WO1994005683A1

WO1994005683A1 - Rokitamycin monohydrate crystal and process for producing the same

Info

Publication number: WO1994005683A1
Application number: PCT/JP1993/001189
Authority: WO
Inventors: Kenji Kinoshita
Original assignee: Asahi Kasei Kogyo Kabushiki Kaisha
Priority date: 1992-09-07
Filing date: 1993-08-25
Publication date: 1994-03-17
Also published as: JPH0687881A

Abstract

A rokitamycin monohydrate crystal (hereinafter referred to as 'RKM hydrate') represented by formula (1), and a process for producing RKM hydrate by crystallizing rokitamycin from the acidic aqueous solution thereof. The novel RKM hydrate is so extremely improved in bitterness over rokitamycin itself that it is unnecessary to hide the bitterness of the rokitamycin heretofore used and it is possible to prepare medicated syrups with the qualities superior to those of the conventional ones in a simpler process from RKM hydrate. Further, RKM hydrate is so excellent in wettability with water that it is possible to prepare tablets with the qualities equivalent to those of the conventional ones without the necessity for conducting the conventional surface treatment with a sucrose/fatty acid ester.

Description

Lokitamycin monohydrate crystal and method for producing the same

The present invention provides the following formula (1)

Fine

Lokutamycin monohydrate crystal represented by the following formula: and loctamicin monohydrate crystal represented by the formula (1) characterized by crystallizing rokitamicin in an acidic aqueous solution, and production thereof About the law. Conventional technology

Lokitamycin (hereinafter abbreviated as RKM) has the following formula (2)

(2)

A compound represented by the formula: which is a member of the kitasamycin-producing bacterium Streptomyces `` Kitasatoensis (Streptomyceskitasatoensis) '' A semi-synthetic macrolide antibiotic obtained by selectively propionylating the tertiary hydroxyl group at the 3 "-position using leukomycin A5 produced by one mutant as a raw material. (Japanese Patent Publication No. 59-46520) and the literature (J. Antibiotics, 34, 1001 (1989)). It is stronger than the four-membered macrolides, kitasamycin, josamycin, midecamycin, and myomycin, and is comparable to the fourteen-membered erythromycin (Id.). It has excellent antibacterial action against ineffective resistant bacteria. For example, tablets for oral administration containing glycine and citrate (US Pat. No. 4,716,153) and dry syrup Cheap as an agent Sex is also high, today, is shall have been widely used.

These 14- and 16-membered macrolide antibiotics have been known to have the disadvantage of having a strong bitter taste. Also, monohydrate or dihydrate crystals of erythromycin, a 14-membered macrolide antibiotic, and its derivatives (J0 urna 1 of Pharmaceutica 1 Science, 67 (8) ppl87) (Aug. 1978), U.S. Pat. No. 2,864,177, and Japanese Unexamined Patent Publication (Kokai) No. S64-38096) are known. A hydrate crystal of syn or its derivative is made for the purpose of improving its solubility. However, these compounds had a strong bitter taste when administered orally similarly to other macrolide antibiotics, and no improvement in bitterness was achieved.

Conventionally, RKM has been industrially synthesized using leucomycin A5 as a raw material, the obtained crude product is purified by column chromatography, the obtained eluate is concentrated, and the concentrated solution is dropped into water to crystallize. The resulting precipitate was collected by filtration and dried to give a product. The raw powder thus crystallized becomes an amorphous and anhydrous RKM (hereinafter abbreviated as RKM anhydrous), and the X-ray diffraction spectrum of this RKM anhydride is shown in Fig. 1. It is shown. It peaks at the fold angle (2 e 12 ° and 19 ⁼⁾ It was clear from the broad spectrum that it was amorphous. Problems to be solved by the invention

