JPS6144811A - Sustained release diclofenac sodium pharmaceutical - Google Patents

Abstract

PURPOSE:The titled pharmaceutical, consisting of rapid- and slow-acting diclofenac sodium, and capable of sustaining the efficacy for a long period. CONSTITUTION:A sustained release diclofenac pharmaceutical consisting of (A) rapid-acting diclofenac sodium prepared by forming untreated or pulverized diclofenac sodium into granules or fine granules with a usual excipient or binder and (B) slow-acting diclofenac sodium formulated by forming a film of an enteric substance, e.g. methacrylic-acid methyl methacrylate copolymer, or water- insoluble substance e.g. ethyl cellulose, on the above-mentioned granules or fine granules or kneading the active constituent with an enteric substance or water- insoluble substance at 6:4-2:8 ratio of the components (A) to (B).

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention provides a sustained-release diclofenac sodium preparation, more specifically, a sustained-release diclofenac sodium preparation with long-lasting efficacy, consisting of fast-acting diclofenac sodium and slow-acting diclofenac sodium. diclofenac sodium preparation.

[Conventional technology]

Diclofenac sodium is a nonsteroidal drug that has analgesic, anti-inflammatory, and antirheumatic effects, and its effects are stronger than those of indomethacin, etc., and its toxicity is low.
Currently widely used in clinical practice.

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 Takashi et al.; Clinical Pharmacology 5 (4): 3
93 (1974)).

Because of this rapid absorption and excretion, it is difficult to maintain the effective drug concentration for a long period of time, and currently available tablets and granules must be taken three times a day.

[Problem that the invention seeks to solve]

If you try to maintain the effective blood concentration for as long as possible, 1
As a result, the concentration in the vehicle becomes extremely high, which is undesirable because side effects and increased toxicity are likely to occur. Therefore, there is a strong desire today to maintain the effective concentration in the vehicle for as long as possible.

[Means for solving problems]

The present inventors conducted research on the sustained release of Schiftefenac sodium under these circumstances, and as a result, completed the present invention.

That is, the present invention provides a sustained-release diclofenac sodium formulation characterized by comprising an immediate-acting diclofenac sodium and a slow-acting diclofenac sodium.

The fast-acting diclofenac sodium of the present invention is diclofenac sodium, which may be left untreated or subjected to a process such as pulverization, and may include lactose, glucose, sucrose, dextrin-maxi-f-4-pyl cellulose, ? It is made into granules or fine granules using a binder such as ribinylhydridone-gum arabic or gelatin using conventional formulation methods. Furthermore, if necessary, gastric soluble polymers such as hydroxyzolobyl methylcellulose and polypynylacetal zoethylaminoacetate can also be used. Delayed-release diclofenac sodium is prepared by coating the above granules or fine granules with an enteric substance or a water-insoluble substance, or by adding an enteric substance or a water-insoluble substance as the main ingredient (diclofenac sodium) and A kneading method in which the mixture is mixed with an excipient and kneaded in a solvent for solubilizing enteric substances or water-insoluble substances, or it is mixed in advance with the main ingredients and the above excipients as a kneading liquid. Granules and fine granules are prepared by a kneading method in which an enteric substance or a water-insoluble substance dissolved in a solubilizing solvent is added and kneaded.

Enteric substances include methacrylic acid-methyl methacrylate copolymer (trade name Eudrakit L-8) with a dissolution pH in the range of 6 to 7, and methacrylic acid-ethyl acrylate cozelimer with a dissolution pH of 5.5. (Product name: Eudrakit L30D---Not applicable when using the beam method) or Hydroxypropyl methyl cellulose phthalate (Product name: HP) whose dissolution pH is in the range of 5 to 5.5
and mixtures thereof, and examples of the water-insoluble substance include ethylcel (trade name: Ethocel).

First, let's talk about the case where it is coated as a film. In the case of enteric-coated substances, it is usually 10 to 45 v/w.
% coating gives slow-release diclofenac sodium, but especially for spherical granules, lO~35 w/
v%, preferably 20-30 v/v%. In rod-shaped granules, it is 25-45 v/v%, preferably 30-40 v/w%. For water-insoluble substances 3~
A desired slow-acting diclofenac sodium can be obtained by coating at low/v%, but preferably 5 to 8 w/w% for both spherical granules and rod-shaped granules.

