JP7233852B2 - Solid formulation with suppressed discoloration - Google Patents

Description

TECHNICAL FIELD The present invention relates to solid preparations containing sodium lauryl sulfate and cellulose ether, which are inhibited from discoloring over time.

Sodium lauryl sulfate, an anionic surfactant, is used as an additive in pharmaceuticals as a stabilizer, surfactant, lubricant, solubilizer, base, binder, brightening agent, excipient, disintegrant, It is used in various applications such as an emulsifier, foaming agent, and dispersant (Non-Patent Document 1). In particular, when used as a solubilizer, it can be expected to improve the gastrointestinal absorption of poorly water-soluble drugs. On the other hand, solid formulations containing sodium lauryl sulfate may develop discoloration or spots over time, and the discoloration is particularly large when stored under warm conditions, and the decrease in commercial value due to the change in appearance is a problem. Become. However, there are few techniques for improving appearance changes of solid preparations containing sodium lauryl sulfate (Patent Document 1 and Non-Patent Document 2).

In Non-Patent Document 2, the cause of discoloration of sodium lauryl sulfate-containing solid preparations is residual sulfuric acid in sodium lauryl sulfate (due to insufficient neutralization treatment in the manufacturing process of sodium lauryl sulfate) and additives (lactose Considering the dehydration reaction with carbohydrates such as sodium lauryl sulfate), it is recommended that the standards for sulfuric acid and impurities remaining in sodium lauryl sulfate be strictly controlled from the compendium in order to suppress discoloration. However, the constant use of such high-purity sodium lauryl sulfate as a raw material for pharmaceuticals poses problems in terms of availability, cost, and the like.

On the other hand, Patent Literature 1 discloses a method of suppressing discoloration and quality deterioration of a formulation by adding a neutral salt or a basic substance to a formulation containing sodium lauryl sulfate. However, the addition of neutral salts and basic substances must be considered in terms of quality as pharmaceuticals, such as decomposition and changes in solubility due to interaction with active ingredients in the formulation.

Therefore, suppression of discoloration over time of solid preparations containing sodium lauryl sulfate can be realized easily and inexpensively without using additives such as high-purity sodium lauryl sulfate or neutral salts and basic substances. It is hoped that it can be done.

Japanese Patent No. 4902928

Pharmaceutical Excipient Encyclopedia 2016 Yakuji Nippousha Geoff Carr, Pharmaceutical Technology EUROPE, August 2015 Vol. 27 No. 8, 32-36

An object of the present invention is to provide a preparation that suppresses discoloration over time of a solid preparation containing sodium lauryl sulfate and cellulose ether, and a method for producing the same.

As a result of intensive studies to solve the above problems, the present inventors have found that the combination of cellulose ether and sodium lauryl sulfate has a significant effect on the discoloration of solid preparations, and that the average molecular weight of cellulose ether and the color of solid preparations. It has been found that there is a correlation with the degree of discoloration, and discoloration of solid preparations over time is remarkably suppressed when cellulose ether having an average molecular weight of 130,000 or more is used. Furthermore, the present inventors have found that discoloration of solid preparations over time can be better suppressed by including a step of spraying and adding sodium lauryl sulfate as a solution in the production of solid preparations, and have completed the present invention. .

That is, the present invention includes the following inventions.
(1) A solid preparation containing sodium lauryl sulfate and cellulose ether, wherein the cellulose ether has an average molecular weight of 130,000 or more.
(2) The solid preparation according to (1), wherein the cellulose ether is low-substituted hydroxypropylcellulose and/or hydroxypropylcellulose.
(3) The solid preparation according to (1) or (2), wherein the ratio of the content of cellulose ether to the content of sodium lauryl sulfate is 0.8 to 1.2.
(4) The solid preparation according to any one of (1) to (3), which further contains an active ingredient.
(5) The solid preparation according to (4), wherein the active ingredient is celecoxib.
(6) The method for producing a solid preparation according to any one of (1) to (5), which comprises spraying and adding sodium lauryl sulfate as a solution.

