CN106822147B

CN106822147B - Composition of ceftriaxone sodium and sulbactam sodium, pharmaceutical preparation containing composition and application of pharmaceutical preparation

Info

Publication number: CN106822147B
Application number: CN201610947706.8A
Authority: CN
Inventors: 不公告发明人
Original assignee: Guangzhou Wellman Drug R & D Co ltd; Nanjing Star Fuxing Pharmaceutical Technology Co ltd; Xiangbei Wellman Pharmaceutical Co ltd
Current assignee: Guangzhou Wellman Drug R & D Co Ltd; Nanjing Star Fuxing Pharmaceutical Technology Co Ltd; Xiangbei Welman Pharmaceutical Co Ltd
Priority date: 2016-11-03
Filing date: 2016-11-03
Publication date: 2021-07-20
Anticipated expiration: 2036-11-03
Also published as: CN111249284B; CN111249284A; CN106822147A

Abstract

The invention provides a composition consisting of ceftriaxone sodium and sulbactam sodium, a pharmaceutical preparation containing the composition and application of the pharmaceutical preparation. The composition is characterized by an X-ray powder diffraction analysis pattern comprising specific diffraction angles. The composite medicine preparation has better bacteriostatic activity and stability, so the composite medicine preparation is very suitable for treating bacterial infection, and is particularly suitable for treating urogenital system infection diseases caused by Neisseria gonorrhoeae with drug resistance to various antibiotics (beta-lactams, tetracyclines, macrolides, fluoroquinolones or aminoglycosides).

Description

Composition of ceftriaxone sodium and sulbactam sodium, pharmaceutical preparation containing composition and application of pharmaceutical preparation

Technical Field

The invention relates to a composition, in particular to a composition consisting of ceftriaxone sodium and sulbactam sodium. The invention also relates to a pharmaceutical preparation containing the composition and application thereof.

Background

Ceftriaxone (ceftriaxone) is the third generation cephalosporin antibiotic, the sodium salt of which is commonly used clinically. Ceftriaxone sodium has good antibacterial activity against a plurality of gram-negative bacteria and part of gram-positive bacteria (such as escherichia coli, klebsiella pneumoniae, neisseria gonorrhoeae and the like), can be used for treating infectious diseases caused by sensitive bacteria, but is not sensitive to methicillin-resistant staphylococcus aureus (MRSA), enterobacter cloacae and the like, so that the use of ceftriaxone sodium is limited to a certain extent. Sulbactam is a beta-lactamase inhibitor. In the prior art, sulbactam sodium and ceftriaxone sodium are prepared into compound preparations, so that the antibacterial spectrum and the sensitivity to drug-resistant bacteria of the ceftriaxone are improved.

The stable quality of the medicine is the key for guaranteeing the safe medication of people. In order to ensure that the ceftriaxone sodium and sulbactam sodium compound preparation has better drug effect compared with a single preparation, the compound preparation is inevitably required to have stable medicine quality. However, compared with the single recipe, the compound recipe presents a greater complexity in the preparation of the formulation, the action of the drug effect, and the like.

Through research, the existing compound preparation of ceftriaxone sodium and sulbactam sodium shows the condition of unstable crystal form.

CN102462684A reports that after ceftriaxone sodium, sulbactam sodium and a freeze-drying protective agent are dissolved in 70% ethanol to form a solution at low temperature under the condition of inert gas, a pH regulator is added, and freeze-drying is carried out to form eutectic powder, and active ingredients can be kept basically not to be degraded within 36 months. However, the eutectic powder contains various components such as ceftriaxone sodium, sulbactam sodium, a freeze-drying protective agent, a pH regulator and the like, and may have certain influence on the bulk drug. It was found by the study that the eutectic powder was stable in content, but did not form a stable crystal. This means that it is still unstable in a crystallographic sense.

The inventor expects to improve the product quality of the ceftriaxone sodium and sulbactam sodium compound preparation, prolong the effective period of the medicine and improve the economy and safety of the medicine through intensive research.

Disclosure of Invention

One of the purposes of the invention is to provide a stable composition consisting of ceftriaxone sodium and sulbactam sodium, so as to solve the problems of poor stability, poor drug effect or short effective period and the like of the existing ceftriaxone sodium and sulbactam sodium compound preparation.

It is still another object of the present invention to provide a pharmaceutical formulation comprising a stable composition consisting of ceftriaxone sodium and sulbactam sodium.

Still another object of the present invention is to provide the use of said pharmaceutical preparation in the preparation of an antibacterial medicament.

The inventor unexpectedly obtains a composition of ceftriaxone sodium and sulbactam sodium with specific crystal forms when improving the preparation process of the compound preparation.

The technical scheme of the invention is as follows:

a composition consisting of ceftriaxone sodium and sulbactam sodium comprising, in its X-ray powder diffraction analysis pattern, the following diffraction angles: 11.2 +/-0.2 degrees, 14.3 +/-0.2 degrees, 17.8 +/-0.2 degrees, 19.3 +/-0.2 degrees, 21.2 +/-0.2 degrees, 22.8 +/-0.2 degrees and/or 23.8 +/-0.2 degrees.

Preferably, the composition of the present invention may further comprise the following diffraction angles in its X-ray powder diffraction analysis pattern: 12.6 +/-0.2 degrees, 16.7 +/-0.2 degrees, 18.4 +/-0.2 degrees, 20.0 +/-0.2 degrees, 20.4 +/-0.2 degrees and/or 28.0 +/-0.2 degrees.

