Nemonoxacin malate capsule and preparation method thereof

Abstract

The application discloses a nemonoxacin malate capsule and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The nemonoxacin malate capsule comprises the following components in parts by weight: 80-90 parts by weight of nemonoxacin malate hemihydrate, 10-20 parts by weight of a filler, and 1 part by weight of a hollow capsule. The filler is composed of essential components and optional components. The essential components are anhydrous lactose and glycerin monostearate compound. The optional components are selected from one or more of polyethylene glycol, hydrogenated vegetable oil, sodium aluminum silicate, magnesium stearate, glycerin distearate, microcrystalline cellulose, chitosan and anhydrous trisodium phosphate. The novel excipients not only effectively establish the good in-vivo and in-vitro correlation of the nemonoxacin malate capsule, but also improve the problems of large individual drug difference and poor stability.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a nemonoxacin malate capsule and a preparation method thereof. BACKGROUND

[0002] Nemonoxacin malate hemihydrate is a non-fluorine-containing quinolone antibacterial drug, which inhibits the replication of bacterial DNA by inhibiting the activity of bacterial DNA gyrase and topoisomerase IV, thereby causing the death of bacteria. Nemonoxacin malate hemihydrate has broad-spectrum antibacterial activity, and is effective against gram-positive bacteria, gram-negative bacteria, anaerobic bacteria and atypical pathogens, especially against streptococci and staphylococci, including multiple drug-resistant streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA). Nemonoxacin malate hemihydrate has concentration-dependent antibacterial activity, and has slower and weaker in-vitro drug resistance development than other quinolones against streptococcus pneumoniae. At present, its dosage forms include capsules and injection solutions. Compared with injection solutions, the advantages of capsules are convenience, safety and compliance of administration, and good portability, transportation and stability.

[0003] The chemical structural formula of nemonoxacin malate hemihydrate is as follows:

[0004]

[0005] Patent (CN 101618039 A: Therapeutic drug for pneumonia) discloses that the capsule content formula of nemonoxacin malate hemihydrate is composed of 345 mg of nemonoxacin malate hemihydrate, 97.1 mg of microcrystalline cellulose and 2.9 mg of magnesium stearate; the total weight of the content is 445.0 mg. However, the reported capsule has poor stability and poor uniformity. SUMMARY

[0006] The purpose of the present application is to provide a nemonoxacin malate capsule and a preparation method thereof, and to solve the problems of poor stability and poor uniformity of the existing nemonoxacin malate hemihydrate capsule. To achieve the above purpose, the technical solution adopted by the present application is as follows:

[0007] In a first aspect, the present application provides a nemonoxacin malate capsule, which comprises the following components by weight:

[0008] Nemonoxacin malate hemihydrate 80-90 parts by weight, filler 10-20 parts by weight, and hollow capsule 1 part by weight;

[0009] The filler is composed of essential components and optional components. The essential components are anhydrous lactose and glycerol monostearate complex; and the optional components are selected from one or more of polyethylene glycol, hydrogenated vegetable oil, sodium aluminum silicate, magnesium stearate, glycerol bisostearate, microcrystalline cellulose, chitosan and anhydrous trisodium phosphate.

[0010] As a preferred design, the capsule of nemonoxacin malate comprises the following components by weight:

[0011] 88.95 parts by weight of nemonoxacin malate hemihydrate, 11.05 parts by weight of a filler, and 1 part by weight of a hollow capsule.

[0012] As a possible design, the filler is anhydrous lactose and glyceryl monostearate complex.

[0013] As a possible design, the hollow capsule is selected from a gelatin hollow capsule, a hypromellose hollow capsule, or a polyvinyl acetate hollow capsule.

[0014] As a preferred design, the hollow capsule is a gelatin hollow capsule.

[0015] In a second aspect, the application provides a preparation method of the capsule of nemonoxacin malate, comprising the following steps:

[0016] S1. mixing and stirring nemonoxacin malate hemihydrate and a filler uniformly to obtain a premix 1;

[0017] S2. granulating the premix 1, wherein the proportion of fine powder and large particles is ≤20%;

[0018] S3. mixing the granules obtained in step S2 to obtain intermediate granules;

[0019] S4. filling the intermediate granules into a hollow capsule to obtain the capsule of nemonoxacin malate.

[0020] As a possible design, the rotation speed and time of mixing in step S1 are 10 rpm and 10 min, respectively; and the rotation speed and time of mixing in step S3 are 15 rpm and 5 min, respectively.

