WO1999030714A1

WO1999030714A1 - Sustained-release theophylline preparation and process for producing the same

Info

Publication number: WO1999030714A1
Application number: PCT/JP1998/005471
Authority: WO
Inventors: Mutsuo Okumura; Masaaki Sunohara; Tadashi Ukigaya
Original assignee: Nikken Chemicals Co., Ltd.
Priority date: 1997-12-17
Filing date: 1998-12-04
Publication date: 1999-06-24
Also published as: JP4221068B2; JPH11180875A

Abstract

A sustained-release theophylline preparation produced by compression molding a homogeneous mixture mainly comprising theophylline and sodium lauryl sulfate as such without subjecting to granulation or humidification and heat treatment.

Description

TECHNICAL FIELD The field of theophylline sustained release tablet and its production method

The present invention relates to a sustained-release tablet of theophylline, and more particularly, to a small-sized and inexpensive sustained-release tablet of theophylline. Background art

Theofirin is a useful drug that is commonly used as a symptomatic treatment for bronchial asthma. However, theophylline has a narrow effective blood concentration range.

Approximately 10 to 20 μg / ml is almost consistent among researchers. It has been pointed out that when the blood concentration of theophylline exceeds 20 Zg / ml, sometimes serious side effects occur on the cardiovascular and central nervous systems. In addition, there is a large difference in blood concentration between individuals, and it is greatly affected by various conditions (heart failure, liver, kidney disease, etc.), age differences, and the presence or absence of smoking. In addition, theophylline has a short biological half-life of about 6 hours in adults and needs to be administered every 6 hours four times a day to maintain effective blood levels. Frequent dosing can be annoying to the patient, reducing patient compliance and exacerbating the condition. In particular, bronchial asthma attacks often occur at dawn, but taking theophylline before bedtime has a sufficient effect on dawn seizures due to its biological half-life. Cannot be expected. For this reason, efforts have conventionally been made to develop sustained-release theophylline formulations, and some formulations have already been marketed.

To date, the theophylline sustained release formulations are insoluble. A type in which a medicinal ingredient is dispersed in a matrix composed of a synthetic resin or lipid to make sustained release (for example, Japanese Patent Application Laid-Open No. Sho 56-122321, US Patent No. ) And capsules and tablets contain several types of small particles (beads) with different release rates. These small particles are composed of an active ingredient layer and an insoluble lipid layer around the core. Are alternately formed (see, for example, US Pat. No. 3,872,998). Some of these theophylline sustained-release preparations are already on the market, but each has drawbacks that cannot be ignored in practical use, and both types are still complete as sustained-release preparations. It is hard to call it something.

In other words, in the former type of preparation, the ratio of the carrier and excipients for dispersing the active ingredient reaches 50% or more of the active ingredient, so that the decrease in the active ingredient content and the size of the tablet can be avoided. In addition, there is a disadvantage that the release of the medicinal component is incomplete. In addition, the latter type of preparation has drawbacks such as requiring a high degree of skill because of the complicated operation required for its preparation, and increasing the production cost.

In recent years, a type of formulation that replaces the sustained-release formulation as described above has been patented (see Japanese Patent Publication No. 11-364444, 7-29927). That is, the former is a non-disintegrating thin plate-like tablet consisting almost exclusively of theophylline. However, as shown in the comparative example of the present invention, the tablet containing only theophylline has a poor dissolution property, and there is a concern that the absorption amount is reduced. The latter is a tablet obtained by compression-molding a mixture consisting essentially of theophylline and ethylcellulose by a direct compression method. It is known that this tablet, when it is a small tablet containing 50 to 20 Omg of theophylline, shows almost the same absorption amount as that of the known formulation. Large tablets containing the above components have incomplete dissolution in the gastrointestinal tract, resulting in reduced absorption and sufficient blood Medium concentration cannot be maintained. Disclosure of the invention

According to the present invention, there is provided a theophylline sustained-release tablet comprising, as main components, theophylline and sodium lauryl sulfate.

According to the present invention, it also includes compression-molding a uniform mixture containing theophyrin and sodium lauryl sulfate as main components by a direct hitting method. And a method for producing a theophylline sustained-release tablet. BRIEF DESCRIPTION OF THE FIGURES

Hereinafter, the present invention will be described with reference to the drawings.

Fig. 1 is a graph showing the results of a dissolution test (Method 2, 50 rotations, 1 JP solution) of the tablets obtained in Examples 1 to 4 and Reference Example 1.

FIG. 2 is a graph showing the results of a dissolution test (the second method, 50 rotations, two liquids in Japan) of the tablets obtained in Examples 1 to 4 and Reference Example 1.