The other technical scheme of the invention is as follows:

a composition consisting of ceftriaxone sodium and sulbactam sodium comprising the following interplanar spacings in an X-ray powder diffraction analysis pattern: 7.9 +/-0.2A, 6.2 +/-0.2A, 5.0 +/-0.2A, 4.6 +/-0.2A, 4.2 +/-0.2A, 3.9 +/-0.2A and/or 3.7 +/-0.2A.

Preferably, the composition of the present invention further comprises the following interplanar spacings in its X-ray powder diffraction analysis spectrum: 7.1 +/-0.2A, 5.3 +/-0.2A, 4.8 +/-0.2A, 4.4 +/-0.2A, 4.3 +/-0.2A and/or 3.2 +/-0.2A.

The composition of the present invention is a crystalline substance (crystal). X-ray powder diffraction analysis is an authoritative means for identifying crystals in the field, and peaks with low 2 theta angles, high crystal face spacing, clear and complete shapes and larger intensity in a spectrum obtained by X-ray powder diffraction analysis can reflect the characteristics of the crystals more frequently. In addition, due to problems such as preferred orientation of the sample, parameters such as the peak height and peak area of a characteristic peak alone are not always characteristic and cannot be used as characterization of the crystal alone. The inventors have scientifically characterized the compositions of the present invention by selecting a series of characteristic 2 theta angles and interplanar spacings according to the general principles of crystallography.

Preferably, the composition of the present invention, when subjected to infrared absorption spectroscopy, can be at the following wavenumber. + -. 5cm^-1Has an absorption peak: 3255. 1742, 1604, 1539, 1398, 1302, 1198, 1124, 1032, 897, 804, 600, and 479.

More preferably, the composition of the present invention can also have the following wave number + -5 cm when being subjected to infrared absorption spectrum analysis^-1Has an absorption peak: 3441. 3116, 2938, 1500, and 1099.

Preferably, the composition of the present invention, when subjected to differential scanning calorimetry, exhibits an exothermic peak at 269.6 ± 0.5 ℃.

For the characterization of crystals, infrared absorption spectroscopy and differential scanning calorimetry may not be as accurate as X-ray powder diffraction analysis, but they are two common means of substance identification and therefore can be used as a reference for the characterization of the compositions of the invention.

The composition of the invention can be prepared by the following method: taking a ceftriaxone sodium raw material and a sulbactam sodium raw material, grinding until the granularity is 25-88 mu m, and uniformly mixing.

Preferably, the particle size can be 25-47 μm, 38-62 μm or 58-88 μm.

Preferably, the grinding of the invention can be carried out by grinding the ceftriaxone sodium raw material and the sulbactam sodium raw material respectively and then grinding together; or directly co-grinding the ceftriaxone sodium raw material and the sulbactam sodium raw material.

Preferably, the particle size according to the present invention may refer to a median particle size distribution D₅₀。

Preferably, the milling according to the invention can be carried out using a ball mill.

Preferably, the mixing according to the invention can be carried out using a single-cone ribbon mixer.

More preferably, the rotating speed of the single-cone helical ribbon mixer can be 25-40 revolutions per minute, and the mixing time can be 10-25 minutes.

In preparing the compositions of the present invention, the inventors employed a milling process. During the grinding process, physical force promotes the full contact between the ceftriaxone sodium and the sulbactam sodium, and directly or indirectly influences the micro-space structure of the substance. The inventors have found that a particular degree of grinding is important to the product, and in some cases the resulting product has a low degree of crystallinity, and that control over the degree of grinding can be achieved to some extent by specifying the particle size of the product after grinding. For example, screens of different mesh sizes may be used for the grinding, or screens of a specific mesh size may be used to screen the product after grinding. The particle size of the product can be determined using methods common in the art.

Although one method of preparing the composition of the invention is illustrated, it is not excluded that there are other methods by which the composition of the invention can be obtained.

In addition, in order to simplify the pharmaceutical process and facilitate the subsequent preparation of pharmaceutical preparations, the two components of the composition of the present invention may be kept in a certain ratio in advance. Preferably, in the composition of the present invention, the ratio (mass ratio) of ceftriaxone sodium (calculated as ceftriaxone) to sulbactam sodium (calculated as sulbactam) may be 1: 1-8: 1. in some embodiments of the invention, the ratio is preferably 1: 1. 2: 1. 3: 1. 4: 1. 5: 1. 6: 1. 7: 1 or 8: 1. more preferably, in the composition of the invention, the ratio of ceftriaxone sodium (calculated as ceftriaxone) to sulbactam sodium (calculated as sulbactam) is 1: 1-4: 1.

although some proportions of components are exemplified, it is not excluded that other proportions may be used to obtain the composition of the invention.

The technical features of the various preferred embodiments described above can be freely combined for the composition and are within the scope of the composition of the present invention.

The invention also adopts the technical scheme that:

a pharmaceutical formulation comprising the composition of the invention.

Preferably, the pharmaceutical preparation of the present invention may contain the composition of the present invention as an active ingredient.

Preferably, the pharmaceutical preparation of the present invention may further comprise pharmaceutically acceptable excipients.

Preferably, the pharmaceutical preparation of the invention can be powder injection or injection, wherein the powder injection can be sterile powder injection or freeze-dried powder injection.

