JPH0157090B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention provides sustained-release diclofenac sodium preparations, more specifically, sustained-release diclofenac sodium preparations with long-lasting efficacy, consisting of fast-acting diclofenac sodium and slow-acting diclofenac sodium. Concerning diclofenac sodium formulation. [Prior art] Diclofenac sodium has analgesic, anti-inflammatory,
A non-steroidal drug with antilithium effect.
Its action is stronger than that of indomethacin, etc.
It is currently widely used in clinical practice because of its low toxicity. However, it is known that diclofenac sodium enters the blood within 30 minutes after oral administration, reaches its maximum blood concentration within 2 hours, and has a short half-life of 1.3 hours [Kato Ryuichi et al.; Clinical Pharmacology 5(4): 393 (1974)]. Because of this rapid absorption and excretion, it is difficult to maintain an effective blood concentration for a long period of time, and currently commercially available tablets must be taken in three divided doses a day. [Problem to be solved by the invention] In order to maintain the effective blood concentration for as long as possible, it is necessary to take a large amount at a time, and as a result, the blood concentration becomes extremely high, resulting in increased side effects and toxicity. etc. are likely to occur, which is not desirable. Therefore, there is a strong desire today to maintain the effective blood concentration and maintain its effect for as long as possible. [Means for Solving the Problems] The present inventors conducted research on sustained release of diclofenac sodium under these circumstances, and as a result, completed the present invention. That is, the present invention provides (A) fast-acting diclofenac sodium, and (B) a methacrylic acid-methyl methacrylate copolymer having a dissolution pH in the diclofenac sodium range of 6 to 7, and a dissolution pH of 5.5.
slow-release diclofenac sodium with an enteric coating of methacrylic acid-ethyl acrylate copolymer or hydroxypropyl methyl cellulose phthalate with a dissolution pH in the range of 5.5,
The present invention provides a sustained-release diclofenac sodium preparation characterized in that (A) and (B) are combined in a weight ratio of 4:6 to 3:7. What is the fast-acting diclofenac sodium of the present invention? Diclofenac sodium may be left untreated or subjected to a process such as pulverization, but it may be added with excipients such as lactose, glucose, sucrose, dextrin, mannitol, starches, etc. Agent: Granules, etc. are prepared using conventional formulation methods using binders such as hydroxypropylcellulose, polyvinylpyrrolidone, gum arabic, and gelatin.
It is made into fine granules. Furthermore, if necessary, gastric soluble polymers such as hydroxypropyl methylcellulose and polyvinyl acetal diethylaminoacetate can also be used. Further, slow-acting diclofenac sodium can be obtained by coating the above granules and fine granules with an enteric substance as a film. Enteric-coated substances include methacrylic acid-methyl methacrylate copolymer (trade name: Eudragit L.S.) whose dissolution pH falls within the range of 6 to 7;
Methacrylic acid-ethyl acrylate copolymer (trade name Eudragit L30D) with a pH of 5.5,
Or hydroxypropyl methyl cellulose phthalate (trade name) whose dissolved pH falls within the range of 5 to 5.5.
HP) and mixtures thereof are used. Delayed-acting diclofenac sodium can be obtained by coating these enteric substances at 10-45 w/w%, but in spherical granules, 10-35 w/w%
%, especially 20 to 30 w/w %, and in rod-shaped granules 25 to 45 w/w %, especially 30 to 40 w/w %. As the solvent for the coating liquid, any suitable solubilizing solvent may be used, and in the case of Eudragit L.S., for example, ethanol, isopropyl alcohol, acetone, and a mixed solvent thereof are preferable. In the case of Eudragit L30D, it is a water-dispersible copolymer that is emulsion polymerized using a surfactant, so it can be coated with water. In the case of HP, for example, a mixed solvent of acetone, ethanol, and methylene chloride is preferable, and it is also possible to coat the HP by dispersing it in water. Plasticizers include glycerin fatty acid ester, polysorbate 80, castor oil, macrogol 400~
6000, triacetin, dimethyl phthalate, dibutyl phthalate, propylene glycol, etc. can be used. The combination ratio of (A) fast-acting diclofenac sodium and (B) fast-acting diclofenac sodium is:
In order to obtain appropriate initial blood concentration and persistence,
It is necessary to adjust the weight ratio of (A):(B) to be in the range of 4:6 to 3:7. [Function] Regarding the above-mentioned enteric substances, the present inventors have repeatedly investigated various substances, and as a result, methacrylic acid-methyl methacrylate copolymer (trade name: Eudragit L.S.), methacrylic acid- It was discovered that ethyl acrylate copolymer (trade name: Eudragit L30D) and hydroxypropyl methylcellulose phthalate (trade name: HP) exhibit excellent sustained release properties. In other words, in addition to the coating agents Eudragit S100 and HP-55 of Examples 1 and 2, the following substances were also formulated in the same manner as in Examples 1 and 2 for preparations coated with the above enteric substances as a film. When 50 mg of Nac sodium was orally administered to beagle dogs, the blood concentration was determined, as shown in Figure 1. As a control, an uncoated diclofenac sodium preparation (containing 25 mg of diclofenac sodium) It was found that Eudragit L・S, L30D, and HP have good sustained release properties compared to the above.