INDUSTRIAL APPLICABILITY According to the present invention, a solid preparation containing sodium lauryl sulfate and cellulose ether, which suppresses discoloration over time, can be provided by a simple method at a low cost.

Discoloration of the tablet surface after storing the tablets obtained in Examples 1 and 2 at 105 ° C. for 12 hours Discoloration of the tablet surface after storing the tablets obtained in Comparative Examples 1 to 3 at 105 ° C. for 12 hours Change in color tone and state of the mixed powder obtained in Test Examples 1 to 3 after storage at 105°C for 12 hours

As used herein, the term "solid formulation" refers to a solid dosage form of a drug used for patient treatment, and examples thereof include tablets, powders, fine granules, granules and capsules.

As used herein, "cellulose ether" includes nonionic cellulose ethers and ionic cellulose ethers. Examples of nonionic cellulose ethers include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxyethylmethylcellulose and hydroxypropylmethylcellulose. Carboxymethyl cellulose, nitrocellulose and the like can be mentioned. In the present invention, nonionic cellulose ethers are preferred, and hydroxypropylcellulose and low-substituted hydroxypropylcellulose are more preferred.

In this specification, the average molecular weight of the cellulose ether is preferably 130,000 or more, more preferably 130,000 to 1,000,000, and particularly preferably 130,000 to 150,000. The average molecular weight of hydroxypropylcellulose is preferably 140,000 or more, more preferably 140,000 to 1,000,000. The average molecular weight of the low-substituted hydroxypropylcellulose is preferably 130,000 or more, more preferably 130,000 to 150,000.

As used herein, the term "solution of sodium lauryl sulfate" refers to a solution obtained by dissolving sodium lauryl sulfate in any solvent, and examples of solvents include water, methanol, ethanol, 2-propanol, and mixed solutions thereof. , preferably water, ethanol, or a mixed solution thereof, more preferably water.

In this specification, the ratio of the content of cellulose ether to the content of sodium lauryl sulfate (cellulose ether/sodium lauryl sulfate) is preferably 0.8 to 1.2, more preferably 0.9 to 1.1, is particularly preferred.

As used herein, the term “solid preparation” includes pharmacologically active ingredients (active ingredients) and various pharmaceutically acceptable additives such as excipients, binders, disintegrants, in addition to sodium lauryl sulfate and cellulose ether. Lubricants, colorants, perfumes, coating agents and the like may optionally be included.

In the present specification, the terms "ingredient having pharmacological activity" and "active ingredient" are not particularly limited as long as they are drugs used for treating diseases, but are preferably poorly water-soluble drugs such as indomethacin, ketoprofen, and flurbiprofen. , loxoprofen, felbinac, diferonac, acetylsalicylic acid, flufenamic acid, mefenamic acid, alclofenac, ibuprofen, sulindac, celecoxib, oxaprozin, fenbufen, naproxen, pranoprofen, oxaprozin, telmisartan, tadalafil, rivaroxaban, rufinamide, itonaconazole, ibrutinib, gefitinib, apixaban, omeprazole, ursodeoxycholic acid, maprotiline hydrochloride, papaverine hydrochloride, norepinephrine, berberine chloride, cetraxate hydrochloride, sulfamethoxazole, metronidazole, diazepam, cimetidine, famotidine, bromhexine hydrochloride, diphenidol hydrochloride, caffeine, digoxin, erythromycin, clarithromycin, kitasamycin, josamycin, azithromycin, abiraterone acetate and the like, and celecoxib and tadalafil are particularly preferred.

As used herein, the term "excipient" refers to lactose, sucrose, fructose, powdered hydrogenated maltose starch syrup, glucose, trehalose, D-mannitol, xylitol, erythritol, D-sorbitol, xylitol, maltitol, crystalline cellulose, crystalline cellulose, carme Sodium loin, dextrin, corn starch, potato starch, wheat starch, hydroxypropyl starch, pregelatinized starch, partially pregelatinized starch, calcium hydrogen phosphate, calcium dihydrogen phosphate, precipitated calcium carbonate, light anhydrous silicic acid, etc. , especially lactose.