Preferably, in the pharmaceutical preparation of the present invention, the ratio (mass ratio) of ceftriaxone sodium (calculated as ceftriaxone) to sulbactam sodium (calculated as sulbactam) may be 1: 1-8: 1. in some embodiments of the invention, the ratio is preferably 1: 1. 2: 1. 3: 1. 4: 1. 5: 1. 6: 1. 7: 1 or 8: 1.

more preferably, in the pharmaceutical formulation of the present invention, the ratio of ceftriaxone sodium (calculated as ceftriaxone) to sulbactam sodium (calculated as sulbactam) may be 1: 1-4: 1.

for pharmaceutical preparations, the technical features of the above preferred embodiments can be freely combined, and all belong to the category of the pharmaceutical preparations of the present invention.

The invention also adopts the technical scheme that:

the composition or the pharmaceutical preparation of the invention is applied to the preparation of medicines for preventing or treating bacterial infection.

Preferably, the antibacterial agent of the present invention may be anti-neisseria gonorrhoeae, and more preferably, it may be drug-resistant neisseria gonorrhoeae.

More preferably, the drug resistance in the present invention may be a resistance to β -lactam, tetracycline, macrolide, aminoglycoside or fluoroquinolone antibacterial drugs.

Description of the drawings: in the present invention,

the term "composition" means: a combination of more than one substance.

The term "pharmaceutical preparation" refers to: the product prepared according to certain dosage form requirements, which meets the requirements of relevant laws and regulations and relevant standards, can be directly provided for a use object. Wherein, the related laws and regulations include but are not limited to drug administration law, drug registration management method, drug production quality management standard, etc.; relevant criteria include, but are not limited to, the Chinese pharmacopoeia.

The sterile powder injection, the freeze-dried powder injection or the injection can be added with or without auxiliary materials according to the needs and prepared by adopting the conventional method in the field.

The "X-ray powder diffraction analysis", "infrared absorption spectrum analysis" and "differential scanning calorimetry analysis" are all performed by analytical methods conventional in the art. In addition, the data in the present invention cannot be completely absolute due to the differences in experimental conditions (including but not limited to sample particle size, sample particle aspect ratio, instrument model, instrument precision, mode of operation, operator, etc.) in the relevant analytical methods, and due to the unavailability of experimental errors (instrument errors, accidental errors, etc.). To scientifically characterize the compositions of the present invention, the inventors have formulated the error range of the data based on the general knowledge in the art (e.g., the diffraction angle error in X-ray powder diffraction analysis as described in the United states pharmacopoeia USP35-NF30 may reach 0.2 °) and the condition of the compositions of the present invention. However, it should be understood that the error ranges are not exhaustive. It will be understood by those skilled in the art that the numerical values may also fluctuate within the ordinary ranges in the art, all falling within the scope of the technical solution of the present invention.

The "peak" in the "characteristic peak", "absorption peak" or "exothermic peak" means: the spectrum obtained using the correlation analysis method exhibited a peak with an intensity greater than that of noise.

"drug resistance" or "drug resistance" refers to: the microorganism has tolerance to the drug, so that the activity of the drug to the microorganism is obviously reduced.

The invention obtains a novel composition of ceftriaxone sodium and sulbactam sodium through research, and the composition and a medicinal preparation prepared from the composition have better antibacterial activity and more excellent stability (physical stability, chemical stability and biological activity stability).

In some embodiments of the invention, the compositions and formulations thereof have good clarity in aqueous solution after 30 months storage, less than 0.5% of each impurity, substantially unchanged crystallinity, and exhibit excellent physical and chemical stability. In addition, unexpectedly, in certain embodiments of the invention, the compositions and pharmaceutical preparations are also improved in antibacterial activity, show better bacteriostatic effect particularly on various drug-resistant neisseria gonorrhoeae, and show excellent stability of biological activity without activity change after 30 months of storage.

Due to excellent stability and biological activity, the composition and the preparation thereof are very suitable for treating bacterial infection, and are particularly suitable for treating urogenital system infection caused by various refractory drug-resistant Neisseria gonorrhoeae.

Drawings

FIG. 1 is an X-ray powder diffraction analysis spectrum of the lyophilized powder injection A in comparative example 1.

FIG. 2 is an X-ray powder diffraction analysis chart of the mixed powder in comparative example 2.

FIG. 3X-ray powder diffraction analysis of composition I of example 1.

FIG. 4 spectrum of IR absorption spectrum analysis of composition I of example 1.

FIG. 5X-ray powder diffraction analysis of composition II of example 2.

FIG. 6 spectrum of IR absorption spectrum analysis of composition II of example 2.

FIG. 7X-ray powder diffraction analysis of composition III of example 3.

FIG. 8 spectrum of IR absorption spectrum analysis of composition III of example 3.

Detailed Description

The crystal is an ordered arrangement mode presented by the particles of the substance on the microscopic level, is limited by the scientific and technical level, and the existence mode of the crystal cannot be effectively predicted at present.

The crystal form (crystal form) of the raw material medicine plays an important role in stabilizing the quality of the medicine. In the aspect of drug quality control, different crystal forms (crystal forms) may have different stabilities, which further affects the drug quality. If the crystal form (crystal form) of the medicine is fixed, the quality is more stable and is easier to control, otherwise, the quality difference among medicine batches can be caused, and the stability of the medicine is different.