As the solvent for the coating liquid, an appropriate solubilizing solvent may be used for both enteric substances and water-insoluble substances, and in the case of Eudrakit L-8, for example, ethanol, isozorobyl alcohol, acetone, and a mixed solvent thereof are preferable. . Furthermore, in the case of Eudrakitsu) L30D, coating with water is possible because it is a water-dispersible courimer made by emulsion polymerization using Kti and a surfactant. In the case of UP, for example, a mixed solvent of acetone-ethanol and methylene chloride is preferable, and it is also possible to disperse it in water and coat it. In the case of Ethocel, for example, ethanol,
Methanol, inzorobil alcohol, and acetate are preferred, and as a coating liquid, in terms of viscosity and operability,
Coating is possible at a solution concentration of 3 to 20%, preferably 4 to 13%.

Glycerin fatty acid ester as a plasticizer? resolvay) 80, castor oil, macrogol 400-6000.
) Liacetin, sibutyl phthalate, sibutyl phthalate, zoropylene glycol, etc. can be used.

In the kneading method, when an enteric substance or a water-insoluble substance is added as a powder during mixing, Eudrakit L-8 or HP uses 40 to 90 W/W% of the weight, preferably 50 to 70 vr.
/w%, and for etocel, it is preferably 20 to 50 w/w%, preferably 30 to 40 w/w% of the weight. As the organic solvent for the kneading solution, the above-mentioned suitable solubilizing solvent may be used, and if necessary, a binder such as hydroxyzorobyl cellulose, polyvinylpyrrolidone, or gum arabic may be used.

Furthermore, when an enteric substance or a water-insoluble substance is solubilized with a solvent and added as a kneading solution, it is 5 to 30 w/v% of the weight, preferably 8 to 20 w/v% of the weight of Eudrakitsu) L-8 or HP. w%, 3 to 20 of the weight for Etcel
w/w%, preferably 5-l5 w/w%
is good. If necessary, the mixture may be kneaded, dried, pulverized, and further kneaded.

When mixing fast-acting diclofenac sodium and slow-acting diclofenac sodium, the mixing specific gravity is fast-acting diclofenac sodium component: slow-acting diclofenac sodium component = 6 = 4 to 2:8, resulting in a moderate initial concentration in the vehicle and a sustained concentration. In order to exhibit the effect, a ratio of 4:6 to 3 near is good.

[Effect]

Regarding enteric-coated substances and water-insoluble substances such as those mentioned above,
The inventors of the present invention have repeatedly investigated various substances, and as a result, methacrylic acid-methyl methacrylate copolymer (trade name Eudrakit L-8) and methacrylic acid-ethyl acrylate copolymer (trade name Eudrakit L3) have been developed.
It has been discovered that 0D)% hydroxyzolobyl methylcellulose phthalate (trade name: HP) and x-methyl cellulose (trade name: Ethocel) exhibit sustained release properties.

In other words, the present inventors used the coating agent Eudrakit 5100 of Examples 1 and 2 for preparations coated with an enteric substance or a water-insoluble substance as a film. In addition to HP-55, the following substances were formulated in the same manner as in Example 1.2, and the concentration in the vehicle was determined when 50q of diclofenac sodium was orally administered to dogs. ], as shown in Figure 2 (in the case of water-insoluble substances), compared with the uncoated diclofenac sodium preparation as a control, Ooid 2 Kit L-8%L30D%H
It was found that P. etocel had good sustained release properties.

Eudrakit 5100 25w/w%
〇-〇 Eudra kit 1, 30D-5E1 25
Δ−ΔHP-55 25
rotoroselac 25
)・Control O×−× Ethocel 5w/w%
0-0 vinyl chloride 5
NiH cocellulose acetate 5
E/Control 0 ×-× Next, in the kneading method, when an enteric substance or a water-insoluble substance is added as a powder during mixing, in addition to the water-insoluble substance Ethocel and the enteric substance HP-55 in Example 5.6. Diclofenac sodium 5 (
When LV was orally administered to dogs, the disintegration degree was determined, and the results were as shown in Figure 3 (for enteric-coated substances) and Figure 4 (for water-insoluble substances). Eudrakit L-8% UP It was found that Ethocel had good sustained release properties. The sample prepared in Example 5 without adding the enteric substance HP-55 was used as a control.

