FR2570603A1 - Sustained release theophylline tablet - Google Patents

Abstract

Tablet consists of theophylline 100 wt. pts. and ethylcellulose 5-200 pts.wt., pref. 20-100 pts.wt. Theophylline and ethylcellulose comprise at least 75 wt.% of tablet.- Elution rate of theophylline can be adjusted by changing mixing proportion of theophylline and ethylcellulose. Additives, e.g.vehicles, lubricant, etc. can be added 25 wt.% or less. Examples of the vehicles are lactose, glucose, mannitol, polyethylene glycol, methy cellulose, etc.

Description

A2 2570603

  PHARMACEUTICAL PELLET OF THEOPHYLLIN RELEASED

  EXTENDED AND PROCESS FOR PREPARING SAME

  The present invention relates to a pharmaceutical tablet of theophyl-

  extended release line and process for its preparation. More specifically, it relates to a pharmaceutical theophylline release tablet.

  containing a specified ratio of theophylline and ethyl cell-

  lose, prepared by a direct compression molding method.

  Theophylline is widely used as an effective drug for the therapy and prevention of bronchial asthma. The dose of theophylline must however be strictly controlled as is known by the state of the art and this because theophylline has a narrow effective concentration range in the blood (i.e. 5 to 20 ig / ml ) and it gives rise to side effects for a concentration which would be (i.e. 25 pg / ml or more) close to the concentration range

  effective in the blood. These side effects include headache, nau-

  and arrhythmia. In addition, the biological half-life of the theo-

  phylline is relatively short (i.e. around 6 hours). Theophyl-

  line must therefore be administered 4 times a day (that is to say every six hours to maintain its effective concentration in the blood). Such a frequent dose is very embarrassing for patients. Also because of the short half-life, when theophylline is administered before going to bed, one cannot expect to get a sufficient effect against the attack

  from asthma to aube, the most favorable period for his attacks.

  Various attempts have been made to develop theophylline sustained release pharmaceutical preparations to overcome the above problems. Several preparations have been proposed or implemented

on the market so far.

  U.S. Patents 3,062,720, 3,402,240 and 3,456,049 describe, for example, sustained release preparations,

  slow or progressive medicinal lozenges including drugs available

  persés in the matrices composed of fats or sensitive waxes-

  are insoluble in water or slightly soluble in water. U.S. Patents 3,080,294, 3,109,775, 3,344,029 and 3,872,998 and Japanese Unexamined Patent Publication (Kokai) No. 56122311 describe extended release pharmaceutical preparations comprising

  drugs in the form of beads with different release rates

  ration, encapsulated in lozenges, tablets or capsules. In addition,

  U.S. Patents 3,039,933, 3,322,633 and 3,632,739

  write sustained-release pharmaceutical lozenges in which ethyl cellulose is contained as a constituent of a matrix component although the use of theophylline is not taught by

these patent descriptions.

  Although these theophylline sustained-release preparations offer

  reduce the back problems with theophylline administration, they do not

  not eliminate them completely. That is, these preparations of theo-

  Extended-release phylline have an effective duration of 8 to 12 hours. Therefore, patients with chronic bronchial asthma should still take these theophylline preparations, two or three times a day, in order

  maintain its effective concentration in the blood. While being better

  re than that of theophylline preparations of conventional type, that is to say

  say non-sustained release, this frequency is even greater than

  desirable for chronic patients.

  The preparations mentioned above making use of a matrix

  soluble in water (or slightly soluble in water) still have the disadvantages that the percentage by weight of the vehicle or support goes up to

  % or more. Thus, the size of the pellets inevitably becomes important.

  aunt in the case of a drug such as theophylline which should be used

  ministrée in large doses. Likewise, the control of the release speed

  ration of the drug is not necessarily easy since depending on the

  types or combinations of substances constituting the matrix, the di-

  ninue quickly over time after administration.

  In addition, the preparations mentioned above, making use of coated pellets (or small powder particles) also exhibit

  the disadvantage that high skill and complicated operations are born

  for the preparation of coated tablets, which results in

high production costs.

  Recently, a new type of theophylline sustained release tablet has been proposed in Japanese Unexamined Patent Publication (Kokai) No. 57-112322 (corresponding to United States patent application

  America serial # 147429 filed May 6, 1980). This lozenge pro-

  applied comprises from 95 to 99.8% by weight of theophylline in the form of a thin flat plate of the non-disintegrating type. This tablet is advantageous

  in the sense that its production is simple and that it contains a large quan-

  tity of effective ingredients. However, it is still disadvantageous in

  meaning that a small pellet containing a small content (i.e.

  i.e. 50 to 150 mg) of theophylline has insufficient strength and too rapid an effective release rate of the ingredient. So, we

  should not yet expect to find a pellet of theophylline sou-

  hatched with satisfactory sustained release properties and a

sufficient strength.