[0021] As a possible design, in step S2, a dry granulator is used for granulation, and the pressure of the compression roller of the dry granulator is 2.0-4.0 MPa, the feeding rotation speed is 25-40 rpm, the compression roller speed is 6-15 rpm, the compression roller gap is 0.1-1.0 mm, the granulation screen is 1.0 mm, and the granulation rotation speed is 60-100 rpm.

[0022] As a possible design, in step S2, the particle size of the fine powder is <150 μm, and the particle size of the large particles is >600 μm.

[0023] As a possible design, in step S4, the filling speed is 1800-2100 granules per minute, and the weight of the content of a single capsule of nemonoxacin malate is 0.389 g.

[0024] The application has the following beneficial effects:

[0025] The present application can easily obtain stable and uniform capsules with good coefficient of variation by selecting at least one of polyethylene glycol, hydrogenated vegetable oil, sodium aluminosilicate, glycerin distearate, microcrystalline cellulose, chitosan, anhydrous trisodium phosphate and anhydrous lactose and glycerin monostearate complex as a filler, and is more suitable for popularization and use. BRIEF DESCRIPTION OF DRAWINGS

[0026] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings needed to be used in the embodiments or prior art description will be briefly introduced as follows. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can also be obtained by those skilled in the art without creative effort.

[0027] Figure 1 is the dissolution curve of the nemonoxacin capsules of the present application in Examples 1-10 and Comparative Example 1 and a commercially available product in a pH 6.8 medium;

[0028] Figure 2 is the dissolution curve of the nemonoxacin capsules of the present application in Examples 1-10 and a commercially available product in a pH 4.5 medium;

[0029] Figure 3 is the dissolution curve of the nemonoxacin capsules of the present application in Example 10 and a commercially available product in a pH 1.2 medium;

[0030] Figure 4 is the average plasma concentration-time curve (T-R) of nemonoxacin in postprandial test samples. DETAILED DESCRIPTION

[0031] In order to make the technical problems, technical solutions and beneficial effects of the present application more clearly understood, the present application will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and do not limit the present application.

[0032] In the present application, "at least one" means one or more, and "more" means two or more. "At least one of the following" or similar expressions means any combination of these items, including any combination of single item or multiple items. For example, "at least one of a, b, or c", or "at least one of a, b, and c", can represent a, b, c, a-b (i.e. a and b), a-c, b-c, or a-b-c, wherein a, b, and c can be single or multiple.

[0033] It should be understood that the magnitude of the serial number of the above processes in various embodiments of the present application does not mean the order of execution, and part or all of the steps can be executed in parallel or in sequence, and the execution order of the processes should be determined by their functions and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.

[0034] The terms used in the embodiments of the present application are only for the purpose of describing specific embodiments, and are not intended to limit the present application. The singular forms "a", "said" and "the" used in the embodiments of the present application and the appended claims are also intended to include the plural forms, unless the context clearly indicates otherwise.

[0035] The weight of the related components mentioned in the specification of the embodiments of the present application can not only refer to the specific content of each component, but also represent the proportional relationship between the weights of each component, therefore, as long as the content of the related components in the specification of the embodiments of the present application is enlarged or reduced in proportion, it is within the scope disclosed in the specification of the embodiments of the present application. Specifically, the mass mentioned in the specification of the embodiments of the present application can be µg, mg, g, kg, etc. mass units commonly known in the chemical field.

[0036] The following will be described in conjunction with specific embodiments.

[0037] Embodiment 1

[0038] Another nemonoxacin malate capsule and a preparation method thereof are disclosed in the embodiment.

[0039] A nemonoxacin malate capsule is composed of the following components:

[0040] 85 parts by weight of nemonoxacin malate hemihydrate, 10 parts by weight of microcrystalline cellulose, 5 parts by weight of magnesium stearate, and 1 part by weight of hydroxypropyl methyl cellulose hollow capsule;

[0041] The nemonoxacin malate capsule is prepared by the following method:

[0042] (1) The nemonoxacin malate hemihydrate, the microcrystalline cellulose and the magnesium stearate are added into the fixed hopper mixer, and mixed at a constant speed for 10 min to obtain a premix 1;

[0043] (2) The premix 1 of step (1) is added into the dry granulator to granulate, the roller pressure is 3.5 MPa, the feeding speed is 25 rpm, the roller speed is 10 rpm, the roller gap is about 1.0 mm, the granulation screen is 1.0 mm, and the granulation speed is 60 rpm. The proportion of fine powder (<150 μm) and large particles (>600 μm) is not more than 20%;

[0044] (3) All the materials are poured into the fixed hopper mixer, the feeding port is closed, and mixed at a constant speed for 10 min to obtain the intermediate product granules;

[0045] (4) Take the intermediate product of step (3) and fill it using a full-automatic hard capsule filling machine, and control the filling amount to be about 389 mg to obtain the nemonoxacin malate capsule.

