CN112915068A

CN112915068A - Sitafloxacin fine granule and preparation process thereof

Info

Publication number: CN112915068A
Application number: CN201911231403.6A
Authority: CN
Inventors: 曹龙祥; 韦明元; 许斌; 万华斌; 蔡虎
Original assignee: Jumpcan Pharmaceutical Group Co ltd
Current assignee: Jumpcan Pharmaceutical Group Co ltd
Priority date: 2019-12-05
Filing date: 2019-12-05
Publication date: 2021-06-08

Abstract

The invention discloses a sitafloxacin fine granule and a preparation process thereof. According to the invention, by adjusting the dosage and the component ratio of the isolation and the coating in the granulation process, the problems of too fast disintegration, caking, poor dispersibility and the like which are easily caused by more types of auxiliary materials and larger prescription amount in the preparation process of the sitafloxacin fine granule can be effectively solved, and the obtained finished product has narrower particle size distribution, uniform mixing and better dissolution effect. The invention has the advantages of cheap and easily obtained auxiliary materials, easy preparation, no need of special equipment, short production period and low cost, and is very suitable for industrial production.

Description

Sitafloxacin fine granule and preparation process thereof

Technical Field

The invention belongs to the technical field of medicines, and mainly relates to a preparation method of sitafloxacin fine granules.

Background

Sitafloxacin (Sitafloxacin, DU-6859a) was a broad-spectrum quinolone antibacterial developed by the first pharmaceutical third corporation of japan (Daiichi Sankyo) and was chemically named 7- [ (7S) -7-amino-5-azaspiro [2.4] hept-5-yl ] -8-chloro-6-fluoro-1- [ (1R,2S) -cis-2-fluorocyclopropyl ] -1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid.

Research shows that the sitafloxacin has broad-spectrum antibacterial activity on a plurality of gram-positive bacteria, gram-negative bacteria and anaerobic bacteria clinical isolates including fluoroquinolone drug-resistant strains, and also has good bactericidal action on a plurality of clinically common fluoroquinolone drug-resistant strains. And the probability of drug resistance mutation of sitafloxacin during treatment is lower than that of other fluoroquinolone drugs.

The invention patents with patent numbers CN102988298A and CN105663054A respectively disclose two preparation methods of sitafloxacin hydrate granules, wherein the former improves the problem of peculiar smell of the sitafloxacin hydrate granules, and the latter effectively covers the bitter taste of the sitafloxacin hydrate, has uniform granules and high dissolution rate, but the two methods do not effectively solve the problems of too fast disintegration, easy caking and poor dispersibility of the granules. The invention patent with the patent number of CN103156821A discloses a sitafloxacin hydrate tablet composition and a preparation method thereof, and the literature, "screening and preparation process of a sitafloxacin hydrate tablet prescription" discloses a preparation method of a sitafloxacin hydrate tablet, and both the sitafloxacin hydrate tablet composition and the preparation method thereof improve the dissolution rate of the tablet.

Compared with other solid preparations such as tablets, capsules, granules and the like, the fine granule has the characteristics of high dissolution rate, high bioavailability, good medicament stability, easy administration and the like. At present, besides the dosage form adopted by a large amount of oral antibiotic medicines, digestive tract medicines, vitamin medicines, cardiovascular and cerebrovascular medicines, health-care medicines and the like are produced in turn by the novel dosage form. The invention with the patent number of CN105708807A discloses a preparation method of epinastine hydrochloride fine granules, wherein a proper amount of essence is added into the preparation to generate a synergistic effect, so that the bitter taste of epinastine is effectively covered, the medication compliance of patients is improved, and the problems that the epinastine hydrochloride fine granules are large in particle size distribution and more in particle fine powder are solved; the invention patent with the patent number of CN109432044A discloses a preparation method of tebipenem ester, and the particles obtained by the method have uniform size, so that the dissolution of the medicine can be ensured, the stability of the medicine is improved, and the unpleasant odor of the medicine can be covered.

