JPH0216729B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compositions containing theophylline or aminophylline.

Theophylline and its derivative aminophylline are widely used as bronchodilators and cardiotonic diuretics, but it is well known that they are drugs for which medication management is extremely important due to their narrow effective blood concentration range. That's right.

To this end, various formulation techniques have been investigated to control the drug release of theophylline or aminophylline. For example, it is described in the document shown below.

(1) M. Weinberger et.al.: New Eng. J. Med.,
308 (13), 760 (1983) (2) L.Hendeles et.al.: Pharmacotherapy 3,
(1, part 1), 2 (1983) (3) T. Ishizaki et.al.: Eur. J. Clin. Pharmacol.
24, 361 (1983) (4) Dasta J.et.al.: Am.J.Hosp.Pharm.36(5),
613-617 (1979) (5) Hasan A.et.al.: International J.Pharm.7
(1980) 77-82 However, in these formulation techniques, the release of theophylline or aminophylline is easily subject to fluctuations and does not always allow for a constant release over the entire release time.

In the first place, the release rate is determined solely by the initial concentration, and in order to maintain a constant amount of release over the entire release time, the release rate must be zero-order. In conventional formulation techniques, the release rate is zero-order within a certain short period of time, but it easily fluctuates and a constant release rate is no longer maintained.

From this point of view, in order to make it possible to manufacture a complete sustained-release formulation of theophylline or aminophylline, the present invention provides a formulation technology in which the release rate of theophylline or aminophylline is always zero-order over a long period of time. is required as a problem to be solved.

The present inventor conducted various studies to solve the above problems, and as a result, the predetermined purpose was achieved by incorporating theophylline or aminophylline into the polyoxyethylene polyoxypropylene copolymer matrix. Knowing this, he completed the present invention.

That is, the object of the present invention is to provide a formulation technology that allows the release rate of theophylline or aminophylline to be always zero-order over a long period of release time, and to achieve the object, the present invention aims to provide a formulation technique in which theophylline or aminophylline is Disclosed are compositions containing theophylline or aminophylline, characterized in that they are contained in an oxyethylene polyoxypropylene copolymer matrix.

The present invention will be explained in detail below.

Polyoxyethylene polyoxypropylene copolymer is obtained from Asahi Denka Co., Ltd. under the product name Pluronic. Although this substance has been found to have a wide variety of uses as a nonionic surfactant in pharmaceuticals and cosmetics, it has not been known as a substance that exhibits the effects of the present invention.

The substance is available in liquid, paste, and flake forms depending on the degree of polymerization, and is provided as Pluronic L, Pluronic P, and Pluronic F, respectively. There is no need for any special limitation as it can be selected as appropriate.

The polyoxyethylene polyoxypropylene copolymer matrix is a matrix having a network structure containing the copolymer as a substantial component. In other words, the polyoxyethylene polypropylene copolymer can construct an independent structure consisting of a fine network structure by itself, and other components can be incorporated into the network structure without losing the form of the structure. It has the property that it can be included as a parent body. Accordingly, in the present invention, the matrix is a matrix having a polyoxyethylene polyoxypropylene copolymer as a main component, and theophylline or aminophylline is contained in this matrix.

Specific embodiments of the matrix include aqueous gels, solid solutions, and the like. That is, for example, by dissolving Pluronic F in water to form a sol and allowing it to stand, an aqueous gel in which Pluronic F has a network structure can be obtained. If Pluronic F is melted and allowed to cool, a solid solution with a network structure can be obtained.

In order to incorporate theophylline or aminophylline into the matrix, it is simply necessary to mix it homogeneously. Therefore, for example, in order to incorporate it into an aqueous gel, it is sufficient to add it to an aqueous sol, mix it homogeneously, and gel it. Moreover, in order to include it in a solid solution, it is sufficient to add it to a melt, mix it homogeneously, and immediately cool it.

There is no particular limitation on the content of theophylline or aminophylline contained in the matrix, with respect to the entire matrix consisting of theophylline or aminophylline and the matrix. That is, as shown in the experimental examples below, the content determines the magnitude of the release rate, but it is not related to changes in the order of the release rate and always enables a zero-order release rate.
The content may be appropriately selected depending on the predetermined release rate, and is not a particularly limiting factor in the present invention.