In addition, this amorphous RKM anhydride has a strong bitter taste, and when formulated as a syrup, RKM is pre-treated by a spray drying method using a polymer film as a coating agent. To improve bitterness. In addition, studies on the physical and chemical properties of RKM anhydride show that RKM anhydride itself is fat-soluble and hardly wets with water. By using a sugar fatty acid ester (hereinafter abbreviated as DK ester) at 4% based on the bulk powder and applying a surface treatment, the formulation was designed to improve dispersibility in gastric juice and speed up dissolution. (Japanese Patent Publication No. 2-591129, Pharmaceutical Sciences, 48, 147 (1988)). As described above, RKM anhydride had properties such as strong bitterness and poor wettability with water. Further, in the production of bulk RKM, it was difficult to further improve the quality by the purification method using only the column chromatography described above.

Therefore, we examined the purification method for the purpose of improving the quality of RKM and found that RKM anhydrous could be crystallized using methanol to obtain new methanol-owned RKM crystals. Was. Figure 2 shows the X-ray diffraction spectrum of this methanol-owned RKM crystal. These are Ί .8, 8.3, 10.3, 10.7, 12.1, 12.6, 14.2, 15.8, 16.6., 18. 2,20.3,21.7,22.1,23.2,24.0,25.5 and 25.5 ° show a sharp diffraction spectrum at diffraction angles (2e). It was obvious that it was gender. However, this also had a bitter taste as well. Means for solving the problem

The inventor of the present invention has conducted intensive studies to solve the above-mentioned problem of bitterness. As a result, there has been no report of a monohydrate of a 16-membered macrolide antibiotic. In addition, RKM anhydride or methanol-containing RKM crystal is dissolved in an aqueous solution of an organic acid such as sulfuric acid, propionic acid, tartaric acid, or citric acid, or an inorganic acid such as phosphoric acid, hydrochloric acid, or sulfuric acid. It has been found that a novel RKM · 1 hydrate crystal can be obtained simply and in high yield by the conversion. Surprisingly, this R KM-1 hydrate was obtained as a crystalline form of the R KM bulk powder with almost no bitterness, and was further improved in high purity, high thermal stability and improved water wetting. They have found that they have good properties, and have completed the present invention.

The present invention has been completed based on the above findings, and has the following formula (1)

OH

, ⁰ Π) 丄 J

A method for producing R KM monohydrate crystals represented by the formula (1), characterized in that R KM monohydrate crystals represented by the formula: It is.

The RKM as a raw material used in the present invention is not limited at all, for example, as long as it is a crude or appropriately purified RKM obtained by the above-described synthesis procedure or a RKM having the same. . For example, RKM anhydride or methanol-containing crystals can be easily used, and in particular, high-purity RKM-monohydrate crystals can be obtained by using RKM methanol-containing crystals. I can do it.

In order to obtain the RKM * monohydrate crystals of the present invention, first, an acidic aqueous solution is prepared. _C For example, an organic acid such as acetic acid, propionic acid, tartaric acid, and citric acid, or phosphoric acid, hydrochloric acid, sulfuric acid, etc. An inorganic acid or a mixture thereof is prepared into an acidic aqueous solution having a pH of 1 to 4. The acid is preferably an organic acid such as acetic acid or propionic acid, or an inorganic acid of phosphoric acid. Then, the acidic aqueous solution prepared in this manner was added with 0 Under cooling and stirring, the RKM anhydride and Z or the methanol-containing RKM crystal are dissolved at a concentration of 20 to 300 mgZml. After complete dissolution, to crystallize the RKM.1 hydrate, sodium hydroxide, sodium carbonate, sodium bicarbonate, hydration hydration, carbonation hydration, and carbonate The above RKM-dissolved acidic aqueous solution is diluted with alkaline water obtained by diluting a hydrogen power, ammonium carbonate, ammonium water or the like to a concentration of about 20%, for example, at a pH of about pH 4 to 6.5, preferably PH 4.4. Adjust to around 5.0. Thereafter, the RKM solution is gradually warmed to room temperature of 20 to 30 and allowed to stand for about 2 to 72 hours to form crystals. The grown crystals are collected by filtration, washed with water, and depressurized. The desired R KM · monohydrate crystals can be obtained by drying.

