JP5202856B2 - Granular solid formulation containing tosfloxacin tosylate - Google Patents

Description

  The present invention is a granular solid containing tosufloxacin tosylate that exhibits good suspendability, reduces unpleasant taste such as astringency, is excellent in dissolution and uniformity of content by particle size, and exhibits a sharp particle size distribution. Relates to the formulation.

  For children and the elderly, granular solid preparations such as powders, fine granules, granules and dry syrup play a major role. These dosage forms can be freely changed in dosage, and are particularly important for improving compliance of children and the elderly. In addition to direct oral administration, granular solid preparations such as powders, fine granules, granules and dry syrup are often taken by suspending in water or the like at the time of taking. In this case, the suspension of the drug should not cause problems such as accumulation of medicine at the bottom of the container, adhesion to the inside of the container, clogging of the hole of the syringe used for administration, and bubbles that cannot be measured accurately when shaken. It is necessary to develop a granular solid preparation with excellent properties. In addition, if the suspension is poor and solid, it may cause discomfort such as roughness in the oral cavity and throat, leading to refusal for children to take medication. Therefore, a granular solid preparation with excellent suspension is desired. . In particular, in the preparation of granular solid preparations that are easy to be taken by children and the elderly, such as powders, fine granules, granules, and dry syrups, more effectively unpleasant tastes such as astringency and bitterness of medicinal ingredients. There is a demand for suppression (Non-Patent Document 1).

  On the other hand, when packaging granular solid preparations with non-uniform particle sizes such as powders, fine granules, granules, and dry syrups, the content variation varies because most models of automatic packaging machines employ a vibration-based dividing method. There is a need for a formulation with less. Moreover, in evaluating the quality of a granular solid preparation from the aspect of medication management, the uniformity of the content by particle size is important (Non-Patent Document 2).

  In consideration of the handling of the granular solid preparation, in the case of the granular solid preparation having a small particle size, there arises a problem of adhesion or scattering to the packaging sheet or container. In the case of a powdered solid preparation having a large particle size, problems such as weighing and escape during packaging work occur. Therefore, development of a fine granule excellent in handling property among granular solid preparations is desired (Non-patent Document 3). Further, by sharpening the particle size distribution, the yield at the time of production is improved, and stable production with high productivity is possible.

  Tosfloxacin tosylate is a new quinolone antibacterial agent having a broad antibacterial spectrum against gram positive bacteria, gram negative bacteria, and anaerobic bacteria (Patent Document 1), and has an unpleasant taste such as astringency. A granular solid preparation containing tosufloxacin tosylate that shows good dissolution and suspendability, reduces unpleasant taste such as astringency, is excellent in content by particle size, and shows a sharp particle size distribution. Not.

Japanese Patent Publication No.63-020828 Pediatric practice, 2000, 63, 11, pp.1692-1704 PHARM TECH JAPAN, 1997, Volume 13, pages 19-30 Japan Powder Industrial Technology Association, "Granulation Handbook", Ohmsha, 1975, p.509-510

  In order to improve medication compliance for children and elderly people, it exhibits good suspension, reduces astringency and other unpleasant tastes, excels in drug dissolution and absorption in the gastrointestinal tract, and from the standpoint of medication management There is a demand for a granular solid preparation containing tosufloxacin tosylate having a sharp particle size distribution that is excellent in uniformity in content by particle size and excellent in handleability and productivity.

  Under such circumstances, the present inventor has conducted extensive research, and as a result, contains (1) tosufloxacin tosylate, (2) sugar or sugar alcohol, and (3) nonionic water-soluble cellulose derivative or polyvinyl alcohol. The granular solid preparation is a granular solid preparation that exhibits good suspendability, reduces unpleasant taste such as astringency, is excellent in dissolution and uniformity of content by particle size, and exhibits a sharp particle size distribution. The headline and the present invention were completed.

  The granular solid preparation of the present invention exhibits good suspendability in water, syrup, and the like, and further reduces unpleasant taste such as astringency. Furthermore, when taking granular solid preparations as liquid preparations, the drug adheres to the container or dropper and foaming properties are reduced, taking the prescribed amount accurately and taking it in a state where unpleasant tastes such as astringency are reduced. It can be used as a preparation for children and the elderly. In addition, it has excellent drug dissolution and absorption in the gastrointestinal tract, excellent content uniformity by particle size, and sharp particle size distribution. It is useful as a preparation with excellent handling and productivity such as packaging.

The present invention is described in detail below.
Unless otherwise indicated,% used in this specification means weight%.
Tosfloxacin tosylate used in the present invention can be produced, for example, by the method described in JP-B-63-020828. The content of tosufloxacin tosylate is preferably 75% or less, particularly preferably 5 to 45%, in the granular solid preparation.

