WO2015133803A1 - 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 hydrates and an antibacterial pharmaceutical compositions comprising their hydrates - Google Patents

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 hydrates and an antibacterial pharmaceutical compositions comprising their hydrates Download PDF

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WO2015133803A1
WO2015133803A1 PCT/KR2015/002065 KR2015002065W WO2015133803A1 WO 2015133803 A1 WO2015133803 A1 WO 2015133803A1 KR 2015002065 W KR2015002065 W KR 2015002065W WO 2015133803 A1 WO2015133803 A1 WO 2015133803A1
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aspartate
zabofloxacin
hydrate
hydrates
tablets
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PCT/KR2015/002065
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French (fr)
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Dong-Rack Choi
Jae-Kyung Lim
Hwan-Bong Chang
Nam-Hyun Baek
Seung-Hwan Kim
Gun-Gook KIM
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Dong Wha Pharm. Co., Ltd.
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Priority to CN201580012053.8A priority Critical patent/CN106103448B/en
Publication of WO2015133803A1 publication Critical patent/WO2015133803A1/en
Priority to SA516371791A priority patent/SA516371791B1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • 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 hydrates and an antibacterial pharmaceutical compositions comprising their hydrates
  • the quinolone carboxylic acid derivatives are synthetic antibiotics that exhibit powerful and broad antibacterial activity and are well known for their usefulness against infectious diseases in humans and animals.
  • antibiotics selected from the quinolone group such as norfloxacin, ofloxacin, or ciprofloxacin, were popularly used to treat human diseases and were recognized for their effectiveness.
  • the European Patent EP 0 994 878 discloses 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 (hereinafter referred to as “zabofloxacin”) as a quinolone antibiotic that eliminated these problems.
  • Zabofloxacin is a new quinolone carboxylic acid antibiotic agent that has outstanding antibacterial activity against not only gram-negative strains, but also gram-positive strains, and is very effective against methicillin-resistant bacteria, on top of being effective against quinolone-resistant strains.
  • the above zabofloxacin aspartate is known to have not only exceptional solubility compared with the generally prepared salts, such as phosphate or hydrochloride, but also outstanding physicochemical properties, such as stability, while having almost no toxicity.
  • the above zabofloxacin aspartate disclosed in the United States Patent No. 8,324,238 has been identified to be an anhydride. Even though the zabofloxacin aspartate anhydride is well known for its outstanding physicochemical properties such as stability, it would absorb moisture if not maintained and stored in the anhydride form, resulting in a drastic fall of its stability. Thus, the formulation of a stable drug not only requires complex processes and air-conditioning equipment, but it also requires strict maintenance of storage conditions. The resolution of these problems has always been necessary.
  • the pores inside the firmly formed tablet structure will expand, thereby increasing the tablet volume and decreasing the hardness which will in the end cause the exterior of the tablet to break easily from external impact.
  • the general indicators of pore expansion caused by absorption of moisture include the percentage of increase in weight, water content, and thickness, as well as the percentage of change in hardness. From these data, the occurrence of pore expansion in the tablet structure due to absorbing moisture can be identified.
  • Preserving the main ingredient content in pharmaceutical products is crucial in ensuring their therapeutic effects, but the absorption of moisture increases the percentage change of the main ingredient content in the end pharmaceutical products.
  • Methods such as direct compression method, pressure granulation method, wet granulation method, and fluid bed granulation method are used to mix the main ingredients and carriers when preparing pharmaceutical products into a fixed form, such as tablet and capsule.
  • a fixed form such as tablet and capsule.
  • bonding solvents such as wet granulation method and fluid bed granulation method
  • the main ingredients will quickly dissolve during mixing, resulting in obtaining granules for formulation improbable.
  • the present inventors were able to solve the problems regarding the reduced stability of the drug and the stability during storage caused by moisture absorption by inventing a drug that does not absorb moisture regardless of storage conditions.
  • the present invention was completed by developing a method of producing tablets with outstanding stability using granulation methods such as direct compression method, pressure granulation method, and wet granulation method that use organic solvents or a mixture of organic solvents and water.
  • the objective of the present invention is to improve the stability of the drug that contains zabofloxacin D-aspartate as the active ingredient and its stability during storage by improving the physicochemical properties of zabofloxacin aspartate, and to improve the stability of the pharmaceutical composition comprising the above active ingredient and a pharmaceutically acceptable carrier thereof
  • the present invention provides zabofloxacin D-aspartate hydrate represented by Formula 2 below.
  • zabofloxacin D-aspartate hydrate is obtained as zabofloxacin D-aspartate ⁇ nH 2 O, wherein n is within values of 1 through 4.
  • Preferred are hydrates, wherein n is 1, 1.5, 2, 2.5, 3, 3.5, or 4, and especially preferred is the hydrate, wherein n is 1.5.
  • the zabofloxacin D-aspartate hydrate of the present invention in particular takes the form of the crystalline zabofloxacin D-aspartate hydrate.
  • the zabofloxacin D-aspartate hydrate can be characterized and distinguished from the anhydride via differential scanning calorimetry (DSC), X-ray powder differential analysis, and infrared spectroscopy.
  • the anhydride of zabofloxacin D-aspartate is characterized by X-ray powder differential analysis patterns comprising 2 ⁇ values of 4.5 and 9.0.
  • the crystalline zabofloxacin D-aspartate sesquihydrate has X-ray powder differential analysis patterns comprising 2 ⁇ values which peak at 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, and the 2 ⁇ values especially show peaks at 4.3 ⁇ 0.2, 8.6 ⁇ 0.2, and 9.8 ⁇ 0.2, as shown in the X-ray powder differential analysis pattern below.
  • the zabofloxacin D-aspartate sesquihydrate is practically in a pure form and is characterized as having KF(Karl Fischer) values of 4.0 ⁇ 5.9% and having peaks on the DSC thermogram at approximately 106.5°C ⁇ 108.5°C and approximately 214°C ⁇ 216°C as shown in Figure 2b.
  • the zabofloxacin D-aspartate trihydrate is characterized as having KF values of 8.5 ⁇ 9.9% and having peaks on the DSC thermogram at approximately 97.0°C ⁇ 99.0°C and approximately 215°C ⁇ 217°C as shown in Figure 2c.
  • the zabofloxacin D-aspartate monohydrate is characterized as having KF values of 3.0 ⁇ 3.9% and having peaks on the DSC thermogram at approximately 109.5°C ⁇ 111.5°C and approximately 214°C ⁇ 216°C as shown in Figure 2a.
  • the zabofloxacin D-aspartate anhydride has KF value less than 0.5% and shows a peak at approximately 214°C ⁇ 216°C on the DSC thermogram as shown in Figure 2d.
