CN106103448A - 1 cyclopropyl 6 fluorine 7 (8 methoxyimino 2,6 diaza spiro [3,4] pungent 6 bases) 4 oxo 1,4 dihydro [1,8] naphthyridines 3 carboxylic acid D aspartic acid salt hydrate and the antibacterial combination comprising their hydrate - Google Patents

Abstract

The present invention relates to 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3,4]oct-6-yl)-4-oxo-1 , 4-dihydro-[1,8]naphthyridine-3-carboxylic acid D-aspartate hydrate and an antibacterial composition comprising their hydrates. The present invention provides a stable Zadofloxacin D-aspartate hydrate, in particular Zadofloxacin D-Aspartate sesquihydrate, in which adsorption and desorption of water hardly occurs. Since the Zadofloxacin D-aspartate hydrate according to the present invention hardly absorbs water, it has excellent physicochemical properties. Therefore, the medicine containing Zadofloxacin D-Aspartate Salt Hydrate of the present invention, especially in tablet form, is not easily destroyed, and the content of main components is almost unchanged, thereby showing excellent drug stability.

Description

1-Cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3,4]octyl- 6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid D-aspartate in salt water Hydrates and antibacterial pharmaceutical compositions comprising their hydrates

technical field

The present invention relates to 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3,4]oct-6-yl)-4-oxo-1 , Hydrates of 4-dihydro-[1,8]naphthyridine-3-carboxylic acid D-aspartate and antibacterial pharmaceutical compositions comprising their hydrates.

Background technique

Quinolonecarboxylic acid derivatives are synthetic antibacterial agents that exhibit potent and broad antibacterial activities and their effectiveness against infectious diseases of humans and animals is well known.

In the prior art, antibacterial agents selected from quinolones such as norfloxacin, ofloxacin, and ciprofloxacin are widely used in the treatment of human diseases, and their effects have been recognized.

These drugs exhibited significant antibacterial activity against Gram-negative bacteria, but moderate or slightly lower antibacterial activity against Gram-positive bacteria. Various studies have been conducted to overcome the above-mentioned problems with existing quinolone antibacterial agents; the most representative drug developed is sparfloxacin, which exhibits excellent antibacterial activity against Gram-positive bacteria. However, sparfloxacin still exhibits weak antibacterial activity against streptococci, methicillin-resistant Staphylococcus aureus (MRSA), and now increasingly quinolone-resistant bacteria, all of which are known to cause respiratory tract infections .

European Patent EP0 994 878 discloses 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3,4]octane as a quinolone antibacterial agent to solve the above-mentioned problems -6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (hereinafter referred to as "zabofloxacin").

Zadofloxacin is a new quinolone carboxylic acid antibacterial agent, which not only shows excellent antibacterial activity against Gram-negative bacteria but also Gram-positive bacteria, and is very effective against methicillin-resistant bacteria and resistant to Quinolones also exert excellent effects.

However, zadofloxacin has a problem of very low solubility. It is well known to those skilled in the art that the preparation of pharmaceuticals is facilitated when the active ingredients of the pharmaceutical composition have high solubility in water or aqueous solutions in a wide pH range. Therefore, in order to increase the bioavailability of zadofloxacin mentioned above, it is necessary to improve the physicochemical properties of the drug to develop salts with higher solubility.

US Patent No. US 8,324,238 discloses Zadofloxacin aspartate represented by Formula 1 below.

<Formula 1>

It is known that the above-mentioned zadofloxacin aspartate has not only extraordinary solubility, but also excellent physicochemical properties such as stability, as compared with commonly produced salts such as phosphate or hydrochloride, while Almost non-toxic.

Zadofloxacin aspartate disclosed in the aforementioned US Pat. No. 8,324,238 has been identified as an acid anhydride. Although it is known that Zadofloxacin aspartic acid anhydride has excellent physical and chemical properties such as stability, if it is not maintained and stored in the state of anhydride, its stability will drop sharply due to moisture absorption. Therefore, the preparation of stable drugs not only requires complex processes and air-conditioning facilities, but it also requires strict maintenance of storage conditions. There is always a need to address these issues.

Once the drug absorbs moisture during storage, it enlarges the pores inside the solid tablet structure, thereby increasing the tablet volume as well as reducing the hardness, which eventually leads to the appearance of a tablet that is easily damaged by external impact. General indicators of pore enlargement due to moisture absorption include percent increase in weight, moisture content, and thickness, and percent change in hardness. The occurrence of porosity enlargement of the tablet structure due to the absorption of moisture can be confirmed from these data.

