JPH04312522A - Production of sustained release tablet - Google Patents

Abstract

PURPOSE:To produce a sustained release preparation having excellent fluidity of powder during tableting, constantly controlling dissolution of medicine by addition of a small amount of gel base. CONSTITUTION:Hydroxypropylmethyl cellulose is suspended in hot water at temperature of dissolution, mixed with tannic acid, acrylic acid-methyl methacrylate-dimethylaminoethyl methacrylate copolymer or methacrylic acid- acrylic ester copolymer and spray dried to give a composition, which is tablet together with a main medicine.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing matrix-type sustained-release tablets in which drugs are released from the tablet at a constant rate, and more particularly to a method for producing gel-matrix-type sustained-release tablets.

0002

[Prior Art] Sustained-release tablets maintain drug efficacy over a long period of time by continuously releasing drugs, reducing the number of times patients have to take them, and drugs that cause toxicity and side effects when the blood concentration exceeds a certain level. It is a useful preparation that has been studied for the purpose of controlling its blood concentration below a certain value. Conventional sustained-release tablets include matrix-type tablets in which a drug is compressed with a water-soluble polymer or wax, and spasta tab-type tablets in which a rapidly dissolving portion and a sustained-release portion are mixed and compressed. Matrix-type sustained-release tablets elute using the driving force of the concentration gradient of the drug that occurs as water permeates, and are also called diffusion-limited tablets. Many wax matrix types are used. The gel matrix type is hydroxypropyl methylcellulose (hereinafter referred to as HPMC)
It is tableted either alone or as a mixed base of HPMC and methylcellulose, sodium salt of carboxymethylcellulose (hereinafter referred to as Na-CMC), etc. together with the main drug.
It is shown in the No. 4311 publication. The wax matrix type is disclosed in Japanese Patent Application Laid-Open No. 14091/1983, which is made by processing a base drug with wax and forming a tablet powder into tablets. However, in the case of a gel matrix type active ingredient that is particularly highly water-soluble, its dissolution cannot be controlled unless a large amount of gel-forming base is used, and cellulose ethers have poor powder fluidity. Since it is not very good, the weight of the tablet tends to fluctuate when a large amount is added. On the other hand, the wax matrix type uses wax that hardly dissolves or swells in the body's digestive juices, so it has the disadvantage that it is difficult to control its elution and the amount of elution tends to fluctuate with slight changes in the process.

0003

[Problems to be Solved by the Invention] Therefore, an object of the present invention is to improve the fluidity of the powder during tableting, and to control the dissolution of the drug at a constant level by adding a relatively small amount of gel base. The present invention provides a method for producing sustained release tablets.

0004

[Means for Solving the Problems] As a result of intensive studies by the present inventors to solve the above problems, HPMC was suspended in hot water at a temperature higher than the melting temperature, and tannic acid, acrylic acid - methyl methacrylate - dimethyl methacrylate After adding an aminoethyl copolymer or a methacrylic acid-acrylic acid ester copolymer, when the composition obtained by spray drying is used to tablet the main drug, the powder has excellent fluidity and a relatively small amount. It was discovered that tablets with excellent sustained release properties could be obtained even with the amount of cellulose ether added, and the present invention was completed.

[0005] The details of the present invention will be explained below.
In the present invention, HPMC is used as the matrix base. In general, water-soluble cellulose ethers form a gel when they come into contact with water, and as the gel layer dissolves, the main drug is released through the gel layer by diffusion, but HPMC has particularly excellent gel-forming properties. Therefore, it is used in the present invention. HPMC used
As the degree of polymerization (viscosity of aqueous solution) increases, the gel layer formed by contact with water becomes stronger,
Since they have a greater ability to suppress the dissolution rate of the main drug, by appropriately selecting and using them, it is possible to obtain tablets with dissolution characteristics suited to the purpose. The amount of HPMC added varies depending on the desired sustained release performance, but is usually 10 to 40% by weight, preferably 15 to 30% by weight, based on the tablet. If it is less than 10% by weight, the tablet will disintegrate at the beginning of dissolution and a large amount of drug will be released at once, making it impossible to control the blood concentration of the drug at a constant level and failing to function as a sustained release tablet. Moreover, if this exceeds 40% by weight, the elution rate in the latter half of elution will be significantly reduced. Note that these matrix bases are added in relatively large amounts as described above, and ionic cellulose ethers such as Na-CMC may react with the main drug, so they cannot be applied to the present invention. Can not.