  • zabofloxacin D-aspartate anhydride has X-ray powder differential analysis patterns at 4.5 ⁇ 0.2, 9.0 ⁇ 0.2, 12.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.3 ⁇ 0.2, 17.8 ⁇ 0.2, 19.2 ⁇ 0.2, 22.7 ⁇ 0.2, and 32.5 ⁇ 0.2.
  • the method of preparation of zabofloxacin D-aspartate hydrate according to the present invention is shown in the examples below.
  • the zabofloxacin D-aspartate hydrate according to the present invention can be prepared by drying the zabofloxacin D-aspartate at 20°C ⁇ 30°C after synthesis.
  • For the zabofloxacin D-aspartate sesquihydrate at a relative humidity(RH) between 30% to 90%, neither adsorption nor desorption of water occurs, and it remains constantly in the form of stable zabofloxacin D-aspartate sesquihydrate.
  • the zabofloxacin D-aspartate sesquihydrate according to present invention when the zabofloxacin D-aspartate sesquihydrate according to present invention was stored under the conditions of temperature at 25 ⁇ 2°C and RH at 80 ⁇ 5% for 24 hours, the water content and the related substances remained constant. Upon testing the stability for long term storage of up to 24 months at normal conditions (25 ⁇ 2°C/60 ⁇ 5% RH), the water content, moisture, and purity remained constant.
  • compositions comprising the zabofloxacin 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, while the preferred route of administration is oral adminstration. Moreover, the formulation of the drug is done via the commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surface active agents.
  • Solid dosage forms for oral administration include tablets, granules, capsules, etc, and these solid formulations can be prepared by mixing one or more excipients, for example, microcrystalline cellulose, low substituted hydroxypropylcellulose, colloidal silicon dioxide, calcium silicate, starch, calcium carbonate, sucrose or lactose, or gelatin; besides these simple excipients, lubricants such as magnesium stearate and talc can also be utilized.
  • excipients for example, microcrystalline cellulose, low substituted hydroxypropylcellulose, colloidal silicon dioxide, calcium silicate, starch, calcium carbonate, sucrose or lactose, or gelatin; besides these simple excipients, lubricants such as magnesium stearate and talc can also be utilized.
  • lubricants such as magnesium stearate and talc can also be utilized.
  • sterilized aqueous solutions non-aqueous solvents, suspensions, and emulsions are used.
  • the administering dose of the zabofloxacin D-aspartate hydrate according to the present invention varies with respect to the patientweight, age, gender, health, diet, adminstration time, route of adminstration, excretion, and severity of the disease.
  • the dosage can be between 1 mg/kg and 50 mg/kg; preferred dosage is between 4 mg/kg and 14 mg/kg; and especially preferred is between 4 mg/kg and 9 mg/kg, either administered once a day, or several times a day in division.
  • the present invention provides stable hydrates of zabofloxacin D-aspartate, wherein adsorption and desorption of water almost do not occur, and this invention specifically provides zabofloxacin D-aspartate sesquihydrate.
  • Zabofloxacin D-aspartate hydrates of the present invention have an outstanding physicochemical property because they barely absorb water.
  • the drugs comprising zabofloxacin D-aspartate hydrate of the present invention do not easily break especially in its tablet form, and the content of the main ingredient changes little, exhibiting an excellent pharmaceutical stability.
  • Figure 1b represents the powder x-ray diffraction pattern of zabofloxacin D-aspartate anhydride.
  • Figure 2d represents the differential scanning calorimetry thermogram of the zabofloxacin D-aspartate anhydride.
  • Figure 3b represents the infrared spectroscopy spectrum of the zabofloxacin D-aspartate anhydride.
  • Figure 4a represents the percentage of change in content over time at 33% relative humidity of the tablet formed with zabofloxacin D-aspartate anhydride and sesquihydrate.
  • Figure 4b represents the percentage of change in content over time at 54% relative humidity of the tablet formed with zabofloxacin D-aspartate anhydride and sesquihydrate.
  • Figure 4c represents the percentage of change in content over time at 75% relative humidity of the tablet formed with zabofloxacin D-aspartate anhydride and sesquihydrate.
  • Powder x-ray diffraction angles (2 ⁇ ) of zabofloxacin D-aspartate sesquihydrate of the present invention are around 4.3, 8.6, 9.8, 12.9, 14.8, 19.9, 20.8, 23.8, 24.7 and 29.0 as shown in Figure 1a.
  • Heat characteristics of zabofloxacin D-aspartate hydrates of the present invention prepared in Examples 1 through 3 above and zabofloxacin D-aspartate anhydride prepared according to Comparative Example 1 were analyzed using TA Instrument DSC Q100, placing the samples on a sealed aluminum plate. An empty aluminum plate was used as a blank. The samples were heated to a temperature range of 25°C to 300°C with a heating rate of 5°C/min. The instrument was calibrated with indium and the differential scanning calorimetry was characterized, and the data are represented in Figures 2a to 2d respectively.
  • the zabofloxacin D-aspartate anhydride has a characteristic differential scanning calorimetry thermogram which has peaks at approximately 214°C to 216°C as shown in Figure 2d.
  • Karl Fischer titration was conducted using Karl Fischer titrator, by adding 200mg of each of zabofloxacin D-aspartate hydrates prepared according to Examples 1 through 3 of the present invention and zabofloxacin D-aspartate anhydride prepared according to Comparative Example 1 into a respective mixture of formamide and methanol(40:60).
  • zabofloxacin D-aspartate monohydrate of the present invention has a characteristic Karl Fischer (KF) value of 3.0 ⁇ 3.9%; the 1.5 hydrate has a KF value of 4.0 ⁇ 5.9%; the trihydrate has a characteristic KF value of 8.5 ⁇ 9.9%.
  • KF Karl Fischer
  • the zabofloxacin D-aspartate anhydride had a KF value below 0.5%.
  • Zabofloxacin D-aspartate sesquihydrate of the present invention prepared according to Example 2 were used to prepare tablets by various granulation methods.
  • Example 4 Preparation of tablets of zabofloxacin D-aspartate sesquihydrate (Example 2) by wet granulation
  • tablets with hardness of 18 to 22KP were prepared by molding with single punch tablet press machine(Model: AR-402, Germany).
  • Example 5 Preparation of tablets of zabofloxacin D-aspartate sesquihydrate (Example 2) by compression granulation
  • tablets with hardness of 18 to 22KP were prepared by molding with single punch tablet press machine(Model: AR-402, Germany).
  • tablets with hardness of 18 to 22KP were prepared by molding with single punch tablet press machine(Model: AR-402, Germany).