The appearance of the tablet is easily damaged, or in other words, the decrease in tablet hardness makes the mechanical tablet packaging process after commercial production of the tablet very difficult; the tablet is also easily damaged in subsequent processes such as transportation, resulting in patients being unable to take the tablet.

Maintaining the content of the main ingredients in pharmaceuticals is critical to ensure their therapeutic effect, and the absorption of water increases the percentage change of the content of main ingredients in the finished pharmaceutical product.

When pharmaceuticals are prepared into fixed dosage forms such as tablets and capsules, methods such as direct compression, pressure granulation, wet granulation, and fluidized bed granulation are used to mix the main ingredients and carriers. In particular, methods using bonded solvents such as wet granulation and fluidized bed granulation, if only water is used as the bonded solvent, the main ingredients dissolve rapidly during mixing, making it impossible to produce granules suitable for molding.

The present inventors, after conducting many studies on improving the physicochemical properties of Zadofloxacin D-aspartate and increasing the stability to moisture, solved the problem caused by moisture by inventing a drug that does not absorb moisture regardless of storage conditions. Reduced stability of the drug due to absorption and stability problems during storage. The present invention has been accomplished by developing a method for manufacturing stable tablets using granulation methods such as direct compression method, pressure granulation method, and wet granulation method using an organic solvent or a mixture of an organic solvent and water.

Contents of the invention

technical problem

The object of the present invention is to improve the stability of a drug comprising Zadofloxacin D-aspartate as an active ingredient and its stability during storage by improving the physicochemical properties of Zadofloxacin D-aspartate, and To improve the stability of a pharmaceutical composition comprising the above active ingredient and a pharmaceutically acceptable carrier.

solution

To achieve the above object, the present invention provides Zadofloxacin D-aspartate hydrate represented by the following formula 2.

<Formula 2>

(wherein n=1～4).

In the present invention, Zadofloxacin D-aspartate hydrate is obtained as Zadofloxacin D-aspartate·nH ₂ O, wherein n is a value of 1-4. Hydrates in which n is 1, 1.5, 2, 2.5, 3, 3.5 or 4 are preferred, and hydrates in which n is 1.5 are especially preferred.

Since the molecular weight of Zadofloxacin D-aspartate is 534.49, in the case of the hydrate where n=1, the theoretical water content is 3.3% (w/w); if n is 1.5, 2 , 2.5, 3, 3.5 or 4, the theoretical water content is 4.8, 6.3, 7.8, 9.2, 10.5 or 11.9% (w/w) respectively. Although the actual average water content of Zadofloxacin D-aspartate hydrate is close to the above theoretical value, there may be differences between batches due to differences in recrystallization conditions or drying conditions during the manufacturing process.

For the Zadofloxacin D-aspartate hydrate of the present invention, Table 1 below shows the range of water content for each water of crystallization.

Table 1

【Table 1】

water content relative to water of crystallization

Hydration number (n) Moisture content (w/w%) 1 3.0～3.9 1.5 4.0～5.9 2 6.0～6.9 2.5 7.0～8.4 3 8.5～9.9 3.5 10.0～10.9 4 11.0～13.0

The zadofloxacin D-aspartate hydrate of the present invention especially takes the form of crystalline zadofloxacin D-aspartate hydrate. Zadofloxacin D-aspartate hydrate can be characterized by differential scanning calorimetry (DSC), X-ray powder differential analysis (X-ray Powder Differential Analysis) and infrared spectroscopy and it is compared with Anhydride distinction.

Zadofloxacin D-aspartic anhydride was characterized by an X-ray Powder Differential Analysis pattern comprising 2Θ values of 4.5 and 9.0. The X-ray powder differential analysis pattern of crystalline Zadofloxacin D-aspartate sesquihydrate is contained in 4.3±0.2, 8.6±0.2, 9.8±0.2, 12.9±0.2, 14.8±0.2, 19.9±0.2, 20.8±0.2, 23.8±0.2, 24.7±0.2, and 29.0±0.2 exhibit peak 2θ, and 2θ values especially exhibit peaks at 4.3±0.2, 8.6±0.2, and 9.8±0.2, as shown in the following X-ray powder The differential analysis pattern is shown.