However, considering the desirability as an actual product, it is preferably within the range of 2 to 80% W/W.

The composition of the present invention is a composition containing as an essential component a substance obtained by incorporating theophylline or aminophylline into a polyoxyethylene polyoxypropylene copolymer matrix. Therefore, the composition of the present invention may be the substance as it is, or it may be prepared by adding other excipients to the substance to form a predetermined formulation, such as an ointment, granule, tablet, etc. Good too. As shown in the experimental examples below, when other additives are added, the magnitude of the release rate changes depending on the type of additive, but the release rate itself remains constant over a long period of release time. It turns out that it remains zero-order.

The composition of the present invention, which is prepared into a predetermined formulation form by adding other excipients, may be manufactured according to a conventional method for manufacturing each formulation form.

The effects of the present invention will be explained using the following experimental examples.

Experimental Example 1 The drug release of theophylline or aminophylline from Pluronic aqueous gel was investigated.

Sample A sol in which theophylline or aminophylline is uniformly dissolved or dispersed at low temperature (drug concentration;
0.25-40w/w%, Pluronic F108 concentration;
30 w/w%) was filled into a stainless steel mortar with an inner diameter of 25 mm and a thickness of 10 mm, and the sample was left in a water-saturated desiccator for 1 hour to gel.

Method: Close one side of the mortar with aluminum foil and use it as an eluent.
This was done using water at 37°C. For detailed equipment and methods, see Chem, Pharm, Bull., 31(6)2069 (1983).
I followed the instructions.

Results The results are shown in Figures 1 to 4. Figure 1 is a graph showing the relationship between the cumulative release amount of theophylline from an aqueous gel and time, and shows the relationship between the ▽ marked line, □ marked line, ○ marked line, △ marked line.
The marked line, ■ marked line, ● marked line, and ▲ marked line indicate the theophylline content of 20%, 10%, 4%, 2%, and 1, respectively.
%, 0.5%, and 0.25%. Note that the theophylline content is defined here as shown in the following formula.

Theophylline content = Theophylline/Theophylline + Pluronic × 100% Figure 2 is a graph showing the relationship between the cumulative amount of aminophylline released from the aqueous gel and time, and shows the 〓 mark line, ◇ mark line, ▽ mark line, □ mark The line, 〇 marked line, and ■ marked line indicate that the aminophylline content is 40%, 30%, and 30%, respectively.
The results are shown for 20%, 10%, 4%, and 1%. In addition, the content rate of aminophyllin is defined here as shown in the following formula.

Aminophylline content = Aminophylline / Aminophylline + Pluronic × 100% Figure 3 shows the release rate of theophylline, that is, the gradient of the straight line, determined for each theophylline content based on Figure 1, and the release rate of theophylline and the theophylline content. It is a graph showing the relationship with the rate.
Similarly, FIG. 4 is a graph showing the relationship between the aminophyllin release rate and the aminophyllin content determined based on FIG. 2.

It is clear from FIGS. 1 and 2 that theophylline or aminophylline is released from the aqueous gel with a zero-order release rate. Furthermore, as shown in FIGS. 3 and 4, the release rate of theophylline or aminophylline is determined only by the content of each, so the release rate that is maintained constant over a long period of release time can be arbitrarily set as desired. becomes clear.

Experimental Example 2 Drug release from a mixed solid system of theophylline or aminophylline and Pluronic was investigated.

Sample A homogeneous mixture of theophylline or aminophylline and pluronic acid (2-80w/w%)
0.5g was pressurized at 100Kg for 3 minutes and tableted to obtain a mixed solid sample.

Method Drug release experiments were performed using the rotating disk method (Wood et al.
al.: J. Pharm Sci., 54, 1068 (1966)) and the rotating basket method (10th edition of the Japanese Bureau), the rotation speed was 100 rpm, and water at 37°C was used as the eluent.