Compared with fine particle preparations of tebipenem pivoxil and epinastine hydrochloride, the clinical requirement on the quality of the fine particle preparation of sitafloxacin is high, and the particle size, the particle size distribution and the fluidity of the particles have certain influence on the in vitro dissolution and in vivo absorption of the medicament. The sitafloxacin fine particle preparation needs more types of auxiliary materials and has larger prescription amount, so the influence of the granularity and the dosage of the auxiliary materials and the weight increment of a coating on the granularity of a final finished product increases the difficulty of granulation besides the granularity of the sitafloxacin raw material, and the granules with narrower particle size distribution, uniform mixing and better dissolution effect are difficult to obtain.

Disclosure of Invention

The invention provides a novel preparation process of sitafloxacin fine granules, which can achieve the following technical effects:

through improving the processes of granulation, isolation, coating and the like, the surface roughness of the particles is reduced, and the obtained particles are loose, uniform in particle size distribution and obviously improved in fluidity;

the particle size of raw and auxiliary materials, intermediates and finished product particles is controlled in the processes of raw and auxiliary material pretreatment, granulation, coating and the like of the sitafloxacin fine granule, so that the problems of large particle size distribution and poor uniformity of the sitafloxacin fine granule are effectively solved, the coating effect is obviously improved, the permeability of the preparation is improved, the bioavailability is improved, and the absorption capacity of the medicine in the body is improved;

by controlling parameters such as isolated weight gain, coating weight gain, dosage of hydroxypropyl cellulose and corn starch and the like, the quality of intermediate and finished product granules is obviously improved, the problems of excessively fast disintegration, caking, poor dispersibility and the like of sitafloxacin granules are effectively solved, the dissolution effect of the medicine is improved, and the stability of the medicine is improved.

On one hand, the application provides a preparation process of sitafloxacin fine granules, which comprises the following steps:

(1) pretreatment: sieving sitafloxacin hydrate with 200 mesh sieve, pulverizing filler, and sieving with 80 mesh sieve; respectively collecting undersize products;

(2) mixing: respectively sieving a disintegrating agent with a formula dosage, the sieved sitafloxacin hydrate obtained in the step (1) and a filling agent through a second pharmacopoeia sieve, and mixing undersize materials to obtain a material 1;

(3) preparation of adhesive solution: dissolving the adhesive with the formula dosage by using purified water to obtain an adhesive solution;

(4) and (3) granulating: mixing the material 1 obtained in the step (2) and the adhesive solution obtained in the step (3) for granulation, drying until the moisture content is less than or equal to 2.0% after the granulation is finished, or stopping drying until the moisture content is less than or equal to 2.0% after the drying is carried out for 20 minutes; obtaining a material 2;

(5) isolation: spraying the isolating liquid on the material 2 obtained in the step (4), namely the inner core of the particle, and then drying until the moisture is less than or equal to 2.0 percent, or drying for 20 minutes until the moisture is not less than 2.0 percent, and stopping drying; sieving with a first pharmacopoeia sieve, and collecting undersize to obtain a material 3;

(6) preparing a coating solution: dissolving a suspending agent with a formula dosage in water at 80 ℃, cooling to room temperature, adding water to the formula dosage, respectively grinding and homogenizing the suspending agent solution and an anti-sticking agent, a plasticizer, a coloring agent, a pore-forming agent, a sweetening agent and a flavoring agent with the formula dosage in a colloid mill for 20 minutes, and uniformly mixing to prepare a pigment suspension; pouring the pigment suspension into the polymer aqueous dispersion, and uniformly stirring at a low speed to prepare a coating solution;

(7) coating: coating the material 3 obtained in the step (5) by using the coating solution prepared in the step (6), drying after coating, measuring the moisture after drying for 4 hours at 40 ℃ by using an oven, and taking out the material when the moisture is less than or equal to 2.0 percent to obtain a material 4;

(8) sieving and total mixing: and (4) sieving the material 4 obtained in the step (7) by a second pharmacopoeia sieve, collecting undersize products, adding a flow aid with a formula dosage, and mixing to obtain the sitafloxacin fine granule.

The filler in the step (1) includes but is not limited to one or more of the following raw materials: mannitol, corn starch, microcrystalline cellulose, lactose and dextrin.

The disintegrating agent in the step (2) includes but is not limited to one or more of the following raw materials: corn starch, microcrystalline cellulose, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and croscarmellose sodium.