Ceftriaxone sodium may exhibit a number of different crystal morphologies. Chinese journal of antibiotics (2007, 32(11): 672-678) reports that the single crystal structure of ceftriaxone sodium is simulated by using software, and provides beneficial reference for researching the crystal of ceftriaxone sodium. The three sub-crystal forms of the ceftriaxone sodium are reported in the pharmaceutical science report (2014, 49(7):1034 and 1038), and the three sub-crystal forms are different in the aspects of salt forming rate, crystallinity, compatibility of butyl rubber plugs and the like and can influence the curative effect of the medicament.

Sulbactam sodium is also a substance that can exhibit different crystal morphologies. Biochemistry (1981, 20(13): 3680-3687) reports that sulbactam sodium can be crystallized from a mixed solvent of ethyl acetate and n-butanol, and discloses a single crystal structure thereof. Huaihai medicine (2005, 23(5): 423) reports that sulbactam sodium is prepared by using different solvents such as acetone, ethyl acetate, methanol, ethanol and the like to obtain four different crystals, and the forms, the densities and the flowability of the crystals are obviously different. CN103113390A discloses a sulbactam crystal which can keep the content stable within 24 months.

Due to the existence of a plurality of different crystals of ceftriaxone sodium and sulbactam sodium, the complexity of compound medicine crystal forms is brought, and unpredictable influence on the crystals can be caused by the preparation process.

The following comparative examples, examples and test examples are not intended to limit the technical solutions and effects of the present invention.

Description of the drawings: in the following comparative, example or test examples:

(1) the dosage of the ceftriaxone sodium/ceftriaxone sodium crystal is metered according to ceftriaxone, and the dosage of the sulbactam sodium/sulbactam sodium crystal is metered according to sulbactam. For example, "500 g of ceftriaxone sodium is taken" means that the amount of ceftriaxone in the taken ceftriaxone sodium is 500 g.

(2) The crystal morphology is measured by adopting an X-ray powder diffraction method and a BRUKER D8 ADVANCEX ray powder diffractometer under the following measuring conditions: CuK alpha radiation, tube pressure 40 kV, scanning range 5-60 degrees, scanning speed 17.7 s/step, step size 0.02 degrees.

(3) In the infrared absorption spectrum analysis, a sample is measured after being tabletted by KBr.

(4) The differential scanning calorimetry adopts a comprehensive thermal analyzer STA409 of Germany NETZSCH company to determine the conditions: the heating rate is 10K/min, and the protective gas N₂Flow rate 30mL/min, purge gas N₂The flow rate is 20mL/min, and the temperature range is 35-300 ℃.

(5) The crystallinity is measured by a method of United states pharmacopoeia USP35-NF 30.

(6) The content of the impurities is determined by HPLC according to the method of European pharmacopoeia EP 8.0.

(7) The clarity of the solution is determined according to the method of the chinese pharmacopoeia 2015 edition.

Comparative example 1

According to the method reported in example 1 of CN102462684A, 100g of ceftriaxone sodium, 50g of sulbactam sodium and 25g of mannitol are placed in 90ml of 70% ethanol solution which is pretreated, cooled to below 10 ℃ and filled in a nonmetal container under the conditions of sterility, protection from light and nitrogen flow, stirred to be completely dissolved, the pH value of the solution is adjusted to 6.5 by 0.1mol/L of sodium bicarbonate solution, sterile filtered, subpackaged, put into a freeze-drying machine filled with inert gas for pre-freezing (-48 to-20 ℃), decompressed, sublimated and dried to obtain a freeze-dried substance which is named as freeze-dried powder A, a sample is taken for crystal morphology determination, and the X-ray powder diffraction pattern is shown in figure 1.

Comparative example 2

The following procedure was followed as described in example 1 in CN 102993215A: condensing 7-ACT and AE-active ester to obtain a crude product of ceftriaxone sodium; adding water 40ml into 5g of crude product to dissolve, adding sodium isooctanoate 4.1g into the solution at 13 ℃, stirring until the solution is clear, adjusting the pH value to 7.00 by using 10% dilute hydrochloric acid, and continuously stirring for 30 minutes to obtain mother liquor; adding anhydrous ethanol slowly into the mother liquor under stirring, stopping stirring and adding when turbidity appears, standing for 25 minutes, and then adding anhydrous ethanol slowly until a large amount of crystals are formed, wherein 150ml of anhydrous ethanol is used; the crystals obtained are filtered and the filter cake is purified by means of absolute ethanol: water = 4: 1, washing the mixture to be neutral, washing the mixture by using absolute ethyl alcohol once, and drying the mixture at the temperature of 35 ℃ under normal pressure to prepare the ceftriaxone sodium.

The following procedure was followed as described in example 1 in CN 103113390A: taking a sulbactam sodium crude product, adding a mixed solvent (3: 1) of N, N-dimethylformamide and water which is 5 times (ml/g) of the crude product, heating to 70 ℃, stirring to be completely dissolved, preserving heat, adjusting the pH value of the solution to 5.5, enabling the solution to flow through a 0.5T direct current magnetic field at the speed of 5m/s, enabling the direction of the magnetic field to be vertical to the flow direction of the solution, adding activated carbon which is 0.3% times (g/ml) of the mixed solvent into the magnetically treated solution for decolorization, stirring for 30min, filtering to obtain a clarified solution, adding ethanol which is 5 times (ml/ml) of the mixed solvent into the clarified solution, filtering to obtain a filter cake, washing the filter cake with distilled water for 3 times, and then drying under reduced pressure for 4h to prepare the sulbactam sodium.