FIG. 3 shows an X-ray diffraction spectrum of the thus obtained RKM · monohydrate crystal of the present invention (hereinafter abbreviated as RKM hydrate). These are 5.2, 6.8, 8.3, 10.3, 11.2, 12.3, 13.3, 13.8, 1.7, 15.1, 1 5.8, 16.4, 17.1, 18.1, 19.1, 19.5, 20.4, 21.5, 22.0, 22.7, 2 3.8, 24.8, 25.1, 26.6 & 28.6 ° A diffraction angle of 2 ° shows a sharp X-ray diffraction spectrum, indicating that it is crystalline. It is obvious.

The RKM hydrate of the present invention is clearly different from the above-mentioned RKM anhydride and methanol-containing crystal in two values of the X-ray diffraction spectrum. Furthermore, the R KM hydrate of the present invention has one water molecule hydrated per R KM molecule from the results of instrumental analysis such as elemental analysis, moisture measurement (Karlfisher method) and thermogravimetric analysis. Was identified and found to be a novel crystal.

The antibacterial activity of the novel RKM hydrate of the present invention was the same as that of the conventional RKM anhydride. Furthermore, the RKM hydrate of the present invention showed no acute death by intraperitoneal administration to mice (5 mice per group) at 2000 mg kg, and no deaths were observed.

The new RKM hydrate obtained in this way has no bitterness and good wettability. Yes, therefore, in oral preparations, especially dry syrups and tablets, as compared to known RKM anhydrides, which have a strong bitter taste and exhibit poor wettability, which is an unfavorable property in preparation. It could be used to advantage. Furthermore, as an advantage in pharmacology, it has become possible to develop new formulations, such as lozenges, granules, ophthalmic ointments, and ointments, using the RKM hydrate of the present invention, which have been difficult in the past. It has very good specificity from a pharmaceutical standpoint.

Further, the RKM hydrate of the present invention has a specific volume of about 30% smaller than conventionally known RKM anhydride, and has high hardness due to being crystalline, so that it is possible to reduce the size and hardness of tablets. In addition, it has extremely excellent characteristics, such as low static charge during grinding. As described above, the RKM hydrate of the present invention is a crystal having various excellent properties as described above, which is extremely preferable for formulation, and can be easily formulated into a formulation suitable for a commonly used formulation. I can do it. Generally speaking, the RKM hydrate preparation may be administered to humans in an amount of 100 to 600 mg once to three times a day as in the case of the conventional RKM preparation. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the X-ray diffraction spectrum of RKM anhydride;

Figure 2 shows the X-ray diffraction spectrum of the methanol-containing RKM crystal;

FIG. 3 shows the X-ray diffraction spectrum of RKM hydrate obtained according to the present invention (Example 1);

FIG. 4 shows a thermal stability curve of R KM hydrate and R KM anhydride obtained at 80 ° C. according to the present invention (Example 1).

FIG. 5 shows the dissolution curve of the acid-free gastric juice model in Formulation 5;

FIG. 6 shows the dissolution curve of the acid-free gastric juice model in Formulation 6;

FIG. 7 shows a dissolution curve of the acid-free gastric juice model in Formulation 7. Example

Next, the present invention will be specifically described with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Reference Example 1 R KM synthesis method

The synthesis method of RKM is described in Patent (JP-B-59-46520, JP-B-63-50337) or literature (J. Antibiotics, 34, 101 (1) 9 8 1))). That is, the leucomycin A ₅ as a starting material, was synthesized according to the following steps, was isolated and purified as R KM anhydride.