Examples of the nonionic water-soluble cellulose derivative used in the present invention include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, and hydroxyethylcellulose. These may be used alone or in combination of two or more. Good. Of these, hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose are preferable, and hydroxypropylcellulose is more preferable.
The content of the nonionic water-soluble cellulose derivative or polyvinyl alcohol in the granular solid preparation is preferably 1.5 to 6%, more preferably 2.5 to 5%.

Examples of the sugar and sugar alcohol used in the present invention include sugars such as sucrose, trehalose, fructose, xylose, maltose, lactose and glucose, erythritol, xylitol, sorbitol, mannitol, lactitol, maltitol, and reduced maltose starch syrup. Sugar alcohols etc. are mentioned, These may mix and use 1 type, or 2 or more types. Of these, sugars such as sucrose, trehalose and lactose, and sugar alcohols such as erythritol, xylitol, mannitol and reduced maltose starch syrup are preferred, and sucrose is more preferred.
The content of sugar and sugar alcohol is preferably 25 to 95%, more preferably 55 to 90% with respect to the granular solid preparation.

In the present invention, additives generally used for drugs can be used as long as the effects of the present invention are not impaired. Examples of such additives include lubricants, flavoring agents, coloring agents, flavoring agents, and surfactants.
Examples of the lubricant include magnesium stearate, talc, hydrous silicon dioxide, and light anhydrous silicic acid.
Examples of the corrigent include aspartame, saccharin, stevia, thaumatin, and acesulfame potassium.
Examples of the colorant include iron sesquioxide, yellow ferric oxide, edible red No. 102, edible yellow No. 4, and edible yellow No. 5.
As flavoring agents, for example, essential oils such as orange oil, lemon oil, peppermint oil, pine oil, essences such as orange essence and peppermint essence, flavors such as cherry flavor, vanilla flavor, fruit flavor, apple micron, banana micron, Examples include powdery fragrances such as peach micron, strawberry micron, orange micron, and vanillin, ethyl vanillin.
Examples of the surfactant include sodium lauryl sulfate and dioctyl sodium sulfosuccinate.
Further, these additives may be used alone or in combination of two or more, and the blending amount is not particularly limited, and is appropriately blended so that the effect is sufficiently exhibited according to each purpose. That's fine.

  The granular solid preparation of the present invention is prepared by a conventional method, using powdery, granule, fine granule, suspension, dry syrup or powder by appropriately using formulation aids such as pharmaceutically acceptable excipients, carriers and diluents. Although it can be used as a preparation such as a body preparation, it is preferably used, for example, directly as fine granules and powders for oral use and as a suspension dispersed in water or syrup. The administration method, dose and number of administrations can be appropriately selected according to the age, weight and symptoms of the patient, but usually the amount that can exert the drug effect is divided into 1 to several times a day. In general, tosfloxacin tosilate may be administered to an adult in a daily dose of 30 to 2000 mg, preferably 30 to 400 mg, divided into 1 to several times.

  The production method of the granular solid preparation of the present invention is not particularly limited, but powders, fine granules, granules and dry syrup are mixed with the above essential components and other additives, fluidized bed granulation, extrusion granulation, wet processing. Can be produced according to conventional methods such as crushing granulation, stirring granulation, dry granulation, etc., but it is possible to obtain a granulated product that is porous and has good solubility, and the same container in which raw material mixing, granulation, and drying are sealed The fluidized bed granulation method can be particularly suitably used because it is an apparatus that is suitable for GMP because of its structure.

  Hereinafter, the present invention will be described in detail with reference to Examples, Comparative Examples, and Test Examples, but these do not limit the present invention. In Comparative Example 5, a preparation in which tosufloxacin tosylate was replaced with pazufloxacin was used.

Test Example 1 Suspension (suspension immediately after suspension and resuspension after standing for a certain time)
Purified water (80 mL) was placed in a prescription bottle (100 mL capacity), and a sample (16 g) was added. After sealing, 20 upside down falls were performed and suspended. Suspension was evaluated immediately after suspension, 1 minute after suspension, and 5 minutes after suspension. In addition, after 30 minutes and 24 hours, 20 inverted falls were performed again, and the suspension was resuspended, and the resuspension properties after 1 minute suspension and 5 minutes suspension were similarly evaluated. Judgment criteria are shown below.
○ Good suspendability (uniform dispersion)
△ Suspension is slightly good (when the upper layer is cloudy and dispersed, but there is a slightly transparent part in the sedimentation layer or upper layer of 1 cm or more)
× Suspension poor (when dispersion is uneven, sedimentation or aggregation is observed)
The results are shown in Table 1.

  The preparations of Examples 1 to 9 showed good suspension and resuspension with respect to the preparations of Comparative Examples 1 to 4.