Taking 1000g of ceftriaxone sodium prepared by the method and 500g of sulbactam sodium, uniformly mixing by using a groove type mixer under aseptic conditions to obtain mixed powder, sampling, and carrying out crystal morphology determination, wherein an X-ray powder diffraction pattern is shown in figure 2. And subpackaging the mixed powder under the aseptic condition to obtain an aseptic powder injection named aseptic powder injection A.

Comparative example 3

2000g of commercially available ceftriaxone sodium and 1000g of sulbactam sodium are taken, mixed uniformly by a groove type mixer under the aseptic condition to obtain mixed powder, a sample is taken for crystal morphology determination, and the X-ray powder diffraction pattern is similar to that in figure 2. And subpackaging the mixed powder under the aseptic condition to obtain an aseptic powder injection named aseptic powder injection B.

Example 1

1200g of ceftriaxone sodium and 600g of sulbactam sodium prepared by the method of comparative example 2 are taken and ground together by a ductile iron until the grain diameter D₅₀The particle size is 25-47 mu m, and the particles are uniformly mixed in a conical screw belt type mixer (HF1600 type), wherein the rotating speed of the machine is set to be 30 revolutions per minute, and the mixing time is 25 minutes. After the operation was completed, the material was removed to obtain a crystalline material, designated composition I.

The crystal morphology was determined by taking samples and the X-ray powder diffraction pattern is shown in FIG. 3, the main data in the pattern are shown in Table 1.

The infrared absorption was measured by infrared absorption spectroscopy, and the spectrum is shown in FIG. 4, and the main infrared absorption peak data are shown in Table 2.

Differential scanning calorimetry analysis was performed and found to have an exothermic peak at 269.51 ℃.

TABLE 1X-ray powder diffraction Pattern principal data for composition I

Serial number	2 theta angle (°)	Spacing of crystal planes (A)	Peak height	Peak area
					1	11.138	7.9372	1502	16530
2	12.521	7.0634	437	4363
					3	14.289	6.1934	11014	68918
4	16.638	5.3238	1798	12883
					5	17.835	4.9692	1569	11493
6	18.432	4.8096	883	7497
					7	19.276	4.6008	2908	21910
8	19.978	4.4406	1034	12897
					9	20.453	4.3386	1342	20418
10	21.171	4.1930	1651	17080
					11	22.736	3.9079	1889	25822
12	23.769	3.7403	1299	15065
					13	27.985	3.1856	2612	25393

TABLE 2 Infrared absorption Spectrum Main data for composition I

Serial number	Wave number (cm)^-1)	Serial number	Wave number (cm)^-1)
				1	3441	10	1302
2	3254	11	1198
				3	3117	12	1124
4	2937	13	1099
				5	1742	14	1032
6	1605	15	897
				7	1539	16	804
8	1501	17	600
				9	1398	18	480

Example 2

Taking 500g of commercially available ceftriaxone sodium and 500g of sulbactam sodium, and grinding the ceftriaxone sodium and the sulbactam sodium together by a ductile iron until the grain diameter D₅₀Is 38 μm to 62 μm. And then uniformly mixed in a single-cone ribbon mixer (HF1600 type), wherein the rotating speed of the machine is set to 40 revolutions per minute, and the mixing time is 20 minutes. After the operation was completed, the material was removed to obtain a crystalline material designated composition II.

The crystal morphology was determined by taking samples and the X-ray powder diffraction pattern is shown in FIG. 5, the main data in the pattern are shown in Table 3.

The infrared absorption was measured by infrared absorption spectroscopy, and the spectrum is shown in FIG. 6, and the main infrared absorption peak data are shown in Table 4.

Differential scanning calorimetry analysis was performed and found to have an exothermic peak at 269.67 ℃.

TABLE 3X-ray powder diffraction principal data for composition II

Serial number	2 theta angle (°)	Spacing of crystal planes (A)	Peak height	Peak area
					1	11.120	7.9500	1250	15628
2	12.521	7.0635	413	3990
					3	14.272	6.2007	8409	51004
4	16.656	5.3181	1282	10862
					5	17.815	4.9746	1514	10864
6	18.431	4.8097	733	6124
					7	19.292	4.5970	2475	16754
8	19.923	4.4528	537	18373
					9	20.453	4.3386	1604	15208
10	21.171	4.1931	1308	13632
					11	22.735	3.9080	1626	23393
12	23.825	3.7317	947	14460
					13	27.966	3.1878	2090	21313

TABLE 4 Infrared absorption Spectrum Main data for composition II

Serial number	Wave number (cm)^-1)	Serial number	Wave number (cm)^-1)
				1	3441	10	1302
2	3254	11	1198
				3	3115	12	1124
4	2939	13	1099
				5	1742	14	1032
6	1605	15	897
				7	1539	16	804
8	1499	17	600
				9	1398	18	478

Example 3

Taking 930g of commercially available ceftriaxone sodium, and grinding; taking 310g of sulbactam sodium, grinding, and then grinding the two raw materials together by a ball mill until the particle diameter D is reached₅₀Is 58 μm to 88 μm. The mixture was placed in a single cone ribbon blender (model HF 1600) and mixed well with the machine speed set at 25 revolutions per minute for 10 minutes. After the operation was completed, the material was taken out, and the obtained crystalline substance was named composition III.

