JPH0729927B2 - Theophylline sustained release formulation - Google Patents

Description

The present invention relates to a theophylline sustained-release preparation, and more particularly to a theophylline sustained-release preparation obtained by directly compressing and molding a mixture containing theophylline and ethyl cellulose.

Theophylline is a useful drug that is commonly used as a symptomatic treatment agent for bronchial asthma, but theophylline has a narrow effective blood concentration range (that is, 10 to 20 mcg / ml), and effective blood concentration and the occurrence of side effects in blood. Since the concentration is close (that is, 25 ug / ml or more), side effects such as headache, nausea, and arrhythmia are likely to appear during treatment, and it is said that the drug is difficult to administer. Since theophylline has a short biological half-life (about 6 hours), it is necessary to administer it 4 times a day, every 6 hours in order to maintain an effective blood concentration. Is really annoying to the patient. Not only that, asthma attacks often occur at dawn, but even if theophylline is taken at bedtime, it is not possible to expect a sufficient effect on dawn attacks due to its biological half-life. .

Therefore, efforts have been continuously made to develop a long-acting theophylline preparation, and some preparations have already been proposed or put on the market.

There are various types of theophylline sustained-release preparations that have been known so far, but when they are roughly classified, they are of the type in which the medicinally active ingredient is dispersed in a matrix composed of an insoluble synthetic resin or lipid for sustained release. (For example US Pat. No. 3062
720, 3402240, 3456049, JP-A-56-122
311), and several small particles (beads) having different release rates are contained in capsules and tablets, and these small particles have alternating active ingredient layers and insoluble lipid layers around the nucleus. Of the type having the structure formed in (for example, U.S. Pat. Nos. 3,080,294, 3,109,775 and 3,440,29).
No., No. 3872998, etc.).

Some of these theophylline sustained-release preparations are already on the market, but each has a drawback that cannot be ignored in practical use, and it is difficult to say that any of these types is a complete sustained-release preparation. In other words, the former type of formulation has a carrier / excipient ratio of 50% or more to disperse the medicinal components, so that the content of medicinal components is not decreased and the size of the tablet is inevitable. The disadvantage is that the release of the components is incomplete. Further, the latter type of formulation has drawbacks such as a high degree of skill required for its preparation and a high production cost because of its complicated operation.

Recently, a new type of formulation replacing the above-mentioned long-acting formulation has been proposed in JP-A-57-112322. This new preparation is a thin, non-disintegrating flat tablet consisting mostly of theophylline, and is characterized by being easy to manufacture and containing a large amount of the medicinal component. However, this formulation has a low theophylline content (eg 50-
When preparing a small tablet (150 mg), there is a drawback that the release rate of the medicinal component becomes too fast and sufficient sustainability cannot be expected.

The present inventors succeeded in developing a specific effect theophylline granule and applied for a patent (Japanese Patent Publication No. 57-53325). However, as a result of further intensive studies, a uniform mixture of theophylline and ethyl cellulose was granulated. The present invention has been completed by finding that a preparation obtained by directly compression-molding without any treatment has extremely stable and good sustained-release effect.

The present invention is a tablet obtained by direct compression molding a uniform mixture of theophylline and ethyl cellulose by a direct compression method (direct powder compression method), that is, without performing granulation or humidification / heat treatment. The tablet contains at least 75 theophylline and ethyl cellulose.
The present invention relates to a sustained-release formulation of theophylline, which is characterized in that the ratio of ethylcellulose to theophylline is from 5 to 200 parts by weight, preferably from 20 to 100 parts by weight, based on 100 parts by weight of the former, and 100% by weight of the former.

According to the present invention, the above-mentioned theophylline sustained-release preparation, theophylline and ethyl cellulose are added so that the ratio of both is 5 to 200 parts by weight of ethyl cellulose to 100 parts by weight of theophylline, and if necessary, a small amount of It is prepared by adding additives and mixing uniformly, and then compression-molding the mixture into a desired size by a direct compression method.

As the theophylline used in the present invention, a commercially available powder product is generally used as it is or after being appropriately pulverized, and if desired, theophylline granules prepared in advance by a dry method can also be used.

