JP4713104B2 - A stable composition containing azithromycins as an active ingredient and having reduced bitterness - Google Patents

Description

  The present invention relates to a stable composition containing azithromycins as an active ingredient, in which bitterness is suppressed.

Several methods for suppressing bitterness are already known, and some basic substances are known to suppress bitterness. For example, magnesium aluminate metasilicate, hydrotalcite, alumina magnesium hydroxide and the like are used to suppress bitterness (for example, see Patent Document 1). However, the use of these compounds with azithromycin may reduce blood levels of azithromycin. Therefore, it is desirable to provide for the use of other compounds that inhibit the bitter taste of compositions containing azithromycin. L-arginine is known as a bitterness inhibitor of L-isoleucine, L-phenylalanine, or quinine solution (for example, refer nonpatent literature 1).
Some examples of suppressing the bitter taste of azithromycin are known (for example, see Patent Document 2). In this patent, alkaline earth oxides, alkaline earth hydroxides or alkali hydroxides are used as bitterness inhibitors.

Japanese Patent Application Laid-Open No. 06-157312.

Chemical & Pharmaceutical Bulletin, 2004, Pharmaceutical Society of Japan, 52 (2) 172-177.

US Pat. No. 5,633,006.

  The present inventors have conducted intensive research for many years on the suppression of the bitterness of pharmaceutical compositions containing azithromycins. Some basic substances were known to suppress bitterness, but many of them had very low composition stability. However, the present inventors have found that the use of L-arginine can provide a stable composition while suppressing the bitter taste of the composition.

  In order to solve the above-mentioned problems, the present invention provides a stable pharmaceutical composition with suppressed bitterness, comprising L-arginine, azithromycins, and a pharmaceutically acceptable carrier. Preferably, L-arginine can be included in the coating layer or core particle of the composition.

  The present invention also provides a method for suppressing the bitter taste of a composition containing azithromycins by adding L-arginine to the composition. Preferably, L-arginine can be added to the coating layer or core particles of the composition.

  The present invention also provides the use of L-arginine for suppressing the bitter taste of compositions comprising azithromycins.

  The present invention further provides a stable pharmaceutical composition with reduced bitter taste, comprising copper chlorophyllin sodium, azithromycins, and a pharmaceutically acceptable carrier.

  Azithromycin is the common name for 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (in the US) and is a broad spectrum antibiotic known to have one of the most potent bitter tastes It is a substance.

  In the present invention, the term “azithromycins” means azithromycin or a hydrate of azithromycin (including but not limited to a monohydrate, a dihydrate) or a solvate of azithromycin (not limited to a monosolvate). Things). Here, the “hydrate” includes a hydrate produced intentionally and a hydrate produced by absorption of moisture in the atmosphere. Solvates are produced by absorbing certain solvents during crystallization.

  The composition of the present invention can be used as an oral administration agent such as a granule, powder or dry syrup. The above-mentioned oral administration agent has the bitter taste inhibitory effect of this invention. In order to prepare a preparation for oral administration, it is often desirable to add excipients, lubricants, disintegrants, stabilizers, flavoring agents, diluents and the like.

  Examples of excipients include organic excipients; ie sugar derivatives such as lactose, sucrose, sucrose, mannitol or sorbitol, starch derivatives such as corn starch, potato starch, alpha starch or dextrin, crystalline cellulose Cellulose derivatives such as gum arabic, dextran, pullulan and the like: and inorganic excipients; ie, light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate or magnesium silicate derivatives such as magnesium aluminate metasilicate, calcium hydrogen phosphate And phosphates such as calcium carbonate, sulfates such as calcium sulfate, and the like.

  Examples of lubricants include stearic acid, calcium stearate, metal stearates such as magnesium stearate, talc, colloidal silica, waxes such as bee gum or gay wax, boric acid, adipic acid, sodium sulfate, etc. Sulfate, glycol, fumaric acid, sodium benzoate, DL-leucine, fatty acid sodium salt, lauryl sulfate such as sodium lauryl sulfate or magnesium lauryl sulfate, silicic acid such as silicic anhydride, silicic acid hydrate; and the above Contains starch derivatives and the like.

  Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol (macrogol), compounds similar to the above-mentioned excipients, and the like.

  Examples of disintegrants are chemically modified, such as low substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or cellulose derivatives such as internally crosslinked sodium carboxymethylcellulose, carboxymethyl starch, sodium carboxymethyl starch or crosslinked polyvinylpyrrolidone. Contains starch and cellulose.

  Examples of stabilizers include paraoxybenzoates such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol, phenols such as benzalkonium chloride, phenol or cresol, thimerosal , Dehydroacetic acid, sorbic acid and the like.

  Examples of flavoring agents include commonly used sweeteners, acidulants, fragrances and the like.

  The composition of this invention can be manufactured with a normal manufacturing method. In the case where L-arginine is contained in the core particle, an ordinary granule production method can be used to produce the core particle containing L-arginine and azithromycins. Examples of such production methods include extrusion granulation method, rolling granulation method, pulverization granulation method, fluidized bed granulation method, spray granulation method, crushing granulation method and the like. When the coating layer contains L-arginine, such a coating layer is prepared by coating the core particles containing azithromycin with a coating agent containing L-arginine using a usual coating method. Can be manufactured.

  As a film coating method, specifically, a film coating solution is sprayed onto core particles, and dried as necessary. The “film coating solution” is prepared, for example, by dissolving or suspending a film coating polymer in a solvent. The film coating solution may further contain, for example, a colorant (preferably yellow ferric oxide), a light-shielding agent (preferably titanium oxide), and the like.