The adhesive in step (3) includes, but is not limited to, one or more of the following raw materials: hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and polyethylene glycol 4000.

The isolating solution in the step (5) is an aqueous solution of an isolating agent, and the isolating agent comprises but is not limited to one or more of the following raw materials: hydroxypropyl cellulose, hydroxypropyl methylcellulose.

The suspending agent in the step (6) comprises but is not limited to one or more of the following raw materials: sodium carboxymethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose.

The antisticking agent in the step (6) comprises but is not limited to one or more of the following raw materials: talcum powder and silica gel micropowder.

The plasticizer in the step (6) includes but is not limited to one or more of the following raw materials: triethyl citrate and polyethylene glycol 400.

The colorant in step (6) includes but is not limited to one or more of the following raw materials: yellow iron oxide and red iron oxide.

The pore-foaming agent in the step (6) includes but is not limited to one or more of the following raw materials: lactose, povidone.

The sweetener in the step (6) includes but is not limited to one or more of the following raw materials: aspartame, sorbitol, mannitol and lactose.

The flavoring agent in the step (6) comprises but is not limited to one or more of the following raw materials: orange essence, apple essence and vanillin essence.

The aqueous polymer dispersion described in step (6), which in some embodiments is an aqueous methacrylic acid and ethyl acrylate copolymer dispersion comprising a methacrylic acid and ethyl acrylate copolymer, polysorbate 80, and sodium dodecyl sulfate.

The glidant in the step (8) comprises but is not limited to one or more of the following raw materials: colloidal silica, talc.

In the implementation process of the invention, all the water used is medical purified water unless specified.

More specifically, the application provides a preparation process of fine sitafloxacin hydrate powder, which comprises the following steps:

(1) pretreatment: sieving sitafloxacin hydrate with 200 mesh sieve, sieving mannitol with 80 mesh sieve, pulverizing microcrystalline cellulose, and sieving with 80 mesh sieve; respectively collecting undersize products;

(2) mixing: respectively sieving corn starch with a formula dosage, the sieved sitafloxacin hydrate obtained in the step (1), microcrystalline cellulose and mannitol through a second pharmacopoeia sieve, and mixing undersize products to obtain a material 1;

(3) preparation of adhesive solution: dissolving hydroxypropyl cellulose (HPC-L) with formula dosage in purified water to obtain adhesive solution;

(5) isolation: spraying the isolating liquid on the material 2 obtained in the step (4), namely the inner core of the particle, and then drying until the moisture is less than or equal to 2.0 percent, or drying for 20 minutes until the moisture is not less than 2.0 percent, and stopping drying; sieving with a first pharmacopoeia sieve, and collecting undersize to obtain a material 3; the isolation solution is hydroxypropyl cellulose solution;

(6) preparing a coating solution: dissolving sodium carboxymethylcellulose in a formula amount in water at 80 ℃, cooling to room temperature, adding water until the total weight of the solution is 250g, respectively grinding and homogenizing the sodium carboxymethylcellulose solution and talcum powder, triethyl citrate, yellow ferric oxide, lactose, aspartame and orange essence in the formula amount in a colloid mill for 20 minutes, and uniformly mixing to obtain a pigment suspension; pouring the pigment suspension into the methacrylic acid and ethyl acrylate copolymer aqueous dispersion, and uniformly stirring at a low speed to prepare a coating solution;

(7) coating: coating the material 3 obtained in the step (5) by using the coating solution prepared in the step (6), drying after coating, measuring the moisture after drying for 4 hours at 40 ℃ by using an oven, and taking out the material when the moisture is less than 2.0% to obtain a material 4;

(8) sieving and total mixing: and (4) screening the material 4 obtained in the step (7) by a second pharmacopoeia sieve, collecting undersize products, adding silicon dioxide with the formula dosage, and mixing to obtain the fine sitafloxacin particle.

