JPS62135419A - Granular composition of diclofenac salt and production thereof - Google Patents

Abstract

PURPOSE:The titled composition, obtained by uniformly coating the surface of small granular cores with a diclofenac salt and a binder and having improved stability. CONSTITUTION:A granular composition of a diclofenac salt obtained by dissolving 1-30% diclofenac salt, e.g. diclofenac sodium, etc., and 0.1-5% binder, e.g. mixture of one or two or more or water-soluble high polymers, pH- dependent high polymers and water-insoluble high polymers, polyvinylpyrrolidone, ethyl cellulose or eudragit, etc., in water.organic solvent, e.g. water.ethanol, etc., and spray coating small granular cores with the resultant solution. Furthermore, coating with a sustained release film, enteric coating, etc., may be carried out to give a continuous multi-layered material. EFFECT:The solution is readily prepared and the subsequent production process can be continuously performed without requiring any lubricant, etc., and scattering of powder.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a granular composition of diclofenac salt having excellent chemical and physical properties, particularly stability, and a method for producing the same.

[Prior Art and Their Problems] Diclofenac salt [chemical name: 2-(2,6-dichloroanilino)phenylacetic acid salt] is known to be a substance having anti-inflammatory and analgesic properties.

The sodium salt can be used in oral preparations such as tablets,
It is formulated and used as granules and fine granules.

By the way, methods for producing granules include compressing and crushing a mixed powder of drugs, excipients, binders, disintegrants, lubricants, etc.; methods of kneading and granulating by adding an appropriate solvent; Possible methods include coating small granular cores with a mixed powder of a drug and an excipient.

In addition, the tablets can be manufactured by adding a lubricant etc. to the granules and compression molding, or by adding a lubricant etc. to the granules and manufacturing by compression molding, or by adding a drug, an excipient, a binder, etc.
A method of manufacturing by directly compression molding a mixed powder of a disintegrant, a lubricant, etc. can be considered.

However, in the above manufacturing method, the drug is formulated in powder form, but known methods for preparing the drug in a solution form include, for example, nicardipine, a PL+ dependent additive, and A method of producing small granules of nicardipine by dissolving a water-soluble polymer in an organic solvent and coating the small granular cores (Japanese Patent Application Laid-open No. 116414/1982), Alternatively, a method for producing a nifedipine preparation by dissolving a water-insoluble polymer and/or a pH-dependent additive in an organic solvent and coating it on fine particles (JP-A-57-85316, JP-A-58-77811)
Publication No.) etc. are known.

However, the production of granules in the prior art as described above has various drawbacks. For example, in the method of coating small granular cores with a mixed powder of a drug and an excipient, preparation of the powder such as sieving, mixing, and drying is complicated and therefore time consuming. Furthermore, due to the conditions for coating small particles, there were disadvantages such as granules adhering to each other and forming aggregates during production, and loss of coated powder resulting in a decrease in drug content.

In addition, adding excipients increases the size of the granules, so if the manufactured granules are to be made into capsules, the capsules must be made larger, and this method is not necessarily preferable considering the stability of the drug. It was impossible.

Furthermore, in the case of diclofenac salt, since it is relatively easily soluble in water, a solubility difference may occur between the diclofenac salt and an excipient that is sparingly soluble in water, resulting in unevenness on the surface of the granules.

This is because when considering that sustained release granules are manufactured by coating the granule surface with a drug-permeable film, etc., the granule surface usually needs to be smooth and the variation in drug content should be small. Therefore, the use of excipients was not very favorable.

In addition, when dissolving drugs and water-soluble polymers in organic solvents and coating them on small granular nuclei without using excipients, conventional methods require a large amount of halogen-based organic solvents (dichloromethane, etc.) and exhaust gas. The present invention has problems in terms of environmental pollution, safety during manufacturing, and residual coating solvent in the formulation, and is relatively time-consuming and not a practical method.7 The present invention solves the above problems. This is an attempt to improve or solve a problem. That is, the purpose is to provide stable granules that are easy to manufacture, have smooth granule surfaces, have little variation in drug content in each granule, and are stable.

[Means for solving problems]

In order to achieve the above objectives (stability of granules, smoothness of the surface of the granules, and improvement in workability), the present inventors have achieved the goal of improving the stability of granules, improving the surface smoothness of the granules, and improving workability without using any excipients, and without using any excipients. Various studies have been conducted on granules that have improved properties and methods for producing them. As a result, we found that diclofenac salt is easily soluble in organic solvents such as ethanol, and slightly less soluble in water, but its solubility increases in a mixed solvent of water and organic solvents (especially ethanol). The present invention has been achieved in which extremely good granules can be produced by dissolving diclofenac salt and coating it on small granular cores.