BEST MODE FOR CARRYING OUT THE INVENTION

The present inventors have found that when the lubricant is added to Teofirin alone or to Teofirin in an amount of 1% by weight or less and tableted, the dissolution of Teofirin becomes surprisingly poor. Was found. Furthermore, the use of highly water-soluble saccharides (sucrose, lactose, etc.) and disintegrating additives (corn starch, etc.) to promote the dissolution of theophylline for the purpose of controlling the dissolution greatly increases the effect of diet. It was also found that they would receive it. Therefore, once-daily administration of a tablet with a high content of theophylline is effective in absorbing theophylline. As a result of intensive research aimed at a drug that can maintain an effective blood concentration without being affected by the diet without reducing the rate, a small amount of sodium rauryl sulfate was added to theophylline. The present invention has been found that a tablet obtained by directly compression-molding a homogeneous mixture containing a tablet is extremely stable and has a good sustained-release effect without being affected by food. Was completed.

That is, the present invention relates to a theophylline sustained release tablet comprising theophylline and sodium lauryl sulfate, and more particularly, to theophylline and sodium lauryl sulfate. Theophylline is obtained by direct compression (direct powder compression method) of a homogeneous mixture consisting of, without granulation, humidification, and heat treatment. Tablet. The ratio of sodium lauryl sulfate to theophylline in the tablet is preferably from 0.1 to 20 parts by weight of sodium lauryl sulfate to 100 parts by weight of theophylline. It is 1.0 to 10 parts by weight ι5 '.

'According to the present invention, the above-mentioned theophylline sustained-release tablet contains the theofilin and sodium lauryl sulfate in a ratio of 100 parts by weight of theophylline to 100 parts by weight of theophylline. Sodium sodium lauryl sulfate is added in an amount of 0.5 to 10 parts by weight, preferably 1.0 to 10 parts by weight, and if necessary, a small amount of an additive is added thereto. After the mixture is uniformly mixed, the mixture can be prepared by compression molding to a desired size by a direct hitting method.o

As the theophylline used in the present invention, a commercially available powdered product is usually used as it is or is appropriately pulverized. If desired, the product is prepared in advance into a theophylline granule by a dry method. Can also be used.

Also, sodium lauryl sulfate is uniformly mixed with the above-mentioned theophylline. Any substance that can be used can be used, and those described in the Japanese Pharmacopoeia can be used.

The dissolution rate of theophylline in the theophylline sustained-release tablet of the present invention is mainly determined by changing the mixing ratio of sodium rauryl sulfate to theophylline. Can be adjusted. In order to obtain a suitable sustained-release effect of theophylline, the mixing ratio of sodium rauryl sulfate to theophyline is set to 100 parts by weight of thelauryl to the amount of lauryl. It is desirable to use 0.1 to 20 parts by weight of sodium sulfate, preferably 1.0 to 10 parts by weight. That is, if the mixing ratio of sodium lauryl sulfate is more than the above range, the elution rate of theofilin becomes too fast to obtain a predetermined sustained-release effect, and it is less than the above range. If it becomes too small, the elution of theophylline becomes insufficient, and it becomes difficult to obtain a desired sustained release effect.

The theophylline sustained-release tablet of the present invention is basically composed of theophylline and sodium lauryl sulfate, and may further contain an excipient and a lubricant, if necessary. And other additives can be appropriately compounded. The amount of such an additive may be used as long as it does not significantly affect the dissolution of theophylline, and the ratio of the additive to the whole tablet is about 25% by weight or less. These additives are used for the purpose of improving the moldability, binding property and tableting property, if necessary, when formulating by compression molding. Examples of the excipient include lactose, sucrose, glucose, mannite, and the like. Examples of the lubricant include magnesium stearate, calcium stearate, light gay anhydride, and hydrous dioxide. Silicon or the like is used.

The method for producing the theophylline sustained release tablet according to the present invention is not particularly limited, but preferably, a uniform mixture of theophylline and sodium lauryl sulfate is subjected to a direct punching method. Manufactured by compression molding more directly I do. Compared with other tablet molding methods, the Manpo method can omit intermediate steps such as condylarization, is extremely simple in operation, and is advantageous in terms of time and economy.