HP-55aow/w% GO Eudrakit 8100 60
△-Δ Eudra Kit L100 60
D-DCAP 6
0 - Control Ox-x Water-insoluble substance content Noq-turn ethocel in Figure 4 30w/w%
(piece () Eudrakit RL 3Q
Δ-Δ vinyl chloride ao
D-D cell μm acetate 3
0 -- Control Ox- In addition to the enteric substance Ethcel, the following substances were used in the same manner as in Example 8.9 to determine the degree of disintegration when 50 μ of diclofenac sodium was orally administered to dogs. ) Figure 6 (in the case of water-insoluble substances) shows that Eudrakit L-8% HP and Ethocel have good sustained release properties. In addition, a sample prepared in Example 8 without adding the enteric-coated substance Eudorakitsu 8100 was used as a control.

Eudrakit 8100 10w/w% 〇-〇 Eudrakit L100 10 Δ-
ΔHP-55 10 Q--mouth CAP 10
・1 control Ox-x Ethocel 5w/w%
C Tobe D Eudrakit RL 5
Δ−Δ Vinyl chloride 5
Rollocellulose phthalate) 5)
- Control 0 x-x [Example] 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 f of diclofenac sodium and 500 t of cornstarch are mixed and pulverized.

Spherical granules are produced by transfer granulation using 20 to 28 mesh sized white sugar 500f as a core and applying an inzolobil alcohol solution of hydroxyzolobil cellulose. 5
It was dried at 5 to 60°C to obtain a fast-acting diclofenac sodium preparation 142Of. Add 500g of these granules to methacrylic acid-methyl methacrylate. Rimmer (Ooid 2
Kit 8100) was coated to 25 w/w% with a coating solution of iso-7'' o-pyl alcohol solution and dried at 55-60°C to obtain slow-acting zoclofenac sodium 600f. Clofenac sodium component: slow-release diclofenac sodium component was mixed in a ratio of 3=7, and the mixture was filled into capsules to obtain a sustained-release diclofenac sodium preparation (containing 50 das of zoclofenac sodium per capsule).

Figure 1 shows the intermediate concentration after oral administration of dog Kl capsules (0
−○] is indicated.

Example 2 Using the fast-acting zoclofenac sodium of Example 1,
As slow-acting ZokuJ fenac sodium, a solution of hydroxyzolobyl methylcellulose (HP-55) in methylene chloride:ethanol = 1:1 was used as the coating solution of Example 1, and the following Example 1 and A sustained-release diclofenac sodium preparation (1 capsule containing 501q of zoclofenac sodium) was obtained in the same manner. 1st
The figure shows the mid-way concentration after oral administration of one dose of Sicel to a dog (oral (1 dose)).
) is shown.

Example 3 Diclofenac sodium 500f% lactose 25 Of,
Cone xp-chi 50f is mixed, and a 50% alcohol solution of broken vinyl pyrrolidone is added and kneaded, then granulated using an extrusion granulator and dried at 55 to 60°C.

The rod-shaped granules were sized using a 16 to 28 mesh trap to obtain an immediate-acting diclofenac sodium preparation 7602. Further, 400 tons of these granules were coated with a mixture of ethyl cellulose (Nidocel) in a ratio of 1:1 of ethanol and acetone to 7%. Dry at 55-60°C, size to 16-28 mesh, slow-release zoclofenac sodium 42
Obtained 0g. Thereafter, the mixture was mixed in the same manner as in Example 1 to obtain a sustained-release cyclo7-enact sodium preparation.

Example 4 500 t% of diclofenac sodium and 250 t of white sugar are mixed together, and a 50% isozolobyl alcohol solution of broken vinyl pyrrolidone is added thereto, kneaded, and granulated. 55-60℃
The mixture was dried and sized to 32 to 150 mesh to obtain 720v of fast-acting diclofenac sodium fine granules. Using 500 g of this fine granule, it was coated in the same manner as in Example 3 and sized to 35 to 150 meshes to obtain 640f of delayed-release diclofenac sodium fine granule. These were mixed at a ratio of immediate-release diclofenac sodium component: slow-release diclofenac sodium component = 426 to obtain a sustained-release diclofenac sodium preparation.