As used herein, the term "disintegrant" includes low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, partially pregelatinized starch, sodium starch glycolate and the like, particularly low-substituted Hydroxypropyl cellulose is preferred.

As used herein, the term "binder" includes hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, potato starch, corn starch, partially saponified polyvinyl alcohol, fully saponified polyvinyl alcohol, polyvinylpyrrolidone, partially pregelatinized starch, and starch glycolic acid. sodium and the like, and hydroxypropylcellulose is particularly preferred.

As used herein, the term "lubricant" includes stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated oil, sodium stearyl fumarate, sucrose fatty acid ester, etc. Magnesium stearate is particularly preferred.

The method for producing the solid preparation containing sodium lauryl sulfate and cellulose ether according to the present invention is not particularly limited, and can be carried out by a method known in the pharmaceutical field. For example, it can be produced by the following method.

After mixing the active ingredient and optional excipients (e.g., lactose), disintegrants (e.g., low-substituted hydroxypropylcellulose, a cellulose ether), binders (e.g., hydroxypropylcellulose, a cellulose ether), the resulting The mixed powder is granulated by spraying an aqueous solution of sodium lauryl sulfate and dried. Fine granules and granules can be obtained by adjusting the particle size of the obtained granules using a grinder, a classifier, or the like. Alternatively, a tablet can be obtained by mixing the granulated granules described above with a disintegrant (eg, low-substituted hydroxypropylcellulose) and a lubricant (eg, magnesium stearate) and then compressing the mixture. Coating liquid containing optional additives [e.g., coating agents (e.g., hydroxypropylmethylcellulose), plasticizers (e.g., macrogol), coloring agents (e.g., ferric oxide, titanium oxide), etc.] for the obtained tablets. After spraying and drying, optional brightening agents (eg, carnauba wax) can be added to obtain film-coated tablets.

A wet granulation method is preferable as a method for producing granulated granules of a solid preparation containing sodium lauryl sulfate and cellulose ether according to the present invention. Wet granulation methods include fluidized bed granulation, stirring granulation, extrusion granulation, kneading granulation, and spray granulation. Among them, agitation granulation method or fluidized bed granulation method is particularly preferable.

EXAMPLES The present invention will be described in detail below with reference to Examples, but the present invention is not limited to these.

Example 1
Celecoxib 2500.0 g, lactose hydrate (manufactured by DFE Pharma) 987.5 g, low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd., LH-11, average molecular weight 130,000) 315.0 g, sodium lauryl sulfate (manufactured by BASF Japan , Corifor SLS Fine) and 67.5 g of hydroxypropyl cellulose (manufactured by Nippon Soda, HPC-L-FP, average molecular weight 140,000) were charged into a high-speed stirring granulator (manufactured by Powrex: VG-25). While stirring, a solution of 225.0 g of sodium lauryl sulfate dissolved in 700.0 g of purified water was sprayed and added, and after granulation, air drying was carried out. To the obtained granules, 135.0 g of low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., LH-11, average molecular weight of 130,000) and 45.0 g of magnesium stearate (Taihei Kagaku Sangyo Co., Ltd.) were added and mixed. Tablets were obtained by compression molding using a tableting machine (manufactured by Hata Iron Works, HT-EX18 type).

Example 2
170.0 g of celecoxib, 67.2 g of lactose hydrate (manufactured by DFE Pharma), and 21.4 g of low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd., LH-11, average molecular weight of 130,000) were fed to a fluid bed granulator (Powrex MP-01 type), and while stirring, 30.6 g of sodium lauryl sulfate (Corifor SLS Fine, manufactured by BASF Japan) and hydroxypropyl cellulose (HPC-L-FP, manufactured by Nippon Soda, average molecular weight of 140,000). ) was dissolved in 200.0 g of purified water. 9.2 g of low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., LH-11, average molecular weight: 130,000) and 3.1 g of magnesium stearate (Taihei Kagaku Sangyo Co., Ltd.) were added to the obtained granules and mixed, followed by rotary milling. Tablets were obtained by compression molding using a tableting machine (manufactured by Hata Iron Works, HT-EX18 type).