[0046] The full-automatic hard capsule filling machine, the dry granulator, and the fixed hopper mixer in this example are all prior art, and will not be described in detail here.

[0047] Example 2

[0048] This example discloses another nemonoxacin malate capsule and a preparation method thereof.

[0049] A nemonoxacin malate capsule is composed of the following components:

[0050] 85 parts by weight of nemonoxacin malate hemihydrate, 10 parts by weight of anhydrous lactose and glycerol monostearate complex, 5 parts by weight of magnesium stearate, and 1 part by weight of gelatin hollow capsule;

[0051] It is prepared according to the following method:

[0052] (1) Put the nemonoxacin malate hemihydrate, the anhydrous lactose and glycerol monostearate complex, and the magnesium stearate into the fixed hopper mixer, and mix at a constant speed for 10 min to obtain premix 1;

[0053] (2) Put the premix 1 of step (1) into the dry granulator, and granulate with a roller pressure of 2.5 MPa, a feeding speed of 30 rpm, a roller speed of 15 rpm, and a roller gap of about 0.1 mm, a granulating screen of 1.0 mm, and a granulating speed of 80 rpm; so that the proportion of fine powder (<150 μm) and large particles (>600 μm) is not more than 20%;

[0054] (3) Pour all the materials into the fixed hopper mixer, close the feeding port, and mix at a constant speed for 10 min to obtain the intermediate product granules;

[0055] (4) Take the intermediate product of step (3) and fill it using a full-automatic hard capsule filling machine, and control the filling amount to be about 389 mg to obtain the nemonoxacin malate capsule.

[0056] Example 3

[0057] This example discloses another nemonoxacin malate capsule and a preparation method thereof.

[0058] A nemonoxacin malate capsule is composed of the following components:

[0059] 85 parts by weight of nemonoxacin malate hemihydrate, 5 parts by weight of chitosan, 5 parts of anhydrous trisodium phosphate, 5 parts by weight of magnesium stearate, and 1 part by weight of gelatin hollow capsule;

[0060] Prepared according to the following method:

[0061] (1) Add nemonoxacin malate hemihydrate, chitosan, anhydrous trisodium phosphate and magnesium stearate into a fixed hopper mixer, mix at a constant speed for 10 min to obtain premix 1;

[0062] (2) Granulate the premix 1 of step (1) in a dry granulator, with a roller pressure of 2.5 MPa, a feeding speed of 30 rpm, a roller speed of 15 rpm, a roller gap of about 0.1 mm, a granulation screen of 1.0 mm, and a granulation speed of 80 rpm. The ratio of fine powder (<150 μm) and large particles (>600 μm) is not more than 20%;

[0063] (3) Pour all the materials into the fixed hopper mixer, close the feeding port, and mix at a constant speed for 10 min to obtain the intermediate product granules;

[0064] (4) Fill the intermediate product of step (3) using a full-automatic hard capsule filling machine, and control the filling amount to be about 389 mg to obtain nemonoxacin malate capsules.

[0065] Example 4

[0066] This example discloses another nemonoxacin malate capsule and a preparation method thereof.

[0067] A nemonoxacin malate capsule, which is composed of the following components:

[0068] 85 parts by weight of nemonoxacin malate hemihydrate, 10 parts by weight of anhydrous lactose and glycerol monostearate complex, 5 parts by weight of polyethylene glycol, and 1 part by weight of gelatin hollow capsule;

[0069] Prepared according to the following method:

[0070] (1) Add nemonoxacin malate hemihydrate, anhydrous lactose and glycerol monostearate complex, and polyethylene glycol into a fixed hopper mixer, mix at a constant speed for 10 min to obtain premix 1;

[0071] (2) Granulate the premix 1 of step (1) in a dry granulator, with a roller pressure of 4.0 MPa, a feeding speed of 30 rpm, a roller speed of 6 rpm, a roller gap of 1.0 mm, a granulation screen of 1.0 mm, and a granulation speed of 90 rpm. The ratio of fine powder (<150 μm) and large particles (>600 μm) is not more than 20%;

[0072] (3) Pour all the materials into the fixed hopper mixer, close the feeding port, and mix at a constant speed for 5 min to obtain the intermediate product granules;

[0073] (4) Take the intermediate product of step (3) and fill it using a full-automatic hard capsule filling machine, control the loading amount to be about 389 mg, and obtain nemonoxacin malate capsules.