On the other hand, the application provides a fine sitafloxacin hydrate preparation prepared by the preparation method, and the fine sitafloxacin hydrate preparation comprises the following components in parts by weight: 8-11 parts of sitafloxacin hydrate, 65-80 parts of filler, 7-11 parts of disintegrating agent, 4-6 parts of adhesive, 2-5 parts of isolating agent, 1-6 parts of film forming agent, 0.02-0.15 part of stabilizing agent, 0.01-0.06 part of emulsifying agent, 0.05-0.4 part of suspending agent, 0.04-0.25 part of coloring agent, 1-10 parts of anti-sticking agent, 0.1-0.6 part of plasticizer, 0.01-0.1 part of pore-forming agent, 0.03-0.2 part of sweetening agent, 0.04-0.25 part of flavoring agent and 0.4-0.6 part of glidant.

In some specific embodiments, the fine sitafloxacin hydrate preparation comprises the following components in parts by weight: 8-11 parts of sitafloxacin hydrate, 50-70 parts of mannitol, 7-11 parts of corn starch, 1.5-2.5 parts of microcrystalline cellulose, 7-10 parts of hydroxypropyl cellulose, 1-6 parts of methacrylic acid and ethyl acrylate copolymer, 0.15 part of polysorbate 800.02, 0.01-0.06 part of sodium dodecyl sulfate, 0.05-0.4 part of sodium carboxymethyl cellulose, 0.04-0.25 part of ferric oxide, 1-10 parts of talcum powder, 0.1-0.6 part of triethyl citrate, 0.01-0.1 part of lactose, 0.03-0.2 part of aspartame, 0.04-0.25 part of orange essence and 0.4-0.6 part of colloidal silicon dioxide.

The product of the invention can effectively solve the problem that the sitafloxacin fine granule is easy to appear due to more types of auxiliary materials and larger prescription amount in the preparation process, and the obtained finished product has narrower particle size distribution, uniform mixing and better dissolution effect. The invention has the advantages of cheap and easily obtained auxiliary materials, easy preparation, no need of special equipment, short production period and low cost, and is very suitable for industrial production.

Drawings

Fig. 1 shows a flow chart of a preparation method of sitafloxacin fine granule.

Fig. 2 shows micrographs of product particles at different stages of the preparation process of example 1, wherein the materials 2, 3 and 4 and the finished product are shown from top to bottom, respectively, and the conditions are 40 × bright field, 40 × polarizing field, 100 × bright field and 100 × polarizing field, respectively, from left to right.

FIG. 3 shows a particle micrograph of the finished product of examples 2 to 9, wherein the finished product of examples 2 to 9 is shown from top to bottom, respectively, under the conditions of 40 Xbright field, 40 Xpolarized field, 100 Xbright field, and 100 Xpolarized field, respectively, from left to right.

FIG. 4 shows micrographs of particles from the end products of examples 10-11, wherein the end products of examples 10 and 11 are shown from top to bottom, respectively, under the conditions of 40 Xbright field, 40 Xpolarized field, 100 Xbright field, and 100 Xpolarized field, respectively, from left to right.

FIG. 5 shows the results of the dissolution curve of the final particles of the different examples in pH5.0 medium.

Detailed Description

The following examples are provided only for further details of the technical solutions of the present invention and should not be construed as limiting the scope of the present invention, and the insubstantial modifications and adaptations of the present invention by those skilled in the art based on the above descriptions are included in the scope of the present invention. The auxiliary materials used in the invention are all commercial products.

The raw material sources are as follows: the mannitol of the present invention is purchased from Shijiazhuang Huaxu pharmaceutical Co., Ltd; the corn starch is purchased from Anhui mountain river pharmaceutic adjuvant, Inc.; the microcrystalline cellulose was purchased from ritenmeir father, germany; the hydroxypropyl cellulose was purchased from japan caokada corporation; the methacrylic acid-ethyl acrylate copolymer aqueous dispersion (ewt chi L30D-55) was purchased from won chu specialty chemicals ltd; the sodium carboxymethylcellulose is purchased from chemical company Limited, Ashland; the yellow iron oxide is purchased from Shanghai Yipin pigment Co., Ltd; the talcum powder is purchased from Guilin Guiguang Talcum development Co Ltd; the triethyl citrate is purchased from Senmura corporation; the lactose is purchased from KANGFU bioengineering GmbH of Zhenjiang city; the aspartame is purchased from ninx pharmaceutical products, ltd, Hunan; the orange essence is purchased from Shanghai Bao Hua Peacock essence Co., Ltd; the colloidal silica was purchased from pharmaceutic adjuvant, Inc., of mountain river, Anhui.