  • the present inventor(s) stored the tablets of Example 4 (zabofloxacin D-aspartate sesquihydrate prepared according to Example 2) of the present invention and the tablets of Comparative Example 2 (zabofloxacin D-aspartate anhydride prepared according to Comparative Example 1) for 10 days at 33%, 54%, and 75% relative humidity and observed their percentage of increase in weight, water content, and thickness and percentage of change in hardness.
  • Example 4 The tablets of Example 4 and the tablets of Comparative Example 2 were stored for 10 days at 33%, 54%, and 75% relative humidity (temperature 25°C), and the average weight of each sample was measured with an electronic scale (AE 260 DeltaRangeR, Mettler Instrument AG, Switzerland). The result is shown in Table 2.
  • Example 4 (tablets comprising zabofloxacin D-aspartate sesquihydrate) according to the present invention stored at 33%, 54%, and 75% relative humidity for 10 days increased in weight by 101.5%, 102.3%, and 103.6% respectively, while Comparative Example 2 (tablets comprising zabofloxacin D-aspartate anhydride manufactured according to Comparative Example 1) increased in weight by 105.5%, 105.4%, and 106.9% respectively.
  • Example 4 The tablets of Example 4 and the tablets of Comparative Example 2 were stored for 10 days at 33%, 54%, and 75% relative humidity (temperature 25°C), and the water content of each sample was measured under the condition of 105°C (0.01%/min content) with an infrared moisture analyzer (Unit: %, Model: AND MX-50, A&D Company, Ltd.). The result is shown in Table 3.
  • Example 4 (tablets comprising zabofloxacin D-aspartate sesquihydrate) according to the present invention stored at 33%, 54%, and 75% relative humidity for 10 days increased in water content by 148.4%, 162.3%, and 176.0% respectively, while Comparative Example 2 (tablets comprising zabofloxacin D-aspartate anhydride) increased in water content by 715.7%, 741.6%, and 807.9% respectively.
  • Example 4 The tablets of Example 4 and the tablets of Comparative Example 2 were stored for 10 days in at 33%, 54%, and 75% relative humidity (temperature 25°C), and each sample was measured with a hardness meter (Unit Kp, Model: 5Y, DR. Schleuniger). The result is shown in Table 4.
  • Example 4 (tablets comprising zabofloxacin D-aspartate sesquihydrate) according to the present invention stored at 33%, 54%, and 75% relative humidity for 10 days decreased in hardness by -19.5%, -36.8%, -56.2% respectively, while Comparative Example 2 (tablets comprising zabofloxacin D-aspartate anhydride) decreased in hardness by -43.6%, -56.3%, -73.1% respectively.
  • Example 4 The tablets of Example 4 and the tablets of Comparative Example 2 were stored for 10 days at 33%, 54%, and 75% relative humidity (temperature 25°C), and each sample was measured with a thickness gauge (Unit mm, Model: ID-c112, Mitutoyo). The result is shown in Table 5.
  • Example 4 (tablets comprising zabofloxacin D-aspartate sesquihydrate) according to the present invention stored in at 33%, 54%, and 75% relative humidity for 10 days increased in thickness by 102.2%, 103.8%, 105.7% respectively, while Comparative Example 2 (tablets comprising zabofloxacin D-aspartate anhydride prepared according to Comparative Example 1) increased in thickness by 105.6%, 106.9%, 109.2% respectively.
  • Example 4 The tablets of Example 4 and the tablets of Comparative Example 2 were stored for 10 days at 33%, 54%, and 75% relative humidity (temperature 25°C), and each sample was measured with a high performance liquid chromatography HPLC (Column C18, UV Absorption spectrophotometer 275nm, injected quantity 20uL, Model: HPLC 5973, waters). The result is shown in Figures 4a through 4c respectively for each relative humidity condition and in Table 6.
  • Example 4 (tablets comprising zabofloxacin D-aspartate sesquihydrate) according to the present invention stored at 33%, 54%, and 75% relative humidity for 10 days decreased in content from the initial 97.1% to 96.23% (-0.87%), 93.72% (-3.38%), and 94.92% (-2.18%) respectively, while Comparative Example 2 (tablets comprising zabofloxacin D-aspartate anhydride) decreased in content in greater magnitude from the initial 97.8% to 93.90% (-4.75%), 93.09% (-4.71%), 91.34% (-6.46%) respectively.
  • the tablets comprising zabofloxacin D-aspartate sesquihydrate according to the present invention increased more in weight, water content, and thickness, and decreased quicker in hardness.
  • the tablets comprising zabofloxacin D-aspartate anhydride increased quicker in weight, water content, and thickness, it can be known that the latter tablets' structural pore expansion progresses rapidly; due to the said volume expansion and decrease in hardness caused by the pore expansion, the tablets' exterior can be broken by a weak external impact.
  • the easy breaking of the tablets' exterior, decrease in hardness makes mechanical packing process following commercial production of the said tablets very difficult, and the tablets also break easily during subsequent processes such as transportation, eventually resulting in the patients being unable to take the tablet.
  • the tablets comprising the anhydride showed a bigger change in content, and a lower content in comparison with the tablets comprising the hydrates. Since the content of the main ingredient in the drug product is the main indicator that guarantees therapeutic effect, the above result shows that in comparison with the tablets comprising the hydrates, the tablets comprising the anhydride are not as preferable.
  • the present invention provides very stable zabofloxacin D-aspartate hydrates wherein adsorption and desorption of water hardly occur.
  • the drugs comprising zabofloxacin D-aspartate hydrates of the present invention exhibit excellent pharmaceutical stability, for it does not easily break, especially in its tablet form, and for it changes little in its content of the main ingredient.

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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 hydrates and an antibacterial composition comprising their hydrates. The present invention provides stable zabofloxacin D-aspartate hydrates wherein adsorption and desorption of water hardly occur, and provides specifically zabofloxacin D-aspartate sesquihydrate. Because the zabofloxacin D-aspartate hydrates according to the present invention hardly absorb moisture, they have an outstanding physicochemical property. Therefore, the drugs comprising zabofloxacin D-aspartate hydrate of the present invention do not easily break, especially in its tablet form, and changes little in the content of the main ingredient, thus exhibiting an excellent pharmaceutical stability.

Description

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 HYDRATES AND AN ANTIBACTERIAL PHARMACEUTICAL COMPOSITIONS COMPRISING THEIR HYDRATES
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 hydrates and an antibacterial pharmaceutical compositions comprising their hydrates
The quinolone carboxylic acid derivatives are synthetic antibiotics that exhibit powerful and broad antibacterial activity and are well known for their usefulness against infectious diseases in humans and animals.
In the past, the antibiotics selected from the quinolone group, such as norfloxacin, ofloxacin, or ciprofloxacin, were popularly used to treat human diseases and were recognized for their effectiveness.