Additionally, in a preferred embodiment, Zadofloxacin D-aspartate sesquihydrate is in virtually pure form and is characterized as having a KF (Karl Fisher) value of 4.0 to 5.9%, and as shown in As shown in 2b, there are peaks at about 106.5°C to 108.5°C and about 214°C to 216°C on the differential scanning calorimetry thermogram.

In another embodiment, Zadofloxacin D-aspartate trihydrate is characterized as having a KF value of 8.5-9.9%, and as shown in Figure 2c, on the differential scanning calorimetry thermogram It has peaks at about 97.0°C to 99.0°C and about 215°C to 217°C.

In yet another embodiment, Zadofloxacin D-aspartate monohydrate is characterized as having a KF value of 3.0-3.9%, and as shown in Figure 2a, on the differential scanning calorimetry thermogram There are peaks at about 109.5°C to 111.5°C and about 214°C to 216°C.

On the other hand, Zadofloxacin D-Aspartic Anhydride has a KF value of less than 0.5%, and exhibits a temperature range of about 214°C to 216°C on the differential scanning calorimetry thermogram as shown in Figure 2d. Peak.

In addition, zadofloxacin D-aspartic acid anhydride has a concentration of 0.2 X-ray powder differential analysis pattern.

The preparation method of Zadofloxacin D-aspartate salt hydrate according to the present invention is described in the following examples. Zadofloxacin D-aspartate hydrate according to the present invention can be prepared by drying Zadofloxacin D-aspartate at 20° C. to 30° C. after synthesis. For zadofloxacin D-aspartate sesquihydrate, at a relative humidity (RH) between 30% and 90%, the adsorption and desorption of water does not occur, and it maintains a stable zirconate fixedly. Dofloxacin D-aspartate sesquihydrate form. In one example, when the zadofloxacin D-aspartate sesquihydrate according to the present invention was preserved for 24 hours at a temperature of 25±2°C and a RH of 80±5%, the water content and Related substances remain constant. When tested for long-term storage stability up to 24 months under normal conditions (25±2°C/60±5%RH), the water content, moisture and purity remained constant.

In addition, the present invention provides a pharmaceutical composition comprising zadofloxacin D-aspartate hydrate as an active ingredient and a pharmaceutically acceptable carrier thereof.

The present invention can be clinically administered orally or parenterally in many forms, and the preferred route of administration is oral administration. Furthermore, the formulation of the drug is carried out by means of commonly used diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants and surfactants.

Solid dosage forms for oral administration include tablets, granules, capsules, etc., and these solid preparations can be obtained by mixing one or more excipients, such as microcrystalline cellulose, low-substituted hydroxypropyl cellulose, colloidal dicellulose Silicon oxide, calcium silicate, starch, calcium carbonate, sucrose or lactose, or gelatin; in addition to these simple excipients, lubricating agents such as magnesium stearate and talc may be used. For the preparation of medicaments for parenteral administration, sterile aqueous solutions, non-aqueous solvents, suspensions and emulsions are used. For non-aqueous solvents and suspending agents, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, or injectable esters such as ethyl oleate can be used.

In addition, the dosage of Zadofloxacin D-aspartate hydrate according to the present invention depends on the patient's body weight, age, sex, health status, diet, administration time, administration route, excretion rate and disease status. Changes in severity. For adults, the dose can be in the range of 1 mg/kg to 50 mg/kg; the preferred dose is 4 mg/kg to 14 mg/kg; and especially preferably 4 mg/kg to 9 mg/kg, once a day or multiple times a day. Second-rate.

Beneficial Effects of the Invention

The present invention provides stable hydrates of Zadofloxacin D-aspartate in which little adsorption and desorption of water occurs, and in particular Zadofloxacin D-aspartate sesquihydrate . The zadofloxacin D-aspartate hydrate of the present invention has excellent physical and chemical properties because it hardly absorbs water.

Therefore, the medicine containing zadofloxacin D-aspartate salt hydrate of the present invention, especially in tablet form, is not easy to be destroyed, and the content of main components is almost unchanged, showing excellent drug stability.