Example 5 Diclofenac sodium 300t% mandiol 1o
Mix 600t of Ofb hydroxypropyl methyl cellulose phthalate (HP-55), add a mixture of methylene chloride:ethanol = l:l, knead, granulate with an extrusion granulator, and dry at 55-60°C. .

The granules were sized by 16 to 28 meshes to obtain 970 g of slow-acting diclofenac sodium. Using the fast-acting diclofenac sodium of Example 3, the same procedure as in Example 1 was carried out to obtain a sustained-release diclofenac sodium preparation (1 capsule containing 50 q of diclofenac sodium). Figure 3 shows the concentration in the car (0-
0).

Example 6 Actual M Mannitol 400 f instead of 100 f of mannitol in Example 5 and 00 t of hydroxyzolobyl methylselmysuphthalate.

Ethylcellulose (Ethocel) 300 f'lli was used in place of the 1:1 mixture of methylene chloride and ethanol, and a mixture of ethanol: isozorobyl alcohol = 1:1, and the following procedure was carried out in the same manner as in Example 5. A diclofenac sodium preparation (containing 50q of diclofenac sodium in 1 capsule) was obtained. Figure M4 shows the concentration in the car (0-0) after oral administration of Kl capsules to dogs.

Example 7 Diclofenac sodium 3 o 100 g of cornstarch and 200 t of Ethocel are mixed and pulverized.

Using 300 f white sugar sized to 20 to 28 mesh as a core, transfer granulation is performed while pouring an ethanol solution to produce spherical granules. It was dried at 55-60°C to obtain 880 ft of slow-acting diclofenac sodium. Using the immediate-release diclofenac sodium of Example 1, the same procedure as in Example 1 was carried out to obtain a sustained-release diclofenac sodium preparation.

Example 8 Diclofenac sodium 40Of, mannitol 50
Mix 0t and add 25% Eudrakit 8100 to this.
A mixed solution of isozorobyl alcohol: water = 9 = 1 40
0ft-Add and mix. Granulate using an extrusion granulator 5
Dry at 5-60°C. The granules were sized with 16 to 28 mesh traps and delayed-acting diclofenac sodium preparation 98
I got 0f. Using the fast-acting diclofenac sodium of Example 3, the procedure was repeated for 4 degrees in the same manner as in Example 3 to obtain a sustained-release diclofenac sodium preparation (1 capsule containing 50 m9 of diclofenac sodium). FIG. 5 shows the concentration (0-0) in the car after oral administration of Kl Cassisel to dogs.

Example 9 The following procedure was the same as in Example 8, except that mannitol 500f'1i-5502 was used as in Example 8, and 10% ethocel in ethanol was used instead of 25% Eudrakit 1i1100 isozolopyl alcohol:water = 9 = 1. A sustained-release diclofenac sodium formulation was obtained. Figure 6 shows the concentration in the car (〇-〇) after oral administration of Kl capsules to dogs.

[Brief explanation of the drawing]

Figures 1 to 6 are curves showing the concentration of diclofenac sodium in the car.

Claims (1)

[Scope of Claims] 1. A sustained-release diclofenac sodium preparation characterized by comprising immediate-acting diclofenac sodium and slow-acting diclofenac sodium. 2. The sustained-release diclofenac sodium preparation according to claim 1, wherein the delayed-release diclofenac sodium is diclofenac sodium coated with an enteric substance or a water-insoluble substance. 3. The sustained-release diclofenac sodium preparation according to claim 1, wherein the delayed-release diclofenac sodium is obtained by mixing diclofenac sodium with an enteric substance or a water-insoluble substance. 4. The enteric substance is a methacrylic acid-methyl methacrylate copolymer having a dissolution pH of 6 to 7, a methacrylic acid-ethyl acrylate copolymer having a dissolution pH of 5.5, or a methacrylic acid-ethyl acrylate copolymer having a dissolution pH of 5 to 5.5. The sustained release diclofenac sodium preparation according to claim 2 or 3, which is hydroxypropyl methyl cellulose phthalate within the range of . 5. The sustained-release diclofenac sodium preparation according to claim 2 or 3, wherein the water-insoluble substance is ethylcellulose. 6. The sustained-release diclofenac sodium preparation according to any one of claims 1 to 5, wherein the blending ratio of fast-acting diclofenac sodium and slow-acting diclofenac sodium is 6:4 to 2:8.