JP3122730B2 - Loxoprofen sodium-containing tablet formulation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to loxoprofen.
The present invention relates to a sodium-containing preparation, and more particularly, to a tablet preparation having excellent bioavailability (bioavailability) of loxoprofen sodium as an active ingredient.

[0002]

[Prior art]

Chemical name: 2- [4- (2-oxocyclopentane-1-)
Loxoprofen sodium, a sodium salt of ilmethyl) phenyl] propionate, is a non-steroidal analgesic and anti-inflammatory agent of the phenylpropionate type. Due to its strong effect, it is used for rheumatoid arthritis, osteoarthritis,
It is a drug used for treatment of low back pain and the like. Loxoprofen sodium itself is a crystalline or crystalline powder, which not only has strong adhesion between drugs,
It is highly adherent to machines and containers.Therefore, when manufacturing a loxoprofen / sodium-containing preparation, formulas with special consideration were studied to prevent explosion due to static electricity and to ensure uniform drug content. ing. For example, Japanese Patent Publication No. 7-74153 discloses that when formulating loxoprofen sodium, the amount of additives to be added together is not more than a specific part by weight with respect to 1 part by weight of loxoprofen sodium. It has been proposed that a formulation having a water absorption capacity less than a certain number is excellent in bioavailability.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have found that it is easier to formulate a tablet formulation containing loxoprofen sodium, and that when the obtained tablet is orally administered, the tablet is produced in the stomach. Collapses quickly,
We examined a formulation that allows the release of loxoprofen sodium, which is the active ingredient, from tablets, and thus allows quick absorption from the digestive tract. As a result, among the various components that are conventionally blended in conventional formulation, loxoprofen
It has been newly found that when formulated with sodium and made into tablets, the preparation can be easily performed, the disintegration of the tablets is good, and the release of loxoprofen / sodium contained therein is good.

That is, the present invention relates to the following formulation: (a) loxoprofen sodium 1 part by weight (b) the following ingredient which is a filler : lactose 2.81 to 2.85 parts by weight corn starch 0.04 to 0.05 parts by weight Part (c) Disintegrant , low substituted hydroxypropylcellulose 0.40 to 0.45 parts by weight (d) Lubricant, magnesium stearate 0.07 to 0.075 parts by weight (e) Trioxide The present invention provides a loxoprofen sodium-containing tablet preparation comprising a small amount of iron and containing 20% loxoprofen sodium as an anhydride based on the total weight of the preparation.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION As described above, in the present invention, among the fillers, binders, and lubricants which are commonly used as optional additives particularly in the preparation technology, certain specific components are formulated at specific mixing ratios. It is characterized by having done. That is, as a conventional filler, microcrystalline cellulose, α-cellulose,
Celluloses such as crosslinked sodium carboxymethylcellulose and derivatives thereof; lactose, corn starch, hydroxypropyl starch, carboxymethyl starch,
There are polysaccharides such as cross-linked starch and amylose, and binders include pregelatinized starch and povidone (pov).
idone), methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and the like, and examples of the lubricant include talc, magnesium stearate, calcium stearate, zinc stearate, and stearic acid. However, when loxoprofen sodium is formulated as a tablet, lactose and corn starch are used as fillers for 1 part by weight of loxoprofen sodium as a filler in consideration of the powdery properties of loxoprofen sodium as an active ingredient. A specific ratio, that is, lactose as a main filler, corn starch as an auxiliary filler, using a specific weight part, a low-substituted hydroxypropylcellulose as a disintegrant, using a specific weight part, and further lubricating. It has been found that a composition containing magnesium stearate in a specific part by weight as an agent gives good results.

Accordingly, a more preferred loxoprofen / sodium-containing tablet preparation of the present invention is as follows: (a) loxoprofen / sodium 1 part by weight (b) lactose 2.81 to 2.85 parts by weight corn starch 0.04 (C) low-substituted hydroxypropylcellulose 0.40 to 0.45 parts by weight (d) magnesium stearate 0.07 to 0.075 parts by weight (e) iron trioxide A loxoprofen sodium-containing tablet preparation containing 20% loxoprofen sodium as an anhydride based on the total weight of the preparation.

[0007] Further, the most preferred specific formulation is:
Considering the clinical use amount of loxoprofen sodium used for anti-inflammatory and analgesic for the symptoms of diseases such as rheumatoid arthritis, osteoarthritis and shoulder periarthritis,
60 mg as anhydrous loxoprofen sodium
(68.1 mg as loxoprofen sodium)
In the case of a 300 mg tablet containing: (a) loxoprofen sodium 68.1 mg (b) lactose 193.9 mg corn starch 3.0 mg (c) low-substituted hydroxypropylcellulose 30.0 mg (d) stearin Loxoprofen / sodium-containing tablet preparation consisting of 5.0 mg of magnesium oxide (e) iron trioxide in a minute amount. It should be noted that iron trioxide in each of the above-mentioned formulations in the present invention is a coloring agent, is added in a very small amount, and does not significantly affect the weight parts of the entire formulation.

The loxoprofen / sodium-containing formulation of the present invention is characterized in that a specific compounding component is used at a specific ratio as described above. It has been found that it is not always essential that the additive amount is 3 parts by weight or less and the total water absorption capacity is 1.7 or more with respect to 1 part by weight of loxoprofen sodium proposed in -74153. did. That is, a 300 mg tablet containing 68.1 mg of loxoprofen sodium (60 mg as an anhydride) based on a particularly preferred specific formulation of the present invention has been specified in the prior art (Japanese Patent Publication No. 7-74153); (1) The additive amount is 3 parts by weight or more based on 1 part by weight of loxoprofen sodium, and
(2) The additive has a total water absorption capacity of not more than 1.7, but this is not the same as the formulation in the prior art in view of the disintegration test of the tablet formulation and the absorption test of loxoprofen / sodium in animals described later. It turned out to be equivalent or better.