The crystal morphology was determined by taking samples and the X-ray diffraction pattern is shown in FIG. 7, the main data in the pattern are shown in Table 5.

The infrared absorption was measured by infrared absorption spectroscopy, and the spectrum is shown in FIG. 8, and the main infrared absorption peak data are shown in Table 6.

Differential scanning calorimetry analysis was performed and found to have an exothermic peak at 269.69 ℃.

TABLE 5X-ray powder diffraction principal data for composition III

Serial number	2 theta angle (°)	Spacing of crystal planes (A)	Peak height	Peak area
					1	11.159	7.9227	1519	16847
2	12.576	7.0326	458	4586
					3	14.294	6.1913	13132	70185
4	16.658	5.3176	1786	11679
					5	17.851	4.9647	1873	10087
6	18.450	4.8049	910	7192
					7	19.315	4.5917	3940	24924
8	19.998	4.4362	859	11627
					9	20.476	4.3338	1901	13788
10	21.208	4.1858	1446	16328
					11	22.701	3.9138	1468	21912
12	23.807	3.7345	1261	15779
					13	27.973	3.1870	1935	23623

TABLE 6 Infrared absorption Spectrum Primary data for composition III

Serial number	Wave number (cm)^-1)	Serial number	Wave number (cm)^-1)
				1	3441	10	1302
2	3256	11	1198
				3	3117	12	1124
4	2937	13	1099
				5	1742	14	1032
6	1603	15	897
				7	1539	16	804
8	1499	17	600
				9	1398	18	480

Examples 4 to 8

Respectively taking 800g of commercially available ceftriaxone sodium and 200g of sulbactam sodium; 1150g of ceftriaxone sodium and 230g of sulbactam sodium; ceftriaxone sodium 2700g and sulbactam sodium 450 g; ceftriaxone sodium 1330g and sulbactam sodium 190 g; 2200g of ceftriaxone sodium and 275g of sulbactam sodium; the procedures of example 2 were carried out to obtain compositions IV to VIII, respectively. The spectra of the five compositions are basically consistent with the spectra obtained in examples 1-3 through X-ray diffraction analysis.

Example 9

Taking 500g of commercially available ceftriaxone sodium and 500g of sulbactam sodium, and grinding the ceftriaxone sodium and the sulbactam sodium together by a ductile iron until the grain diameter D₅₀104 to 175 μm. The remaining material mixing operation was the same as in example 2. And after the operation is finished, taking out the materials, and subpackaging the materials under the aseptic condition to obtain the sterile powder injection C.

Then taking 500g of commercially available ceftriaxone sodium and 500g of sulbactam sodium, and grinding the ceftriaxone sodium and the sulbactam sodium together by a ductile iron until the grain diameter D₅₀To less than 10 μm. The remaining material mixing operation was the same as in example 2. And after the operation is finished, taking out the materials, and subpackaging the materials under the aseptic condition to obtain the aseptic powder injection D.

Example 10

And (3) respectively taking the compositions in the embodiments 1 to 8, and subpackaging under an aseptic condition to obtain aseptic powder injections I to VIII.

And (3) respectively taking the compositions in the embodiments 1 to 8, and operating according to the conventional process of the freeze-drying agent to obtain freeze-dried powder injections I to VIII.

The compositions of examples 1 to 8 were each dissolved in 50 times (ml/g) of 0.9% aqueous sodium chloride solution and dispensed to obtain injections I to VIII.

Test example 1: stability test

Stability tests were performed on the compositions I to VIII, the sterile powder injection I, the sterile powder injection II, the sterile powder injection IV, the lyophilized powder injection I, the lyophilized powder injection II, the sterile powder injection a, the sterile powder injection B, the sterile powder injection C, the sterile powder injection D, and the lyophilized powder injection a in the above comparative examples or examples.

And (3) test environment: placing the mixture in an environment with the temperature of 25 +/-2 ℃ and the relative humidity of 60 +/-10 percent for 30 months.

And (3) test results: the clarity of the solution, the contents of impurities 1,2, 3 and 4 (wherein impurities 1,2 and 3 are respectively impurity A, B, E of ceftriaxone sodium described in EP8.0, and impurity 4 is impurity A of sulbactam sodium described in EP 8.0), the crystallinity and the like were measured, and the main test results are shown in tables 7 to 10.

Table 7: stability test Each sample Condition at 0 month

Table 8: stability test conditions of samples of 12 months

Table 9: stability test 24 months for each sample

Table 10: stability test 30 months for each sample

As can be seen from the results of the stability test, after 12 months, the compositions and formulations in the examples were different in crystallinity, impurities, clarity of solution, etc., compared to the comparative examples, and after 30 months, the difference was more significant.

The formulation in the comparative example did not exhibit crystallinity, no crystallinity data; the compositions and formulations in the examples have a crystallinity of up to 90% and remain essentially unchanged for 30 months, indicating good physical stability.

The formulations in the comparative examples showed slight clouding at 24-30 months, while the compositions and formulations in the examples showed no clouding.

Although the content of four impurities in the preparation in the comparative example is basically equivalent to that of the composition and the preparation in the invention at 0 month, the impurities are increased obviously after time change, particularly the content of the impurity 1 (ceftriaxone isomer impurity) and the impurity 4 (sulbactam ring-opening degradation impurity) respectively exceeds 1 percent and 0.5 percent at 24-30 months, and the requirement of EP8.0 cannot be met; the compositions and formulations in the examples, however, showed insignificant increase in four impurities, all within the limits, indicating good chemical stability. This finding reveals that there may be a close relationship between the generation of specific impurities and crystal morphology.

