CN112545996B - Cephalosporin granules and preparation method thereof - Google Patents

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a cephalosporin granule and a preparation method thereof. The cephalosporin granules comprise the following components in parts by weight: 20 to 40 portions of cephalosporin active ingredient, 2 to 10 portions of disintegrant, 0.5 to 2 portions of adhesive, 0.5 to 2 portions of glidant and 240 to 480 portions of flavoring agent. The cephalosporin granules disclosed by the invention have the advantages that the safety and the effectiveness of cephalosporin preparations are powerfully guaranteed, the taste is improved by adopting a taste masking technology, the medication compliance of patients, especially children patients, is improved, meanwhile, the formula and the preparation method are simple, the production cost is low, the production efficiency is high, the cephalosporin granules are suitable for continuous industrial production, and the market prospect is good.

Description

Cephalosporin granules and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a cephalosporin granule and a preparation method thereof.

Background

The cephalosporin is an antibiotic obtained by semi-synthesizing and transforming a side chain of natural cephalosporin C obtained by culturing cephalosporium coronarium as a raw material. Cephalosporin antibiotics are semi-synthetic antibiotics containing cephem in molecules, belong to beta-lactam antibiotics, are derivatives of 7-aminocephalosporanic acid in the beta-lactam antibiotics, have a bactericidal effect by inhibiting bacterial cell wall synthesis, are stable to most beta lactamases, and are sensitive to cephalosporins by a plurality of penicillinase and cephalosporinase producing strains.

Cephalosporins have good antibacterial activity against gram-positive cocci such as pneumococcus and streptococcus pyogenes, gram-negative bacilli such as influenza bacilli (including enzyme-producing strains), moraxella catarrhalis (including enzyme-producing strains), escherichia coli, proteus mirabilis, and gonococci (including enzyme-producing strains) both in vitro and in vivo. Cephalosporin drugs can be distributed on various parts of the body, so that various tissues and organs are infected, and the cephalosporin drugs can be selected as long as pathogenic bacteria are sensitive to the cephalosporins. It is a bactericide which kills bacteria at sufficient concentrations, unlike those known as tetracycline, erythromycin, chloramphenicol, which primarily inhibits bacterial growth at conventional dosages. Therefore, the cephalosporin drugs can be used for more serious infection and have higher practical value in clinic. The cephalosporin has the advantages of high efficiency, low toxicity, wide clinical application, small dosage, wide antibacterial spectrum, strong antibacterial activity, low drug resistance, high safety, quick action effect, high cure rate, penicillinase resistance, rare anaphylactic reaction and the like, can not only destroy the cell wall of bacteria, but also sterilize in the reproductive period of the bacteria, and has almost no toxicity to organisms. About 30 of them are commonly used, and they are classified into first, second, third and fourth generations according to their invention years and antibacterial properties.

Therefore, the cephalosporin antibiotics always occupy a larger share in the medicine market due to the advantages of wide antibacterial spectrum, strong antibacterial effect, lower toxicity, less anaphylactic reaction and the like, are prepared into granules with good mouthfeel, quick oral administration absorption and high bioavailability, can better play the drug effect and improve the drug compliance of patients, particularly children patients. However, cephalosporin raw materials are very easy to absorb moisture, are unstable in quality and easy to degrade under wet and hot conditions, related substances are increased, the safety and effectiveness of the cephalosporin raw materials are affected, cephalosporin active ingredients are bitter, and the products on the market at present have poor quality stability and poor taste.

Patent document CN101816635A discloses a cephalosporin suspension granule and a preparation method thereof, wherein a cephalosporin active ingredient is used as a main ingredient, a certain amount of disintegrant and suspending agent are added into a prescription, so that dissolution of the active ingredient can be ensured, the solution has a good suspending effect, and a fluidized bed drying technology is adopted.