Description of drawings

Figure 1a shows the powder x-ray diffraction (XRD) pattern of Zadofloxacin D-aspartate n=1.5 hydrate;

Fig. 1 b represents the powder x-ray diffraction pattern of zadofloxacin D-aspartic anhydride;

Figure 2a represents the differential scanning calorimetry (DSC) thermogram of Zadofloxacin D-aspartate n=1 hydrate;

Figure 2b shows the differential scanning calorimetry thermogram of Zadofloxacin D-aspartate n=1.5 hydrate;

Figure 2c shows the differential scanning calorimetry thermogram of Zadofloxacin D-aspartate n=3 hydrate;

Figure 2d shows the differential scanning calorimetry thermogram of Zadofloxacin D-aspartic acid anhydride;

Fig. 3 a represents the infrared (IP) spectrum of Zadofloxacin D-aspartate n=1.5 hydrate;

Figure 3b represents the infrared spectrum of Zadofloxacin D-Aspartic Anhydride;

Figure 4a represents the percentage change of the tablet formed by Zadofloxacin D-aspartic anhydride and sesquihydrate over time at 33% relative humidity;

Figure 4b represents the percentage change of the tablet formed by Zadofloxacin D-aspartic anhydride and sesquihydrate over time at 54% relative humidity;

Figure 4c shows the percent content change over time for tablets formed from zadofloxacin D-aspartic anhydride and sesquihydrate at 75% relative humidity.

detailed description

The above-mentioned preparation method of the present invention is described in more detail through examples below, but the scope of the present invention is not limited by examples.

<Example 1> 1-cyclopropyl-6-fluoro-7-[(8Z)-8-(methoxyimino-2,6-diaza-spiro[3,4]oct-6- yl) Preparation of ]-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid D-aspartate n=1 hydrate

Add 85 g of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3,4]oct-6- base)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid and 32.4 g of D-aspartic acid and slowly heated to 55 ° C ~ 58 ° C, in the The mixture was stirred for 30 minutes at temperature. Then, after adding 3.8 g of activated carbon to the reaction mixture and stirring at 55°C to 58°C for 30 minutes, the hot mixture was filtered and then cooled to 20°C to 30°C. To the precipitated reaction mixture, 406 ml of absolute ethanol was added and stirred at 10° C. to 20° C. for 2 hours, then filtered and the precipitate was washed. The wet precipitate was added to a liquid mixture of 680 ml of ethyl acetate, 43 ml of ethanol, and 17 ml of purified water, followed by stirring at 50°C to 60°C for 5 hours or more. After the reactant was stirred at 20°C to 30°C for 2 hours, it was filtered and dried to obtain 97.5 g of the target compound (KF=3.4%).

<Example 2> 1-cyclopropyl-6-fluoro-7-[(8Z)-8-(methoxyimino-2,6-diaza-spiro[3,4]oct-6- yl) Preparation of ]-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid D-aspartate n=1.5 hydrate

Add 85 g of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3,4]oct-6- base)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid and 32.4g D-aspartic acid and slowly heated to 55℃～60℃, at this temperature The mixture was stirred for 30 minutes. Then, after adding 3.8 g of activated carbon to the reaction mixture and stirring at 55°C to 60°C for 30 minutes, the hot mixture was filtered and cooled to 20°C to 30°C. After adding 406 ml of absolute ethanol to the precipitated reaction mixture and stirring at 5° C. to 25° C. for 1 to 2 hours, it was filtered and washed (absolute ethanol), and then dried to obtain 101.1 g of the target compound (KF=4.9%).

Melting point: 209.1°C (DSC)

¹ H-NMR (DMSO-d ₆ , ppm): 0.95(m,2H), 1.23(m,2H), 2.60(dd,1H, J=8.8Hz, J=17.7Hz), 2.73(dd,1H, J＝3.9Hz, 17.7Hz), 3.53(m, 1H), 3.81(dd, 1H, J＝3.7Hz, 8.9Hz), 3.97(s, 3H), 4.29(bs, 2H), 4.32～4.39(m ,4H),4.45(bs,2H),7.50(d,1H,J=12.4Hz),8.44(s,1H)

<Example 3> 1-cyclopropyl-6-fluoro-7-[(8Z)-8-(methoxyimino-2,6-diaza-spiro[3,4]oct-6- yl) Preparation of ]-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid D-aspartate n=3 hydrate

Add 85 g of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3,4]oct-6- base)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid and 32.4g D-aspartic acid and slowly heated to 55℃～58℃, at this temperature The mixture was stirred for 30 minutes. After adding 3.8 g of activated carbon to the reaction mixture and stirring at 55°C to 58°C for 30 minutes, the hot mixture was filtered and then cooled to 20°C to 30°C. After adding 406 ml of absolute ethanol to the precipitated reaction mixture and stirring at 20° C. to 30° C. for 5 hours, it was filtered, washed (using absolute ethanol) and dried to obtain 103.5 g of the target compound (KF=9.4%).