(1) Protection of 2 'hydroxyl group

Roikomai Shin A ₅ bulk powder anhydrous 1 5 0 g, isolated from the culture solution, 2 Jikukoru Etan was dissolved in 2 5 0 ml, stirring at room temperature, it was added dropwise 2 1 ml of acetic anhydride, 1 between 5:00 Reacted. Next, 1 L of ice-cold water was added, the pH was adjusted to 10 with 7% aqueous ammonia, and the mixture was stirred for about 1 hour to separate the 1,2-dichloroethane phase. After drying then the resulting 1> 2-dichloroethane phase over anhydrous magnesium sulfate 1 0 g, to concentrated under reduced pressure to dryness, 2 '-0- give the § cetyl leucomycin A _{5 5} 0 g.

(2) Protection of hydroxyl groups at positions 3 and 9

The 2 '- 0 Asechiruroi Komai thin Alpha ₅ [delta] 0 g of anhydrous 1> was dissolved in 2 Jikurorue Tan 2 5 0 ml, was then added Toribenjirua Mi emissions 5 0 g. While stirring and cooling, 33 ml of trimethylchlorosilane was added dropwise and reacted for 15 hours. Next, the reaction solution was added dropwise to 1 L of water prepared in advance in another container, the pH was adjusted to 9.5 with 7% aqueous ammonia, and the 1> 2-dichloroethane phase was separated. Then, the obtained 1,2-dichloroethane phase was dried over anhydrous magnesium sulfate (10 g), concentrated to dryness under reduced pressure, and concentrated to 2'-10-acetyl-13> 9-di-trimethylsilyl leucomy. to obtain a thin a ₅ 6 3 g.

(3) Propionylation of tertiary hydroxyl group at 3 "-position

Above-, 2 '— 0—acetyl-3,9—di-1 0—trinotylsilylloy The emissions A ₅ 6 3 g was dissolved in anhydrous 1> 2 Jikuroruetan 2 5 0 ml, then after the addition of tri Benjiruami down 1 5 0 g, under ice-cooling, was added dropwise Puropioniruku port Rye de 5 0 ml, Then, the mixture was refluxed at 75'C for about 20 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, and then added dropwise to a previously prepared mixture of 1,2-dichloroethane (250 ml) and water (1 L). After the adjustment, the 1,2-dichloroethane phase was separated. Then, the obtained 1,2-dichloroethane phase was dried over 10 g of anhydrous magnesium sulfate, concentrated under reduced pressure to dryness, and 2′-0-acetyl-17,18-ethanol-18,3 "—Gee 0—propionyl 3,9—Geetrimethylsilylleucomycin A ₅ and 2 '— 0—Acetyl-3” — 0—Propionyl-1,3,9_di-1 0—Trimethylsilylleucomycin to obtain a mixture 6 8 g of a _5.

(4) Elimination reaction of protecting group

68 g of the above mixture was dissolved in a mixed solvent of 2.5 L of methanol and 275 ml of 8% calcium carbonate, and reacted at room temperature for 1 hour. The reaction mixture was adjusted to pH 7.5 with acetic acid, heated under reflux at 63 ° C for 20 hours, cooled to 5 or less, and filtered to form tribenzylamine crystals in the reaction mixture. Different. The crystals of the tribenzylamine were washed with 90% methanol 220 ml cooled in the following manner. The filtrate and the washing solution were combined, and methanol was completely distilled off under reduced pressure. Then, the residue was dissolved in 300 ml of benzene, partitioned, and the remaining aqueous phase was separated off. The benzene phase was washed with 300 ml of water and then concentrated under reduced pressure to about 100 ml.

(5) Isolation and purification

Approximately 100 ml of the above benzene concentrate is adsorbed on a silica gel gel (30 mm ^ X600 mmL) filled with benzene, and then benzene: ethyl acetate: methanol (36 : 4: 1, v / v). The eluate is sampled over time and analyzed by high-performance liquid chromatography (hereinafter abbreviated as HPLC). About 65 O ml fractions with an RKM content of 90% or more are collected and concentrated under reduced pressure. To dryness. This enrichment residue Was dissolved in 6 O ml of ethanol, and the ethanol solution was dropped into 800 m of water. As a result, RKM was precipitated as a white precipitate. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to obtain 5 g of RKM3.