[0074] Example 5

[0075] This example discloses another nemonoxacin malate capsule and a preparation method thereof.

[0076] A nemonoxacin malate capsule is composed of the following components:

[0077] 85 parts by weight of nemonoxacin malate hemihydrate, 8 parts by weight of anhydrous lactose and glycerol monostearate complex, 5 parts by weight of magnesium stearate, 2 parts by weight of hydrogenated vegetable oil, and 1 part by weight of polyvinyl acetate hollow capsule;

[0078] It is prepared according to the following method:

[0079] (1) Put nemonoxacin malate hemihydrate, anhydrous lactose and glycerol monostearate complex, and magnesium stearate and hydrogenated vegetable oil into a fixed hopper mixer, mix at a constant speed for 10 min, and obtain premix 1;

[0080] (2) Put the premix 1 of step (1) into a dry granulator, and the pressure of the compression roller is 3.0 MPa, the feeding speed is 25 rpm, the compression roller speed is 8 rpm, the compression roller gap is 0.1 mm, the granulation screen is 1.0 mm, and the granulation speed is 80 rpm. The ratio of fine powder (<150 μm) and large particles (>600 μm) is not more than 20%;

[0081] (3) Pour the material obtained in step (2) into a fixed hopper mixer, close the feeding port, and mix at a constant speed for 5 min to obtain intermediate product granules;

[0082] (4) Take the intermediate product of step (3) and fill it using a full-automatic hard capsule filling machine, control the loading amount to be about 389 mg, and obtain nemonoxacin malate capsules.

[0083] Example 6

[0084] This example discloses another nemonoxacin malate capsule and a preparation method thereof.

[0085] A nemonoxacin malate capsule is composed of the following components:

[0086] 85 parts by weight of nemonoxacin malate hemihydrate, 8 parts by weight of anhydrous lactose and glycerol monostearate complex, 5 parts by weight of magnesium stearate, 2 parts by weight of hydrogenated vegetable oil, and 1 part by weight of polyvinyl acetate hollow capsule;

[0087] It is prepared according to the following method:

[0088] (1) Put nemonoxacin malate hemihydrate, anhydrous lactose and glyceryl monostearate complex, and magnesium stearate, sodium aluminum silicate into a fixed hopper mixer, and mix at a constant speed for 5 min to obtain premix 1;

[0089] (2) Granulate the premix 1 of step (1) in a dry granulator, with a roller pressure of 2.0 MPa, a feeding speed of 25 rpm, a roller speed of 6 rpm, a roller gap of 0.5 mm, a granulation screen of 1.0 mm, and a granulation speed of 60 rpm. The proportion of fine powder (<150 μm) and large particles (>600 μm) is not more than 20%;

[0090] (3) Pour the material obtained in step (2) into a fixed hopper mixer, close the feeding port, and mix at a constant speed for 10 min to obtain intermediate product granules;

[0091] (4) Fill the intermediate product of step (3) using a full-automatic hard capsule filling machine, and control the filling amount to be about 389 mg to obtain nemonoxacin malate capsules.

[0092] Example 7

[0093] This example discloses another nemonoxacin malate capsule and a preparation method thereof.