According to this granule production method, the solution is easy to prepare;
No granule agglomerations are observed during the coating process, no lubricants are required, there is no scattering of powder, and the subsequent formulation process can be carried out continuously. In addition, the obtained diclofenac salt granules have excellent stability, and regardless of the crystal form of the diclofenac salt used, the crystal form of the diclofenac salt on the surface is fine, and the granule surface is smooth with no irregularities. It also handles well,
Moreover, it has the feature that there is little variation in the amount of drug contained in each granule.

That is, the present invention provides diclofenac salt granules in which small granular cores are coated with diclofenac salt and a binder, as well as diclofenac salt and binder dissolved in a water-organic solvent,
The present invention relates to a method for producing diclofenac salt granules by spraying this solution onto small granular cores.

The present invention will be explained in detail below.

First, in the present invention, "diclofenac salt" refers to inorganic salts such as diclofenac sodium, diclofenac potassium, diclofenac ammonium, diclozenaf calcium, and diclofenac aluminum, and organic salts such as diclozenac dimethylaminoethanol and diclofenac trimethylamine. .

In the present invention, the "small granular nucleus" that is the core of the granular granule is
It is a small particle with a particle size of about 0.1 to 3 mm manufactured from refined white sugar, a refined white sugar-cornstarch mixture, etc. Such examples include Nonbarrel (trade name, Freund Sangyo (trade name)).
(manufactured by 11 companies) can be suitably used.

The "binder" in the present invention includes a water-soluble polymer, p
) One or a mixture of two or more of I-dependent polymers and water-insoluble polymers can be used. Examples of the water-soluble polymer include hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, methylcellulose, and the like. Examples of pH-dependent polymers include hydroxypropyl methylcellulose phthalate, Eudragit Shika S (trade name, manufactured by Rohm and Haas, component nialic acid-methacrylic acid ester copolymer), carboxymethyl ethyl cellulose, etc. However, examples of water-insoluble polymers include Eudragit RL or R3 (trade name, manufactured by Rohm and Haas, component: nialic acid-methacrylic acid ester copolymer), ethyl cellulose, and the like.

These polymers may be used alone or in combination.

Preferably, polyvinylpyrrolidone, ethylcellulose,
Good results are obtained using Eudragit RL or R3.

In the present invention, as the "water-organic solvent mixed solvent", water-ethanol and water-ethanol-acetone mixed solvents are preferably used. Furthermore, the use of halogenated organic solvents such as loloform and dichloromethane is undesirable in view of environmental pollution due to exhaust gas, solvent residue, and the like. In the above, for example, the mixing ratio of water and ethanol is preferably in the range of 5:95 to 3:7 by volume. Especially about 1:9
A mixing ratio of is suitable.

Figure 1 shows the solubility of diclofenac sodium depending on the mixing ratio of this mixed solvent.

Next, the method for producing the granules of the present invention will be exemplified below.

First, diclofenac salt and the above-mentioned binder are dissolved in a water-based organic solvent. The concentration of the binder varies depending on the type of binder used, but is generally in the range of 0.1 to 5% (weight ratio), particularly preferably in the range of 0.3 to 1.0%. Within this range, no agglomerate formation due to scattering of powder or adhesion of granules to each other is observed, no addition of a lubricant such as talc is required, and therefore coating is easy.

The concentration of diclofenac salt is preferably in the range of 1% to 30% (weight ratio), particularly in the range of 10 to 20%. Concentrations in this range have the advantage that there is no crystal precipitation of diclofenac salt even when the environmental temperature is relatively low, so there is no need to heat the solution.

Incidentally, as a method for coating the small granular cores with the solution of the diclofenac salt and binder, a spray coating method is applied.

The surface of the granules obtained as above, in which the small nucleated particles are coated with diclofenac salt, is further coated with a sustained-release film, an enteric film, etc. to form a continuous multilayer coated body. You can also do that. In this case, in the conventional powder coating method, the powder within the coating layer scatters significantly, and
While the number of steps and processes increases, the solution coating method has the advantage that there is almost no scattering of powder within the coating layer, and continuous multilayer coating is possible.

Hereinafter, the method for producing granules of the present invention will be explained with reference to Examples.

〔Example〕

Example 1 1 kg of Non-Barrel 103 (trade name, manufactured by Freund Sangyo (#@ company, ingredient: purified white P) was placed in a centrifugal flow device,
To this, 300 g of diclofenac sodium and 5 g of polyvinylpyrrolidone K-904 were added in a water/ethanol solution (
1:9, v/v) 1500mf! A completely dissolved solution was sprayed by a conventional method and dried at 40° C. for 16 hours to obtain granules.