<Comparative Example 1> 1-cyclopropyl-6-fluoro-7-[(8Z)-8-(methoxyimino-2,6-diaza-spiro[3,4]oct-6- yl) Preparation of ]-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid D-aspartic acid anhydride

Add 85 g of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3,4]oct-6- base)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid and 32.4g D-aspartic acid and slowly heated to 55℃～58℃, at this temperature Stir for 30 minutes. After adding 3.8 g of activated carbon to the reaction mixture and stirring at 55°C to 58°C for 30 minutes, the hot mixture was filtered and then cooled to 20°C to 30°C. After adding 406 ml of absolute ethanol to the precipitated reaction mixture and stirring at 20° C. to 30° C. for 2 hours, it was filtered and washed. After adding the wet precipitate to 850 ml of acetone and stirring it at 20° C. to 40° C. for about 14 hours, it was filtered and dried to obtain 96.4 g of the target compound (KF=0.2%).

Melting point (m.p.): 206.2°C (DSC)

¹ H-NMR (DMSO-d ₆ , ppm): 0.93(m,2H), 1.23(m,2H), 2.60(dd,1H, J=8.6Hz, J=17.5Hz), 2.73(dd,1H, J＝3.9Hz, 17.5Hz), 3.50(m, 1H), 3.81(dd, 1H, J＝3.7Hz, 8.9Hz), 3.97(s, 3H), 4.28(bs, 2H), 4.32～4.39(m ,4H),4.45(bs,2H),7.44(d,1H,J=12.4Hz),8.40(s,1H)

<Experiment 1> XRD measurement

XRD research was carried out on the zadofloxacin D-aspartate sesquihydrate prepared according to the above-mentioned Example 2 and on the zadofloxacin D-aspartate anhydride prepared according to Comparative Example 1. X-ray powder diffraction data of Zadofloxacin D-aspartate salt were obtained using a Bruker D8-Focus powder diffractometer with copper Kα (40 kV, 40 mA) as the radiation source. Data were acquired at room temperature over a 2Θ range of 2° to 40° with a step width of 0.02° and 16 seconds per step.

As shown in Figure 1a, the powder X-ray diffraction angle (2θ) of Zadofloxacin D-aspartate sesquihydrate of the present invention is at 4.3, 8.6, 9.8, 12.9, 14.8, 19.9, 20.8, 23.8, Around 24.7 and 29.0.

In contrast, the powder X-ray diffraction angle (2θ) of Zadofloxacin D-aspartic anhydride exhibited peaks around 4.5, 9.0, 12.9, 14.4, 15.3, 17.8, 19.2, 22.7 and 32.5.

<Experiment 2> Differential Scanning Calorimetry

Using TA Instrument DSC Q100, the sample is placed on a sealed aluminum pan, for the Zadofloxacin D-aspartate hydrate of the present invention prepared in the above-mentioned Examples 1 to 3 and prepared according to Comparative Example 1 The thermal properties of Zadofloxacin D-aspartic anhydride were analyzed. Use empty aluminum pans as blanks. The sample was heated at a heating rate of 5°C per minute at a temperature ranging from 25°C to 300°C. Using an indium calibration setup and characterizing differential scanning calorimetry, the data are shown in Figures 2a-2d, respectively.

As shown in Figure 2a, the n=1 hydrate of Zadofloxacin D-aspartate has a characteristic differential scanning calorimetry thermal analysis with peaks at about 109.5°C to 111.5°C and about 214°C to 216°C picture. As shown in Figure 2b, the n=1.5 hydrate of Zadofloxacin D-aspartate has a unique differential scanning calorimetry thermal analysis with peaks at about 106.5°C to 108.5°C and about 214°C to 216°C picture. As shown in Figure 2c, the n=3 hydrate of Zadofloxacin D-aspartate has a unique differential scanning calorimetry thermal analysis with peaks at about 97.0°C to 99.0°C and about 215°C to 217°C picture.

In contrast, as shown in Figure 2d, Zadofloxacin D-aspartic anhydride has a characteristic differential scanning calorimetry thermogram with a peak at about 214°C to 216°C.

<Experiment 3> Infrared Spectroscopy

Zadofloxacin D-aspartate sesquihydrate according to Example 2 of the present invention and Zadofloxacin D-aspartic acid anhydride prepared according to Comparative Example 1, using Thermo SCIENTIFIC NICOLET 6700, by ATR Technique performed infrared spectroscopy and the resulting spectra are shown in Figure 3a and Figure 3b, respectively.