These drugs show outstanding antibacterial activity against gram-negative strains, but show mediocre to somewhat low antibacterial activity against gram-positive strains. Various researches were conducted in order to eliminate the problems the existing quinolone antibiotics had; the most notable drug developed was sparfloxacin, which showed a superior antibacterial activity against gram-positive strains. However, even sparfloxacin showed weak antibacterial activity against streptococci, methicillin-resistant Staphylococcus aureus(MRSA), and the gradually spreading quinolone-resistant strains, all of which are well-known to cause respiratory infections.
The European Patent EP 0 994 878 discloses 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 (hereinafter referred to as “zabofloxacin”) as a quinolone antibiotic that eliminated these problems.
Zabofloxacin is a new quinolone carboxylic acid antibiotic agent that has outstanding antibacterial activity against not only gram-negative strains, but also gram-positive strains, and is very effective against methicillin-resistant bacteria, on top of being effective against quinolone-resistant strains.
However, the problem with zabofloxacin was that it had very low solubility. It is well known to a person skilled in the art that the preparation of a drug is easier when the active ingredient in the pharmaceutical composition has high solubility in either water or aqueous solution of a broad pH range. Therefore, in order to increase the bioavailability of the above zabofloxacin, it was necessary to improve the physicochemical properties of the drug to develop a salt with higher solubility.
The United States Patent No. 8,324,238 discloses the zabofloxacin aspartate represented by Formula 1 below.
<Formula 1>
Figure PCTKR2015002065-appb-I000001
The above zabofloxacin aspartate is known to have not only exceptional solubility compared with the generally prepared salts, such as phosphate or hydrochloride, but also outstanding physicochemical properties, such as stability, while having almost no toxicity.
The above zabofloxacin aspartate disclosed in the United States Patent No. 8,324,238 has been identified to be an anhydride. Even though the zabofloxacin aspartate anhydride is well known for its outstanding physicochemical properties such as stability, it would absorb moisture if not maintained and stored in the anhydride form, resulting in a drastic fall of its stability. Thus, the formulation of a stable drug not only requires complex processes and air-conditioning equipment, but it also requires strict maintenance of storage conditions. The resolution of these problems has always been necessary.
Once the drug absorbs moisture during storage, the pores inside the firmly formed tablet structure will expand, thereby increasing the tablet volume and decreasing the hardness which will in the end cause the exterior of the tablet to break easily from external impact. The general indicators of pore expansion caused by absorption of moisture include the percentage of increase in weight, water content, and thickness, as well as the percentage of change in hardness. From these data, the occurrence of pore expansion in the tablet structure due to absorbing moisture can be identified.
The easy breaking of the tablet exterior, or in other words the decrease in the tablet hardness, makes the mechanical tablet packing process following the commercial production of the tablets very difficult; the tablets also break easily during subsequent processes such as transportation, eventually resulting in the patients being unable to take the tablet.
Preserving the main ingredient content in pharmaceutical products is crucial in ensuring their therapeutic effects, but the absorption of moisture increases the percentage change of the main ingredient content in the end pharmaceutical products.
Methods such as direct compression method, pressure granulation method, wet granulation method, and fluid bed granulation method are used to mix the main ingredients and carriers when preparing pharmaceutical products into a fixed form, such as tablet and capsule. Particularly for methods that use bonding solvents, such as wet granulation method and fluid bed granulation method, if only water is used as the bonding solvent, the main ingredients will quickly dissolve during mixing, resulting in obtaining granules for formulation improbable.
After conducting many researches to improve the physicochemical properties of the zabofloxacin D-aspartate and to increase its stability against moisture, the present inventors were able to solve the problems regarding the reduced stability of the drug and the stability during storage caused by moisture absorption by inventing a drug that does not absorb moisture regardless of storage conditions. The present invention was completed by developing a method of producing tablets with outstanding stability using granulation methods such as direct compression method, pressure granulation method, and wet granulation method that use organic solvents or a mixture of organic solvents and water.
The objective of the present invention is to improve the stability of the drug that contains zabofloxacin D-aspartate as the active ingredient and its stability during storage by improving the physicochemical properties of zabofloxacin aspartate, and to improve the stability of the pharmaceutical composition comprising the above active ingredient and a pharmaceutically acceptable carrier thereof
To accomplish the objective described above, the present invention provides zabofloxacin D-aspartate hydrate represented by Formula 2 below.
<Formula 2>
Figure PCTKR2015002065-appb-I000002
In the present invention, zabofloxacin D-aspartate hydrate is obtained as zabofloxacin D-aspartate·nH2O, wherein n is within values of 1 through 4. Preferred are hydrates, wherein n is 1, 1.5, 2, 2.5, 3, 3.5, or 4, and especially preferred is the hydrate, wherein n is 1.5.
Since the molecular weight of zabofloxacin D-aspartate is 534.49, the theoretical water content is 3.3%(w/w) for the hydrate, wherein n is 1; 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. Even though the actual average water content of zabofloxacin D-aspartate hydrate is close to the above theoretical values, differences amongst individual batches can occur from the differences in recrystallization conditions or drying conditions during the manufacturing process.
As for zabofloxacin D-aspartate hydrate of the present invention, the range of water content for each water of crystallization is shown in Table 1 below.
Table 1
Figure PCTKR2015002065-appb-T000001
The zabofloxacin D-aspartate hydrate of the present invention in particular takes the form of the crystalline zabofloxacin D-aspartate hydrate. The zabofloxacin D-aspartate hydrate can be characterized and distinguished from the anhydride via differential scanning calorimetry (DSC), X-ray powder differential analysis, and infrared spectroscopy.
The anhydride of zabofloxacin D-aspartate is characterized by X-ray powder differential analysis patterns comprising 2θ values of 4.5 and 9.0. The crystalline zabofloxacin D-aspartate sesquihydrate has X-ray powder differential analysis patterns comprising 2θ values which peak at 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, and the 2θ values especially show peaks at 4.3±0.2, 8.6±0.2, and 9.8±0.2, as shown in the X-ray powder differential analysis pattern below.
Figure PCTKR2015002065-appb-I000003
Moreover, in a preferred embodiment, the zabofloxacin D-aspartate sesquihydrate is practically in a pure form and is characterized as having KF(Karl Fischer) values of 4.0~5.9% and having peaks on the DSC thermogram at approximately 106.5℃~108.5℃ and approximately 214℃~216℃ as shown in Figure 2b.
In another embodiment, the zabofloxacin D-aspartate trihydrate is characterized as having KF values of 8.5~9.9% and having peaks on the DSC thermogram at approximately 97.0℃~99.0℃ and approximately 215℃~217℃ as shown in Figure 2c.
In yet another embodiment, the zabofloxacin D-aspartate monohydrate is characterized as having KF values of 3.0~3.9% and having peaks on the DSC thermogram at approximately 109.5℃~111.5℃ and approximately 214℃~216℃ as shown in Figure 2a.