Patent document CN104116713A discloses cefdinir particles and a preparation method thereof, wherein active ingredients are micronized by a supercritical fluid technology to make the particle size less than 10 μm, so that dissolution can be increased, an extrusion spheronization technology is adopted to prepare particles of 40 meshes, and the particles are dried for 3-5 hours at 35-40 ℃ to prepare dry particles, so that the moisture content of the dry particles is less than 3%. However, the granule still has the problems of high moisture content, easy influence on the stability of the storage process, too long drying time of the granule and low production efficiency.

In conclusion, the existing cephalosporin granular preparation and the process thereof still have the problems of high moisture content, influence on safety and effectiveness, poor taste, complex operation, low production efficiency and the like, so that the development of the cephalosporin granular preparation with low moisture content, good stability, good taste and high production efficiency is urgently needed.

Disclosure of Invention

The invention firstly provides the cephalosporin granules and the preparation method thereof, the moisture of the cephalosporin granules prepared by the preparation method is well reduced, the stability is improved, the mouthfeel is good, and the production efficiency is correspondingly improved.

The invention provides a cephalosporin granule which comprises the following components in parts by weight: 20 to 40 portions of cephalosporin active ingredient, 2 to 10 portions of disintegrant, 0.5 to 2 portions of adhesive, 0.5 to 2 portions of glidant and 240 to 480 portions of flavoring agent.

Preferably, the cephalosporin granules comprise the following components in parts by weight: 30 parts of cephalosporin active ingredient, 5 parts of disintegrant, 1 part of adhesive, 1 part of glidant and 360 parts of flavoring agent.

Preferably, the cephalosporin active ingredient is at least one of cefprozil, cefaclor, cefradine, cephalexin, cefixime and cefdinir.

Preferably, the disintegrant is at least one of low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, and croscarmellose sodium.

Preferably, the binder is at least one of xanthan gum, gum arabic and sodium alginate.

Preferably, the glidant is at least one of aerosil, silicon dioxide, magnesium stearate and talc.

Preferably, the flavoring agent is at least one of a sweetener, an acidulant and a flavoring agent; the sweetener is at least one selected from sucrose, fructose, glucose, maltose, lactose, sorbitol, saccharin, cyclamate, sucralose, stevioside, maltitol, mannitol, and aspartame; the sour agent is at least one of citric acid, malic acid, tartaric acid, gluconic acid and ascorbic acid; the flavoring agent is selected from orange flavoring agent.

More preferably, the flavoring agent is a sweetener selected from at least two of sucrose, fructose, glucose, maltose, lactose, sorbitol, saccharin, cyclamate, sucralose, steviol glycoside, maltitol, mannitol, and aspartame.

Preferably, the cephalosporin granules further comprise the following components in parts by weight: 0.04 to 0.08 portion of edible pigment and 10 to 20 portions of essence.

More preferably, the edible pigment is carmine or lemon yellow, and the essence is strawberry essence or orange essence.

Correspondingly, the invention also provides a preparation method of the cephalosporin granules, which has the advantages of simple and feasible process, short drying time and high production efficiency and is suitable for industrial mass production of preparations.

The preparation method of the cephalosporin granules specifically comprises the following steps:

s1, preparing a bonding solution by taking a formula amount of a bonding agent;

s2, grinding the cephalosporin active ingredient to a particle size smaller than or equal to 25 mu m, respectively sieving a disintegrating agent and a flavoring agent, mixing the cephalosporin active ingredient, the disintegrating agent and the flavoring agent according to the formula amount, adding the bonding solution, stirring, preparing a soft material, and preparing wet granules by using a cylindrical granulator;

s3, putting the wet granules into a continuous flow type dryer, and drying at the temperature of 45-50 ℃ until the moisture content is less than or equal to 0.30% to obtain dry granules;

s4, screening and straightening the dry particles to obtain qualified particles of 24-200 meshes;

s5, sieving the flow aid with the formula amount, mixing the flow aid with part of qualified granules in a small rubber bag for 1-2 min, then putting the mixture with the rest qualified granules and a flavoring agent into a mixer, uniformly mixing, and discharging to obtain the cephalosporin granules.