<Experiment 4> Karl Fischer titration

By adding 200 mg each of Zadofloxacin D-aspartic acid salt hydrate prepared according to Examples 1 to 3 of the present invention and Zadofloxacin D-aspartic acid anhydride prepared according to Comparative Example 1 to formamide and methanol (40:60) by Karl Fischer titration using a Karl Fischer titrator.

The results show that Zadofloxacin D-aspartate monohydrate of the present invention has a unique Karl Fischer (KF) value of 3.0 to 3.9%; 1.5 hydrate has a KF value of 4.0 to 5.9%; trihydrate It has a unique KF value of 8.5-9.9%. Zadofloxacin D-aspartic anhydride has a KF value lower than 0.5%.

Zadofloxacin D-aspartate sesquihydrate of the present invention prepared according to Example 2 was used to make tablets by various granulation methods.

<Example 4> prepare the tablet of Zadofloxacin D-aspartate sesquihydrate (embodiment 2) by wet granulation

Zadofloxacin D-aspartate sesquihydrate, 11% (w/w) prepared according to Example 2 using a high-speed mixer (model: FUKEA POTEC, Japan) to mix 70% (w/w) After adding microcrystalline cellulose, 1.3% (w/w) crospovidone, a liquid mixture of 23% (w/w) absolute ethanol and 2.3% (w/w) hydroxypropyl cellulose was added and combine the mixture. After the mixture was discharged and dried at a temperature of 55° C. or lower in an air dryer (model: OF-22GW, Korea), fine fluid particles were obtained. After mixing 11% (w/w) microcrystalline cellulose, 3.4% (w/w) crospovidone and 1% (w/w) sodium octadecyl fumarate with the granules, the A single tablet press (model: AR-402, Germany) molded to prepare tablets with a hardness of 18-22 KP.

<Example 5> prepare the tablet of Zadofloxacin D-aspartate sesquihydrate (embodiment 2) by pressure granulation

Zadofloxacin D-aspartate sesquihydrate, 11% (w/w) prepared according to Example 2 using a high-speed mixer (model: FUKEA POTEC, Japan) to mix 70% (w/w) microcrystalline cellulose, 1.3% (w/w) crospovidone and 2.3% (w/w) hydroxypropyl methylcellulose. Pellets from the resulting mixture are extruded to form pellets. After mixing the granules with 11% (w/w) microcrystalline cellulose, 3.4% (w/w) crospovidone and 1% (w/w) sodium octadecyl fumarate, the Tablets with a hardness of 18-22 KP were molded using a single tablet press (model: AR-402, Germany).

<Example 6> preparation of the injection of Zadofloxacin D-aspartate sesquihydrate (embodiment 2)

70% (w/w) of Zadofloxacin D-aspartate sesquihydrate prepared according to Example 2, 29.5% (w/w) of lactic acid and 0.5% (w/w) of After sodium bisulfate was dissolved in purified water for injection, the pH of the solution was adjusted to 3.5-4.5 with 1N-sodium hydroxide, and then filtered. A dry powder injection was prepared by drying the injection solution filled in the vial for freeze drying according to the freeze drying method using a freeze dryer (model: FD5510, Korea).

<Comparative example 2> prepare the tablet of Zadofloxacin D-aspartic acid anhydride (comparative example 1) by wet granulation method

Utilize a high-speed mixer (model: FUKEA POTEC, Japan) to mix 70% (w/w) of zadofloxacin D-aspartic acid anhydride prepared according to comparative example 1, the microcrystalline fiber of 11% (w/w) After 1.3% (w/w) crospovidone and 1.3% (w/w) crospovidone, a liquid mixture of 23% (w/w) absolute ethanol and 2.3% (w/w) hydroxypropylmethylcellulose was added. Combine the mixture. After discharging the mixture, particulate matter was obtained by drying at a temperature lower than 55° C. using an air blow dryer (model: OF-22GW, Korea). After mixing 11% (w/w) of microcrystalline cellulose, 3.4% (w/w) of crospovidone and 1% (w/w) of sodium octadecyl fumarate, the A tablet press (model: AR-402, Germany) molded to prepare tablets with a hardness of 18-22 KP.