  Therefore, a main object of the present invention is to

  undermine the above-mentioned drawbacks of prior art and procedure

  a long-release theophylline tablet capable of providing

  a stable and effective concentration in the center of theophylline pen-

  for 12 to 24 hours when administered once or twice a day.

  Another object of the present invention is to provide a pharmaceutical theophylline sustained release tablet of small size and

  easily applicable with a relatively high content of theophylline.

  Yet another object of the present invention is to provide a sustained release theophylline pharmaceutical tablet having a

  consistent quality and easily prepared.

  According to the present invention, the sustained release pharmaceutical tablet comprises theophylline and ethyl cellulose uniformly

  disperses therein in an amount of 5 to 200 parts by weight of ethyl-

  cellulose compared to 100 parts by weight of theophylline, the hardness of

  the tablet is etanrit from 0.5 to 16.0 kg. -

  According to the present invention, the process for preparing a pharmaceutical theophylline sustained release tablet comprises the steps of: uniformly mixing 100 parts by weight of theophylline and 5 to 200 parts by weight of ethyl cellulose: and molding, by compression , of the mixture which

  results by a direct compression method to form a pellet.

  The present invention will be better understood from the description

  exposed below with reference to the drawing in which fioure 1 is a

  curve showing the change over time of the concentra-

  theophylline in human blood given by a lozenge

  with conventional prolonged release and by the tablet prepared in the example

ple 2 according to the present invention.

  As mentioned above, according to the present invention, the sustained release theophylline pharmaceutical lozenge can be prepared by uniformly mixing theophylline and ethylcellulose in a weight ratio of theophyllinethyl ethyl cellulose

  : 5 to 200, preferably 100: 10 to 100 and possibly, after mixing

  dipped a small amount of lubricant, to be molded by compression

  swelling resulting from a direct compression method. It is thus possible to produce a pharmaceutical sustained release tablet having the desired size. The theophylline usable in the present invention may be any commercially available product found, for example,

  in powder form. Theophylline powder can be used directly

  in the production of the desired pellet, according to the present invention

  tion, or be used after being properly crushed, crushed or pulverized. The ethyl celluloses which can be used in the present invention are those which are compatible with theophylline. Any ethyl cellulose

  commercially available can be used appropriately. These pro-

  commercially available products are, for example, the standard "Ethocel"

  or medium (manufactured by Dow Chemical Co., Ltd) of finely di-

  referred to with a dimension of 20 mesh or less are preferably used

  rence, 32 mesh or less. being the preferred size.

  The rate of release (or dissolution) of theophylline contained in the theophylline sustained release tablet according to the present

  invention can be easily controlled by changing the amount of ethyl-

  cellulose mixed with theophylline. Generally speaking, the rate of release decreases as the amount of mixed ethyl cellulose is increased. The theophylline release rate can also be

  controlled by changing the hardness of the tablet.

  Generally, the rate of release of theophylline decreases

  with increasing hardness of the pellet.

  The amount of ethyl cellulose mixed according to the present invention should be from 5 to 200 parts by weight, preferably from 10 to 100 parts by weight.

  weight based on 100 parts by weight of theophylline. A quantity of

  thyl-mixed cellulose lower than the range specified above results in a too rapid release rate of theophylline which does not

  does not provide the desired sustained release effect of theophylline.

  On the contrary, an amount of mixed ethylcellulose greater than the interval specified above gives insufficient release of the

  theophylline which does not provide sufficient medicinal effect.

  In addition, as mentioned above, while the theo-

  phylline sustained release according to the present invention comprises sensi-

  blending the specified amount of theophylline and ethylcellu-

  lose, it may optionally contain conventional ingredients such as an excipient or a lubricant in an amount such that the rate of release of theophylline is not adversely affected. These excipients

  are, for example, lactose, sucrose, glucose, mannitol and crystal cellulose-

  line (for example "Avicel"). Lubricants which can be used during tableting are, for example, magnesium stearate, calcium stearate, light silicic anhydride (for example "Carplex" manufactured by

  Shionogi and Co. Ltd) and "Aérosil" (manufactured by Nippon Aérosil Co.).

  As mentioned above, according to the present invention, the desired sustained release tablet of theophylline can be prepared by

  direct compression molding of a uniform mixture in the specified ratio

  cified with theophylline and ethyl cellulose. This compression method

  direct is very advantageous by comparison with other methods of

  lage of pellet c 1 a s s i q u e because intermediate steps such as the granulation step can be omitted and the preparation operation is very simple. Thus, the process for preparing the theophylline lozenge

  sustained release according to the present invention is very rapid and economical

mique.

  The resulting sustained release theophylline tablet,

  according to the present invention, has a hardness of 0.5 to 16 kg as determined

  born by a Kiya hardness tester {nanufactured by Kiya

Seisakusho Ltd).