[0094] A nemonoxacin malate capsule is composed of the following ingredients:

[0095] 85 parts by weight of nemonoxacin malate hemihydrate, 8 parts by weight of anhydrous lactose and glyceryl monostearate complex, 5 parts by weight of sodium aluminum silicate, 2 parts by weight of glyceryl distearate, and 1 part by weight of gelatin hollow capsules;

[0096] and is prepared by the following method:

[0097] (1) Put nemonoxacin malate hemihydrate, anhydrous lactose and glyceryl monostearate complex, and sodium aluminum silicate, glyceryl distearate into a fixed hopper mixer, and mix at a constant speed for 10 min to obtain premix 1;

[0098] (2) Granulate the premix 1 of step (1) in a dry granulator, with a roller pressure of 4.0 MPa, a feeding speed of 40 rpm, a roller speed of 15 rpm, a roller gap of 0.8 mm, a granulation screen of 1.0 mm, and a granulation speed of 75 rpm. The proportion of fine powder (<150 μm) and large particles (>600 μm) is not more than 20%;

[0099] (3) Pour the material obtained in step (2) into a fixed hopper mixer, close the feeding port, and mix at a constant speed for 5 min to obtain intermediate product granules;

[0100] (4) Take the intermediate product of step (3) and fill it using a full-automatic hard capsule filling machine, control the loading amount to be about 389 mg, and obtain nemonoxacin malate capsules.

[0101] Example 8

[0102] This example discloses another nemonoxacin malate capsule and a preparation method thereof.

[0103] A nemonoxacin malate capsule is composed of the following components:

[0104] 85 parts by weight of nemonoxacin malate hemihydrate, 15 parts by weight of anhydrous lactose and glycerol monostearate complex, and 1 part by weight of gelatin hollow capsule;

[0105] It is prepared according to the following method:

[0106] (1) Add nemonoxacin malate hemihydrate and anhydrous lactose and glycerol monostearate complex into a fixed hopper mixer, mix at a mixing speed of 10 rpm for 10 min, and obtain premix 1;

[0107] (2) Granulate the premix 1 of step (1) in a dry granulator, the pressure of the compression roller is 4.0 MPa, the feeding speed is 30 rpm, the speed of the compression roller is 6 rpm, the gap between the compression rollers is 1.0 mm, the screen mesh for granulation is 1.0 mm, and the granulation speed is 100 rpm. The proportion of fine powder (<150 μm) and large particles (>600 μm) is not more than 20%;

[0108] (3) Pour all the materials into the fixed hopper mixer, close the feeding port, mix at a mixing speed of 15 rpm for 10 min, and obtain intermediate product granules;

[0109] (4) Take the intermediate product of step (3) and fill it using a full-automatic hard capsule filling machine, control the loading amount to be about 389 mg, and obtain nemonoxacin malate capsules.

[0110] Example 9

[0111] This example discloses another nemonoxacin malate capsule and a preparation method thereof.

[0112] A nemonoxacin malate capsule is composed of the following components:

[0113] 85 parts by weight of nemonoxacin malate hemihydrate, 15 parts by weight of anhydrous lactose and glycerol monostearate complex, and 1 part by weight of gelatin hollow capsule;

[0114] It is prepared according to the following method:

[0115] (1) Add the nemonoxacin malate hemihydrate, anhydrous lactose and glyceryl monostearate complex into a fixed hopper mixer, mix at a mixing speed of 10 rpm for 10 min to obtain premix 1;

[0116] (2) Granulate the premix 1 of step (1) in a dry granulator, with a roller pressure of 4.0 MPa, a feeding speed of 30 rpm, a roller speed of 6 rpm, a roller gap of 1.0 mm, a granulating screen of 1.0 mm and a granulating speed of 100 rpm. The ratio of fine powder (<250 μm) and large particles (>1400 μm) is not more than 20%;

[0117] (3) Pour all the materials into the fixed hopper mixer, close the feeding port, mix at a mixing speed of 15 rpm for 10 min to obtain the intermediate product granules;

[0118] (4) Fill the intermediate product of step (3) using a full-automatic hard capsule filling machine, and control the filling amount to be about 389 mg to obtain the nemonoxacin malate capsules.

[0119] Example 10

[0120] This example discloses another nemonoxacin malate capsule and a preparation method thereof.

[0121] A nemonoxacin malate capsule is composed of the following components:

[0122] 88.95 parts by weight of nemonoxacin malate hemihydrate, 11.05 parts by weight of anhydrous lactose and glyceryl monostearate complex, and 1 part by weight of gelatin hollow capsule;

[0123] Prepared according to the following method:

[0124] (1) Add the nemonoxacin malate hemihydrate, anhydrous lactose and glyceryl monostearate complex into a fixed hopper mixer, mix at a mixing speed of 10 rpm for 10 min to obtain premix 1;

[0125] (2) Granulate the premix 1 of step (1) in a dry granulator, with a roller pressure of 4.0 MPa, a feeding speed of 30 rpm, a roller speed of 6 rpm, a roller gap of 1.0 mm, a granulating screen of 1.0 mm and a granulating speed of 100 rpm. The ratio of fine powder (<150 μm) and large particles (>600 μm) is not more than 20%;

[0126] (3) Pour all the materials into the fixed hopper mixer, close the feeding port, mix at a mixing speed of 15 rpm for 10 min to obtain the intermediate product granules;

[0127] (4) Take the intermediate product of step (3) and fill it using a full-automatic hard capsule filling machine, and control the filling amount to be about 389 mg to obtain nemonoxacin malate capsules.