Test example 2: in vivo bacteriostasis test

In test example 1, stability test samples were taken at 0 month for in vivo bacteriostatic test; and then extracting the stability test sample at 30 months, and performing an in vivo bacteriostasis test. Both in vivo bacteriostatic tests were performed as follows.

Test materials

Test samples: experimental example 1 compositions I to VIII, sterile powder injection I, sterile powder injection II, sterile powder injection IV, lyophilized powder injection I, lyophilized powder injection II, lyophilized powder injection a, sterile powder injection B at 0 month and 30 months in the stability test; and contrast drugs of ceftriaxone sodium, levofloxacin hydrochloride, azithromycin, doxycycline hydrochloride and spectinomycin hydrochloride. Wherein, the control drug is purchased for matching with the test sample of 0 month for testing at the time of 0 month of the stability test, and purchased for matching with the test sample of 30 months for testing at the time of 30 months of the stability test, and the production dates of the two batches are within one month when the two batches are purchased.

Animals: ICR mice, 18-22g weight, male and female halves.

The strain is as follows: ATCC700603 (Klebsiella pneumoniae), ATCC43069 (Neisseria gonorrhoeae), Q-R (quinolone resistant Neisseria gonorrhoeae), T-R (tetracycline resistant Neisseria gonorrhoeae), PP-R (beta-lactam resistant Neisseria gonorrhoeae), MAC-R (macrolide resistant Neisseria gonorrhoeae), SPE-R (spectinomycin resistant Neisseria gonorrhoeae), QS-R (ceftriaxone resistant Neisseria gonorrhoeae). Wherein ATCC700603 and ATCC43069 are purchased from ATCC, QS-R reference is prepared by the method of Chinese tropical medicine, 2010,10(8),946-948, and other strains are clinically isolated.

A protective agent: high activity dry yeast.

Test method

Bacterium detoxification: the experimental bacteria incubated for 18 hours were diluted to 10% with 5% high activity dry yeast^-2And 10^-3The mouse is intraperitoneally injected with 0.5ml of the strain to cause a sepsis model caused by systemic infection of the experimental mouse, the mouse is not infected and dies due to any protective measures, aseptic operation thoracotomy is timely carried out on the mouse which is infected and dead, heart blood or intracavity effusion is uniformly coated on a corresponding agar plate, and the agar plate is incubated at 37 ℃ for 18 hours and then identified to be consistent with the given infectious strain. Then the bacteria is used for infecting mice, and the virulence of the bacteria can be enhanced and is relatively stable by the method for 1-2 times.

Determination of minimum lethal bacterial load (MLD): diluting the experimental strain to 10% with 5% high-activity dry yeast^-1、10^-2、10^-3、10^-4Diluted bacteria liquid with different concentrations are respectively injected into the abdominal cavity of the experimental animal (0.5 ml/mouse) to establish an infectious septicemia model. The number of deaths of the mice was recorded after infection, with the minimum bacterial load to 100% deaths of the mice being 1MLD, and the bacterial load used in the animal protection test, and the concentration of bacteria below which one log concentration group infected animals all survived was called 0.1 MLD. 1MLD bacteria concentration was used as a positive control for infection experiments in the experiments; a bacterial concentration of 0.1MLD was used as a negative control for infection. Either the positive or negative control groups were given bacteria alone without any antibiotic treatment. The positive control group should have a mortality rate of 70% or more, and the negative control group should have a mortality rate of 30% or less.

Preliminary tests to determine the dose range of the test samples: mice were infected with 1MLD strain formulated with 5% high activity dry yeast, immediately and 6 hours later, pre-tested with three different concentrations of test sample dose (4 mice per dose group), high, medium and low, and the number of surviving mice after infection was recorded, and the dose for animal protection test was designed based on the results. The difference of the drug dose concentrations of all groups can be larger when the drug dose is initially taken, and the difference can be reduced after the range is determined, and then the test is carried out until the proper drug dose concentration is found (namely, more than 70% of infected animals in the highest concentration dose group survive, and no less than 70% of infected animals in the lowest dose group die).

Animal protection test: in the preliminary experiment, after the dosage concentration of each drug of 100% mouse death and no death is found according to the infection of the mouse with test bacteria, the mice which are fasted for 18h before the experiment and have no water supply and the weight of 18-22g are respectively divided into male and female parts at random: (1) ATCC700603 group, (2) ATCC43069 group, (3) Q-R group, (4) T-R group, (5) PP-R group, (6) MAC-R group, (7) SPE-R group, (8) QS-R group, 5 test sample concentrations in each group, 10 animals in each group, and 10 animals as blank control (given equal volume of sterile water for injection), 1MLD bacterial liquid 0.5ml per mouse intraperitoneally injected, resulting in infection model, different concentrations of test sample liquid 0.2 ml per mouse subcutaneously injected immediately and 6 hours after infection, respectively, continuously observed for 7 days, and record death of each group of animals. Dead mice were dissected and visually observed. The 50% Effective Dose (ED) of each test agent is calculated by Bliss method₅₀) And 95% confidence limit, and carrying out t test to compare the significance of the difference among the groups. ED (electronic device)₅₀Smaller indicates better protection of the test sample against bacterial infection in the animal.