Further, in the step S3, the wet granules are put into a continuous flow dryer, the continuous flow dryer is composed of a plurality of trays, the wet granules are placed in each tray, and then the tray is rotated 30 degrees counterclockwise and 360 degrees counterclockwise at regular intervals, so that the wet granules are dried until the moisture content is less than or equal to 0.30%.

Furthermore, the continuous flow dryer consists of 12 trays, 3kg of wet granules are placed in each tray, and then the tray is rotated 30 degrees counterclockwise every 40 seconds for 360 degrees, and the tray takes 8min to dry until the moisture content is less than or equal to 0.30%. By controlling the adding amount of the wet particles and the rotation parameters of the continuous flow type dryer, the particles are always in a flowing state in the drying process, the drying temperature is controlled to be 45-50 ℃, the drying time is 8min, the moisture content can be controlled to be below 0.3 percent, the drying efficiency can reach 270kg/h, the damage and the loss of the particles are greatly reduced, and the production efficiency is improved.

Therefore, compared with the prior art, the invention has the advantages that:

(1) In the preparation process of the cephalosporin granules, the flavoring agent is added internally and externally, namely, the active ingredients of the medicament are mixed with the disintegrating agent, the flavoring agent and the like, then the adhesive is added for wet granulation to achieve the effect of preliminarily covering the bad taste of the medicament, and the glidant, the flavoring agent and the prepared wet granules are mixed to further increase the taste covering effect so as to achieve the purpose of improving the taste, thereby improving the medication compliance of patients, particularly children patients.

(2) The continuous flow type dryer adopted by the preparation method of the cephalosporin granules is used for granulating the added wet granules, the granules are rotated once (30 degrees) anticlockwise every 40 seconds, and the drying can be completed after rotating for a circle (360 degrees) for 8 minutes, so that the damage and loss of the granules are greatly reduced, the drying efficiency can reach 270kg/h, the production efficiency is effectively improved, and the preparation method is suitable for industrial mass production of preparations. And by controlling the drying temperature to be 45-50 ℃ and controlling the particle moisture to be below 0.3%, the problems of instability, rise of related substances and the like caused by extremely easy moisture absorption of cephalosporins are solved, and the safety and the effectiveness of the cephalosporins are ensured; in addition, the moisture of the cephalosporin granules is controlled below 0.3%, so that the stability in the storage process is ensured, and the shelf life of the product is prolonged.

(3) The preparation method of the cephalosporin granules comprises the steps of crushing the cephalosporin active ingredients before granulation to ensure that the particle size is less than or equal to 25 mu m, and the dissolution rate after 15 minutes is more than 81% (test conditions are pH6.8, paddle method, 50 turns), thereby further increasing the dissolution performance of the cephalosporin active ingredients, improving the bioavailability of insoluble drugs, and reducing the toxic and side effects of the drugs.

Drawings

FIG. 1 is a schematic front view of a continuous flow dryer according to the present invention;

FIG. 2 is a schematic top view of the continuous flow dryer of the present invention;

FIG. 3 is a schematic diagram of a top view of a gas flow distribution plate of the continuous flow dryer of the present invention;

FIG. 4 is a schematic top view of a bin of the continuous flow dryer of the present invention;

fig. 5 is a schematic view of the structure of the air treatment system of the continuous flow dryer of the present invention.

Description of the reference numerals:

10-main body, 101-feeding hole, 102-discharging hole, 103-air inlet hole, 104-air outlet hole, 105-observation window, 20-air flow distribution plate, 201-second through hole, 30-storage bin, 301-first through hole, 302-material tray, 40-rotating motor, 50-vacuum discharge pipe, 601-fresh air filter screen, 602-fresh air temperature and humidity processing system, 603-first fan, 604-three-stage air filter, 605-front section heater, 606-second fan, 607-third fan, 608-rear section heater and 609-high efficiency air filter.

Detailed Description

The present invention will be described in further detail with reference to specific examples.