  According to the present invention, ethyl cellulose also functions

  as an excipient and therefore the use of other excipients is not generally

  not necessary. For this reason, the tablet can be shaped in a very small form compared to the tablets.

  classics. A typical dimension of theophylline lozenge to release

  The extended ration of the present invention is approximately 5-10 mm in diameter and 2.0-4.6 mm thick. So, the tablet of

  Theophylline sustained release according to the present invention is advantageously

  geuse in the sense that it can be very easily administered orally. In addition, the sustained-release theophylline tablet according to the present invention releases very gradually and substantially

  complements theophylline. Therefore, when theophyll- lozenge

  sustained release line according to the present invention is administered to an oral patient, there is not the excessive increase in theophylline concentration in the blood immediately after administration which is usually observed in the case of lozenges and the effective concentration of theophylline in the blood can be maintained stably 12 to 24 hours after the optimum level of theophylline in the blood is reached. Consequently, the frequency of administration can advantageously be reduced to once or twice a day when

  uses the present theophylline tablet.

  As already mentioned above, the theophylline concentration in the blood of 5 to 20 pg / ml must be maintained in order to obtain a therapeutic effect in the treatment of bronchial asthma. Therefore, when the present theophylline lozenge is used for this purpose, lozenges containing an amount of 500 to 800 mg in terms of theophylline

  (i.e. 2 to 4 lozenges containing 200 mg of theophylline) are allowed

  taken orally once or twice a day.

Examples

  The present invention will now be illustrated in more detail by

  the following examples without being limited thereto.

  Example 1 (preparation example) An amount of 10 g of theophylline, 8 g of ethyl cellulose (for example "Ethocel Standard 10" manufactured by Dow Chemical Co. Ltd), 0.36 g of calcium stearate and 0, 09 g of light silicic anhydride (for example

  "Carplex" manufactured by Shionogi and Co. Ltd) are introduced into a reci-

  pient. The mixture is vigorously mixed by a Micro-V type mixer

  (Tsutsui Rikagaku Kikai Co. Ltd) to prepare a uniform mixture.

  The mixture is compression molded by a Rotary Tablord machine (HT-9, Hata Iron Works). Theophylline pellets are thus obtained

  having a weight of 184.5 mg, a diameter of 8 min and a thickness of 4 mmn.

  Example 2 (preparation example) Theophylline tablets having a weight of 164 mg, a diameter of 7 mm and a thickness of 3.8 mm, are prepared in the same way as in Example i from 10 g of theophylline, 6 g of ethyl cellulose (eg Ethocel Standard 100, manufactured by Dow Cheiical Co. Ltd), 0.32 g of calcium stearate and 0.08 g of light silicic anhydride used

in Example 1.

  Example 3 (preparation example) Theophylline tablets having a weight of 82 mg, a diameter of 6 mm and a thickness of 2.4 mm, are prepared in the same way as in Example 1 from 10 g of theophylline, 6 g ethyl cellulose

  used in Example 2, 0.32 g of magnesium stearate and 0.08 g of an-

  light silicic hydride used in Example 1.

  Example 4 (preparation example) Theophylline tablets having a weight of 184.5 mg, a diameter of 8 mm and a thickness of 3.8 mm are prepared in the same way as in

  Example 1 from 30 g of theophylline, 6 g of ethyl cellulose used

  in example 1, 0.72 g of calcium stearate and 0.18 g of anhydride

  light silicic acid used in Example 1.

  Example 5 (preparation example) Theophylline tablets having a weight of 71.75 mg, a diameter of 5 mm and a thickness of 3.7 mm are prepared in the same way as in

  Example 1 from 50 g of theophylline, 20 g of ethyl cellulose used

  read in Example 2, 1.4 g of magnesium stearate and 0.35 g of anhydride

  light silicic acid used in Example 1.

  Example 6 (preparation example) Theophylline tablets having a weight of 252.8 mg, a diameter of 8 mm and a thickness of 4.6 mm are prepared in the same way as in

  Example 1 from 60 g of theophylline, 12 g of ethyl cellulose used

  In example 1, 1.44 g of calcium stearate and 0.36 g of anhydride

  light silicic acid used in Example 1.

  Example 7 (preparation example) Theophylline tablets having a weight of 350.6 mg, a diameter of 10 mm and a thickness of 4.3 mm are prepared in the same way as in

  Example i from 90 g of theophylline, 12 g of ethyl cellulose used

  see in Example 1, 2.04 g of calcium stearate and 0.51 g of anhydride

  light silicic acid used in Example 1.

  Example 8 (release test) The pellets prepared in examples 1 to 5 above are evaluated, in terms of rate of release (or dissolution) of theophylline, according to the second method of dissolution test (ie to say a method

  Paddle speed, 100 rpm) defined in the Japanese Pharmacopoeia (10th edition).