Comparative example 1
Celecoxib 170.0 g, lactose hydrate (manufactured by DFE Pharma) 67.5 g, low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd., LH-31, average molecular weight 100,000) 21.4 g, sodium lauryl sulfate (manufactured by BASF Japan , Corifor SLS Fine) and 4.6 g of hydroxypropyl cellulose (manufactured by Nippon Soda, HPC-L-FP, average molecular weight 140,000) were put into a high-speed stirring granulator (manufactured by Powrex: VG-01 type). , while stirring, 70.0 g of purified water was added, and after granulation, air drying was carried out. To the obtained granules, 9.2 g of low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., LH-31, average molecular weight of 100,000) and 3.1 g of magnesium stearate (Taihei Kagaku Sangyo Co., Ltd.) were added and mixed, followed by rotary milling. Tablets were obtained by compression molding using a tableting machine (manufactured by Hata Iron Works, HT-EX18 type).

Comparative example 2
Celecoxib 2500.0 g, lactose hydrate (manufactured by DFE Pharma) 987.5 g, low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd., LH-21, average molecular weight 120,000) 315.0 g, sodium lauryl sulfate (manufactured by BASF Japan , Corifor SLS Fine) and 67.5 g of hydroxypropyl cellulose (manufactured by Nippon Soda, HPC-L-FP, average molecular weight 140,000) were charged into a high-speed stirring granulator (manufactured by Powrex: VG-25). While stirring, 800.0 g of purified water was added, and after granulation, air drying was carried out. To the obtained granules, 135.0 g of low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., LH-21, average molecular weight of 120,000) and 45.0 g of magnesium stearate (Taihei Kagaku Sangyo Co., Ltd.) were added and mixed. Tablets were obtained by compression molding using a tableting machine (manufactured by Hata Iron Works, HT-EX18 type).

Comparative example 3
Celecoxib 170.0 g, lactose hydrate (manufactured by DFE Pharma) 67.5 g, low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd., LH-11, average molecular weight 130,000) 21.4 g, sodium lauryl sulfate (manufactured by BASF Japan , Corifor SLS Fine) and 4.6 g of hydroxypropyl cellulose (manufactured by Nippon Soda, HPC-SSL, average molecular weight 40,000) were charged into a high-speed stirring granulator (manufactured by Powrex: VG-01 type) and stirred. While granulating, a solution obtained by dissolving 15.3 g of sodium lauryl sulfate in 60.0 g of purified water was added, and the mixture was granulated and then air-dried. 9.2 g of low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., LH-11, average molecular weight: 130,000) and 3.1 g of magnesium stearate (Taihei Kagaku Sangyo Co., Ltd.) were added to the obtained granules and mixed, followed by rotary milling. Tablets were obtained by compression molding using a tableting machine (HT-EX18, manufactured by Hata Iron Works).

Table 1 shows the composition per tablet obtained in Examples and Comparative Examples. The units of numerical values in the table are milligrams (mg).

<Experimental example 1>
50 tablets obtained in Examples 1 and 2 and Comparative Examples 1 to 3 were each stored in a constant temperature layer at 105 ° C. for 12 hours, and the surface, back and side surfaces of the tablets were visually observed to check for discoloration or spots. The number of tablets found was recorded.