The continuous flow dryer in the embodiment of the invention has the following specific structure:

as shown in fig. 1 to 5, continuous flow type desicator includes main part 10, feed bin 30, air distribution plate 20, rotating element, air treatment system, vacuum discharging pipe 50, rotating element is rotating electrical machines 40, feed bin 30 air distribution plate 20 rotating electrical machines 40 are located inside main part 10, main part 10 upper portion is equipped with feed port 101, discharge opening 102, observation window 105, main part 10 upper portion is the toper, and the toper end is equipped with venthole 104, main part 10 lower part is equipped with inlet port 103, the inlet port 103 top sets up air distribution plate 20, air distribution plate 20 evenly is equipped with a plurality of second through-holes 201, air distribution plate 20 top sets up feed bin 30 with rotating electrical machines 40, rotating electrical machines 40 drives feed bin 30 is in overlooking the direction counter-clockwise rotation.

The storage bin is annular, the storage bin 30 is provided with twelve charging trays 302, the twelve charging trays 302 are annularly arranged on the storage bin 30, the charging hole 101 is positioned above one charging tray 302, and the discharging hole 102 is positioned above the other charging tray 302. Each tray 302 is provided with a plurality of first through holes 301; the rotating motor 40 is located in the middle of the stock bin 30 and below the air outlet, and is fixedly connected with the stock bin 30.

The wet granules to be dried are added from the feed hole 101 to the hopper 30 from the lower portion of the main body 10The air inlet hole 103 let in pure hot air to main part 10 in, second through-hole 201 is closely distributed on airflow distribution plate 20 and holds the hot air and pass through, shunt the hot air, make the hot air full inside main part 10, the hot air continues to pass through first through-hole 301 back, with wet granule contact, the hot air makes wet granule suspension, the hot air carries out the heat exchange with wet granule, the hot air takes away the moisture evaporation of wet granule, the hot air flows and the wet granule carries out the matter heat transfer mode of gas-solid two phase suspension contact, reach the dry purpose of wet granule. In the convection drying process, the hot air transfers heat energy to the surface of the wet particles and then transfers the heat energy from the surface to the interior of the wet particles, which is a heat transfer process; after the wet particles are heated, the surface moisture is firstly gasified, the internal moisture is diffused to the surface of the wet particles and is continuously gasified to the air, so that the moisture of the wet particles is gradually reduced, and the drying is finished, which is a mass transfer process. The continuous fluidized bed dryer can continuously dry, the bin 30 has twelve trays 302, 3kg of wet granules are put into each tray 302, and then the rotating motor 40 drives the bin 30 to rotate 30 degrees counterclockwise every 40 seconds, and the rotating time is 8min after 360 degrees. By controlling the adding amount of the wet granules and the rotation parameters of the continuous flow type dryer, the granules are always in a flowing state in the drying process, the drying temperature is not too high, the drying time is not too long, namely, the moisture can be controlled below 0.3 percent, and the continuous industrial drying of the granular preparation is realized. When the mass heat transfer is carried out between the hot air and the wet particles, the bin 30 is driven by the rotating motor 40 to rotate anticlockwise, and the bin 30 drives the wet particles to rotate, so that the wet particles are dried more uniformly, and the drying time is shorter; the bin 30 and the wet granules are also less likely to stick together due to the rotation of the bin 30. An operator observes whether the medicine is dried or not through the observation window 105, after the bin 30 rotates for a circle, if the medicine is dried, the machine is operated to control the vacuum discharge pipe 50, particles which are located below the discharge hole 102 and are dried are discharged, the dried particles are pumped out to leave the continuous flow type dryer, and if the medicine is not dried, the operator needs to continue to wait until the drying operation is finished; after the dried pellets of one tray 302 are extracted, the bin 30 rotates, the vacuum outlet tube 50 can then extract the dried pellets of the next tray 302,the charging tray 302 after discharging continues to rotate to the lower part of the charging hole 101, wet particles are added into the charging tray 302 from the charging hole 101, then the storage bin 30 continues to rotate and dry, the circulation is continuous, and continuous drying is realized. All parameters of the equipment are detected by sensors. The air supply quantity and the air exhaust quantity are not less than 2100m ³ Not more than 2300m ³ . If both air volumes are out of these ranges, the air volume balance may be disturbed, and poor drying may occur.