The ethyl cellulose is not particularly limited as long as it can be uniformly mixed with the above-mentioned theophylline, and commercially available products such as "ETOCEL" standard or medium (trade name: Dow Chemical Co. product). Can be used.

The dissolution rate of theophylline in the theophylline sustained-release preparation of the present invention can be adjusted mainly by changing the mixing ratio of ethyl cellulose to theophylline.

In the present invention, in order to obtain a suitable sustained-release effect of theophylline, it is desirable that the mixing ratio of ethyl cellulose to theophylline is 5 to 200 parts by weight, preferably 20 to 100 parts by weight, relative to 100 parts by weight of theophylline.

That is, if the mixing ratio of ethyl cellulose is less than the above range, the dissolution rate of theophylline becomes too fast and the predetermined sustained release effect cannot be obtained, and if it is more than the above range, theophylline is not sufficiently eluted and a sufficient drug effect is expected. become unable.

Further, the theophylline sustained-release preparation of the present invention is basically composed of theophylline and ethyl cellulose, but it is also possible to optionally contain additives such as an excipient and a lubricant, if necessary. is there. As the amount of additive used,
It does not matter as long as it does not significantly affect the elution of theophylline, and the proportion of the whole tablet is about 25% by weight or less.

These additives are used for the purpose of improving the moldability, binding property, tableting property, etc., if necessary, when producing tablets by compression molding. For example, lactose, sucrose, glucose, mannitol, etc. are used as excipients. As the lubricant, magnesium stearate, calcium stearate, aluminum stearate, "Carplex" (trade name: Shionogi Pharmaceutical Co., Ltd. product), "Aerosil" (Japan Aerosil Co., Ltd. product), etc. are used. To be

The theophylline sustained-release preparation of the present invention is produced by directly compression-molding a homogeneous mixture containing theophylline and ethyl cellulose by a direct compression method, which is an intermediate step such as granulation as compared with other tablet molding methods. Can be omitted, and the operation is extremely simple, which is advantageous in terms of time and economy.

The sustained-release theophylline preparation of the present invention has a certain tablet hardness (0.5 to 12.0 kg / cm ² ) and is excellent in moldability. In the theophylline sustained-release preparation of the present invention, ethyl cellulose also plays a role as an excipient, and does not necessarily require an extra other additive. Therefore, the size of the obtained tablet is usually 5 to 10 mm in diameter, Thickness 2.1-4.5mm
However, it has an advantage that it is significantly smaller than conventional theophylline-containing preparations, and is therefore convenient in terms of ease of drinking, especially for children.

Further, there are advantages that the elution rate of theophylline is not affected by PH and enzymes in the digestive fluid, the elution rate is highly uniform, and the theophylline is almost completely eluted. In addition, when it is actually administered orally, it suppresses an excessive increase in blood concentration of theophylline immediately after the administration, promptly reaches the optimum blood concentration, and stabilizes theophylline over a long period of 10 to 26 hours. Since the effective blood concentration can be maintained, the number of administrations can be twice a day or less.

Examples of the sustained-release theophylline preparation of the present invention are shown below, and the dissolution test of the obtained preparation is shown as a test example.

Example 1 10 g of theophylline, 8 g of ethyl cellulose (“Etocel Standard 10” manufactured by Dow Chemical Co., Ltd.), 0.36 g of calcium starate, and 0.09 g of Carplex (product of Shionogi Pharmaceutical Co., Ltd.) were placed in a container and each component was evenly distributed. After mixing, the mixture was compression molded into tablets having a weight of 184.5 mg, a diameter of 8 mm and a thickness of 4 mm.

Example 2 100 g of theophylline, 60 g of ethyl cellulose (“Etocel Standard 100” manufactured by Dow Chemical Company), 40 lactose
g, 4 g of calcium starate, 1 g of carplex in a container, mix evenly each component, then compression mold and weigh
The tablets were 205 mg in diameter, 8 mm in diameter, and 4 mm in thickness.