On the other hand, the zabofloxacin D-aspartate anhydride has KF value less than 0.5% and shows a peak at approximately 214℃~216℃ on the DSC thermogram as shown in Figure 2d.
Additionally, zabofloxacin D-aspartate anhydride has X-ray powder differential analysis patterns at 4.5±0.2, 9.0±0.2, 12.9±0.2, 14.4±0.2, 15.3±0.2, 17.8±0.2, 19.2±0.2, 22.7±0.2, and 32.5±0.2.
The method of preparation of zabofloxacin D-aspartate hydrate according to the present invention is shown in the examples below. The zabofloxacin D-aspartate hydrate according to the present invention can be prepared by drying the zabofloxacin D-aspartate at 20℃~30℃ after synthesis. For the zabofloxacin D-aspartate sesquihydrate, at a relative humidity(RH) between 30% to 90%, neither adsorption nor desorption of water occurs, and it remains constantly in the form of stable zabofloxacin D-aspartate sesquihydrate. In one example, when the zabofloxacin D-aspartate sesquihydrate according to present invention was stored under the conditions of temperature at 25±2℃ and RH at 80±5% for 24 hours, the water content and the related substances remained constant. Upon testing the stability for long term storage of up to 24 months at normal conditions (25±2℃/60±5% RH), the water content, moisture, and purity remained constant.
Also, the present invention provides pharmaceutical compositions comprising the zabofloxacin 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, while the preferred route of administration is oral adminstration. Moreover, the formulation of the drug is done via the commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surface active agents.
Solid dosage forms for oral administration include tablets, granules, capsules, etc, and these solid formulations can be prepared by mixing one or more excipients, for example, microcrystalline cellulose, low substituted hydroxypropylcellulose, colloidal silicon dioxide, calcium silicate, starch, calcium carbonate, sucrose or lactose, or gelatin; besides these simple excipients, lubricants such as magnesium stearate and talc can also be utilized. For the preparation of a drug for parenteral administration, sterilized aqueous solutions, non-aqueous solvents, suspensions, and emulsions are used. For non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, and vegetable oil such as olive oil, or injectable esters such as ethyl oleate can be used.
Furthermore, the administering dose of the zabofloxacin D-aspartate hydrate according to the present invention varies with respect to the patientweight, age, gender, health, diet, adminstration time, route of adminstration, excretion, and severity of the disease. For adults, the dosage can be between 1 mg/kg and 50 mg/kg; preferred dosage is between 4 mg/kg and 14 mg/kg; and especially preferred is between 4 mg/kg and 9 mg/kg, either administered once a day, or several times a day in division.
The present invention provides stable hydrates of zabofloxacin D-aspartate, wherein adsorption and desorption of water almost do not occur, and this invention specifically provides zabofloxacin D-aspartate sesquihydrate. Zabofloxacin D-aspartate hydrates of the present invention have an outstanding physicochemical property because they barely absorb water.
Therefore, the drugs comprising zabofloxacin D-aspartate hydrate of the present invention do not easily break especially in its tablet form, and the content of the main ingredient changes little, exhibiting an excellent pharmaceutical stability.
Figure 1a represents the powder x-ray diffraction (XRD) pattern of zabofloxacin D-aspartate n=1.5 hydrate.
Figure 1b represents the powder x-ray diffraction pattern of zabofloxacin D-aspartate anhydride.
Figure 2a represents the differential scanning calorimetry (DSC) thermogram of zabofloxacin D-aspartate n=1 hydrate.
Figure 2b represents the differential scanning calorimetry thermogram of zabofloxacin D-aspartate n=1.5 hydrate.
Figure 2c represents the differential scanning calorimetry thermogram of zabofloxacin D-aspartate n=3 hydrate.
Figure 2d represents the differential scanning calorimetry thermogram of the zabofloxacin D-aspartate anhydride.
Figure 3a represents the infrared (IR) spectroscopy spectrum of zabofloxacin D-aspartate n=1.5 hydrate.
Figure 3b represents the infrared spectroscopy spectrum of the zabofloxacin D-aspartate anhydride.
Figure 4a represents the percentage of change in content over time at 33% relative humidity of the tablet formed with zabofloxacin D-aspartate anhydride and sesquihydrate.
Figure 4b represents the percentage of change in content over time at 54% relative humidity of the tablet formed with zabofloxacin D-aspartate anhydride and sesquihydrate.
Figure 4c represents the percentage of change in content over time at 75% relative humidity of the tablet formed with zabofloxacin D-aspartate anhydride and sesquihydrate.
The preparation method of the present invention as mentioned above will be described more specifically by the Examples below, but the scope of the present invention is not limited at all by the Examples.
<Example 1> Preparation of 1-cyclopropyl-6-fluoro-7-[(8Z)-8 -(methoxyimino-2,6-diaza-spiro[3,4]oct-6-yl)]-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid D-aspartate n=1 hydrate
85g of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza- spiro[3,4]oct-6-yl)-4-oxo1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid and 32.4g of D-aspartic acid were added into 406ml of anhydrous ethanol and 595ml of purified water and were slowly heated to 55~58℃, at which the mixture was stirred for 30 minutes. Then, 3.8g of activated carbon was added into the reaction mixture and after stirring for 30 minutes at 55~58℃, the hot mixture was filtered and then cooled to 20~30℃. 406ml of anhydrous ethanol was added into the precipitated reaction mixture and stirred for 2 hours at 10~20℃, then the precipitate was filtered and washed. After the addition of the wet precipitate into a liquid mixture of 680ml of ethylacetate, 43ml of ethanol and 17ml of purified water, it was stirred for more than 5 hours at 50~60℃. After stirring the reactant for 2 hours at 20~30℃, it was filtered and dried, and 97.5g of the title compound was obtained(KF=3.4%).
<Example 2> Preparation of 1-cyclopropyl-6-fluoro-7-[(8Z)-8 -(methoxyimino-2,6-diaza-spiro[3,4]oct-6-yl)]-4-oxo-1,4-dihydro-[1,8] naphthyridine-3-carboxylic acid D-aspartate n=1.5 hydrate
85g of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza- spiro[3,4]oct-6-yl)-4-oxo1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid and 32.4g of D-aspartic acid were added into 406ml of anhydrous ethanol and 595ml of purified water and were slowly heated to 55~60℃ at which the mixture was stirred for 30 minutes. 3.8g of activated carbon was then added into the reaction mixture and after stirring for 30 minutes at 55~60℃, the hot mixture was filtered and then cooled to 20~30℃. After adding 406ml of anhydrous ethanol into the precipitated reaction mixture and stirring for 1~2 hours at 5~25℃, it was filtered and washed (with anhydrous ethanol), which was then dried to obtain 101.1g of the title compound (KF=4.9%).