The physicochemical properties of the RKM thus obtained are described in Patent (Japanese Patent Publication No. 59-46520) and in the literature (J. Antibiotics, 34, 101 (1989)). ) Was consistent with the known results. The X-ray diffraction spectrum shows the same X-ray diffraction pattern as that shown in Fig. 1 and it is clear that it is amorphous. This method was identified as an anhydride from the results of (1 method) and thermogravimetric analysis. Reference Example 2 Manufacturing method of methanol possessed by RKM

35 g of the RKM anhydride obtained in Reference Example 1 was dissolved in 120 ml of methanol with stirring for 40 minutes (RKM concentration: about 300 mg / ml;). Distilled water was added to this solution under stirring at 40'C until it became cloudy, then cooled to 1O'C or less, and stirred for another 20 hours to form crystals. After washing with water, 25 g (wet weight) of methanol containing RKM (see FIG. 2) was obtained. Example 1 Method for producing RKM hydrate

25 g (wet weight) of the RKM methanol-containing crystal obtained in Reference Example 2 was dissolved in 100 ml of 3% aqueous acetic acid cooled to 10%. Thereafter, the pH was adjusted to pH 5 with 10% aqueous sodium hydroxide, left at room temperature (about 26 to 24 hours) for 24 hours, and the resulting crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain RKM water. 8 g of the hydrate was obtained.

The crystal was analyzed by X-ray diffraction (X-ray diffractometer manufactured by Rigaku Denki Co., Ltd.), and the pattern shown in FIG. 3 was shown. This is clearly different from the RKM anhydride conventionally produced industrially (see Fig. 1). Elemental analysis values (empirical formula; C ₄₂ H ₆₉ N 0 ₁₅ 'Hz 0) are as shown in Table 1. Table 1

Moisture (Kalfisher moisture meter manufactured by Kyoto Denshi Kogyo Co., Ltd.): about 2.1% (theoretical value as monohydrate; 2.13%).

Melting point: around 1 1 2 'C.

Thermogravimetric analysis (MacScience thermal analyzer); Weight change of about 2% near melting point ¾: ττ;

Differential scanning calorimetry (Mac Science's thermal analyzer): An endothermic peak of about 2 Ocal / g was observed near the melting point.

From the above-mentioned instrumental analysis values, and from the fact that weight loss was not observed even after further drying, it was identified that this crystal has one molecule of RKM and one molecule of water. Was. Further, the mass fraction folding (MA SS) spectrum, '.eta. and' ³ C-nuclear magnetic resonance (NMR) spectra, infrared absorption (IR) spectrum, ultraviolet absorption (UV) scan Bae-vector , Optical rotation ([»]) and other physicochemical properties obtained from the instrumental analysis results are described in patents (Japanese Patent Publication No. 59-46520) and literature (J. Antibiotics, 34, 1). 001 (1981)) was consistent with the known results.

Furthermore, the result of thin-layer chromatography of RKM hydrate using a developing solvent of chromate form: methanol: glacial acetic acid: water (80: 7: 7: 1) has a value of 1 ^ 0. A single spot was shown in 36 (sulfuric acid coloring, ultraviolet absorption, etc.), which was consistent with the Rf value of RKM. And its biological activity is S. aur eus ATCC C 6 5 3 8 P, S.

ogenes NY 5, M. 1 υ te υ s ATCC 9 3 4 1 It showed the same antibacterial activity against the conventional bacteria as RKM anhydride. Example 2 Method for producing RKM hydrate

500 g (wet weight) of RKM methanol-containing crystal obtained in the same manner as in Reference Example 2 above was dissolved in 2 L of 3% aqueous acetic acid cooled to 10 ° C. Then, the pH was adjusted to pH 5 with 10% aqueous sodium hydroxide, 5 g of RKM hydrate obtained in Example 1 was added, and the mixture was allowed to stand at room temperature (about 26) for 24 hours. The resulting crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain RKM hydrate (showing the same X-ray diffraction pattern as shown in FIG. 3;