  The pellets are dissolved in the first and second test solution

  defined in the pharmacopoeia of Japan to make the test solution and the solution

  tion test is collected over time.

  The amounts of theophylline dissolved in each test solution

  are determined by measuring the absorption at 270 nm.

  The results are shown in Table I

TABLE I

  _ ___ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __... .___ _ __ __ _ __ _

  Solution theophylline dissolution rate time in% dissolution test Exempie in hours 1 2 3 4 5

1 * 1 1 24.3 24.2 32.2 25.8 37.8

II * 2 2 36.7 38.5 41.9 43.5 52.7

II * 2 4 52.6 57.4 53.6 65.6 67.1

  Il2 6 68.8 72.2 62.4 84.6 79.8 Il * 28 83.0 86.3 70.4 95.4 91.0

II'2 10 95.2 98.0 77.3 99.8 98.9

  1 the first test solution defined in the pharmacopoeia of Japan

  contains dilute NaCl and HCl (pH_ = 1.2).

  2 the second test solution defined in the pharmacopoeia of Japan

contains KH2PO4 and NaOH (pH = 6.8).

  Example 9 (application example) Transitional changes in theophylline levels in human blood from theophylline lozenges prepared in example 2

  above and a suitable theophylline sustained release tablet

  containing 100 mg of theophylline are evaluated by a method of

random crossing.

  Two grains of the sample tablets are administered to five adults.

  your healthy males aged 33 to 52 (38.4 on average) and

  a body weight of 51 to 68 kg (59.4 average). The two types mention-

  born above sample lozenges are administered alternately

  with a removal period of one week between the first and the second

  x administration of the two samples. For those tested, we

  Prevent ingestion of food and drink containing xanthine such as tea, coffee and coca cola for 12 hours before administration until the end of the test period. Blood samples are taken before administration (i.e. 0 hours) and 2, 4, 6, 9, 12 and 26 hours after administration. The serum is separated from the sample blood and is

  stored frozen until dispensed.

  Theophylline content in blood is determined by measuring absorption at 280nm using phase chromatography

liquid at high speed.

  The results are shown in Table 2 and Figure 1. As is clear from the results shown in Table 2 and Figure 1, the change in theophylline concentration in the blood from

  the current tablet is weak and the desired concentration of theophyll-

  line in the blood is maintained for an extended period (between 2 and 26 hours) compared to the theophylline release tablet

extended classic.

TABLE 2

  pastille person time in hours tested 0 ___ _ test1ee2 4 6 9 12 26 control (no- A ND 3.1 4.8 5.2 4.2 3.6 1.7 tille class- B ND 2.9 5.2 5.3 4.3 3.8 1.9 sic C ND 2.5 4.2 5.3 4.2 3.5 ND

D ND 3.5 5.4 5.5 4.8 3.4 ND

E ND 1.5 3.2 5.2 5.4 3.7 ND

  average - 2.70 4.56 5.30 4.58 3.60 0.72

S E - 0.34 0.40 0.05 0.23 0.07 0.44

  pellet of A ND ND 2.6 3.4 2.7 2.9 1.7 Example 2 B ND 1.8 2.8 3.4 3.0 2.6 1.9

C ND 1.8 2.5 3.5 3.1 2.7 2.0

D ND 2.3 2.9 3.2 2.6 2.5 1.6

E ND 1.6 3.0 3.5 3.4 2.8 1.5

  average - 1.50 2.76 3.40 2.96 2.70 1.74

S E - 0.39 0.09 0.05 0.14 0.07 0.09

  ND: less than 0.5 mcg / ml (unit: mcg / ml).

Z5 70603

Claims (5)

  1.- Pharmaceutical prolonged-release tablet comprising theophylline and ethylcellulose uniformly dispersed therein in an amount of 5 to 200 parts by weight of ethylcellulose relative to 100 parts by weight of theophylline, the hardness of the tablet being from 0.5 to 16.0 kg.   2.- Pharmaceutical tablet with prolonged release according to the claim   cation 1, in which the amount of ethyl cellulose is 10 to 100 per   parts by weight relative to 100 parts by weight of theophylline.   3.- Pharmaceutical tablet with prolonged release according to the claim   cation 2, in which the tablet is prepared by a compression method direct communication.   4.- Process for the preparation of a pharmaceutical theophylline sustained release tablet comprising the steps of:   - uniform mixture of 100 parts by weight of theophylline and 5 to 200 per-   parts by weight of ethyl cellulose; and   -molding by compression of the resulting mixture by a method of com-   direct pressure to form a pellet.   5.- The method of claim 4, wherein the amount of ethyl-   cellulose is 10 to 100 parts by weight relative to 100 parts in weight of theophylline.