As shown in Table 2 and FIGS. 1 and 2, it was confirmed that as the average molecular weights of low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose increased, the number of tablets discolored by heating decreased. On the other hand, all 50 tablets of Comparative Example 3 using hydroxypropylcellulose with an average molecular weight of 40,000 showed severe discoloration and spots.
The tablet of Example 1 using low-substituted hydroxypropyl cellulose with an average molecular weight of 130,000 and hydroxypropyl cellulose with an average molecular weight of 140,000 was greatly improved in discoloration as compared with the comparative example. In addition, the tablet of Example 2, in which low-substituted hydroxypropyl cellulose with an average molecular weight of 130,000 and hydroxypropyl cellulose with an average molecular weight of 140,000 were used, and sodium lauryl sulfate was sprayed and added as an aqueous solution, sodium lauryl sulfate was powdered. It was confirmed that the number of discolored tablets was further reduced when compared with the tablets of Example 1, which were added as an aqueous solution after adding as an aqueous solution.

<Experimental example 2>
(Composition change test of sodium lauryl sulfate and low-substituted hydroxypropyl cellulose)
Test example 1
Powders of sodium lauryl sulfate (Corifor SLS Fine, manufactured by BASF Japan) and low-substituted hydroxypropyl cellulose (LH-11, manufactured by Shin-Etsu Chemical Co., Ltd., average molecular weight of 130,000) were powder-mixed at a mass ratio of 1:1. A mixed powder was prepared.

Test example 2
Powders of sodium lauryl sulfate (Corifor SLS Fine, manufactured by BASF Japan) and low-substituted hydroxypropyl cellulose (LH-21, manufactured by Shin-Etsu Chemical Co., Ltd., average molecular weight of 120,000) were mixed at a mass ratio of 1:1 and mixed. powder was prepared.

Test example 3
Powders of sodium lauryl sulfate (Corifor SLS Fine, manufactured by BASF Japan) and low-substituted hydroxypropyl cellulose (LH-31, manufactured by Shin-Etsu Chemical Co., Ltd., average molecular weight of 100,000) are mixed at a mass ratio of 1:1 and mixed. powder was prepared.

The mixed powders of Test Examples 1 to 3 were heated at 105° C. for 12 hours, and each appearance change was observed.

As shown in FIG. 3, the mixed powder of sodium lauryl sulfate and low-substituted hydroxypropyl cellulose having an average molecular weight of 130,000 remained white without any discoloration or change in state (Test Example 1). On the other hand, mixed powder of sodium lauryl sulfate and low-substituted hydroxypropyl cellulose having an average molecular weight of 120,000 changed color from brown to blackish brown, and strong aggregates were observed (Test Example 2). Furthermore, the mixed powder of sodium lauryl sulfate and low-substituted hydroxypropylcellulose having an average molecular weight of 100,000 turned into a dark brown paste (Test Example 3). From this result, it became clear that the smaller the average molecular weight of the low-substituted hydroxypropyl cellulose, the more intense the change due to the interaction with sodium lauryl sulfate.

According to the present invention, in solid preparations containing sodium lauryl sulfate and cellulose ether used as additives for pharmaceuticals, in order to prevent deterioration of commercial value due to changes in appearance over time, high-purity additives Since there is no need to use special components such as alkaline salts and basic substances, and it can be produced with general production equipment, it can be provided at a low cost by a simple method.

Claims (5)

A solid preparation containing sodium lauryl sulfate, magnesium stearate, cellulose ether and lactose, characterized in that the cellulose ether is low-substituted hydroxypropyl cellulose with an average molecular weight of 130,000 or more and hydroxypropyl cellulose with an average molecular weight of 130,000 or more. A solid formulation. 2. The solid preparation according to claim 1, wherein the ratio of the content of cellulose ether to the content of sodium lauryl sulfate is 0.8-1.2. 3. The solid preparation according to claim 1, further comprising an active ingredient. 4. The solid preparation according to claim 3, wherein the active ingredient is celecoxib. A solid preparation containing sodium lauryl sulfate, magnesium stearate, cellulose ether and lactose, characterized in that the cellulose ether is low-substituted hydroxypropyl cellulose with an average molecular weight of 130,000 or more and hydroxypropyl cellulose with an average molecular weight of 130,000 or more. A method for producing a solid formulation comprising the step of spraying and adding sodium lauryl sulfate as a solution.

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