Melting point: 209.1℃ (DSC)
1H-NMR(DMSO-d6, 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> Preparation of 1-cyclopropyl-6-fluoro-7-[(8Z)-8 -(methoxyimino-2,6-diaza-spiro[3,4]oct-6-yl)]-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid D-aspartate n=3 hydrate
85g of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza- spiro[3,4]oct-6-yl)-4-oxo1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid and 32.4g of D-aspartic acid were added into 406ml of anhydrous ethanol and 595ml of purified water and were slowly heated to 55~58℃ at which the mixture was stirred for 30 minutes. 3.8g of activated carbon was added into the reaction mixture and after stirring for 30 minutes at 55~58℃, the hot mixture was filtered and then cooled to 20~30℃. After adding 406ml of anhydrous ethanol into the precipitated reaction mixture and stirring for 5 hours at 20~30℃, it was filtered, washed (with anhydrous ethanol) and dried, and 103.5g of the title compound was obtained(KF=9.4%).
<Comparative Example 1> Preparation of 1-cyclopropyl-6-
fluoro-7-[(8Z)-8-(methoxyimino-2,6-diaza-spiro[3,4]oct-6-yl)]-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid D-aspartate anhydride
85g of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-
spiro[3,4]oct-6-yl)-4-oxo1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid and 32.4g of D-aspartic acid were added into 406ml of anhydrous ethanol and 595ml of purified water and were slowly heated to 55~58℃ at which the mixture was stirred for 30 minutes. 3.8g of activated carbon was added into the reaction mixture and after stirring for 30 minutes at 55~58℃, the hot mixture was filtered and then cooled to 20~30℃. After adding 406ml of anhydrous ethanol into the precipitated reaction mixture and stirring for 2 hours at 20~30℃, it was filtered and washed. After adding the wet precipitate into 850ml of acetone and stirring it for over 14 hours at 20~40℃, it was filtered and dried, and 96.4g of title compound was obtained(KF=0.2%).
Melting point(m.p): 206.2℃ (DSC)
1H-NMR(DMSO-d6, 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 measurements
An XRD study was conducted on the zabofloxacin D-aspartate sesquihydrate prepared according to Example 2 above and on zabofloxacin D-aspartate anhydride prepared according to Comparative Example 1. The X-ray powder diffraction data of zabofloxacin D-aspartate were obtained by using Bruker D8-Focus powder diffractometer, and Copper Kα(40 kV, 40 mA) was used as a source of radiation. Data were obtained for the 2θ range of 2°to 40°at room temperature, with a step width of 0.02°and 16 seconds per step.
Powder x-ray diffraction angles (2θ) of zabofloxacin D-aspartate sesquihydrate of the present invention are around 4.3, 8.6, 9.8, 12.9, 14.8, 19.9, 20.8, 23.8, 24.7 and 29.0 as shown in Figure 1a.
In comparison, the zabofloxacin D-aspartate anhydride showed powder x-ray diffraction angles (2θ) that peak around 4.5, 9.0, 12.9, 14.4, 15.3, 17.8, 19.2, 22.7 and 32.5 as shown in Figure 1b.
<Experiment 2> Differential Scanning calorimetry
Heat characteristics of zabofloxacin D-aspartate hydrates of the present invention prepared in Examples 1 through 3 above and zabofloxacin D-aspartate anhydride prepared according to Comparative Example 1 were analyzed using TA Instrument DSC Q100, placing the samples on a sealed aluminum plate. An empty aluminum plate was used as a blank. The samples were heated to a temperature range of 25℃ to 300℃ with a heating rate of 5℃/min. The instrument was calibrated with indium and the differential scanning calorimetry was characterized, and the data are represented in Figures 2a to 2d respectively.
As shown in Figure 2a, zabofloxacin D-aspartate n=1 hydrate has a characteristic differential scanning calorimetry thermogram which has peaks at approximately 109.5℃ to 111.5℃ and approximately 214℃ to 216℃. As shown in Figure 2b, zabofloxacin D-aspartate n=1.5 hydrate has a characteristic differential scanning calorimetry thermogram which has peaks at approximately 106.5℃ to 108.5℃ and approximately 214℃ to 216℃. As shown in Figure 2c, zabofloxacin D-aspartate n=3 hydrate has a characteristic differential scanning calorimetry thermogram which has peaks at approximately 97.0℃ to 99.0℃ and approximately 215℃ to 217℃.
In comparison, the zabofloxacin D-aspartate anhydride has a characteristic differential scanning calorimetry thermogram which has peaks at approximately 214℃ to 216℃ as shown in Figure 2d.
<Experiment 3> Infrared spectroscopy
Infrared spectroscopy was conducted on zabofloxacin D-aspartate sesquihydrate according to Example 2 of the present invention and zabofloxacin D-aspartate anhydride prepared according to Comparative Example 1 using Thermo SCIENTIFIC NICOLET 6700 with ATR technique and the resulting spectra have been represented in Figures 3a and 3b, respectively.
<Experiment 4> Karl Fischer titration
Karl Fischer titration was conducted using Karl Fischer titrator, by adding 200mg of each of zabofloxacin D-aspartate hydrates prepared according to Examples 1 through 3 of the present invention and zabofloxacin D-aspartate anhydride prepared according to Comparative Example 1 into a respective mixture of formamide and methanol(40:60).
The results show that zabofloxacin D-aspartate monohydrate of the present invention has a characteristic Karl Fischer (KF) value of 3.0~3.9%; the 1.5 hydrate has a KF value of 4.0~5.9%; the trihydrate has a characteristic KF value of 8.5~9.9%. The zabofloxacin D-aspartate anhydride had a KF value below 0.5%.
Zabofloxacin D-aspartate sesquihydrate of the present invention prepared according to Example 2 were used to prepare tablets by various granulation methods.
<Example 4> Preparation of tablets of zabofloxacin D-aspartate sesquihydrate (Example 2) by wet granulation
After mixing 70%(w/w) of zabofloxacin D-aspartate sesquihydrate prepared according to Example 2, 11%(w/w) of microcrystalline cellulose, and 1.3%(w/w) of crospovidone using a high speed mixer(Model: FUKEA POTEC, Japan), a liquid mixture of 23%(w/w) of anhydrous ethanol and 2.3%(w/w) of hydroxypropyl cellulose were added, and the mixture was combined. After discharge of the mixture and drying at a temperature below 55℃ with a fanned drying oven(Model: OF-22GW, Korea), granules of good flowability were obtained. After mixing 11%(w/w) of microcrystalline cellulose, 3.4%(w/w) of crospovidone and 1%(w/w) of sodium stearyl fumarate with the granules, tablets with hardness of 18 to 22KP were prepared by molding with single punch tablet press machine(Model: AR-402, Germany).