Approximately 250 g was obtained. Example 3 Method for producing R KM hydrate

First, 6 ml of propionic acid was dissolved in 100 ml of water, and 35 g (wet weight) of RKM methanol-containing crystal obtained in the same manner as in Reference Example 2 in acidic water cooled to 10 ml. After dissolving, the pH was adjusted to pH 5 with 10% aqueous sodium hydroxide, then 1 g of the RKM hydrate crystal obtained in Example 1 was added, and the solution was added at room temperature (about 26 ° C). After standing for a period of time, the resulting crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain RKM hydrate (showing the same X-ray diffraction pattern as the X-ray diffraction pattern shown in FIG. 3; 12 g was obtained. Example 4 Method for producing R KM hydrate

After dissolving 35 g (wet weight) of RKM methanol-containing crystal obtained in the same manner as in Reference Example 2 above in 100 ml of 3% phosphoric acid aqueous solution cooled to 10%, 10% water was added. The pH was adjusted to pH 5 with aqueous sodium oxide, then 1 g of the RKM hydrate crystal obtained in Example 1 was added, and the mixture was allowed to stand at room temperature (about 26) for 24 hours. The crystals obtained were collected by filtration, washed with water, and dried under reduced pressure to obtain RKM hydrate (showing the same X-ray diffraction pattern as the X-ray diffraction pattern shown in FIG. 3; Log) was obtained. - Example 5 Method for producing RKM hydrate

35 g of RKM anhydride obtained in Reference Example 1 was dissolved in 150 ml of 3% acetic acid aqueous solution cooled to 10%. Then, the pH was adjusted to pH 5 with 10% aqueous sodium hydroxide, 1 g of RKM hydrate obtained in Example 1 was added, and the mixture was allowed to stand at room temperature (about 26 T) for 24 hours. The resulting crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain RKM hydrate (having the same X-ray diffraction pattern as the X-ray diffraction pattern shown in FIG. 3 and being identical to the crystal of Example 1). 16 g was obtained. Experimental example

Next, a comparison experiment between the RKM hydrate of the present invention and an amorphous RKM anhydride produced by conventional industrial production will be described.

Experimental Example 1 Stability test

The RKM hydrate and the RKM anhydride obtained in the same manner as in Example 1 were stored for 80 weeks under severe conditions for 4 weeks, sampled daily, and measured for water content (Karl Fisher Method) and HPLC analysis to determine the absolute amount of RKM. A sample for HPLC measurement was prepared by weighing about 5 mg of each RKM bulk powder and dissolving it in 5 ml of acetonitrile: 0.1% aqueous acetic acid (1: 1) solution. The results are shown in FIG. 4 (in the figure, 1-11 is RKM hydrate and 1 □ _ is RKM anhydride). RKM hydrate had better thermal stability than the anhydride.

Analysis conditions;

Column: stainless steel, 4 mm 0 X lo O nm, ljnisil Q _: C18, 5 // m Mobile phase: 0.2 M ammonium acetate solution: methanol: acetonitril =

(31.5: 62.0: 6.5)

Detector: Spectrophotometer (wavelength: 2 32 nm)

Column temperature: 40

Flow rate: 0.8 ml / mi η. Experimental example 2 Sensory test

For RKM hydrate and anhydride, syrups were prepared under the following formulation conditions. A functional test (about 60 minutes after preparation) was performed on selected syrups by 10 selected panelists (adults). The results are shown in Table 2 (A: no bitterness, B: neither, C: bitter).

Formulation 1: 2 g of RKM hydrate, 0.8 g of glycine and 12 g of sucrose were mixed in a mortar and suspended in 80 ml of distilled water.

Formulation 2: 2 g of RKM anhydride, 0.8 g of glycine, and 12 g of sucrose were mixed in a mortar and suspended in 80 ml of distilled water.