Test results

Tables 11 and 12 show the primary results of the animal protection tests. In vivo antibacterial ED with Table 11 as stability test month 0 sample₅₀Value, ED for in vivo inhibition of stability test 30 months samples in Table 12₅₀The value is obtained.

Table 11: stability test 0 month test sample in vivo bacteriostatic ED₅₀Value (mg/kg)

Table 12: stability test in vivo antibacterial ED of 30 month test sample₅₀Value (mg/kg)

Note: the "/" in tables 11 and 12 indicates not performed.

The test results show that the compositions and preparations in the examples have better antibacterial activity, in particular show significantly stronger inhibitory activity against various drug-resistant Neisseria gonorrhoeae, and the activity can be 2-3 times higher in some cases than the preparations in the comparative examples.

In addition, the compositions and preparations in the embodiments have quite good biological activity stability, especially the inhibition effect on the drug-intolerant and various drug-resistant Neisseria gonorrhoeae can be always kept stable, and the biological activity is basically unchanged after 30 months. The formulation of the comparative example showed a significant reduction in activity after 30 months.

Industrial applicability

The composition consisting of ceftriaxone sodium and sulbactam sodium and the pharmaceutical preparation containing the composition have better activity and more excellent stability (physical stability, chemical stability and biological activity stability), are suitable for treating bacterial infection, and are particularly suitable for treating urogenital infectious diseases caused by refractory Neisseria gonorrhoeae resistant to various antibiotics.

Although the invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it is possible to make reasonable modifications and improvements based on the present invention by those skilled in the art. Accordingly, it is intended that all such modifications and improvements be included within the scope of the invention without departing from the spirit thereof. The foregoing background, summary, and detailed description are provided for the purpose of illustration only and are not intended to be a representation of the prior art which is in accordance with the present invention.

Claims

1. A composition consisting of ceftriaxone sodium and sulbactam sodium comprising, in its X-ray powder diffraction analysis pattern, the following diffraction angles: 11.2 +/-0.2 degrees, 14.3 +/-0.2 degrees, 17.8 +/-0.2 degrees, 19.3 +/-0.2 degrees, 21.2 +/-0.2 degrees, 22.8 +/-0.2 degrees and 23.8 +/-0.2 degrees.

2. The composition of claim 1, further comprising, in its X-ray powder diffraction analysis pattern, the following diffraction angles: 12.6 +/-0.2 degrees, 16.7 +/-0.2 degrees, 18.4 +/-0.2 degrees, 20.0 +/-0.2 degrees, 20.4 +/-0.2 degrees and 28.0 +/-0.2 degrees.

3. A composition consisting of ceftriaxone sodium and sulbactam sodium, comprising the following interplanar spacings in an X-ray powder diffraction analysis pattern: 7.9 +/-0.2A, 6.2 +/-0.2A, 5.0 +/-0.2A, 4.6 +/-0.2A, 4.2 +/-0.2A, 3.9 +/-0.2A and 3.7 +/-0.2A.

4. The composition of claim 3, further comprising the following interplanar spacings in an X-ray powder diffraction analysis pattern thereof: 7.1 +/-0.2A, 5.3 +/-0.2A, 4.8 +/-0.2A, 4.4 +/-0.2A, 4.3 +/-0.2A and 3.2 +/-0.2A.

5. The composition according to any one of claims 1 to 4, characterized in that it has an infrared absorption spectrum at a wavenumber of ± 5cm^-1Has an absorption peak: 3255. 1742, 1604, 1539, 1398, 1302, 1198, 1124, 1032, 897, 804, 600, and 479.

6. The composition according to any one of claims 1 to 4, further characterized by a wavenumber of ± 5cm in the infrared absorption spectrum^-1Has an absorption peak: 3441. 3116, 2938, 1500, and 1099.

7. The composition of any one of claims 1 to 4, having an exothermic peak at 269.6 ± 0.5 ℃ in a differential scanning calorimetry pattern.

8. A process for preparing a composition according to any one of claims 1 to 4, comprising the steps of: taking a ceftriaxone sodium raw material and a sulbactam sodium raw material, grinding until the particle size is 25-88 mu m, and uniformly mixing to obtain the composition.

9. The method of claim 8, wherein the particle size is 25 μm to 47 μm, 38 μm to 62 μm, or 58 μm to 88 μm.

10. A pharmaceutical preparation comprising the composition of any one of claims 1 to 4.

11. The pharmaceutical preparation of claim 10, wherein the pharmaceutical preparation is a powder injection or an injection.

12. The pharmaceutical preparation of claim 11, wherein the powder injection is a sterile powder injection or a lyophilized powder injection.

13. The pharmaceutical preparation according to claim 10, wherein the mass ratio of ceftriaxone sodium calculated as ceftriaxone to sulbactam sodium calculated as sulbactam in the pharmaceutical preparation is 1: 1-8: 1.

14. the pharmaceutical formulation of claim 13, wherein the mass ratio is 1: 1-4: 1.

15. use of the pharmaceutical preparation according to claim 10 for the preparation of a medicament for the prophylaxis or treatment of a bacterial infection disease.

16. The use of claim 15, wherein the bacterium is resistant neisseria gonorrhoeae.

17. The use of claim 16, wherein the resistance is to a β -lactam antibiotic, a tetracycline antibiotic, a macrolide antibiotic, a fluoroquinolone antibiotic, or an aminoglycoside antibiotic.

18. The use of claim 15, wherein the infectious disease is a urogenital infectious disease.