<Example 5> Preparation of tablets of zabofloxacin D-aspartate sesquihydrate (Example 2) by compression granulation
70%(w/w) of zabofloxacin D-aspartate sesquihydrate prepared according to Example 2, 11%(w/w) of microcrystalline cellulose, 1.3%(w/w) of crospovidone and 2.3%(w/w) of hydroxypropyl methylcellulose were mixed using a high speed mixer(Model: FUKEA POTEC, Japan). The granules from the resulting mixture were extruded to form granules. After mixing the granules with 11%(w/w) of microcrystalline cellulose, 3.4%(w/w) of crospovidone and 1%(w/w) of sodium stearyl fumarate, tablets with hardness of 18 to 22KP were prepared by molding with single punch tablet press machine(Model: AR-402, Germany).
<Example 6> Preparation of injections of zabofloxacin D-aspartate sesquihydrate (Example 2)
After dissolving 70%(w/w) of zabofloxacin D-aspartate sesquihydrate prepared according to Example 2, 29.5%(w/w) of lactic acid, and 0.5%(w/w) of sodium bisulfite into purified water for injection, the pH of the solution was adjusted to 3.5~4.5 with 1N-sodium hydroxide and then filtered. Dry powder injections were prepared by drying the injections filled in freeze dry vials according to freeze dry method using a freeze dryer (Model: FD5510, Korea).
<Comparative Example 2> Preparation of tablets of the zabofloxacin D-aspartate anhydride (Comparative Example 1) by wet granulation
After mixing 70%(w/w) of zabofloxacin D-aspartate anhydride prepared according to Comparative Example 1, 11%(w/w) of microcrystalline cellulose, and 1.3%(w/w) of crospovidone using a high speed mixer(Model: FUKEA POTEC, Japan), a liquid mixture of 23%(w/w) of anhydrous ethanol and 2.3%(w/w) of hydroxypropyl methylcellulose were added. The mixture was combined. Granules were obtained after emission of the mixture by drying at a temperature below 55℃ with a fanned drying oven(Model: OF-22GW, Korea). After mixing 11%(w/w) of microcrystalline cellulose, 3.4%(w/w) of crospovidone and 1%(w/w) of sodium stearyl fumarate with the granules, tablets with hardness of 18 to 22KP were prepared by molding with single punch tablet press machine(Model: AR-402, Germany).
<Experiment 5> Measuring moisture absorbing property
When pharmaceutical products in storage absorb moisture, the expansion of the pores inside firmly formed tablets can be observed. The general indicators of pore expansion caused by moisture absorption include percentage of increase in weight, water content, and thickness, as well as the percentage of change in hardness. From these data, the occurrence of pore expansion in the tablet structure due to absorbing moisture can be identified.
Thus, the present inventor(s) stored the tablets of Example 4 (zabofloxacin D-aspartate sesquihydrate prepared according to Example 2) of the present invention and the tablets of Comparative Example 2 (zabofloxacin D-aspartate anhydride prepared according to Comparative Example 1) for 10 days at 33%, 54%, and 75% relative humidity and observed their percentage of increase in weight, water content, and thickness and percentage of change in hardness.
1) Percentage of increase in weight
The tablets of Example 4 and the tablets of Comparative Example 2 were stored for 10 days at 33%, 54%, and 75% relative humidity (temperature 25℃), and the average weight of each sample was measured with an electronic scale (AE 260 DeltaRangeR, Mettler Instrument AG, Switzerland). The result is shown in Table 2.
Example 4 (tablets comprising zabofloxacin D-aspartate sesquihydrate) according to the present invention stored at 33%, 54%, and 75% relative humidity for 10 days increased in weight by 101.5%, 102.3%, and 103.6% respectively, while Comparative Example 2 (tablets comprising zabofloxacin D-aspartate anhydride manufactured according to Comparative Example 1) increased in weight by 105.5%, 105.4%, and 106.9% respectively.
Table 2
Figure PCTKR2015002065-appb-T000002
2) Percentage of increase in water content
The tablets of Example 4 and the tablets of Comparative Example 2 were stored for 10 days at 33%, 54%, and 75% relative humidity (temperature 25℃), and the water content of each sample was measured under the condition of 105℃ (0.01%/min content) with an infrared moisture analyzer (Unit: %, Model: AND MX-50, A&D Company, Ltd.). The result is shown in Table 3.
Example 4 (tablets comprising zabofloxacin D-aspartate sesquihydrate) according to the present invention stored at 33%, 54%, and 75% relative humidity for 10 days increased in water content by 148.4%, 162.3%, and 176.0% respectively, while Comparative Example 2 (tablets comprising zabofloxacin D-aspartate anhydride) increased in water content by 715.7%, 741.6%, and 807.9% respectively.
Table 3
Figure PCTKR2015002065-appb-T000003
3) Percentage of change in hardness
The tablets of Example 4 and the tablets of Comparative Example 2 were stored for 10 days in at 33%, 54%, and 75% relative humidity (temperature 25℃), and each sample was measured with a hardness meter (Unit Kp, Model: 5Y, DR. Schleuniger). The result is shown in Table 4.
Example 4 (tablets comprising zabofloxacin D-aspartate sesquihydrate) according to the present invention stored at 33%, 54%, and 75% relative humidity for 10 days decreased in hardness by -19.5%, -36.8%, -56.2% respectively, while Comparative Example 2 (tablets comprising zabofloxacin D-aspartate anhydride) decreased in hardness by -43.6%, -56.3%, -73.1% respectively.
Table 4
Figure PCTKR2015002065-appb-T000004
4) Percentage of increase in thickness
The tablets of Example 4 and the tablets of Comparative Example 2 were stored for 10 days at 33%, 54%, and 75% relative humidity (temperature 25℃), and each sample was measured with a thickness gauge (Unit mm, Model: ID-c112, Mitutoyo). The result is shown in Table 5.
Example 4 (tablets comprising zabofloxacin D-aspartate sesquihydrate) according to the present invention stored in at 33%, 54%, and 75% relative humidity for 10 days increased in thickness by 102.2%, 103.8%, 105.7% respectively, while Comparative Example 2 (tablets comprising zabofloxacin D-aspartate anhydride prepared according to Comparative Example 1) increased in thickness by 105.6%, 106.9%, 109.2% respectively.
Table 5
Figure PCTKR2015002065-appb-T000005
5) Percentage of change in content
The tablets of Example 4 and the tablets of Comparative Example 2 were stored for 10 days at 33%, 54%, and 75% relative humidity (temperature 25℃), and each sample was measured with a high performance liquid chromatography HPLC (Column C18, UV Absorption spectrophotometer 275nm, injected quantity 20uL, Model: HPLC 5973, waters). The result is shown in Figures 4a through 4c respectively for each relative humidity condition and in Table 6.