Sitafloxacin hydrate was obtained from the society of medicinal and pharmaceutical industries, ltd.

Example 1 the preparation method was:

(1) pretreatment of raw materials and auxiliary materials: the sitafloxacin hydrate is manually sieved by a 200-mesh sieve, the mannitol is manually sieved by a 80-mesh sieve, and the microcrystalline cellulose is crushed and sieved by the 80-mesh sieve.

(2) Mixing: weighing the sieved sitafloxacin hydrate, microcrystalline cellulose, mannitol and corn starch according to the prescription amount, and sieving and mixing the weighed materials by a second pharmacopoeia sieve.

(3) Preparation of adhesive solution: adding the calculated hydroxypropyl cellulose HPC-L into a beaker, and adding purified water for dissolving.

(4) And (3) granulating: and placing the raw material and auxiliary material mixture into a top spraying device of a fluidized bed, and spraying an adhesive solution after premixing and preheating. And (3) drying after granulation is finished, starting to detect moisture after drying for 3 minutes, sampling every 5 minutes to determine the moisture content of the granules, stopping drying when the moisture content detected by sampling is less than or equal to 2.0%, and stopping drying when the moisture content can not meet the moisture requirement after drying for 20 minutes. And (3) adjusting and recording the parameters of the fluidized bed in real time in the granulation process to keep good temperature, fluidization and boiling states of the materials, and calculating the yield.

(5) Isolation: and placing the particle inner cores in a fluidized bed bottom spraying device, setting preset parameters of a fluidized bed bag isolation layer, and spraying an isolation liquid after preheating. And (3) drying after the isolation is finished, detecting the moisture after the isolation is finished, measuring the moisture content of the granules every 5 minutes, stopping drying when the moisture content detected by sampling is less than or equal to 2.0%, and stopping drying when the moisture content cannot meet the moisture requirement after the isolation is finished for 20 minutes. And in the isolation process, parameters of the fluidized bed are adjusted and recorded in real time to keep good temperature, fluidization and boiling states of the materials. And (4) screening by a pharmacopoeia No. one sieve to remove large particles on the sieve, and calculating the yield.

(6) Preparing a coating solution: slowly pouring the sodium carboxymethylcellulose into water at the temperature of 80 ℃ while stirring, stirring until the sodium carboxymethylcellulose is dissolved, cooling, and adding water until the total weight is 250 g. Respectively pouring the sodium carboxymethyl cellulose solution and the prescribed amount of talcum powder, triethyl citrate, yellow ferric oxide, lactose, aspartame and orange essence into a colloid mill, cleaning with the rest water, grinding and homogenizing for 20 minutes to prepare the pigment suspension. The pigment suspension is slowly poured into the aqueous polymer dispersion while stirring at low speed, and stirring is continued until the coating process is finished. The coating liquid mass of each prescription is calculated and weighed. With the small volume of the coating liquid, the rotating speed of the stirring paddle should be adjusted slowly to avoid the generation of foam.

(7) Coating: spraying coating liquid after the fluidized bed is preheated. And (5) drying after coating is finished, drying for 2min, drying by using drying ovens with different temperatures and time, and monitoring the moisture of the particles by using a rapid moisture tester. And in the coating process, parameters of the fluidized bed are adjusted and recorded in real time to keep good temperature, fluidization and boiling states of the materials. The resulting particles were weighed and the yield calculated.

(8) Sieving: sieving the prepared particles by a second pharmacopoeia sieve, discarding large particles which can not pass the second pharmacopoeia sieve, and calculating the yield.

(9) Total mixing: weighing the sieved particles, weighing the silicon dioxide with the corresponding prescription amount, adding the silicon dioxide into the obtained particles, and manually mixing.

The formulation is shown in table 1.

Table 1a fine sitafloxacin formulation example 1

And (3) injecting 1, namely taking purified water as an adhesive, a solvent for preparing a spacer solution and a dispersion medium for preparing a coating solution, and removing the purified water in the process.