Example 3 10 g of theophylline, 6 g of ethyl cellulose (the same as in Example 2), 0.32 g of calcium stearate and 0.08 g of carplex were placed in a container, and the components were uniformly mixed and compression-molded to weigh 164 mg, diameter 7 mm, and thickness. The tablets were 3.8 mm.

Example 4 10 g of theophylline, 6 g of ethyl cellulose (the same as in Example 2), 0.32 g of magnesium stearate and 0.08 g of carplex were placed in a container, and the components were uniformly mixed and then compression molded to obtain a weight of 82 mg, a diameter of 6 mm, and a thickness. 2.4 mm tablets.

Example 5 30 g of theophylline, 6 g of ethyl cellulose (the same as in Example 1), 0.72 g of calcium stearate and 0.18 g of carplex were placed in a container, and the components were uniformly mixed and then compression molded to obtain a weight of 184.5 mg, a diameter of 8 mm, and a thickness. 3.8 mm tablets.

Example 6 50 g of theophylline, 20 g of ethyl cellulose (the same as in Example 2), 1.4 g of magnesium stearate and 0.35 g of carplex were placed in a container, and the components were uniformly mixed and compression-molded to weigh 71.75 mg, diameter 5 mm, The tablets were 3.7 mm thick.

Example 7 60 g of theophylline, 12 g of ethyl cellulose (the same as in Example 1), 1.44 g of calcium stearate and 0.36 g of carplex were placed in a container, and the components were uniformly mixed and then compression molded to give a weight of 252.8 mg, a diameter of 8 mm, The tablets were 4.6 mm in thickness.

Example 8 90 g of theophylline, 12 g of ethyl cellulose (the same as in Example 1), 2.04 g of calcium stearate and 0.51 g of carplex were placed in a container, and the components were uniformly mixed and then compression molded to give a weight of 350.6 mg, a diameter of 10 mm, The tablets were 4.3 mm thick.

Test Example 1 (dissolution test) According to the second method (paddle method) of the 10th revised Japanese Pharmacopoeia (hereinafter referred to as "JP") dissolution test method, the tablet prepared in the example was used as a sample, and the JP 1st test liquid was used as a sample. And the eluate is collected over time using the second test solution, and the absorbance at 270 nm is measured,
The elution amount of theophylline was calculated.

The results are shown in Table 1.

Test Example 2 (Transition of Human Blood Concentration) The sustained release property of the present invention was applied to 5 healthy adult males-aged 33 to 52 years old (average 38.4 years old), weight 51 to 68 kg (average 59.4 kg). Formulation (Formulation of Example 3: containing 10 mg of theophylline) and known sustained-release theophylline formulation (100 mg of theophylline).
2 tablets each) were administered by the random crossover method, and changes in blood concentration of each tablet were compared.

The above-mentioned two types of preparations are administered with a 1-week washout period between them, and the subjects are allowed to take xanthine-containing foods (tea, coffee, cola, etc.) 12 hours before taking the drug and during the duration of this study. Intake was prohibited.

Blood samples should be collected before and after drug administration2.
Serum separated from blood samples collected at 4, 9, 12 and 26 hours was frozen and stored until the time of measurement.

The concentration of theophylline in serum was quantified by determining the absorbance value at 280 nm by high performance liquid chromatography.

The results are shown in Table 2 and FIG.

As is clear from Table 2 and FIG. 1, the preparation of the present invention has less fluctuation in blood concentration and a long time (2 to 26 hours) as compared with the known theophylline sustained-release preparation.
Maintain blood levels.

[Brief description of drawings]

FIG. 1 shows changes in human blood concentration in correspondence with Table 2.

Claims (2)

[Claims] Claims: 1. A tablet obtained by directly compression-molding a uniform mixture of theophylline and ethylcellulose without granulating or humidifying / heating treatment, and the ratio of theophylline and ethylcellulose in the tablet. Is at least 75% by weight, and the ratio of ethyl cellulose to theophylline is 5 to 200 parts by weight of the latter with respect to 100 parts by weight of the former,
Theophylline sustained-release preparation. 2. The sustained-release preparation of theophylline according to claim 1, wherein the ratio of ethyl cellulose to theophylline is 100 to 100 parts by weight of the former and 20 to 100 parts by weight of the latter.