Formulation 3: RKM anhydride 400 mg Mg and 0.8 g sucrose were combined in a mortar and suspended in 80 ml of distilled water.

Formula 4: 20 mg of RKM anhydride, 0.8 g of glycine and 12 g of sucrose were mixed in a mortar and suspended in 80 ml of distilled water.

Table 2

In the case of RKM hydrate, almost no bitterness was felt. On the other hand, when the RKM anhydride is used as it is without performing a microcapsule treatment such as spray-drying with a polymer film that is a means for masking bitterness, the above-mentioned sensory test is performed. As is evident from the above, RKM anhydride showed bitterness even at 1/100 amount of RKM hydrate, whereas the formulation using RKM hydrate significantly reduced bitterness. It was. Reference example 3

Next, preparation examples of dry syrup of RKM hydrate crystals will be described.

1 ^} \ 4 hydrate 100 g titer and JP refined sucrose (Mitsui refined sugar, trade name; white Zara AA) 5 43.9 g and JP crystal cellulose (Asahi Kasei Kogyo, trade name; Avicel RC — 59 1) 30 g was mixed, and 10 g of hydroxypropylcellulose (Shin-Etsu Chemical, trade name; HPC— (L)) was dissolved in 200 ml of distilled water as a binder. Granulation was performed using a fluidized bed granulator (Fuji Sangyo Co., Ltd., SP RAY-G RAN UL AT ORMODELS TR EA-1) using a conventional method. The obtained granules were sized to obtain 550 g of granules A having a particle size of 30 to 83 mesh. After passing through 83 meshes, granules are similarly made into granules by the above-mentioned fluidized bed granulator, and 30 to 83 mesh fractions are collected. 680 g of granules B were obtained. Separately, 40 g of Aminoacetic Acid (JP, Showa Denko, trade name; glycine “fine powder”) and 263 g of D-mannitol (Towa Kasei, trade name, Mannit P) are used as binders. The granulation was performed in the same manner as Granule A using a solution prepared by dissolving 5 g of hydroxypropylcellulose in distilled water in 100 ml of distilled water, and granules C 300 having a particle size of 30 to 83 mesh were produced. g was obtained. Granule B 33.5 g and granule C 16.5 g were mixed to obtain 500 g (100 mg titer in lg) of a dry syrup preparation containing RKM hydrate. This dry syrup is usually administered to a child three times a day with a dose of l to 2 g (titer of 100 to 200 mg as RKM). Reference example 4

100 g of RKM hydrate, 100 g of purified sucrose in Japan and 30 g of crystalline cellulose in Japan are mixed, and 10 g of hydroxypropyl cellulose in Japan is distilled as a binder. Using a solution dissolved in 0 ml, granulation was performed by a usual method using a fluidized bed granulator. The obtained granules were sized to obtain 550 g of granules A having a particle size of 30 to 83 mesh. After passing through this 83 mesh, granules are similarly formed into granules by the above-mentioned fluidized bed granulator, and 30 to 83 mesh categories are collected. g of granules B were obtained.

Separately, 40 g of JP Aminoacetic Acid and 260 g of D-Mannitol are mixed, and 5 g 'of hydroxypropylcellulose of JP is dissolved in 100 ml of distilled water as a binder. Granulated in the same manner as Granule A using a suspension of 3 g of locally precipitated calcium carbonate (Shiraishi calcium, trade name: Corocalco WB), and granules C 300 having a particle size of 30 to 83 mesh. g was obtained. Granule B3 43.5 g and granule C16.5.5 g were mixed to obtain 500 g (100 mg titer in lg) of a dry mouth preparation containing RKM hydrate. . Experimental Example 3 Dissolution (wet) test