Results The results are shown in Figures 5 to 7. Figure 5 is a graph showing the relationship between the cumulative amount of theophylline released from a mixed solid system and time determined by the rotating disk method. Theophylline content is 80%, 60%, 40%, and 10%, respectively.
The results are shown below. FIG. 6 is a graph showing the relationship between the cumulative amount of aminophylline released from a mixed solid system and time, determined by the rotating disk method.
The aminophylline content of the ▽marked line, □marked line, ○marked line, △marked line, and ◇marked line is 80%, 60%, and 40, respectively.
%, 10%, and 2%.

Figure 7 is a graph showing the relationship between the cumulative amount of theophylline or aminophylline released from a mixed solid system and time using the rotating basket method. The results are shown when the aminophylline content is 40% and 10%, and the ● and ▲ lines show the results when the aminophylline content was 40% and 10%, respectively. In addition,
The content of theophylline and the content of aminophylline are similarly defined by the formulas described in the Results section of Experimental Example 1.

From FIGS. 5 to 7, it can be seen that although the release rate of theophylline or aminophylline from the mixed solid system is determined by the content of each, the order of the release rate is maintained at zero order over a long period of release time; Moreover, it turns out that this holds true regardless of the test method.

Experimental Example 3 The effect of other additives on release was investigated when other additives were added to form the composition of the invention.

Samples and Methods Among the samples related to theophylline in Experimental Example 1, an aqueous gel with a drug concentration of 4% was selected, and (1)
A sample with gum arabic added to 10% W/W, (2) a sample with polyvinylpyrrolidone (K-90) added to the same 10% W/W, (3) methyl cellulose (MC-25). (4) Hydroxypropyl methylcellulose (TC-5R) was added at 10% W/W.
A sample with W added and (5) a sample with no additive were prepared. The same method as in Experimental Example 1 was carried out for each sample.

Results The results are shown in Figure 8. Figure 8 is a graph showing the relationship between the cumulative amount of theophylline released from the aqueous gel and time, and the ▽ marked line, □ marked line, ◇ marked line, △ marked line, and ○ marked line indicate addition of gum arabic and addition of polyvinylpyrrolidone, respectively. , results with addition of methylcellulose, addition of hydroxypropylmethylcellulose, and no addition are shown.

Figure 8 shows that the release rate of theophylline from the aqueous gel changes depending on the type of additive, but the order of the release rate itself remains zero order over a long period of release time. do.

The present invention will be explained in more detail with reference to Examples.

Example 1 1 kg of theophylline and 1 kg of Pluronic F108 were mixed in a 20 super mixer at 60°C for 5 minutes.
The mixture was crushed, 1.5 kg of lactose, 0.48 kg of Avicel, and 0.02 kg of calcium stearate were added, and each tablet was compressed to 200 mg.

[Brief explanation of drawings]

FIG. 1 is a graph showing the relationship between the cumulative amount of theophylline released from an aqueous gel and time. FIG. 2 is a graph showing the relationship between the cumulative amount of aminophylline released from the aqueous gel and time. FIG. 3 is a graph showing the relationship between the theophylline release rate and theophylline content. FIG. 4 is a graph showing the relationship between aminophylline release rate and aminophylline content. FIG. 5 is a graph showing the relationship between the cumulative amount of theophylline released from the mixed solid system and time determined by the rotating disk method. FIG. 6 is a graph showing the relationship between the cumulative amount of aminophylline released from the mixed solid system and time, determined by the rotating disk method. FIG. 7 is a graph showing the relationship between the cumulative amount of theophylline or aminophylline released from a mixed solid system and time, determined by the rotating basket method. FIG. 8 is a graph showing the relationship between the cumulative amount of theophylline released from the aqueous gel and time in relation to other additives.

Claims (1)

Claims: 1. A composition containing theophylline or aminophylline, characterized in that theophylline or aminophylline is contained in a polyoxyethylene polyoxypropylene copolymer matrix. 2 The content of theophylline or aminophylline is 2 to 80% W/with respect to the entire polyoxyethylene polyoxypropylene copolymer matrix.
The theophylline- or aminophylline-containing composition according to claim 1, wherein W is W.