<Experimental Example 5> Measurement of Moisture Absorption Performance

When the drug product in storage absorbs moisture, the porosity inside the firmly formed tablet can be observed to expand. General indicators of pore enlargement include percent increase in weight, moisture content and thickness, and percent change in hardness. From these data it was possible to identify the occurrence of pore enlargement in the tablet structure due to the absorption of moisture.

Therefore, the inventors combined the tablet of Example 4 of the present invention (zadofloxacin D-aspartate sesquihydrate prepared according to Example 2) and the tablet of Comparative Example 2 (according to Comparative Example 1 The prepared zadofloxacin (D-aspartic acid anhydride) was stored at 33%, 54% and 75% relative humidity for 10 days, and the percentage increase and hardness change percentage of weight, water content and thickness were observed.

1) Weight gain percentage

The tablet of Example 4 and the tablet of Comparative Example 2 were stored for 10 days at 33%, 54% and 75% relative humidity (temperature 25° C.), and were weighed using an electronic scale (AE 260 DeltaRangeR, Mettler Instrument AG, Switzerland) ) to measure the average weight of each sample. The results are shown in Table 2.

According to Example 4 of the present invention (tablets comprising Zadofloxacin D-aspartate sesquihydrate), the weight increased by 101.5%, 101.5%, and 10 days after storage at 33%, 54%, and 75% relative humidity for 10 days 102.3% and 103.6%, while the weight of Comparative Example 2 (tablet containing zadofloxacin D-aspartic acid anhydride prepared according to Comparative Example 1) increased by 105.5%, 105.4% and 106.9%, respectively.

Table 2

【Table 2】

2) Percent increase in water content

After storing the tablet of Example 4 and the tablet of Comparative Example 2 at 33%, 54% and 75% relative humidity (temperature 25° C.) for 10 days, the moisture content was measured using an infrared moisture measuring instrument (unit: %, model: AND MX-50, A&D Company, Ltd.) Measure the water content of each sample under the condition of 105°C (0.01%/min content). The results are shown in Table 3.

According to Example 4 of the present invention (tablets comprising Zadofloxacin D-aspartate sesquihydrate) stored at 33%, 54% and 75% relative humidity for 10 days, the water content increased by 148.4 %, 162.3%, and 176.0%, while the water content of Comparative Example 2 (tablet containing zadofloxacin D-aspartic acid anhydride) increased by 715.7%, 741.6% and 807.9%, respectively.

table 3

【table 3】

3) Percent change in hardness

The tablet of embodiment 4 and the tablet of comparative example 2 are stored under 33%, 54% and 75% relative humidity (temperature 25 ℃) 10 days, and utilize hardness measuring instrument (unit Kp, model: 5Y, DR , Schleuniger) to measure each sample. The results are shown in Table 4.

Example 4 according to the present invention (tablets comprising Zadofloxacin D-aspartate sesquihydrate) decreased hardness by -19.5% after storage at 33%, 54% and 5% relative humidity for 10 days, respectively , -36.8%, -56.2%, while the hardness of Comparative Example 2 (tablet containing Zadofloxacin D-aspartic acid anhydride) decreased by -43.6%, -56.3% and -73.1%, respectively.

Table 4

【Table 4】

4) Thickness increase percentage

After storing the tablet of Example 4 and the tablet of Comparative Example 2 at 33%, 54% and 75% relative humidity (temperature 25° C.) for 10 days, the thickness was measured using a thickness measuring instrument (unit: mm, model: ID-C112) , Mitutoyo) to measure each sample. The results are shown in Table 5.

According to Example 4 of the present invention (tablets comprising Zadofloxacin D-aspartate sesquihydrate) stored at 33%, 54% and 75% relative humidity for 10 days, the thickness increased by 102.2%, respectively. 103.8%, 105.7%, while the thickness of Comparative Example 2 (tablet containing zadofloxacin D-aspartic acid anhydride prepared according to Comparative Example 1) increased by 105.6%, 106.9%, 109.2%, respectively.

table 5

【table 5】

5) Percent change in content

After the tablet of embodiment 4 and the tablet of comparative example 2 are stored at 33%, 54% and 75% relative humidity (temperature 25 ℃) after 10 days, utilize high-speed liquid chromatography HPLC (column C18, ultraviolet absorption spectrometry Photometer 275nm, injection volume 20uL, model: HPLC 5973, waters) Measure each sample. The results are shown in Figures 4a-4c and Table 6 for each relative humidity, respectively.