Furthermore, the tannic acid, acrylic acid-methyl methacrylate-dimethylaminoethyl methacrylate copolymer or methacrylic acid-acrylic acid ester copolymer used in the present invention may be commercially available. The copolymers are commercially available under the names Eudragit RL30D and Eudragit L30D, respectively. The amount of these added varies depending on the desired sustained release performance or the HPMC used, but in the case of tannic acid, it is usually 0.75 to 10% by weight, especially 2.5% by weight based on the HPMC.
It is preferably 10% by weight, and preferably 3-25% by weight in the case of acrylic acid-methyl methacrylate-dimethylaminoethyl methacrylate copolymer or methacrylic acid-acrylic acid ester copolymer. If they are below the lower limit of this range, the effect of their addition will not be sufficient, and even if they exceed the upper limit of this range, the effect of addition will hardly change, so there is no need to add them in larger amounts.

[0007] By adding tannic acid, acrylic acid-methyl methacrylate-dimethylaminoethyl methacrylate copolymer or methacrylic acid-acrylic acid ester copolymer to HPMC and spray drying, compared to the case of HPMC alone, Sustained release performance can be obtained with a small amount of addition, but
The reason is surmised as follows. Generally, cellulose ethers form adducts with polyhydric phenols, but it is known that tannic acid, which is a type of polyhydric phenol, also forms adducts with water-soluble cellulose ethers, making it insoluble in water. There is. HP treated with tannic acid of the present invention
In tablets made of spray-dried particles of MC, HPMC absorbs water and forms a gel layer when taken, but HPMC
It is thought that an excellent sustained release effect can be obtained because the dissolution rate of C is low and erosion of the gel layer is suppressed. In addition,
In the case of tannic acid, sustained release properties can be obtained even by mixing HPMC and powder, but according to the method of the present invention, excellent sustained release performance can be obtained even if the amount of tannic acid added is small. On the other hand, in the case of acrylic acid-methyl methacrylate-dimethylaminoethyl methacrylate copolymer, the HPMC particles are covered with an insoluble copolymer, thereby achieving the same effect as when tannic acid is added. it is conceivable that. In addition, since methacrylic acid-acrylic acid ester copolymer has the property of dissolving when the pH increases, by adding it and spray drying, it is possible to make the sustained release ability pH-dependent. As a result, it was shown that it is possible to suppress the decline in the dissolution rate in the latter half of drug dissolution considering the transfer of the tablet in the gastrointestinal tract. This is because methacrylic acid-acrylic acid ester copolymer works in the same way as acrylic acid-methyl methacrylate-dimethylaminoethyl methacrylate copolymer in the acidic region equivalent to the inside of the stomach, and at a pH equivalent to the intestines, the particle surface It is thought that the copolymer coated on the gel was dissolved, increasing the solubility of HPMC and promoting drug elution due to gel erosion. Also, generally HP
Cellulose ethers such as MC have a fibrous shape and therefore do not have very good fluidity, but spray drying makes the particles spherical and improves their fluidity, so they can be compressed into tablets with excellent fluidity. You can get the end.

[0008] The production of the sustained-release tablets will be explained in accordance with the actual formulation. After thoroughly mixing the spray-dried mixture and the main drug using a V-type mixer or the like, the desired tablets can be obtained by tabletting in a conventional manner. In addition, an appropriate amount of excipients such as starch and lactose or a lubricant such as magnesium stearate may be added to this tablet powder as necessary.