The granulation effect of example 1 is shown in fig. 2, and the surface roughness of the granules decreases with the granulation, isolation and coating processes. As shown in Table 1, the average particle diameter increased after segregation of the particles, the particle size distribution tended to disperse, and the fluidity did not change much. The finished product in example 1 shows the phenomenon of particle caking in the dissolution test, and has great influence on the determination result of the dissolution curve. In addition, the content results show that the content reduction is serious in the granulation process, and measures are required to be taken to avoid the content reduction.

(2) Examples 2 to 9

To improve the problems of the granules prepared in example 1, the experiment at this stage changed the formula of the coating solution, reduced the amount of hydroxypropyl cellulose in the formula, and examined the differences in the properties of the finished product under different isolation and weight gain conditions of the coating.

The fluidity of the isolated inner core of the particle becomes good, the particle size of the particle is slightly reduced by 2.5 percent of isolated weight increase, the particle size distribution tends to be concentrated, and the fluidity is obviously increased; the granularity of the particles which are isolated and weighted by 5 percent is obviously increased, the concentration degree of the granularity is almost unchanged, and the fluidity is obviously improved. Under the condition of 2.5 percent of isolated weight gain, the particle size of the coated particles is not changed greatly compared with that before coating, the particle size distribution tends to be dispersed, and the fluidity is slightly increased; under the condition of 5 percent isolated weight gain, the particle size and the distribution condition of the coated particles are not changed greatly and the fluidity is slightly increased compared with the particle size and the distribution condition before coating. Meanwhile, along with the increase of the weight of the coating, the opacity, the granularity and the fluidity of the particles under a microscope are increased, and the moisture content of the particles is gradually increased due to the increase of the liquid spraying amount under the same drying efficiency.

TABLE 2A Fine formulation of sitafloxacin hydrate, examples 2-9

TABLE 3 Fine formulation of sitafloxacin hydrate examples 2-9 spacer/binder solution formulations (5%, 2500g)

Name (R)	Dosage of
		Hydroxypropyl cellulose	125g
Water (W)	2375g

TABLE 4 Fine sitafloxacin formulation example 2-9 coating solution formulation (1000g)

Note: each 1% weight of the polymer corresponds to 2.96% weight of the solid content during coating.

TABLE 5 Fine sitafloxacin formulation examples 2-9 granular products corresponding to isolation and coating weight gain

(3) Examples 10 to 11

Examples 10 and 11 achieve the goal of suppressing the disintegration rate of the self-made granules by increasing the dosage of hydroxypropyl cellulose and decreasing the dosage of corn starch. The dissolution test result (fig. 4) shows that the amount of the formulated corn starch has a certain influence on the dissolution curve, after the amount of the formulated corn starch is reduced, the dissolution rate of the particles of example 11 is obviously reduced in the medium with pH5.0 compared with the particles of example 10, and the dissolution amount at the end point is also obviously reduced, and the expected results are consistent when the action scheme is established in the medium with pH5.0, namely, the slow disintegration is not beneficial to the dissolution of the sitafloxacin bulk drug in the high-solubility medium.

TABLE 6A fine sitafloxacin formulation examples 10-11

Second, testing and effect

Detection of an intermediate: after the granulating step, taking two samples of the upper part, the middle part, the lower part, the left part and the right part of the core pile in the granules respectively, wherein each sample is about 500mg to detect the content uniformity; about 30g of the obtained granules were sampled and used for observation by a polarizing microscope, and the particle size distribution thereof after being screened by a second, third, fourth, fifth, sixth, seventh, eighth and ninth pharmacopeia sieve was examined according to a double screening method in a second pharmacopeia particle size screening method of 2015 edition-manual screening method, and the angle of repose, the flow rate and the Carl coefficient of the granules were measured by using a JL-A3 type powder characteristic tester. During sampling, the uniform sampling is carried out on all parts of the particle pile.