[0128] Comparative Example 1

[0129] This comparative example discloses another nemonoxacin malate capsule and a preparation method thereof.

[0130] A nemonoxacin malate capsule is composed of the following components:

[0131] 88.95 parts by weight of nemonoxacin malate hemihydrate, 11.05 parts by weight of magnesium stearate, and 1 part by weight of gelatin hollow capsules;

[0132] It is prepared according to the following method:

[0133] (1) Add nemonoxacin malate hemihydrate and magnesium stearate into a fixed hopper mixer, mix at a mixing speed of 10 rpm for 10 min to obtain premix 1;

[0134] (2) Add the premix 1 of step (1) into a dry granulator to granulate, the pressure of the compression roller is 4.0 MPa, the feeding speed is 30 rpm, the speed of the compression roller is 6 rpm, the gap between the compression rollers is 1.0 mm, the screen mesh for granulation is 1.0 mm, and the granulation speed is 100 rpm. The proportion of fine powder (<150 μm) and large particles (>600 μm) is not more than 20%;

[0135] (3) Pour all the materials into the fixed hopper mixer, close the feeding port, and mix at a mixing speed of 15 rpm for 10 min to obtain the intermediate product granules;

[0136] (4) Take the intermediate product of step (3) and fill it using a full-automatic hard capsule filling machine, and control the filling amount to be about 389 mg to obtain nemonoxacin malate capsules.

[0137] 1. In vitro study

[0138] The nemonoxacin malate capsules prepared according to the preparation methods of Examples 1-10 and Comparative Example 1 were subjected to pH 6.8 medium dissolution data experiments together with a commercially available product (trade name: Taizhixin, manufacturer: Zhejiang Pharmaceutical Co., Ltd. Xinchang Pharmaceutical Factory).

[0139] The dissolution rate of the capsules prepared according to the preparation method of Examples 1-10 and Comparative Example 1 was determined according to the second method of Chinese Pharmacopoeia (2025 edition) General Rule 0931, with a medium volume of 900 ml, a medium temperature of 37.5°C±0.5°C, a dissolution instrument rotation speed of 50 rpm, sampling detection at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, and 60 min, respectively, and simultaneously adding the same volume of medium after sampling. The sample was filtered with a 0.45 um microporous filter membrane, and the absorbance was determined at a wavelength of 293 mm by ultraviolet spectrophotometry. The cumulative dissolution rate of different samples in different media at different times was calculated and the dissolution rate curve was drawn.

[0140] The dissolution rate data of the capsules of nemonoxacin malate prepared according to the preparation method of Examples 1-10 and Comparative Example 1 and the commercially available product in pH 6.8 medium are shown in Table 1.

[0141] Table 1 Summary of dissolution data in pH 6.8 medium

[0142]

[0143] The dissolution rate curve of the capsules of nemonoxacin malate prepared according to the preparation method of Examples 1-10 and Comparative Example 1 and the commercially available product in pH 6.8 medium is shown in Figure 1 .

[0144] The dissolution rate data of the capsules of nemonoxacin malate prepared according to the preparation method of Examples 1-10 and Comparative Example 1 and the commercially available product in pH 4.5 medium are shown in Table 2.

[0145] Table 2 Summary of dissolution data in pH 4.5 medium

[0146]

[0147] The dissolution rate curve of the capsules of nemonoxacin malate prepared according to the preparation method of Examples 1-10 and Comparative Example 1 and the commercially available product in pH 4.5 medium is shown in Figure 2 .

[0148] The dissolution rate data of the capsules of nemonoxacin malate prepared according to the preparation method of Example 10 and the commercially available product in pH 1.2 medium are shown in Table 3.