Example 4 (tablets comprising zabofloxacin D-aspartate sesquihydrate) according to the present invention stored at 33%, 54%, and 75% relative humidity for 10 days decreased in content from the initial 97.1% to 96.23% (-0.87%), 93.72% (-3.38%), and 94.92% (-2.18%) respectively, while Comparative Example 2 (tablets comprising zabofloxacin D-aspartate anhydride) decreased in content in greater magnitude from the initial 97.8% to 93.90% (-4.75%), 93.09% (-4.71%), 91.34% (-6.46%) respectively.
Table 6
Figure PCTKR2015002065-appb-T000006
From the results above, it can be known that in comparison with the tablets comprising zabofloxacin D-aspartate sesquihydrate according to the present invention, the tablets comprising zabofloxacin D-aspartate anhydride increased more in weight, water content, and thickness, and decreased quicker in hardness.
Therefore, from the result that in comparison with the tablets comprising zabofloxacin D-aspartate sesquihydrate according to the present invention, the tablets comprising zabofloxacin D-aspartate anhydride increased quicker in weight, water content, and thickness, it can be known that the latter tablets' structural pore expansion progresses rapidly; due to the said volume expansion and decrease in hardness caused by the pore expansion, the tablets' exterior can be broken by a weak external impact. The easy breaking of the tablets' exterior, decrease in hardness, makes mechanical packing process following commercial production of the said tablets very difficult, and the tablets also break easily during subsequent processes such as transportation, eventually resulting in the patients being unable to take the tablet.
Also, regarding the physiochemical stability, or the percentage of change in content, of the drug product, the tablets comprising the anhydride showed a bigger change in content, and a lower content in comparison with the tablets comprising the hydrates. Since the content of the main ingredient in the drug product is the main indicator that guarantees therapeutic effect, the above result shows that in comparison with the tablets comprising the hydrates, the tablets comprising the anhydride are not as preferable.
Thus, in comparison with zabofloxacin D-aspartate anhydride disclosed in the United States Patent No. US 8,324,238, the present invention provides very stable zabofloxacin D-aspartate hydrates wherein adsorption and desorption of water hardly occur. And it can be known that the drugs comprising zabofloxacin D-aspartate hydrates of the present invention exhibit excellent pharmaceutical stability, for it does not easily break, especially in its tablet form, and for it changes little in its content of the main ingredient.

Claims (9)

  1. A zabofloxacin D-aspartate hydrate represented by Formula 2 below, wherein the water content thereof measured with Karl Fischer titration is 3~13wt%.
    <Formula 2>
    Figure PCTKR2015002065-appb-I000004
  2. The zabofloxacin D-aspartate hydrate according to Claim 1, wherein n in Formula 2 equals 1.5 and the water content thereof measured with Karl Fischer titration is 4.0~5.9 wt%.
  3. The hydrate according to Claim 2, wherein the said hydrate is a crystalline hydrate with peaks at the diffraction angles(2θ) of 4.3±0.2, 8.6±0.2, and 9.8±0.2 in x-ray diffractogram.
  4. The crystalline zabofloxacin D-aspartate hydrate according to Claim 3, wherein the said hydrate peaks at the diffraction angles (2θ) of 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, 29.0±0.2 in x-ray diffractogram.
  5. The method of preparing zabofloxacin D-aspartate sesquihydrate comprising the steps of:
    i) adding zabofloxacin and D-aspartic acid to a mixed solvent of purified water and ethanol, and heating the resulting mixture at 55℃~60℃; and
    ii) cooling the mixture of step i) at 20℃~30℃ to receive crystals; and
    iii) adding ethanol to the precipitated crystals of step ii), and stirring the resulting mixture for 1~2 hours at 5℃~25℃.
  6. An antibacterial pharmaceutical compositions comprising the zabofloxacin D-aspartate hydrate according to Claim 1 as an active ingredient and pharmaceutically acceptable excipients.
  7. The antibacterial pharmaceutical compositions according to Claim 6, wherein the hydrate is zabofloxacin D-aspartate sesquihydrate.
  8. The antibacterial pharmaceutical compositions according to Claim 6 or Claim 7, wherein the compositions are prepared in the form of tablet, capsule, or injection.
  9. The antibacterial pharmaceutical compositions according to Claim 8, wherein the tablet is prepared from granules prepared by direct compression method, pressure granulation method, or wet granulation method.
PCT/KR2015/002065 2014-03-04 2015-03-04 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 hydrates and an antibacterial pharmaceutical compositions comprising their hydrates WO2015133803A1 (en)

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SA516371791A SA516371791B1 (en) 2014-03-04 2016-09-04 l-Cyclopropyl -6- Fluoro -7- (8-Methoxyimino-2,6-Diaza – Spiro [3,4]OCT-6-YL) -4-OXO-l,4- Dihydro-[l,8] Naph-Thyridine-3-Carboxylic Acid D-Aspartate Hydrates And An Antibacterial Pharmaceutical Compos

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999000393A1 (en) * 1997-06-26 1999-01-07 Dong Wha Pharmaceutical Industrial Co., Ltd. Quinolone carboxylic acid derivatives
KR20080092893A (en) * 2007-04-13 2008-10-16 동화약품공업주식회사 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 aspartic acid salt, process for the preparation thereof and pharmaceutical composition comprising the same for antimicrobial

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3537761A1 (en) * 1985-10-24 1987-04-30 Bayer Ag INFUSION SOLUTIONS OF 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7- (1-PIPERAZINYL) -QUINOLINE-3-CARBONIC ACID

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999000393A1 (en) * 1997-06-26 1999-01-07 Dong Wha Pharmaceutical Industrial Co., Ltd. Quinolone carboxylic acid derivatives
KR20080092893A (en) * 2007-04-13 2008-10-16 동화약품공업주식회사 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 aspartic acid salt, process for the preparation thereof and pharmaceutical composition comprising the same for antimicrobial

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HYEKYUNG HAN ET AL.: "Comparison of pharmacokinetics between new quinolone antibiotics: the zabofloxacin hydrochloride capsule and the zabofloxacin as- partate tablet", CURRENT MEDICAL RESEARCH AND OPINION, vol. 29, no. 10, 2013, pages 1349 - 1355 *
LIAN-SHUN FENG ET AL.: "Synthesis of naphthyridone derivatives containing 8- alkoxyimino-1, 6-dizaspiro[3.4]octane scaffolds", TETRAHEDRON, vol. 67, no. 43, 2011, pages 8264 - 8270, XP028389480, ISSN: 0040-4020 *

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