Since the theophylline sustained release tablet according to the present invention does not necessarily require other additives, the size of the obtained tablet is significantly smaller than that of a conventional theophylline-containing preparation. It has the advantage of being able to be in a form, and furthermore, the elution rate of theophylline is not affected by the pH of the digestive fluid or enzymes, the elution rate is high, and the elution rate is high. The advantage is that the elution of the phosphorus is almost complete. Also, when this is actually administered orally to humans, it suppresses excessive increase in the blood concentration of Teofirin immediately after administration, promptly reaches the optimum blood concentration, and extends the Tephrin for a long time. Because it can maintain a stable and effective blood concentration, the frequency of administration can be 1-2 times a day. The dose of theophylline is generally 200 to 400 mg / day / person.o

Example

Examples of the theophylline sustained release tablet of the present invention are shown below, and the test examples of the dissolution test and oral administration test of the obtained tablet are described in detail. Needless to say, it is not limited to this.

Example 1

Take 80 g of theophylline, 8 g of sodium raurylsulfate, 0.888 g of calcium stearate, and 0.44 g of hydrous silicon dioxide in a container, and mix each component uniformly. After mixing, tablets were compression-molded with a modified punch (length 13 mm, minor diameter 6.5 mm) at 1.0 to 1.5 t to obtain tablets with a weight of 447 mg and a thickness of 5.1 mm. .

Example 2 80 g of theophylline, sodium sodium lauryl sulfate;;: g, 0.82 g of calcium stearate, 0.4 g of hydrous silicon dioxide are placed in a container, and each component is placed in a container. Was uniformly mixed, and then compression-molded with a modified punch at 1.0 to 1.5 t to obtain tablets having a weight of 41.7 mg and a thickness of 4.9 mm.

Example 3

Take 80 g of theophylline, 0.8 g of sodium raurylsulfate, 0.8 g of calcium stearate, and 0.4 g of hydrous silicon dioxide in a container, and homogenize each component. After compression, the mixture was compression-molded with a modified punch at 1.0 to 1.5 to obtain tablets having a weight of 410 mg and a thickness of 4.8 mm.

Example 4

Take 80 g of theophylline, 0.4 g of sodium raurylsulfate, 0.8 g of calcium stearate, and 0.4 g of hydrous silicon dioxide in a container, and mix each ingredient. After uniform mixing, the mixture was compression-molded with a modified punch at 1.0 to 1.5 t to give tablets with a weight of 408 mg and a thickness of 4.8 mm.

Example 5

Take 80 g of theophylline, 8 g of sodium raurylsulfate, 0.888 g of calcium stearate, and 0.44 g of hydrous silicon dioxide in a container, and mix each component uniformly. After mixing, the mixture was compression-molded with a sugar-coated punch (9 mm, 0) at 1.0 to 1.5 t to give tablets weighing 23 mg.

Example 6

Take 80 g of theophylline, 8 g of sodium raurylsulfate, 0.88 g of calcium stearate, and 0.44 g of hydrous silicon dioxide in a container and mix each component uniformly. After mixing, the mixture was compression-molded with a sugar-coated punch (7 mm, 0) at 1.0 to 1.5 t into tablets weighing 112 mg.

Reference example 1

Theophylline 80 g カ Canolecium stearate 0.8 g を 0.4 g of hydrous manganese dioxide in a container, mix each component uniformly, then atypical Using a pestle, the tablets were compression-molded at 1.0 to 1.5 t into tablets having a weight of 40 ti mg and a thickness of 4.8 mm.

Reference example 2

80 g of theophylline, 4 g of ethylcellulose, 8 g of lactose, 6 g of corn starch, 0.98 g of calcium stearate, 0.49 g of hydrated gay oxide After mixing the components uniformly, the mixture was compression-molded at 1.0 to 1.5 t using a modified punch to give tablets having a weight of 49.7 mg and a thickness of 5.7 mm.

Reference example 3

Take 80 g of theophylline, 4 g of ethylcellulose, 4 g of corn starch, 0.88 g of calcium stearate, and 0.44 g of hydrous silicon dioxide in a container. After uniform mixing, tablets were compression-molded with a modified punch at 1.0 to 1.5 t to obtain a tablet having a weight of 447 mg, a minor axis of 6.5 mm, and a thickness of 5.2 mm.

Reference example 4

80 g of theophylline, 8 g of low-substituted hydroxypropyl cellulose, 4 g of sodium raurylsulfate, 0.88 g of calcium stearate, 0.44 g of hydrous silicon dioxide The mixture was placed in a container, and the components were uniformly mixed. After that, the mixture was compression-molded with a modified punch at 1.0 to 1.5 t into a tablet with a weight of 467 mg and a thickness of 5.5 mm.