Example 2 Ethylcellulose was used instead of polyvinylpyrrolidone K-90, and the same procedure as in Example 1 was carried out to obtain granules.

Example 3 The procedure was repeated in the same manner as in Example 1, using Eudragit R3-100 (trade name, manufactured by Rohm and Haas, component: niacryl acid-methyl methacrylate copolymer) instead of polyvinylpyrrolidone K-90. Granular granules were obtained.

Example 4 HP-5 instead of polyvinylpyrrolidone K-90
5 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd. (l Kikusha, component: hydroxypropyl methyl cellulose phthalate)) and operated in the same manner as in Example 1 to obtain granules.

Example 5 Non-barrel 1032.5kg centrifugal flow! 1 750 g of diclofenac sodium 1 25 g of polyvinylpyrrolidone K-9011 in a water/ethanol solution (1:9, v/v) 375 Qmj! A completely dissolved solution was sprayed using a conventional method to obtain granules. Further, a solution prepared by completely dissolving 3025 g of polyvinylpyrrolidone K in 250 g of ethanol was sprayed onto this in a conventional manner.

At that time, talc or the like was added to prevent the granules from adhering to each other. The granules were further dried at 40°C to obtain desired granules.

Example 6 1031 kg of non-barrel was placed in a centrifugal flow device, and 300 g of diclofenac sodium was added thereto.

Eudragit R3-100 100g in water/ethanol/acetone solution (2:10:9, V/V) 1600m
f! A completely dissolved solution was sprayed in a conventional manner and dried at 40°C to obtain desired granules.

Example 7 2.5 kg of Nonbarrel 103 was placed in a centrifugal flow device, and 750 g of diclofenac sodium and 25 g of polyvinylpyrrolidone K-9011 were completely dissolved in a water/ethanol solution (1:9, v/v) of 3750. The liquid was sprayed in a conventional manner to obtain granules. This was further sprayed with a solution in which 25 g of polyvinylpyrrolidone K-30 was completely dissolved in water/ethanol (6 liquids (1:9, V/V) 250 ml!). Ethyl cellulose 128
g5TC-5R (trade name, manufactured by Shin-Etsu Chemical Co., Ltd. (4), ingredients: hydroxypropyl methylcellulose) 32g1 8g of triethyl citrate in a water/ethanol solution (5:9)
The solution completely dissolved in 3200 ml of 5v/v) was further sprayed. At that time, talc was added to prevent the granules from adhering to each other. The granules were dried at 40°C to obtain desired sustained release granules.

Example 8 1031 kg of non-barrel was placed in a centrifugal flow device, and 300 g of diclofenac sodium was added thereto.

Eudragit R3-1004, 5g in water/ethanol solution (1:9, v/v) 15001T11! A completely dissolved solution is sprayed using a conventional method to remove granules. In addition, 100 g of Eudragit R3-100 and 10 g of triethyl citrate were added in a water/ethanol solution (5:9
5.v/v) The solution completely dissolved in 1000mffi,
It was sprayed using a conventional method. At that time, talc was added to prevent the granules from adhering to each other. This lees was dried at 40°C to obtain desired sustained release granules.

Example 9 1031 kg of non-barrel was placed in a centrifugal flow device, and 300 g of diclofenac sodium was added thereto.

Eudragit R3-1004, 5g in water/ethanol solution (1:9, v/v) 1500mj! A completely dissolved solution was sprayed using a conventional method to obtain granules. In addition, 240 g of Eudragit L-100 and 24 g of triethyl citrate were added in a water/ethanol solution (5:95, v.
/v) A solution completely dissolved at 4000 mi was sprayed by a conventional method. At that time, talc was added to prevent the granules from adhering to each other. The granules were dried at 40°C to obtain the desired enteric coated granules.

〔Effect of the invention〕

In the small granules of the present invention, the surface of the small core is coated with uniform and fine crystalline diclofenac salt, and the surface of the small granules is smooth. Therefore, it is easy to handle for the next manufacturing process. It also has the advantage that there is no scattering of powder, and subsequent manufacturing steps can be carried out continuously.

Furthermore, since no powder such as an excipient is used, complicated and time-consuming operations such as sieving, mixing, and drying that occur when the powder and diclofenac salt are mixed are omitted. Therefore, many problems associated with this, such as labor and loss of raw materials, are solved, and it can be said that it has extremely excellent industrial effects.