The upper portion of the main body 10 is provided with an observation window 105 for facilitating observation of the inside of the main body 10 and the dryness of the wet granules. The upper portion of the main body 10 is tapered to guide the hot air in the main body 10 to the air outlet 104. The diameter of the vacuum discharge pipe 50 is smaller than that of the discharge hole 102, so that the vacuum discharge pipe 50 can conveniently extend into the discharge hole 102 for discharging.

As shown in fig. 5, the air inlet 103 is externally connected to an air processing system, and the air processing system includes a fresh air filter 601, a fresh air temperature and humidity processing system 602, a first fan 603, a three-stage air filter 604, a front section heater 605, a second fan 606, a third fan 607, a rear section heater 608, and a high efficiency air filter 609. The fresh air filter screen 601, the fresh air temperature and humidity processing system 602, the first fan 603, the three-stage air filter 604, the front section heater 605, the second fan 606, the third fan 607, the rear section heater 608, and the high efficiency air filter 609 are sequentially connected one by one.

Outdoor fresh air blown in by the fan is filtered by a fresh air filter screen 601 and enters a fresh air temperature and humidity processing system 602. The fresh air temperature and humidity processing system 602 performs condensation and dehumidification processing on fresh air, and the temperature of formed cold air is 14 ℃ and the relative humidity is 95% RH. After the cold air is filtered and dedusted by the three-stage air filter 604 (primary, middle and high three-stage filtration), the cold air is heated and dehumidified by the front-stage heater 605, and then heated and dehumidified by the rear-stage heater 608 into hot air having a temperature of 45 to 55 ℃ and a relative humidity of 12% RH. The hot air is filtered by the high efficiency air filter 609 and blown into the intake hole 103.

Example 1 cefprozil granules of the invention and a process for their preparation

The formula is as follows: 20kg of cefprozil, 3kg of low-substituted hydroxypropyl cellulose, 0.5kg of tragacanth, 1kg of silicon dioxide, 140kg of cane sugar, 100kg of sorbitol, 10kg of strawberry essence and 0.04kg of carmine.

The preparation method comprises the following steps: s1, taking the edible pigment according to the formula amount, dissolving the edible pigment with water, filtering the solution through a 200-mesh screen, adding ethanol with the volume fraction of 95%, adding the adhesive according to the formula amount, and uniformly stirring to obtain an adhesive solution;

s2, crushing cefprozil to a particle size smaller than or equal to 25 microns, respectively sieving a disintegrating agent, a flavoring agent (comprising sucrose and sorbitol) and essence with a 60-mesh sieve, then mixing cefprozil, the disintegrating agent and the essence with a formula amount with sucrose, uniformly mixing, adding an adhesive solution, stirring, preparing a soft material, and sieving with a 40-mesh cylindrical granulator to prepare wet granules;

s3, putting the wet particles into 12 trays of a continuous flow dryer, putting 3kg of the wet particles in each tray, drying at 45-50 ℃, rotating 30 degrees counterclockwise every 40 seconds for 360 degrees, and taking 8 minutes to prepare dry particles with the moisture content less than or equal to 0.30%;

s4, screening and straightening the dry particles to obtain qualified particles of 24-200 meshes;

s5, sieving the flow aid with a 40-mesh sieve according to the formula amount, mixing the flow aid with part of qualified granules in a small rubber bag for 1-2 min, adding the rest qualified granules and sorbitol into a mixer, uniformly mixing, and discharging to obtain the cefprozil granules.

Example 2 cefdinir granules and preparation method thereof

The formula is as follows: 30kg of cefdinir, 5kg of low-substituted hydroxypropyl cellulose, 1kg of xanthan gum, 1kg of magnesium stearate, 200kg of lactose, 160kg of mannitol, 15kg of strawberry essence and 0.06kg of carmine.