According to Example 4 of the present invention (tablets comprising Zadofloxacin D-aspartate sesquihydrate) stored at 33%, 54% and 75% relative humidity for 10 days, the content increased from 97.1% of the initial Respectively reduced to 96.23% (-0.87%), 93.72% (-3.38%) and 94.92% (-2.18%), while the content of Comparative Example 2 (comprising the tablet of Zadofloxacin D-Aspartic Anhydride) The reduction in the larger size from the initial 97.8% was 93.90% (-4.75%), 93.09% (-4.71%), 91.34% (-6.46%), respectively.

Table 6

【Table 6】

From the above results, it can be seen that compared with the tablet comprising Zadofloxacin D-aspartic acid salt sesquihydrate according to the present invention, the tablet comprising Zadofloxacin D-aspartic acid anhydride has a higher weight, Water content and thickness increased more and hardness decreased faster.

Therefore, it can be seen from the results that compared with the tablet comprising zadofloxacin D-aspartate sesquihydrate according to the present invention, the tablet comprising zadofloxacin D-aspartate anhydride Increase faster on weight, water content and thickness, can know that the structural pore enlargement of the latter tablet proceeds rapidly; Due to said pore enlargement and hardness reduction caused by pore enlargement, the appearance of the tablet can be disturbed by weak external impact destroy. The appearance of the tablet is easily broken, and the decrease in hardness makes the mechanical packaging process after the commercial production of the tablet very difficult, and the tablet is also easily broken during subsequent processes such as transportation, thereby causing patients to be unable to take the tablet.

In addition, with regard to the physicochemical stability, or percentage change in content, of the drug product, tablets containing anhydrides exhibited greater changes in content and lower content compared to tablets containing hydrates. Since the content of main ingredients in pharmaceutical products is the main index to ensure the therapeutic effect, the above results show that tablets containing anhydrides are not preferred compared to tablets containing hydrates.

Thus, the present invention provides a very stable zadofloxacin D-aspartic acid in which little adsorption and desorption of water occurs, as compared to the zadofloxacin D-aspartic acid anhydride disclosed in U.S. Patent No. US 8,324,238. salt hydrate. And it can be known that the medicine comprising Zadofloxacin D-aspartate hydrate of the present invention shows excellent drug stability, especially in its tablet form, because it is not easy to be destroyed, the content of main components Little to no change.

Claims (9)

1. A Zadofloxacin D-aspartate hydrate, represented by the following formula 2, wherein the water content of the hydrate measured by Karl Fischer titration is 3 to 13 wt%. <Formula 2> (where n=1 to 4). 2. Zadofloxacin D-aspartate hydrate according to claim 1, wherein, the n of formula 2 is equal to 1.5 and the water content of the hydrate measured by Karl Fischer titration is 4.0～ 5.9 wt%. 3. The hydrate according to claim 2, wherein the hydrate is a crystalline hydrate having peaks at diffraction angles (2θ) of 4.3±0.2, 8.6±0.2, and 9.8±0.2 in an X-ray diffraction pattern thing. 4. The crystalline Zadofloxacin D-aspartate hydrate according to claim 3, wherein the hydrate is at 4.3 ± 0.2, 8.6 ± 0.2, 9.8 ± 0.2, Diffraction angles (2θ) of 12.9±0.2, 14.8±0.2, 19.9±0.2, 20.8±0.2, 23.8±0.2, 24.7±0.2, and 29.0±0.2 have peaks. 5. A method for manufacturing Zadofloxacin D-aspartate sesquihydrate, comprising the following steps: i) adding zadofloxacin and D-aspartic acid to a mixed solvent of purified water and ethanol and heating the resulting mixture at 55°C to 60°C; ii) cooling the mixture of step i) at 20°C to 30°C to obtain crystallization; iii) Add ethanol to the precipitated crystals of step ii), and stir the resulting mixture at 5°C-25°C for 1-2 hours. 6. An antibacterial pharmaceutical composition, comprising Zadofloxacin D-aspartate hydrate according to claim 1 as an active ingredient and a pharmaceutically acceptable excipient. 7. The antibacterial pharmaceutical composition according to claim 6, wherein the hydrate is zadofloxacin D-aspartate sesquihydrate. 8. The antibacterial pharmaceutical composition according to claim 6 or 7, wherein the composition is manufactured in the form of tablets, capsules or injections. 9. The antibacterial pharmaceutical composition according to claim 8, wherein the tablet is prepared from granules produced by direct compression, pressure granulation, or wet granulation.