[0149] Table 3 Summary of dissolution data in pH 1.2 medium

[0150]

[0151] The dissolution rate curve of the capsules of nemonoxacin malate prepared according to the preparation method of Example 10 and the commercially available product in pH 1.2 medium is shown in Figure 3 .

[0152] 2. Particle size study

[0153] Take the contents of the intermediate particles of Example 10 and the commercially available product, place them on different size screens, and shake sieve to the point where no particles fall, weigh, and obtain. The particle size distribution data are shown in Table 4.

[0154] Table 4 Summary of particle size study results

[0155]

[0156] From the in vitro dissolution data and the particle size study results, it can be seen that the nemonoxacin malate intermediate particles prepared in Example 10 have less fine powder; the dissolution RSD of the capsules in pH 6.8 medium and pH 4.5 medium is significantly smaller than that of the commercially available product. The preferred formulation process (the formulation disclosed in Example 10) has smaller batch-to-batch variation than the commercially available product.

[0157] 3. In vivo study

[0158] Nemonoxacin malate capsules prepared according to the preparation method of Example 10 and commercially available products (trade name: Taizhensheng, manufacturer: Zhejiang Pharmaceutical Co., Ltd. Xinchang Pharmaceutical Factory) were used for single oral administration after meals, random, open, two-sequence, two-period crossover bioequivalence test:

[0159] According to the requirements in the "Good Clinical Practice", ICH-M13A "Bioequivalence of oral solid immediate-release preparations" and the Chinese Pharmacopoeia 2020 edition Appendix General 9011 "Guiding principles for human bioavailability and bioequivalence of drug preparations", the study plan was developed according to the pharmacokinetic study literature of nemonoxacin malate capsules in humans.

[0160] The individual pharmacokinetic study data (plasma concentration, main pharmacokinetic parameters, and main pharmacokinetic parameter ratio) of nemonoxacin malate capsules prepared according to the preparation method of Example 10 and commercially available products after meals are shown in Table 5.

[0161] Table 5 Summary of individual pharmacokinetic study data of Example 10 and commercially available products after meals

[0162]

[0163] Table 6 Comparison of variation coefficients of pharmacokinetic studies after meals of Example 10 and commercially available products

[0164]

[0165] The average time-concentration curve (T-R) of nemonoxacin in the plasma samples of the post-meal test of nemonoxacin malate capsules prepared according to the preparation method of Example 10 and commercially available products is shown in Table 6. Figure 4

[0166] ​From the in vivo data, it can be seen that the in vivo absorption behavior of the nemonoxacin malate capsules (0.25 g) prepared according to Example 10 is basically the same as that of the commercial product, but the in vivo coefficient of variation is smaller than that of the commercial product.

[0167] 1. Stability study

[0168] The nemonoxacin malate capsules prepared according to the preparation method of Example 10 were tested together with the commercial product (trade name: Taizhensheng, manufacturer: Xinchang Pharmaceutical Factory of Zhejiang Pharmaceutical Co., Ltd.) for related substance 0 days and accelerated 3 months data, and the experimental conditions were: temperature 40℃±2℃, relative humidity 75%±5%.

[0169] Determination by high performance liquid chromatography (Chinese Pharmacopoeia 2025 Edition General 0512).

[0170] Test solution: Take about 30 mg of the contents of the product (equivalent to about 20 mg of nemonoxacin), accurately weigh, dissolve and quantitatively dilute to prepare a solution containing about 0.2 mg of nemonoxacin per 1 ml.

[0171] Control solution: Take appropriate amounts of nemonoxacin malate reference substance, impurity 2405AZ02, impurity 2405AZ04, impurity 2405AZ05, impurity 2405AZ06 and impurity 2405AZ07, accurately weigh, dissolve in solvent and quantitatively dilute to prepare a mixed solution containing about 0.4 μg of nemonoxacin, impurity 2405AZ02, impurity 2405AZ04, impurity 2405AZ05, impurity 2405AZ06 and impurity 2405AZ07 per 1 ml.

[0172] System suitability solution: Take appropriate amounts of each reference solution, accurately weigh, dissolve in solvent and quantitatively dilute to prepare a mixed solution containing about 0.2 mg of nemonoxacin, 0.2 μg of impurity 2405AZ02 and impurity 2405AZ04, and 0.4 μg of impurity 2405AZ05, impurity 2405AZ06 and impurity 2405AZ07 per 1 ml.

[0173] Sensitivity solution: accurately measure an appropriate amount of the reference solution, quantitatively dilute with solvent to prepare a solution containing about 0.1 μg of nemonoxacin per 1 ml.