The preparation method comprises the following steps: s1, taking the edible pigment according to the formula amount, dissolving the edible pigment with water, filtering the solution through a 200-mesh screen, adding ethanol with the volume fraction of 95%, adding the adhesive according to the formula amount, and uniformly stirring to obtain an adhesive solution;

s2, crushing cefdinir to a particle size smaller than or equal to 25 microns, respectively sieving a disintegrating agent, a flavoring agent (comprising lactose and mannitol) and essence with a 60-mesh sieve, then mixing the cefdinir, the disintegrating agent and the essence with the formula amount with the lactose, uniformly mixing, adding an adhesive solution, stirring, preparing a soft material, and sieving with a 40-mesh cylindrical granulator to prepare wet granules;

s3, putting the wet particles into 12 trays of a continuous flow dryer, putting 3kg of the wet particles in each tray, drying at 45-50 ℃, rotating 30 degrees counterclockwise every 40 seconds for 360 degrees, and taking 8 minutes to prepare dry particles with the moisture content less than or equal to 0.30%;

s4, screening and straightening the dry particles to obtain qualified particles of 24-200 meshes;

s5, sieving the flow aid with a 40-mesh sieve according to the formula amount, mixing the flow aid with part of qualified granules in a small rubber bag for 1-2 min, putting the mixture with the rest qualified granules and mannitol into a mixer, uniformly mixing, and discharging to obtain the cefdinir granules.

Example 3 cefixime granules according to the invention and a process for the preparation thereof

The formula is as follows: 20kg of cefaclor, 7kg of carboxymethyl starch sodium, 0.5kg of tragacanth, 0.5kg of silicon dioxide, 130kg of fructose, 120kg of mannitol, 50kg of stevioside, 10kg of orange essence and 0.04kg of lemon yellow.

The preparation method refers to example 1, wherein fructose is mixed in step S2, and mannitol and stevioside are mixed in step S5.

Example 4 cefaclor granules according to the invention and process for their preparation

The formula is as follows: 30kg of cefaclor, 5kg of croscarmellose sodium, 1kg of acacia, 2kg of silicon dioxide, 200kg of glucose, 120kg of sorbitol, 80kg of aspartame, 15kg of strawberry essence and 0.06kg of carmine.

The preparation method refers to example 1, wherein glucose is added and mixed in step S2, and sorbitol and aspartame are added and mixed in step S5.

Example 5 cefradine granules and preparation method thereof

The formula is as follows: 40kg of cefradine, 10kg of low-substituted hydroxypropyl cellulose, 2kg of tragacanth, 1kg of superfine silica gel powder, 180kg of cane sugar, 100kg of mannitol, 100kg of aspartame, 15kg of strawberry essence and 0.08kg of carmine.

The preparation method refers to example 1, wherein sucrose is added and mixed in step S2, and mannitol and aspartame are added and mixed in step S5.

Test example and quality control of cephalosporin granules

Product index detection

Taking the cefprozil granular product in example 1, continuously trial-producing 5 batches (RD 001-005), and respectively giving 10 experts with the prepared granules to evaluate the taking taste and the taste masking effect, wherein 10 experts uniformly show that no bitter taste and no bad taste are felt, thus proving that the preparation process can effectively mask the bad taste of the cefprozil medicaments, thereby improving the medication compliance of patients, particularly children patients.

And the moisture, dissolution rate, related substances and content indexes of the prepared granules were measured, and the results are shown in table 1 below.

TABLE 1 detection results of cefprozil granule product index

As can be seen from table 1 above, before the cefprozil granule product in example 1 of the present invention is tested in various extreme environments, the quality detection results of stability, dissolution rate, etc. all meet the requirements.

The cefradine granule product of example 5 was sampled and prepared into 5 batches (RD 001-005) continuously, and the characteristics, taste, moisture, dissolution rate, acidity, cephalexin and content index were measured, and the results are shown in Table 2 below.

TABLE 2 detection results of cefradine granule product index

As can be seen from table 2 above, before the cefradine granule product in example 5 of the present invention is tested in various extreme environments, the quality test results of stability, dissolution rate, etc. all meet the requirements.