Detecting an intermediate: after the isolating step, taking two samples of the upper part, the middle part, the lower part, the left part and the right part of the core pile in the particles respectively, wherein the content uniformity of each sample is about 500 mg; about 30g of the obtained granules were sampled and used for observation by a polarizing microscope, and the particle size distribution thereof after being screened by a second, third, fourth, fifth, sixth, seventh, eighth and ninth pharmacopeia sieve was examined according to a double screening method in a second pharmacopeia particle size screening method of 2015 edition-manual screening method, and the angle of repose, the flow rate and the Carl coefficient of the granules were measured by using a JL-A3 type powder characteristic tester. During sampling, the uniform sampling is carried out on all parts of the particle pile.

Detecting an intermediate body: after the sieving step, taking two samples at the upper part, the middle part, the lower part, the left part and the right part of the core pile in the granules respectively, wherein each sample is about 500mg to detect the content uniformity; about 30g of the obtained granules were sampled and used for observation by a polarizing microscope, and the particle size distribution thereof after being screened by a second, third, fourth, fifth, sixth, seventh, eighth and ninth pharmacopeia sieve was examined according to a double screening method in a second pharmacopeia particle size screening method of 2015 edition-manual screening method, and the angle of repose, the flow rate and the Carl coefficient of the granules were measured by using a JL-A3 type powder characteristic tester. During sampling, the uniform sampling is carried out on all parts of the particle pile.

As shown in fig. 2, in example 1, the surface roughness of the granules decreases with the granulation, isolation and coating processes.

As shown in Table 7, the particles of example 1 increased in average particle diameter after segregation, tended to disperse in particle size distribution, and showed little change in flowability.

TABLE 7 results of intermediate and final product testing in example 1

The finished product in example 1 shows the phenomenon of particle caking in the dissolution test, and has great influence on the determination result of the dissolution curve.

Examples 2 to 9

To improve the problems of example 1, the experiment at this stage optimizes the formulation of the coating solution, and attempts to reduce the amount of hydroxypropyl cellulose in the isolation layer in the prescription and examine the property differences of the finished granule product under different isolation and coating weight gains.

The results of the tests on the finished products of examples 2 to 9 are shown in Table 8. The fluidity of the isolated inner core of the particle becomes good, the particle size of the particle is slightly reduced by 2.5 percent of isolated weight increase, the particle size distribution tends to be concentrated, and the fluidity is obviously increased; the granularity of the particles with the isolation weight increment of 5.0 percent is obviously increased, the concentration degree of the granularity is almost unchanged, and the fluidity is obviously improved. Under the condition of 2.5 percent of isolated weight gain, the particle size of the coated particles is not changed greatly compared with that before coating, the particle size distribution tends to be dispersed, and the fluidity is slightly increased; under the condition of 5 percent isolated weight gain, the particle size and the distribution condition of the coated particles are not changed greatly and the fluidity is slightly increased compared with the particle size and the distribution condition before coating. Meanwhile, along with the increase of the weight of the coating, the opacity, the granularity and the fluidity of the particles under a microscope are increased, and the moisture content of the particles is gradually increased due to the increase of the liquid spraying amount under the same drying efficiency.

Table 8: examples 2 to 9 test results of finished products

Examples 10 to 11

Examples 10-11 the disintegration rate of the self-made granules was suppressed by increasing the amount of hydroxypropyl cellulose and decreasing the amount of corn starch.

The dissolution measurement result is shown in fig. 5, and the result shows that the formula amount of the corn starch has a certain influence on the dissolution curve, after the formula amount of the corn starch is reduced, the dissolution speed of the particles in the example 11 is obviously reduced in a medium with a pH value of 5.0 compared with the particles in the example 10, the dissolution amount at the end point is also obviously reduced, the effect in the medium with a pH value of 5.0 is consistent with the expected result when a scheme is established, namely, the slow disintegration is not beneficial to the dissolution of the sitafloxacin raw material drug in a high-solubility medium.

Table 9: examples 10 to 11 test results of finished products

Claims

1. The fine sitafloxacin granule is characterized by comprising an inner core, an isolating layer, a coating layer and a flow aid; wherein, the weight portion of the inner core is 78 to 90 portions; 2-5 parts of isolating layer; 5-18 parts of coating layer, 0.4-0.6 part of glidant and 150-200 mu m of sitafloxacin fine granules.