[0009] Based on the specific tablet formulation of the present invention, a tablet to be applied in actual medical treatment is produced, for example, as follows. That is, any known formulation means such as so-called dry mixing and wet mixing is used, and more specifically, loxoprofen sodium, lactose, corn starch, low-substituted hydroxypropylcellulose, and iron sesquioxide are mixed. Then, water was added and granulated. The granulated product was dried at 40 ° C. for 12 hours, sized, and tableted with magnesium stearate. In the above-mentioned production method, tableting was smooth without powder sticking to a tableting machine, which has conventionally been a problem in the formulation of loxoprofen sodium.

[0010]

EXAMPLES The characteristics of tablets based on the loxoprofen sodium-containing formulation of the present invention, the dissolution test of the obtained tablets, and the results of the absorption test of the tablets in humans are described below. Formulation preparation: Loxoprofen sodium, lactose, corn starch,
After low-substituted hydroxypropylcellulose and iron sesquioxide were mixed with a high-speed mixer, an appropriate amount of water was added thereto and kneaded. Dry the kneaded material (40
℃, 12 hours), and then sieved (24 mesh)
Then, magnesium stearate was added and mixed with a V-type mixer for 5 minutes. The mixture thus obtained is
Tableting was performed using a flat punch having a diameter of 9.0 mm. The control example was similarly formulated.

[0011]

[Table 1]

[0012] When a formulation was attempted using the above formulation,
Good tableting was achieved with the formulation of the present invention. Test Example 1: Dissolution test : The following formulation: (a) loxoprofen sodium 68.1 mg (b) lactose 193.9 mg corn starch 3.0 mg (c) low-substituted hydroxypropylcellulose 30.0 mg (d) magnesium stearate A tablet consisting of 5.0 mg (e) iron trioxide in a micro total amount of 300.0 mg was produced by the production method described above.

Using the six tablets, a dissolution test was carried out at 37 ° C. using an aqueous solution according to the dissolution test prescribed in the Japanese Pharmacopoeia. As a control formulation, a loxonin (registered trademark) tablet [Sankyo Co., Ltd.], which is on the market as a tablet containing 68.1 mg of loxoprofen sodium (60 mg as an anhydride), was also subjected to a dissolution test under the same conditions. Was. As a result, no significant difference was observed in the degree of dissolution of loxoprofen between the tablet based on the formulation of the present invention and the loxonin tablet as the control formulation. Therefore, when administered to humans, the tablet of the present invention rapidly elutes loxoprofen in the stomach and is efficiently absorbed. That point was confirmed by the following test.

Test Example 2: Absorption test Method: One tablet of the present invention and one loxonin tablet (60 mg as loxoprofen) for 12 healthy adult males
Was orally administered, and then the loxoprofen concentration in the serum was measured using high performance chromatography. Results: The results are shown in FIG. As is clear from the results in the figure, it was found that both the tablet of the present invention and the roxone tablet were rapidly absorbed, and their bioavailabilities were equivalent.

[0015]

As described above, the loxoprofen / sodium-containing tablet preparation of the present invention takes into account the powder properties of loxoprofen / sodium and formulates a specific component among fillers and lubricants in a specific mixing ratio. It is characterized by having done. In particular, when formulating loxoprofen sodium as a tablet, lactose and corn starch are used as fillers in a specific ratio, based on 1 part by weight of loxoprofen sodium, that is, lactose is used as a main filler, and corn starch is used as a filler. Was used as an auxiliary filler in a specific part by weight, among hydroxypropylcellulose as a disintegrant, a low-substituted hydroxypropylcellulose was used in a specific part by weight, and magnesium stearate as a lubricant was further compounded in a specific part by weight. Those give good results. That is, in the actual production of tablets, the tableting is smooth without the occurrence of “sticking” of the powder to a tableting machine or the like, the disintegration of the obtained tablet is better, the content in the tablet It has advantages such as good absorption of loxoprofen / sodium as the main component. These advantages are the result of the specific formulation of the present invention, and its usefulness is particularly remarkable.

[Brief description of the drawings]

FIG. 1 shows the results of Test Example 2.

──────────────────────────────────────────────────続 き Continued on the front page (58) Fields surveyed (Int.Cl. ⁷ , DB name) A61K 31/192 A61K 9/20 A61K 47/26 A61K 47/36 A61K 47/38 CA (STN) EMBASE (STN ) MEDLINE (STN)

Claims (2)

(57) [Claims] 1. The following formulation: (a) loxoprofen sodium 1 part by weight (b) the following ingredient as a filler , lactose 2.81 to 2.85 parts by weight corn starch 0.04 to 0.05 parts by weight (c) ) is a disintegrant, low substituted hydroxypropylcellulose 0.40-0.45 parts by weight (d) lubricants, from 0.07 to 0.075 parts by weight of magnesium stearate (e) iron sesquioxide fine amount A loxoprofen / sodium-containing tablet preparation comprising 20% of loxoprofen / sodium as an anhydride with respect to the total weight of the preparation. 2. The following formula: (a) loxoprofen sodium 68.1 mg (b) lactose 193.9 mg corn starch 3.0 mg (c) low substituted hydroxypropylcellulose 30.0 mg (d) magnesium stearate 5.0 mg (E) 300 mg loxoprofen sodium containing iron sesquioxide
Tablet formulation.