. Dilution of the crushed tablets with lubricant-free theophylline followed by replating increased the dissolution rate. The crushed, diluted 35 and recompressed tablets containing 0.13 resp. 0.2% by weight of magnet ----------- 8102 168 ί-! —— ---—— i; Containing <1, r / sium stearate were well within the above target dissolution limits.

Bioavailability, multiple dose study.

. Controlled-release tablets according to the invention (for 5, this study referred to as product B) of the composition and form of tablet No.202, referred to in the first of the above tables, were compared on their bioavailability at multiple dosing with a commercially available immediate-release theophylline tablet (designated product A 'for this study). The multiple dose study was conducted in a two-period, random crossover, open label design, using 18 normal volunteers. Each volunteer was evaluated with a physical examination, medical history, complete blood chemistry [including differential white cell count and standard medical analysis 12] and urinalysis.

Only those volunteers were accepted for the study who met the following criteria; a. non-smoking male persons aged 21 - 40 years, b. in excellent health on the basis of history, physical examination, and the tests described above, c. no history of drugs or alcohol abuse, 3 d. plasma theophylline disappearance greater than or equal to 2.7 dm / h and plasma half-life less than or equal to 9 hours, as determined in the preliminary test dose phase of the study described below, ë. weight between 63.5 and 90.7 kg and within 10% of the normal weight, given the height, f. no theophylline containing medication used for 15 days prior to the study and no other medication of any kind for 7 days prior to the study.

The dose was individualized for each subject in a pre-test dose phase, with the disappearance rate and the half-life of the theophylline in the blood plasma determined after a single dose. A single oral 400 mg dose of product A 35 was taken approximately 8 hours before noon after a 12 hour fast.

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The drug was swallowed with 100 cm of water and chocolate, tea, coffee, coca cola or other caffeine-containing foods or drinks were not allowed to be consumed for 24 hours before or 24 hours after the test dose. Subjects fasted for 2 hours 5 hours after the test dose and 5 cm blood samples were collected just; before swallowing the test dose and 0.5, 1, 2, 3, 4, 5, 7, 9, 12, and 24 hours after the test dose. Plasma hydrophilin levels were out! ; each of these samples was measured and the data was used to determine disappearance rates and plasma half-lives. The appropriate test dose for each subject to obtain a mean continuous plasma concentration of 13 µg / cm and a peak plasma concentration of 15 µg / cm3 was then calculated. The following table contains clinical information for each of the 18 participants, including the dose size as determined for use in the multiple dose study phase, and a dose; drawing about the adverse drug reactions observed.

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The individuals were then assigned to one of two equal groups on a random schedule. One group received product A on a dosing schedule from day 1 to day 4, taking their medicine orally. 8 hours before noon and 2 hours after noon; 5.8 hours after noon and 2 hours before noon and at 8 am before noon on day 5. The persons who received product B took; take their medicine orally at 8 a.m. before noon and 8 a.m. after noon on days 1 - 4 and at only 8 a.m. before noon on day 5.

No medication was administered on days 6 and 7, which days were used to wash out the previous medication, after which each participant was switched to the other test product, which according to the above, every 6 hours or every 12 hours schedule was administered. All 3 drug doses were swallowed with 100 cm of water. Blood samples were collected as shown in the table below. In each case, samples were taken for drug administration at 8:00 am, 2:00 pm, and 8:00 pm.

Blood sample schedule

Product Day time of day _ _ am_ _p.m._ 20 A 3 8, 2 8 4 8, 9, 10, 11, 12 2, 8 5 8, 9, 10, 11, 12 2, 4, 6 , 8 6 8, 12 B 38. 8 25. 4 8, 9, 10, 11, 12 2, 4, 6, 8 5 8, 9, 10, 11, 12 2, 4, S, 8 6 8, 10 ,. 12 2, 4, 6, 8

The plasma theophylline concentrations were determined by analysis and the results shown in the following table were calculated: 01 0 2 1 6 8:; - 2i -, ί i. Ο 00 1-)% «* * £ Lf} CO If) 0

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Data for only 16 of the 18 subjects were used, i because two subjects, one of whom had product A and the other had product B., discontinued the study due to headache or nausea.

Dosage with the sustained-release tablet according to the 5 'invention (product B) every 12 hours led to approximately the same average steady state and maximum plasma theophylline concentrations as achieved when dosed with the commercially available immediate release preparation (product A) at 6 hour intervals . A greater difference between the maximum and minimum plasma 10 concentrations was observed in product B, but this difference was not considered to be large enough to affect clinical behavior. The areas below the plasma concentration against 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 demonstrate that product B of the invention when administered on a 12 hour dosing schedule resulted in plasma theophylline concentrations comparable to those obtained with product A, a commercially available immediate release formulation, when administered on a 6 hour dosing schedule. The plasma theophylline concentrations achieved were within the generally recommended 3 therapeutic range, from 10-20 µg / cm. To further illustrate this last point, the mean theophylline plasma concentration values, which are at the different time intervals after the morning dose on days 4 and 5 (conditions of stable state) with the current sustained release tablet (product B) were achieved, shown in the following table.

"8102168 - 23 - ί ί" 3

Mean theophylline plasma concentration Cgg / cm 3 hours after the day 4 day 5 8 am dose 0 10.8 10.0 5 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 10 8 13.2 11.8 10 11.2 10.2 12 9.5 8.6

The higher values at time 0 (before the 8 o'clock dose) seem to indicate a daily variation in the body's removal of theophylline.