A dissolution test was performed using a powder obtained by mixing RKM hydrate and anhydride in a mortar in accordance with the prescription composition based on the basic composition of the tablet. Formulation 5 of RKM hydrate and Formulation 6 below for RKM anhydride were used in the following tests. The dissolution test conditions were as follows: 160 ml of acid-free gastric juice model (40 ml of physiological saline, 120 ml of distilled water: 120 ml) was kept at 37 ° C in a 200 ml beaker, and stirred with a stirrer. Under stirring (approximately 200 rpm), add a single clinical dose of the drug (containing 200 mg of RKM), collect the eluate over time, filter, and determine the drug concentration using HPLC as above. It was measured under the conditions. As a control, a dissolution test was performed using a powder (formulation 7) obtained by surface-treating RKM anhydride with DK ester. The results are shown in Fig. 5 (for prescription 5), Fig. 6 (for prescription 6), and Fig. 7 (for prescription 7). In order to estimate the bioavailability of a drug product (hereinafter abbreviated as B.), dissolution tests are generally performed. However, the dissolution test method is described in the literature (Japanese Patent Publication No. 2-5912). No. 9, Gazette. Pharmaceutical Science. 48 No. 2, 147, 198 88).

Formula 5: RKM hydrate 200 mg

Glycine 340 mg genoic acid 70 mg Formula 6: R KM anhydride 200 mg

Glycine 340 mg Cuenoic acid 70 mg Formulation 7: DK ester surface treatment R KM anhydride (10 parts of RKM anhydride placed in a mortar, 0.4 part by weight of sucrose fatty acid ester F-160) Is suspended in 10 parts by weight of water, thoroughly moistened with mixing, and dried under reduced pressure.)

2 1 0 mg

Glycine 340 mg Cuenoic acid 70 mg As is clear from Figs. 5, 6 and 7, the RKM hydrate of formula 5 requires a pretreatment by DK ester surface treatment as in formula 7. Even without this, it showed an excellent dissolution curve similar to the formulation of Formulation 7, which was listed as a control. However, in the case of Formula 6 RKM anhydride, a delay in the dissolution rate was observed because it was difficult to wet with water. From these results, it was shown that RKM hydrate was a crystal having an excellent property of being very well wetted with water and being rapidly dispersed in the dissolution test solution. Experimental example 4 Bulk density (specific volume) test

In a test tube with a scale (10 ml), add each of R KM hydrate and R KM anhydride 2 g of the powder was filled, tapping was performed from a height of 4 to 5 cm, and the volume of the tapping was measured. Table 3 shows the results. RKM hydrate has a specific volume of about 30% smaller than that of anhydrous, and can reduce the size of tablets and the like, making it possible to formulate drinkable formulations.

3 ¾

The invention's effect

Based on the above results, the present invention provides a novel RKM hydrate having significantly improved bitterness over RKM. No need to mask the bitterness by encapsulating RKM in the mic mouth by spray-drying method using a molecular film as a coating agent, without processing the raw powder, and with the same or better quality as the conventional product. Because it is possible to formulate syrups, and because RKM hydrate has excellent water wettability, it does not require conventional surface treatment with DK ester when formulating as tablets-dissolution test Based on the results, we will formulate tablets of the same quality as conventional products in terms of E.A. (bioavailability). As described above, the RKM hydrate obtained by the present invention is a crystal having the above-mentioned extremely excellent properties even in the formulation. Furthermore, the RKM hydrate of the present invention obtained by the above-mentioned production method has a high purity, a high yield, a high thermal stability, and a single active ingredient or a fixed ratio of active ingredients suitable for the purpose on an industrial scale. It can also provide a separation and purification method that can produce products.

Claims

Below

Scope of request

Expression

(,

One-I

Lokitamycin monohydrate crystal represented by

2. Formula (1) characterized in that rokitamicin is crystallized in an acidic aqueous solution.

For the production of rokitamicin 'monohydrate crystals represented by

3. The production method according to claim 2, wherein the acidic aqueous solution is an aqueous solution of an organic acid or an inorganic acid having a pH of 1 to 4.

4. The method according to claim 3, wherein the organic acid is acetic acid or propionic acid.

5. The method according to claim 3, wherein the inorganic acid is phosphoric acid.