Test Example 2 Suspension (Defoaming)
Purified water (80 mL) was placed in a prescription bottle (100 mL capacity), and a sample (16 g) was added. After sealing, 20 upside down falls were performed and suspended. The height of the bubble layer after 1 minute of suspension was measured. The results are shown in Table 2.

  In the preparations of Comparative Examples 2 to 4, bubbles remained after 1 minute of suspension, but in the preparations of Examples 1 to 4, all of the bubbles disappeared after 1 minute of suspension, and good defoaming properties were exhibited.

Test Example 3 Taste Sensory Test for Unpleasant Taste A taste sensory test was conducted on 10 panelists. As the test preparation, the preparation of Example 2 and the preparation of Comparative Example 1 were used.
The panelist included a sample in which 1 g of the test preparation was suspended in 5 mL of purified water in the mouth for 30 seconds, and compared unpleasant taste (astringency) during and after taking. About the order of taking both preparations, the panelists were divided into two groups of half each, and they were divided into the group of the example preparation, the order of the comparative preparation, the group of the comparative preparation, and the order of the example preparation. 10 minutes after the first preparation was taken and the taste disappeared in the mouth, the second preparation was taken. For evaluation, the following scores were used to compare the unpleasant taste of the comparative formulation and the example formulation.
Score 5 Example formulation is clearly astringent 4 Example formulation is slightly astringent 3 Equivalent 2 Comparative example formulation is slightly astringent 1 The comparative example formulation is clearly astringent.

  As a result of comparing both preparations with respect to astringency, the panelists who answered that the comparative preparations were more or less astringent were 8 in total and 6 after taking for the total of 10 people, as well as for example preparations Among them, 1 was taken and 0 after taking, and the excellent effect of the present invention on the suppression of astringency was shown.

Test Example 4 Dissolution of Drug According to the 14th revised Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method), 900 mL of water is used as a test solution, and 1 g of each test preparation (containing 147 mg of tosufloxacin tosylate (100 mg as tosfloxacin) In Comparative Example 5, 100 mg of pazufloxacin was added, and the dissolution test was performed at 37 ° C. and 50 rpm. A test solution was taken at regular intervals, and the elution rate (unit:%) was measured by the absorbance method. The results are shown in Table 4.

The preparations of Comparative Examples 1 to 4 containing no nonionic water-soluble cellulose derivative or polyvinyl alcohol did not reach an elution rate of 85% in 15 minutes.
Further, the preparation of Comparative Example 5 containing pazufloxacin and hydroxypropyl cellulose did not reach the dissolution rate of 85% in 15 minutes.
On the other hand, the preparations of Examples 1 to 9 quickly eluted with an elution rate after 15 minutes of 88.9 to 96.8%, and showed excellent dissolution properties compared to the comparative examples.

Test Example 5 Uniformity of Content by Particle Size The formulation of Example 2 was classified using a 42 mesh, 60 mesh and 80 mesh sieve, and the tosfloxacin content of the formulation of Example 2 was taken as 100%. Asked. The results are shown in Table 5.

実施例の製剤は、いずれの粒度においても均一な含量を示した。

The formulation of the example showed a uniform content at any particle size.

Test Example 6 Particle Size Distribution The granulated powder was classified using a 30 mesh and 150 mesh sieve, and the ratio for each particle size was determined. The results are shown in Table 6.

  The formulation of the example showed a sharp particle size distribution compared to the formulation of the comparative example.

Next, the present invention will be described with reference to examples, but the present invention is not limited thereto.
Example 1
Tosfloxacin tosilate 73.5g, Saccharose (Nisshin Sugar Co., Ltd.) 411.5g, Aspartame (Ajinomoto Co., Inc.) 5g were weighed, sieved, and tumbling fluidized granulator / dryer (Multiplex MP-01: manufactured by POWREC) And mixed. Thereafter, 250 g of a 3% hydroxypropylcellulose (HPC-L: Nippon Soda) aqueous solution was sprayed and granulated. After drying, it was sieved to obtain a granulated product. 2.3 g of hydrous silicon dioxide (manufactured by DMV Japan) was mixed with the obtained granulated product so that the ratio of hydrous silicon dioxide was 0.5% of the preparation to obtain a granular solid preparation.

Example 2
In the same manner as in Example 1, 500 g of a 3% hydroxypropylcellulose (HPC-L: Nippon Soda) aqueous solution was sprayed as a spray liquid during granulation to obtain a granular solid preparation.

Example 3
In the same manner as in Example 1, 375 g of a 6% hydroxypropylcellulose (HPC-L: Nippon Soda) aqueous solution was sprayed as a spray liquid during granulation to obtain a granular solid preparation.

Example 4
In the same manner as in Example 1, 500 g of 6% hydroxypropylcellulose (HPC-L: Nippon Soda) aqueous solution was sprayed as a spraying solution at the time of granulation to obtain a granular solid preparation.