Test example 1 (dissolution test)

13th revised Japanese Pharmacopoeia (hereinafter abbreviated as "JP") Tablets prepared in Examples 1 to 4 and Reference Example 1 were used as samples according to the second method (paddle method) of the dissolution test method. The dissolution test was conducted using the first test solution (hereinafter abbreviated as “1st JP solution”) and the 2nd test solution (hereinafter abbreviated as “2nd JP solution”) of the JP Disintegration Test. After the start of the test, the eluate of each sample was collected over time. After diluting the sample solution with 0.1 N hydrochloric acid, the absorbance at 27 lnm is used to remove the sample. The amount of eluted lin was calculated. The results are not shown in FIGS.

As a result of performing a dissolution test with one solution of JP, the dissolution was accelerated according to the content of sodium lauryl sulfate, and the dissolution of theophylline was determined by the amount of sodium lauryl sulfate added. It was recognized that it could be controlled. The elution of the two Japanese Pharmacopoeia solutions can be clearly accelerated by adding sodium lauryl sulfate compared to Reference Example 1.

Test Example 2 (Human oral administration test)

Male and female volunteers aged 20 to 30 years and weighing 50 to 80 kg (6 subjects) were given the tablets prepared in Reference Examples 2 and 3 and the tablet prepared in Example 1 under fasted and fed conditions. Oral administration. After the administration, blood was collected over time to examine changes in the blood concentration of theophylline. Blood concentration of theophylline was calculated by the HPLC method. The results are shown in Table 1. Table 1: Oral administration studies in humans

Note: Fasting and feeding in Reference Example 2 and Example 1 were each performed by the crossover test.

C max: maximum blood concentration, T max: time to reach maximum blood concentration

A U C: Area under the blood concentration curve

In the tablet prepared in Reference Example 2, the blood concentration of theophylline increases rapidly after oral administration, but the fasted and fed levels of theophylline increase. Tablets with different blood concentration changes contain corn starch as a disintegrating additive to promote the dissolution of theophylline, which increases with food intake You can see that it is affected. On the other hand, when the tablet prepared according to Example 1 was orally administered, the blood concentration of theophylline rapidly increased. In addition, the results show that the blood concentration changes in the fasted state and the ingested state are exactly the same, indicating that this tablet was not affected by food at all and had a stable and good sustained release effect. .

In addition, the following are the theophylline obtained when orally administered two theodol tablets 200 (containing 200 mg of theophylline) (Nikken Chemical Co., Ltd.) currently marketed below. The kinetic parameters of the drug are shown in Table 2. The AUC and C max when the tablet of the present invention was orally administered at the time of fasting were two tablets of commercially available Theodor Tablet 200 (Niken Kagaku Co., Ltd.). Results after administration (eg, Kazuo Kawakatsu, Shoji Takeyama, Mitsuru Kawaai Allergy, 37, 256 (1988) ". Also, Riko Morishita, Tsuneji Nagai, Takashi Ishizaki, Toshiyuki Suganuma, Keiko Kushida, Akemi Minegishi Allergy , 35, 1099 (1 986) ²⁾ ), indicating that this tablet is extremely useful for bronchial asthma attacks.

Table 2: Kinetic parameters in humans after a single administration of 400 mg of theophylline

Evening

Industrial applicability The sustained release tablet of aofirin of the present invention can suppress an excessive increase in the blood concentration of theophylline immediately after administration, and can quickly reach the optimal blood concentration. Furthermore, it can be manufactured more compactly and inexpensively than conventional ones, is not easily affected by diet, and can maintain a stable effective blood concentration of theofilin for a long time.

Claims

The scope of the claims

1. Sustained-release tablets of theophylline containing theophylline and sodium lauryl sulfate as main components.

2. Theophylline sustained-release tablets obtained by directly compression-molding a homogeneous mixture containing theophylline and sodium lauryl sulfate as main components.

3. The theoline according to claim 1 or 2, wherein the amount of sodium lauryl sulfate is 0.1 to 20 parts by weight based on 100 parts by weight of theophyrin. Sustained-release tablets.

4. The teoff according to claim 1 or 2, wherein the amount of sodium sodium lauryl sulfate is 1.0 to 10 parts by weight based on 100 parts by weight of the olefin. Irin sustained release tablets.

5. Slow release of theophylline, which comprises compression-molding a uniform mixture containing theophylline and sodium lauryl sulfate as main components by a direct hitting method. Method for producing a dispersible tablet.

6. The theophylline sustained-release according to claim 5, wherein the amount of sodium sodium lauryl sulfate is 0.1 to 20 parts by weight based on 100% by weight of theophylline. Tablet manufacturing method.

7. The sustained-release tablet of theofilin according to claim 5, wherein the amount of sodium lauryl sulfate is 1.0 to 10 parts by weight based on 100 parts by weight of theophylline. Production method.