2. A fine sitafloxacin powder formulation as claimed in claim 1, wherein the inner core comprises the main drug sitafloxacin, a filler, a disintegrant, a binder; wherein the main drug sitafloxacin is 8-11 parts by weight, the adhesive is 4-6 parts by weight, the filling agent is 65-80 parts by weight, and the disintegrating agent is 7-11 parts by weight.

3. A fine sitafloxacin formulation according to claim 1, wherein the coating layer comprises film forming agents, stabilising agents, emulsifying agents, suspending agents, colouring agents, anti-sticking agents, plasticisers, pore-forming agents, sweetening agents and flavouring agents; wherein the weight portions of the film forming agent are 1 to 6 portions, the weight portion of the stabilizing agent is 0.02 to 0.15 portion, the weight portion of the emulsifying agent is 0.01 to 0.06 portion, the weight portion of the suspending agent is 0.05 to 0.4 portion, the weight portion of the coloring agent is 0.04 to 0.25 portion, the weight portion of the anti-sticking agent is 1 to 10 portions, the weight portion of the plasticizing agent is 0.1 to 0.6 portion, the weight portion of the pore-forming agent is 0.01 to 0.1 portion, the weight portion of the sweetening agent is 0.03 to 0.2 portion, and the weight portion of the flavoring agent is 0.04 to 0.25 portion.

4. The fine sitafloxacin powder preparation according to claim 2, wherein the main drug sitafloxacin is sitafloxacin hydrate.

5. The preparation method of the sitafloxacin fine granule is characterized by comprising the following steps:

(1) pretreatment: sieving sitafloxacin hydrate, pulverizing filler, and sieving; respectively collecting undersize products;

(2) mixing: respectively sieving the disintegrating agent, the sieved sitafloxacin hydrate obtained in the step (1) and the filler through a second pharmacopoeia sieve, and mixing undersize products to obtain a material 1;

(3) preparation of adhesive solution: dissolving the adhesive by using purified water to obtain an adhesive solution;

(4) and (3) granulating: mixing the material 1 obtained in the step (2) and the adhesive solution obtained in the step (3) for granulation, and drying after granulation to obtain a material 2;

(5) isolation: spraying the isolation liquid on the material 2 obtained in the step (4), namely the inner core of the particles, drying, screening by a first pharmacopeia screen, and collecting undersize to obtain a material 3;

(6) preparing a coating solution: dissolving a suspending agent in water at the temperature of 80 ℃, cooling to room temperature, adding water, respectively grinding and homogenizing the suspending agent solution and the colorant, the antisticking agent, the plasticizer, the pore-forming agent, the sweetener and the flavoring agent according to the formula amount in a colloid mill, and uniformly mixing to obtain a pigment suspension; pouring the pigment suspension into the polymer aqueous dispersion, and uniformly stirring to obtain a coating solution;

(7) coating: coating the material 3 obtained in the step (5) by using the coating liquid prepared in the step (6), and drying after coating to obtain a material 4;

6. The production method according to claim 5, wherein the termination conditions of the drying step in the steps (4) and (7) are: drying until the water content is less than or equal to 2.0 percent, and stopping drying; or stopping drying when the water content is not more than 2.0% after drying for 20 minutes.

7. The method according to claim 2 and 5, wherein the filler comprises one or more of mannitol, corn starch, microcrystalline cellulose, lactose and dextrin; the disintegrating agent is one or more of corn starch, microcrystalline cellulose, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and croscarmellose sodium; the adhesive comprises one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and polyethylene glycol 4000.

8. The composition according to claims 3 and 5, wherein the suspending agent comprises one or more of sodium carboxymethylcellulose, methylcellulose, hydroxypropyl cellulose and hypromellose; the colorant comprises one or more of yellow iron oxide and red iron oxide; the anti-sticking agent comprises one or more of talcum powder and micro silica gel; the plasticizer comprises one or more of triethyl citrate and polyethylene glycol 400; the pore-forming agent comprises one or more of lactose and polyvidone; the sweetener comprises: one or more of aspartame, sorbitol, mannitol and lactose; the flavoring agent comprises one or more of orange essence, apple essence and vanillin essence.