Example 5
In the same manner as in Example 1, 300 g of 5% hydroxypropylcellulose (HPC-SSL: Nippon Soda) aqueous solution was sprayed as a spraying solution at the time of granulation to obtain a granular solid preparation.

Example 6
In the same manner as in Example 1, 600 g of a 2.5% hydroxypropylcellulose (HPC-M: Nippon Soda) aqueous solution was sprayed as a spray liquid at the time of granulation to obtain a granular solid preparation.

Example 7
In the same manner as in Example 1, 300 g of a 5% hydroxypropylmethylcellulose 2910 (TC-5EW: Shin-Etsu Chemical Co., Ltd.) aqueous solution was sprayed as a spray liquid during granulation to obtain a granular solid preparation.

Example 8
In the same manner as in Example 1, 300 g of 2.5% methylcellulose (Metroses SM-4: Shin-Etsu Chemical Co., Ltd.) aqueous solution was sprayed as a spraying solution at the time of granulation to obtain a granular solid preparation.

Example 9
In the same manner as in Example 1, 600 g of a 2.5% aqueous solution of polyvinyl alcohol (GOHSENOL EG-25: Nippon Synthetic Chemical) was sprayed as a spray liquid during granulation to obtain a granular solid preparation.

Comparative Example 1
In the same manner as in Example 1, 300 g of purified water was sprayed as a spray liquid during granulation to obtain a granular solid preparation.

Comparative Example 2
In the same manner as in Example 1, 1000 g of 1.5% sodium carboxymethylcellulose aqueous solution (CMC Daicel 1160: Daicel Chemical Industries) was sprayed as a spray liquid during granulation to obtain a granular solid preparation.

Comparative Example 3
In the same manner as in Example 1, 600 g of a 2.5% corn starch (Corn Starch W: Nippon Shokuhin Kako) aqueous solution was sprayed as a spray liquid during granulation to obtain a granular solid preparation.

Comparative Example 4
In the same manner as in Example 1, 300 g of 5% polyvinylpyrrolidone (Prasudone K-29 / 32: ASP Japan) aqueous solution was sprayed as a spray liquid at the time of granulation to obtain a granular solid preparation.

Comparative Example 5
Using pazufloxacin instead of tosufloxacin tosylate in Example 1 and setting the amount to 400 g scale in the same manner as in Example 1, 5% hydroxypropylcellulose (HPC-L: Nippon Soda) as a spray liquid during granulation 240 g of an aqueous solution was sprayed to obtain a granular solid preparation.

  Tables 7 to 9 show a list of formulations of Examples and Comparative Examples.

The pharmaceutical formulations of Examples 1 to 4 are pharmaceutical formulations in which the amount of hydroxypropylcellulose added is changed.
The pharmaceutical formulations of Examples 5-9 are pharmaceutical formulations using different grades of hydroxypropylcellulose, hydroxypropylmethylcellulose 2910, methylcellulose and polyvinyl alcohol in place of the hydroxypropylcellulose used in Examples 1-4.
The preparation of Comparative Example 1 is a formulation containing no nonionic water-soluble cellulose derivative or polyvinyl alcohol.
The pharmaceutical formulations of Comparative Examples 2 to 4 are pharmaceutical formulations using normal binders sodium carboxymethylcellulose, corn starch, and polyvinylpyrrolidone.
The pharmaceutical formulation of Comparative Example 5 is a pharmaceutical formulation using pazufloxacin instead of tosufloxacin tosylate.
Each preparation can be obtained by appropriately weighing in terms of the charged amount and manufacturing based on the above examples and the formulations shown in Tables 7-9.

Claims (7)

  A granular solid preparation containing (1) tosufloxacin tosylate, (2) a sugar or sugar alcohol, and (3) a nonionic water-soluble cellulose derivative or polyvinyl alcohol.   The granular solid preparation according to claim 1, wherein the nonionic water-soluble cellulose derivative or polyvinyl alcohol is contained in an amount of 1.5 to 6% based on the granular solid preparation.   The granular solid preparation according to claim 1 or 2, wherein the nonionic water-soluble cellulose derivative is one or more selected from hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose.   The granular solid preparation according to claims 1 to 3, wherein the nonionic water-soluble cellulose derivative is hydroxypropylcellulose.   The granular solid preparation according to any one of claims 1 to 4, wherein the sugar or sugar alcohol is at least one selected from sugars of sucrose, trehalose and lactose and sugar alcohols of erythritol, xylitol, mannitol and reduced maltose starch syrup.   The granular solid preparation according to claim 1, wherein the sugar or sugar alcohol is sucrose. The granular solid preparation according to claim 1, wherein the granular solid preparation is a powder, fine granules or dry syrup.