[0009]

[Examples] Hereinafter, specific embodiments of the present invention will be explained with reference to Examples and Comparative Examples, but the present invention is not limited to the description of these Examples. Examples 1 to 3 and Comparative Examples 20 g of HPMC (manufactured by Shin-Etsu Chemical Co., Ltd., 60SH-50) was suspended in 500 ml of hot water at 90°C, a predetermined amount of tannic acid was added, and while maintaining the temperature at 90°C, Spray drying was carried out using a spray dryer model L-12, and a product having a particle size of 70 to 120 μm was obtained by sieving. 75 mg of theophylline was mixed with 75 mg of this base and compressed at a pressure of 2 t/cm2 to form flat tablets with a diameter of 8 mm, which were used as sustained release tablets of Examples 1 to 3. In addition, similar tablets were prepared using untreated HPMC to provide sustained-release tablets as comparative examples. The composition of each tablet obtained was as shown in Table 1.

0010

[Table 1]

[0011] The tablets obtained in Examples 1 to 3 and Comparative Example above were subjected to a dissolution test under the following conditions, and the results are shown in FIG. Method: Japanese Pharmacopoeia 11 paddle method (number of rotations: 100
rpm) Test solution: Japanese Pharmacopoeia No. 1 solution (pH: 1.2) From this, it was found that in Examples 1 to 3, elution was extremely suppressed compared to the comparative example.

Examples 4 to 6 The tannic acids of Examples 1 to 3 were mixed with an aqueous dispersion of acrylic acid-methyl methacrylate-dimethylaminoethyl methacrylate copolymer (Eudragid RL manufactured by Rehm Pharma).
30D) and the same operation was performed. The composition of each tablet obtained was as shown in Table 2.

[0013]

[Table 2]

[0014] The dissolution test of each tablet obtained in Examples 4 to 6 and Comparative Example above was conducted in the same manner as in Example 1.
The results are shown in FIG. 2 as a relationship between the amount of RL30D (acrylic acid-methyl methacrylate-dimethylaminoethyl methacrylate copolymer) added to HPMC and T50 (50% elution time). From this, it was found that elution was suppressed in Examples 4 to 6 compared to Comparative Example.

Example 7 The same procedure as in Examples 1 to 3 was carried out except that the tannic acid in Examples 1 to 3 was replaced with a methacrylic acid-acrylic acid ester copolymer (Eudragid L30D manufactured by Rehm Pharma). The composition of each tablet obtained was as shown in Table 3.

[0016]

[Table 3]

[0017] The tablets obtained in Examples 2 and 7 and Comparative Example above were subjected to a dissolution test under the following conditions, and the results are shown in FIG.

[0018]

Effects of the Invention: According to the method of the present invention, the powder has good fluidity during tableting, and furthermore, the elution of the drug can be controlled at a constant level by adding a relatively small amount of gel base, resulting in sustained release. Tablets are obtained.

[Brief explanation of the drawing]

[Figure 1] The results of the dissolution test for each tablet obtained in Examples 1 to 3 and Comparative Examples are shown as the dissolution rate (vertical axis) and elapsed time (horizontal axis).
This is a graph showing the relationship between

FIG. 2 is a graph showing the results of the dissolution test for each tablet obtained in Examples 4 to 6 and Comparative Examples in terms of the relationship between the amount of RL30D added to HPMC (horizontal axis) and the 50% dissolution time (vertical axis). It is.

FIG. 3 shows the results of the dissolution test for each tablet obtained in Examples 2, 7 and Comparative Example, showing the dissolution rate (vertical axis) and elapsed time (horizontal axis).
This is a graph showing the relationship between

Claims (3)

[Claims] Claim 1: Hydroxypropyl methylcellulose is suspended in hot water at a temperature higher than its dissolution temperature, and tannic acid, acrylic acid-
Sustained release characterized by adding a methyl methacrylate-dimethylaminoethyl methacrylate copolymer or a methacrylic acid-acrylic acid ester copolymer and then spray-drying the resulting composition to tablet the main drug. Method of manufacturing sex tablets. 2. The method for producing sustained-release tablets according to claim 1, wherein tannic acid is added in a proportion of 0.75 to 10% by weight based on hydroxypropyl methylcellulose. Claim 3: A claim in which the acrylic acid-methyl methacrylate-dimethylaminoethyl methacrylate copolymer or the methacrylic acid-acrylic acid ester copolymer is added in a proportion of 3 to 25% by weight based on hydroxypropyl methylcellulose. Item 1. The method for producing sustained release tablets according to item 1.