(II) test of influence factors

The cefdinir granule product of the embodiment 2 of the invention and the product of the embodiment 4 of patent document CN101816635A (hereinafter referred to as comparative example 1) are respectively put into a sealed and clean container, and high temperature, high humidity and illumination tests are carried out according to the general principle of 9001 stability test of the four parts of pharmacopoeia 2015 edition of china, and the test conditions are as follows:

high temperature: the samples were taken at 60 ℃ and 40 ℃ for 10 days, and then on the 5 th and 10 th days, and examined according to the stability emphasis test items.

High humidity: the mixture was kept at 25 ℃ under conditions of 90% + -5% relative humidity and 75% + -5% relative humidity for 10 days, and samples were taken on day 5 and day 10, and examined according to the stability emphasis test items.

Illumination: the sample was placed under the condition of 4500Lx + -500 Lx for 10 days, and sampled on the 5 th and 10 th days, and the samples were examined according to the stability focus item, especially the appearance change of the sample should be noticed. The results of the measurements are given in Table 3 below:

TABLE 3 test results of the influencing factors

As can be seen from table 3 above, when the cefdinir granule product of the embodiment 2 of the present invention is placed under strong light and high temperature of 60 ℃, the appearance color of the cefdinir granule product hardly changes, the related substances are slightly increased, and other indexes are not changed. Meanwhile, compared with the comparative example 1, the cefdinir granule product in the example 2 of the invention is more stable in dissolution, related substances, content and the like under the conditions of high temperature, high humidity and illumination.

(III) accelerated test

The cefdinir granule product of the invention example 2 and the product of the comparative example 1 are respectively placed for 6 months under the conditions that the temperature is 40 +/-2 ℃ and the relative humidity is 75 +/-5%, samples are taken once at the end of 1 st month, 2 nd month, 3 rd month and 6 th month respectively, the determination is carried out according to the key stability investigation items, and the detection results are shown in the following table 4.

TABLE 4 accelerated test results

As can be seen from Table 4, the cefdinir granule product of example 2 of the present invention is more stable in moisture, dissolution rate, related substances and contents than the product of comparative example 1 under the conditions of 40 ℃. + -. 2 ℃ and 75%. + -. 5% of relative humidity.

(III) Long term test

Taking the cefdinir granule product of the example 2 and the product of the comparative example 1, respectively placing for 12 months under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 60 +/-5%, respectively sampling once at the end of 3 rd month, 6 th month, 9 th month and 12 th month, and determining according to stability key examination items, wherein the detection results are shown in the following table 5.

TABLE 5 Long-term test results

As can be seen from table 5 above, the cefdinir granule product of example 2 of the present invention is more stable than the product of comparative example 1 in terms of moisture, dissolution rate, related substances and contents at a temperature of 25 ℃ ± 2 ℃ and a relative humidity of 60% ± 5%, which suggests that the formulation and preparation method of the cefdinir granule of the present invention can strongly ensure the safety and effectiveness of the cefdinir preparation.

The foregoing is a further detailed description of the invention in connection with specific preferred embodiments and it is not intended to limit the invention to the specific embodiments described. For those skilled in the art to which the invention pertains, numerous simple deductions or substitutions may be made without departing from the spirit of the invention, which shall be deemed to belong to the scope of the invention.

Claims (9)

1. The cephalosporin granules are characterized by comprising the following components in parts by weight: 20 to 40 parts of cephalosporin active ingredient, 2 to 10 parts of disintegrant, 0.5 to 2 parts of adhesive, 0.5 to 2 parts of glidant and 240 to 480 parts of flavoring agent;

the preparation method of the cephalosporin granules comprises the following steps:

s1, preparing a bonding solution by taking a formula amount of a bonding agent;

s2, smashing the cephalosporin active ingredients to a particle size smaller than or equal to 25 microns, respectively sieving the disintegrating agent and the flavoring agent, mixing the cephalosporin active ingredients, the disintegrating agent and the flavoring agent according to a formula ratio, adding the bonding solution, stirring, preparing a soft material, and preparing wet granules by using a cylindrical granulator;