[0174] Chromatographic conditions: octadecylsilane-bonded silica gel as the filler; triethylamine phosphate solution as mobile phase A and methanol as mobile phase B, gradient elution; flow rate of 0.6 ml per minute; column temperature of 30℃; detection wavelength of 297 nm; injection volume of 20 μl.

[0175] Determination method: accurately measure the reference solution and the test solution and inject them into the liquid chromatograph, and record the chromatogram.

[0176] The related substance data of the capsules of nemonoxacin malate prepared according to the preparation method of Example 10 and the commercially available product after 0 days and 3 months of acceleration are shown in Table 7. As shown in the table, the related substance of the capsules of nemonoxacin malate prepared in Example 10 does not increase significantly compared with the commercially available product, and the stability is better after 3 months of storage under the accelerated conditions of a temperature of 40℃±2℃ and a relative humidity of 75%±5%; therefore, the self-prepared capsules of nemonoxacin malate prepared using the new excipient have a higher related substance level than the commercially available product.

[0177] Table 7: Results of related substance study

[0178] The present application remedies the deficiencies of the existing capsules of nemonoxacin malate, and the use of the new excipient not only effectively establishes a good in-vivo and in-vitro correlation of the capsules of nemonoxacin malate, but also improves the problems of large individual drug difference and poor stability.

[0179] The above only describes the preferred embodiments of the present application and is not intended to limit the present application, and any modifications, equivalent replacements and improvements made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A capsule of nemonoxacin malate, characterized in that, The components include the following parts by weight: Nemonoxacin malate hemihydrate 80-90 parts by weight, filler 10-20 parts by weight, and hollow capsule 1 part by weight; The filler is composed of essential components and optional components: the essential components are anhydrous lactose and glycerin monostearate complex; the optional components are selected from one or more of polyethylene glycol, hydrogenated vegetable oil, sodium aluminosilicate, magnesium stearate, glycerin distearate, microcrystalline cellulose, chitosan, and anhydrous trisodium phosphate.

2. The capsule of nemonoxacin malate according to claim 1, characterized in that, The components include the following parts by weight: Nemonoxacin malate hemihydrate 88.95 parts by weight, filler 11.05 parts by weight, and hollow capsule 1 part by weight.

3. The capsule of nemonoxacin malate according to claim 1, characterized in that, The filler is anhydrous lactose and glycerin monostearate complex.

4. The capsule of nemonoxacin malate according to claim 1, characterized in that, The hollow capsule is selected from gelatin hollow capsules, hypromellose hollow capsules, or polyvinyl acetate hollow capsules.

5. The capsule of nemonoxacin malate according to claim 4, characterized in that, The hollow capsule is a gelatin hollow capsule.

6. The process for the preparation of nemonoxacin malate capsules according to claim 1, wherein, The preparation method includes the following steps: S1. Mix nemonoxacin malate hemihydrate and filler to obtain a premix 1; S2. Granulate the premix 1, wherein the proportion of fine powder and large particles is ≤20%; S3. Mix the granules obtained in step S2 to obtain intermediate granules; S4. Fill the intermediate granules into hollow capsules to obtain the nemonoxacin malate capsules.

7. The process for the preparation of capsules of nemonoxacin malate according to claim 6, characterized in that, The rotation speed and time of mixing in step S1 are 10 rpm and 10 min, respectively; the rotation speed and time of mixing in step S3 are 15 rpm and 5 min, respectively.

8. The process for the preparation of capsules of nemonoxacin malate according to claim 6, characterized in that, In step S2, a dry granulator is used for granulation, and the pressure of the compression roller of the dry granulator is 2.0-4.0 MPa, the feeding rotation speed is 25-40 rpm, the compression roller speed is 6-15 rpm, the compression roller gap is 0.1-1.0 mm, the granulation screen is 1.0 mm, and the granulation rotation speed is 60-100 rpm.

9. The process for the preparation of capsules of nemonoxacin malate according to claim 6, characterized in that, In step S2, the particle size of the fine powder is <150 μm, and the particle size of the large particles is >600 μm.

10. The process for the preparation of capsules of nemonoxacin malate according to claim 6, characterized in that, In step S4, the filling speed is 1800-2100 particles per minute, and the single-particle content weight of the nemonoxacin malate capsule is 0.389 g.

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