Next, test results showing that the stability of the granular granules of the present invention are superior to conventional ones are shown.

Stability test Diclofenac sodium granules of the present invention (Examples 1 to 3)
(obtained in Comparative Examples 1 to 6 described later) and granules prepared by blending diclofenac sodium, excipients, and commonly used stabilizers and coating with a binder (obtained in Comparative Examples 1 to 6 described below)
A comparative test was conducted on stability over time.

Comparative Example 1 500 g of diclofenac sodium, 465 g of cornstarch, and 62 g of talc were mixed, passed through a sieve (145 mesh), and dried at 40° C. for 12 hours. Put 1031 kg of non-barrel into a centrifugal flow device, and add 3% (W) of polyvinylpyrrolidone K-90 while applying the above powder.
/V) Containing water/ethanol solution (3:2) 700m
1 was sprayed to granulate the mixture, and the mixture was further dried at 40° C. for 16 hours to obtain granules.

Comparative Example 2 250 g of diclofenac sodium, 222 g of corn starch, and 30 g of talc were mixed, passed through a sieve (145 mesh), and dried at 40° C. for 12 hours. Put 30.5 kg of non-barrel l O into a centrifugal flow device, and add 30.5 kg of polyvinylpyrrolidone K-90 while pouring the above powder.
% (W/V), calcium edetate 0.3% (W/V)
V) Containing water/ethanol solution (3:2) 350mi
! The mixture was sprayed and granulated, and further dried at 40°C for 16 hours to obtain granulated Song Pei grains.

Comparative Example 3 Granular granules were obtained in the same manner as in Comparative Example 2, using sodium hydrogen sulfite instead of calcium edetate.

Comparative Example 4 Granular granules were obtained in the same manner as in Comparative Example 2, using sodium china sulfate instead of calcium edetate.

Comparative Example 5 Granular granules were obtained in the same manner as in Comparative Example 2, using L-cystine hydrochloride instead of calcium edetate.

Comparative Example 6 After mixing 250 g of diclofenac sodium, 222 g of cornstarch, 30 g of talc, and Ig of butylated hydroxytoluene (BHT), the mixture was passed through a sieve (145 mesh) and dried at 40° C. for 12 hours. Non-barrel 10
30.5 kg was placed in a centrifugal flow device, and while applying the above powder, 3% (W/W) polyvinylpyrrolidone K-90 was added.
V) Containing water/ethanol solution (3:2) 350 mj
! The mixture was sprayed, granulated, and further dried at 40°C for 16 hours to obtain granules.

(Stability test) The test was carried out by storing each neck grain for one month at 55°C and 60% relative humidity, or for 6 months at 40°C and 75% relative humidity, and then observing the coloration and using liquid chromatography. The decomposition products were analyzed.

The results are shown in Table 1.

As is clear from the results, the granules of the present invention had almost no coloration and no decomposition products were observed. In comparison, the granular neck particles coated in powder form were colored pale brown, and decomposition products (2 types) were observed. This decomposition product is a reduction product of diclofenac, [:2- (2,6-
dichloroanilino)benzaldehyde and 2-(2,
6-dichloroanilino)benzyl alcohol].

That is, these include diclofenac, binders, excipients,
It is thought to be a product based on interaction with lubricants, etc. Incidentally, their formation could not be avoided even by adding commonly used stabilizers (chelating agents, antioxidants, etc.).

[Brief explanation of drawings]

FIG. 1 shows the solubility of diclofenac sodium in a water-ethanol mixed solvent. The vertical axis shows the amount of solvent (millimeter) required to dissolve 1 g of diclofenac sodium on a logarithmic scale, and the horizontal axis shows the solvent composition ratio of water and ethanol. Figure 1 Water 0% 50% 100%

Claims (6)

[Claims] (1) A granular composition of diclofenac salt, characterized in that the surface of small granular cores is uniformly coated with diclofenac salt and a binder. (2) The granular composition of diclofenac salt according to claim (1), wherein the diclofenac salt is diclofenac sodium. (3) A method for producing a granular composition of diclofenac salt, which comprises dissolving diclofenac salt and a binder in a mixed solution of water and an organic solvent, and spraying this solution onto small granular nuclei. (4) Claim No. 1 in which the organic solvent is ethanol (
3) A method for producing a granular composition of diclofenac salt according to item 3). (5) The mixed solvent of water and organic solvent is water-ethanol=1
:9 (volume ratio). (6) The method for producing a granular composition of diclofenac salt according to claim (3), wherein the diclofenac salt is diclofenac sodium.