s3, putting the wet granules into a continuous flow type dryer, and drying at the temperature of 45-50 ℃ until the moisture is less than or equal to 0.30% to prepare dry granules;

s4, screening and finishing the dry granules to obtain qualified granules of 24-200 meshes;

s5, sieving a flow aid in a formula amount, mixing the flow aid with part of qualified granules in a small rubber bag for 1 to 2min, then putting the mixture with the rest qualified granules and a flavoring agent into a mixer, uniformly mixing, and discharging to prepare the cephalosporin granules;

in the step S3, the wet granules are put into a continuous flow dryer, the continuous flow dryer is composed of a plurality of trays, the wet granules are placed in each tray, and then the tray is rotated 30 degrees counterclockwise and rotated 360 degrees every certain time, so that the wet granules are dried until the moisture content is less than or equal to 0.30%.

2. The cephalosporin granules as claimed in claim 1, which comprise the following components in parts by weight: 30 parts of cephalosporin active ingredient, 5 parts of disintegrant, 1 part of adhesive, 1 part of glidant and 360 parts of flavoring agent.

3. The cephalosporin granules of claim 1, wherein the cephalosporin active ingredient is at least one of cefprozil, cefaclor, cefradine, cephalexin, cefixime and cefdinir.

4. The cephalosporin granule according to claim 1, wherein the disintegrant is at least one of low-substituted hydroxypropylcellulose, sodium carboxymethyl starch and croscarmellose sodium.

5. The cephalosporin granule according to claim 1, wherein the binder is at least one of xanthan gum, gum arabic and sodium alginate.

6. The cephalosporin granule according to claim 1, wherein the glidant is at least one of aerosil, silicon dioxide, magnesium stearate and talc.

7. The cephalosporin granule of claim 1, wherein the flavoring agent is at least one of a sweetener, an acidulant, and a flavoring agent; the sweetener is at least one selected from sucrose, fructose, glucose, maltose, lactose, sorbitol, saccharin, cyclamate, sucralose, stevioside, maltitol, mannitol, and aspartame; the sour agent is at least one of citric acid, malic acid, gluconic acid and ascorbic acid; the flavoring agent is selected from orange flavoring agents.

8. The cephalosporin granules according to any one of claims 1-7, further comprising the following components in parts by weight: 0.04 to 0.08 part of edible pigment and 10 to 20 parts of essence; the edible pigment is carmine or lemon yellow; the essence is strawberry essence or orange essence.

9. A preparation method of the cephalosporin granules as claimed in any one of claims 1-7, characterized by comprising the following steps:

s1, preparing a bonding solution by taking a formula amount of a bonding agent;

s2, smashing the cephalosporin active ingredients to a particle size smaller than or equal to 25 microns, respectively sieving the disintegrating agent and the flavoring agent, mixing the cephalosporin active ingredients, the disintegrating agent and the flavoring agent according to a formula ratio, adding the bonding solution, stirring, preparing a soft material, and preparing wet granules by using a cylindrical granulator;

s3, putting the wet granules into a continuous flow type dryer, and drying at the temperature of 45-50 ℃ until the moisture is less than or equal to 0.30% to prepare dry granules;

s4, screening and straightening the dry granules to obtain qualified granules of 24 to 200 meshes;

s5, sieving a flow aid in a formula amount, mixing the flow aid with part of qualified granules in a small rubber bag for 1 to 2min, then putting the mixture with the rest qualified granules and a flavoring agent into a mixer, uniformly mixing, and discharging to prepare the cephalosporin granules;

in the step S3, the wet granules are put into a continuous flow dryer, the continuous flow dryer is composed of a plurality of trays, the wet granules are placed in each tray, and then the tray is rotated 30 degrees counterclockwise and rotated 360 degrees every certain time, so that the wet granules are dried until the moisture content is less than or equal to 0.30%.

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