8102168

Claims (30)

3 C '-Η "------ ~ -' i 1! - 24 -„ ί *; I 1 * »· j 1 - ί, · 1; 1. Pharmaceutical tablet for sustained-release a- (Therapeutic dose of theophylline over a dosing interval up to 12 hours after ingestion, comprising 95 - 99.8 wt.% theophylline, and for the remainder conventional pharmaceutical tablet ingredients selected to obtain a tablet which is dissolved during the dissolution period. remains intact, which tablet has a pair of substantially flat opposed faces joined by side walls and has a thickness of 2 - 3 mm, A pharmaceutical tablet according to claim 1, which, when administered to an adult human at consecutive 12 hour intervals, gives a continuous blood serum concentration of 10-20 µg / cm theophylline during said intervals. The pharmaceutical tablet according to claim 1, which contains 100 mg - 500 mg of theophylline. Pharmaceutical tablet according to claim 1, with a thickness of 2.3 - 2.8 mm. Pharmaceutical tablet according to claim 1, which contains 0.2-0.6 wt% magnesium stearate as tableting lubricant. Pharmaceutical tablet according to claim 1, containing 0.3-0.5 wt.% Magnesium stearate as tableting lubricant. The pharmaceutical tablet according to claim 1, consisting essentially of 99.6% by weight of theophylline and 0.4% by weight of magnesium stearate. Pharmaceutical tablet according to claim 7, which contains 300 mg of theophylline. Pharmaceutical tablet according to claim 1 or 8, which has a two-part incision on one of the planar surfaces and a pair of three-part incisions on the opposite planar surface. Pharmaceutical tablet according to claim 9, wherein the side walls define a rectangle. 8102168 Λ e i i ------ "'' I - 25 - i t '' I. A pharmaceutical tablet for maintaining a therapeutically effective blood concentration of theophylline over a dosing interval up to 12 hours after ingestion, comprising at least 95% by weight of theophylline in a therapeutically effective amount and, 5. for the remainder, conventional pharmaceutical tablet ingredients selected to yield the tablet, which dissolves at least 83% by weight upon contact with water over a period of about 4 hours without disintegrating the tablet, with a pair of substantially planar opposites, surfaces 10 connected by side walls and a thickness of 2-3 mm. The pharmaceutical tablet according to claim 11, which contains a bronchodilation effective dose of about 100-500 mg theophylline. The pharmaceutical tablet according to claim 12, which, upon administration to a human at successive intervals of about 8-12 hours, maintains a bronchodilation effective blood serum concentration of theophylline during that interval. The pharmaceutical tablet according to claim 13, wherein the therapeutically maintained blood serum concentration is in the range of about 10-20 µg / cm. Pharmaceutical tablet according to claim 11, which has a thickness of 2.3-2.8 mm. Pharmaceutical tablet according to claim 11, containing at least 99% by weight of theophylline and a tableting lubricant. Pharmaceutical tablet according to claim 16, which contains 0.1-0.6 wt.% Magnesium stearate as tableting lubricant. Pharmaceutical tablet according to claim 16, containing 0.3 - 0.5 wt% magnesium stearate as tableting lubricant. 19. A pharmaceutical tablet according to claim 11, consisting essentially of 99.6 wt.% Theophylline and 0.4 wt.% Magnesium stearate. The pharmaceutical tablet according to claim 11, which contains 300 mg of theophylline. 21. Pharmaceutical tablet according to claim 11 or 19, which is provided with line-shaped incisions through which the tablet can both "8102168"; "" - 26 - t "i ί i split in half as Ran in three. Pharmaceutical tablet according to claim 21, comprising a two-part linear cut on one of the planar surfaces and a pair of three-part linear cuts on the | 5 opposite flat plane. The pharmaceutical tablet according to claim 21, wherein the side; [walls define a rectangle. 24. A method for maintaining a therapeutically effective blood serum concentration of theophylline over an extended treatment period, wherein a pharmaceutical tablet is administered orally to a patient requiring theophylline therapy, of which at least 83% by weight on contact dissolved with water over a period of about 4 hours without disintegration, and comprising at least 95 wt% theophylline in a therapeutically effective amount, the remainder being conventional pharmaceutical tablet ingredients selected to give a tablet the cladding remains intact, which tablet has a pair of substantially planar, opposed side-walled surfaces and has a thickness of 2-3 mm, the tablet being administered on a repeat dose schedule at dosing intervals up to 12 hours. The method of claim 24, wherein the therapeutically effective dose is a bronchodilation effective dose and the therapeutically effective blood serum concentration is substantially in the range of about 10 -20 µg / cm. The method of claim 24, wherein the dosing interval is in the range of about 8-12 hours. The method of claim 24, wherein the tablet contains 100-500 mg of theophylline. The method of claim 24, wherein the tablet has a thickness of 2.3-2.8 mm. The method of claim 24, wherein the tablet contains at least 99% by weight of theophylline and a tableting lubricant. The method of claim 24, wherein the tablet contains 0.1-0.6 wt% magnesium stearate as tableting lubricant. “81 0 2 1 6 8” '- 27 - The method of claim 24, wherein the tablet contains 0.3-0.5 wt% magnesium stearate as tableting lubricant. The method of claim 24, wherein the tablet essentially consists of 99.6 wt% theophylline and 0.4 wt% magnesium stearate. * * ..... 8102168