[Table] [Examples] Next, the present invention will be specifically described with reference to Examples, but the present invention is not limited thereto in any way. Example 1 500 g of diclofenac sodium and 500 g of corn starch were mixed and pulverized. Using 500 g of white sugar sized to 20 to 28 mesh as a core, rolling granulation is performed while pouring an isopropyl alcohol solution of hydroxypropyl cellulose to obtain spherical granules. 55～
It was dried at 60°C to give 1420 g of fast-acting diclofenac sodium. 500 g of the granules were coated with a coating solution of isopropyl alcohol solution of methacrylic acid-methyl acrylate copolymer (Eudragit S100) at 25% w/w. It was dried at 55-60°C to obtain 600 g of slow-acting diclofenac sodium. These are mixed at a ratio of 3:7 of fast-acting diclofenac sodium component: slow-acting diclofenac sodium component, and this is filled into capsules to form a sustained-release diclofenac sodium preparation (diclofenac sodium 50 mg in 1 capsule). ) was obtained. Figure 1 shows the blood concentration (〇-〇) after oral administration of 1 capsule to beagle dogs. Example 2 The fast-acting diclofenac sodium of Example 1 was used, and hydroxypropyl methyl cellulose phthalate (HP-
Using a 1:1 methylene chloride:ethanol solution of 55), the same procedure as in Example 1 was carried out to obtain a sustained-release diclofenac sodium preparation (one capsule containing 50 mg of diclofenac sodium). Figure 1 shows the blood concentration (□-□) after oral administration of one capsule to a beagle dog. Example 3 56.4 g of diclofenac sodium and 143.6 dl of cornstarch are mixed and pulverized. Using 500 g of slow-acting diclofenac sodium obtained in Example 1 as a core, rolling granulation is performed while pouring an ethanol solution of hydroxypropyl cellulose to obtain spherical granules. 700 g of sustained release diclofenac sodium was obtained which was dried at 55-60°C. This was divided into packages to obtain sustained-release diclofenac sodium preparations (one package containing diclofenac sodium 50 mg). Figure 2 shows the blood concentration (〇-〇) after orally administering one packet to a beagle dog, and the blood concentration after administering a fast-acting diclofenac sodium preparation (containing 25 mg of diclofenac sodium) as a control. ×―
x) is shown. Example 4 500 g of slow-acting diclofenac sodium obtained in Example 1, 56.4 g of diclofenac sodium,
380 g of crystalline cellulose and 2.9 g of magnesium stearate were mixed and formed into 250 mg tablets using a conventional method to obtain a sustained-release diclofenac sodium preparation (each tablet containing 50 mg of diclofenac sodium). Figure 2 shows the blood concentration (●-●) after oral administration of one tablet to a beagle dog. Example 5 1 capsule of the extended-release diclofenac sodium preparation obtained in Example 1 (each capsule contains 50 mg of diclofenac sodium), and a fast-acting diclofenac sodium preparation (contains 25 mg of diclofenac sodium) as a control. Each was orally administered to nine healthy male adults in the fasted state, and the blood concentration was determined (Figure 3). As is clear from FIG. 3, the preparation obtained in Example 1 exhibited good sustained release properties.

[Brief explanation of drawings]

Figures 1 to 3 are curves showing the blood concentration of diclofenac sodium.

Claims (1)

[Claims] 1 (A) fast-acting diclofenac sodium, and (B)
Methacrylic acid-methyl methacrylate copolymer with a dissolved PH in the range of 6-7, methacrylic acid-ethyl acrylate copolymer with a dissolved PH in the range of 5.5 or hydroxypropyl with a dissolved PH in the range of 5-5.5 in diclofenac sodium. A sustained-release diclofenac characterized by combining delayed-release diclofenac sodium coated with an enteric coating of methylcellulose phthalate in a weight ratio of (A):(B) of 4:6 to 3:7. Fenac sodium preparation.