  The “polymer for film coating” includes hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, acrylic resin (methacrylic acid, acrylic acid copolymer, aminoalkyl methacrylate copolymer, etc.), Including shellac, polyvinyl acetate phthalate, gum arabic, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose and the like. The “solvent” includes water, alcohols (eg, ethanol, isopropyl alcohol, n-propyl alcohol, methanol, etc.), acetone, ethyl acetate, dichloromethane, chloroform, hexane, toluene, heptane and the like.

  The amount of the “film coating polymer” used may be selected according to the type of solid preparation. For example, when the solid preparation is a tablet, it is about 0.5 to 10% by weight of the tablet. The spraying temperature is usually 25 to 80 ° C. The spraying time is usually 5 minutes to 24 hours. The drying temperature is usually 30 to 80 ° C. The drying time is usually 1 minute to 24 hours.

  The sugar coating method is performed according to a conventional method.

  The following examples are provided to illustrate the present invention. However, these examples should not be construed as limiting the invention in any manner. Various modifications of these embodiments are possible within the scope of the present invention.

Example 1
An azithromycin dihydrate composition (batch size 1000 g) containing L-arginine in the coating layer was prepared. The preparation method is shown below.
(1) Preparation of core particles 104.8 g of azithromycin dihydrate, 270 g of microcrystalline cellulose (excipient), 4 g of low-substituted hydroxypropylcellulose (binder) and 2.5 g of hydroxypropylmethylcellulose 2910 (binder) The mixture was mixed in a granulator and granulated while spraying purified water. More specifically, granulation was performed at an agitator rotation speed of 120 rotations and a rotor rotation speed of 80 rotations. The spray rate of purified water was 1760 g / min for the first 45 minutes and then 800 g / min for about 50 minutes. Total granulation time was 95 minutes. The end of granulation was performed by monitoring the moisture value and visually confirming it. The granulated product was dried and sieved to obtain particles having the desired particle size (105 μm-420 μm). The obtained particles were used as core particles in the following process.
(2) Preparation of Film Coated Particle 40 g of water-insoluble polymer (aminoalkyl methacrylate copolymer E (trade name: Eudragit E100)) was dissolved in 54.5% diluted ethanol to obtain a coating solution. In the granulator, the core particles prepared in the above (1) were sprayed with the coating solution to coat the core particles with the film coat layer. The obtained particles were dried and sieved to obtain film-coated particles having a target particle size (444 μm or less).
(3) Preparation of sugar coat particles A sugar coat layer was formed on the film coat particles prepared in (2) above. Specifically, a sucrose solution having a concentration of about 50% prepared by dissolving sucrose in purified water was obtained. In this solution, yellow ferric oxide (pigment) was dissolved. Further, 20 g of titanium oxide (light-shielding agent) was dispersed in this solution, and this suspension solution was sprayed onto the film coat particles prepared in (2) in a granulator. During spraying, 20 g of L-arginine was supplied, and 3 g of pineapple flavor and 5 g of xanthan gum (viscous agent) were also supplied. The obtained particles were dried and sieved to obtain sugar coated particles having a target particle size (708 μm or less).

Example 2
A composition containing L-arginine in the core particles is made by the same process as in Example 1 except that L-arginine is added at the granulation stage of the core particles instead of the sugar coat stage.

Example 3
A composition containing comparative azithromycin dihydrate was prepared by the same process as that of Example 1 except that no L-arginine was added.

上記の試験結果から、本発明の実施例１の組成物は、アジスロマイシン２水和物の苦味発現が効果的に抑制できることが実証された。 Example 4
A bitterness comparison test was conducted with 10 panelists. The azithromycin dihydrate formulation prepared according to Example 1 and Example 3 above was used for testing. The panelist's preferences were confirmed in two different ways. A sample was prepared by adding 2 ml of water to 2 g of the composition and kneading. The specimen was placed in the mouth for 1 minute, then exhaled and the mouth rinsed with water. A panelist compared and evaluated the bitterness felt when the specimen was held in the mouth and after the mouth was rinsed. In order to eliminate the influence of the order of the specimens to be tested, the test was performed by a crossover test, and the specimen testing order was switched between half of the panelists and the remaining half of the panelists. The results are shown in Table 1.

From the above test results, it was demonstrated that the composition of Example 1 of the present invention can effectively suppress the expression of bitter taste of azithromycin dihydrate.

When bitterness-inhibiting effect was also examined for other basic substances, anhydrous trisodium phosphate, sodium hydroxide and potassium carbonate were found to be effective, but sodium pyrophosphate, magnesium aluminum silicate, calcium carbonate, anhydrous phosphate Bitter taste suppression effect was not recognized with disodium hydrogen and dipotassium phosphate.
In addition, copper chlorophyllin sodium, which is an organic basic substance similar to L-arginine, exhibited a good bitterness suppressing effect.

以上のように、Ｌ−アルギニン又は銅クロロフィリンナトリウムを組成物に使用することにより、優れた苦味抑制作用及び安定性を奏することを見出した。 Example 5
The stability of the composition of the present invention was tested. The sample in which the bitterness suppressing effect was recognized in the above bitterness comparison test was used for the stability test. A specimen for stability test was put in a bottle and a severe test was conducted at 50 ° C. Stability (mainly solidification and discoloration) was confirmed. As a result, L-arginine and copper chlorophyllin sodium showed good stability, but some other problems occurred as shown in the table below in the other samples.

As described above, it has been found that by using L-arginine or copper chlorophyllin sodium in the composition, an excellent bitterness suppressing effect and stability are exhibited.

Claims (2)

A stable pharmaceutical composition with suppressed bitterness, comprising L-arginine, azithromycins, and a pharmaceutically acceptable carrier , characterized in that L-arginine is contained in the coating layer of the composition. And said composition. The composition according to claim 1, wherein the azithromycin is azithromycin dihydrate.