CN111000805B - Sultamicin granular preparation and preparation method thereof - Google Patents

Sultamicin granular preparation and preparation method thereof Download PDF

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CN111000805B
CN111000805B CN202010008072.6A CN202010008072A CN111000805B CN 111000805 B CN111000805 B CN 111000805B CN 202010008072 A CN202010008072 A CN 202010008072A CN 111000805 B CN111000805 B CN 111000805B
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sultamicin
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李红组
吴光美
任鹏
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Shenzhen Beimei Pharmaceutical Co ltd
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    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
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Abstract

The invention relates to a sultamicin granular preparation and a preparation method thereof. The sultamicin granular preparation comprises the following components in percentage by mass: 5 to 8 percent of sultamicin, 80 to 90 percent of sweetening agent, 1.0 to 2.5 percent of ion regulator and 0.5 to 13.0 percent of essence. The sultamicin granular preparation has good stability and good use safety.

Description

Sultamicin granular preparation and preparation method thereof
Technical Field
The invention relates to the field of pharmacy, in particular to a sultamicin granular preparation and a preparation method thereof.
Background
The chemical name of sultamicin is (+) hydroxymethyl- (2S, 5R, 6R) -6- [ (R) -2-amino-2-phenylacetamide]-3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3, 2, 0 ] s]N-heptane-2-carboxylic acid ester (2S, 5R) -3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3, 2, 0 ]]N-heptane-2-carboxylic acid ester S, S-dioxide. Molecular formula C25H30N4O9S2The structural formula is as follows:
Figure BDA0002354671480000011
in the clinical anti-infection selection drugs, the beta-lactam antibiotics always have an advantage position due to the characteristics of low toxicity and strong effect, and the allergy problem is correspondingly controlled along with the improvement of the product quality and the continuous improvement of clinical detection means. However, in recent years, the resistance of bacteria to such antibiotics is becoming more serious, especially to the clinical antibiotics such as penicillin and ampicillin. The ampicillin resistance rate of common pathogenic bacteria is reported to reach 70%. The main reason for the drug resistance of bacteria to beta-lactam antibiotics is that beta-lactamase is generated, so that the beta-lactam antibiotics are hydrolyzed to lose antibacterial activity, and therefore, the beta-lactamase inhibitor is prepared to solve the drug resistance of bacteria. The sulbactam is an ester drug which integrates ampicillin and sulbactam, the ampicillin is penicillin antibiotic, the sulbactam has weak bacteriostatic action and is a competitive and irreversible lactamase inhibitor, and after the sulbactam is combined with lactam antibiotic ampicillin for use, good synergistic action can be obtained, the sulbactam not only protects the ampicillin from being damaged by hydrolysis of lactamase, but also expands the antibacterial spectrum of the ampicillin.
Sultamicin is a medicine sensitive to moisture, and raw materials can be decomposed into ampicillin and sulbactam under the influence of moisture. Sultamicin can be decomposed into ampicillin and sulbactam in vivo to play a role, the oral bioavailability of the sultamicin is 80 percent and is not influenced by food, and the oral bioavailability of the ampicillin is only 50 percent. If the sultam is degraded into ampicillin and sulbactam before entering the body, the bioavailability is greatly reduced, and the degradation of the sultam is avoided. The stability of sultamicin is poor, and the sultamicin is easy to degrade under the conditions of high humidity and non-low temperature, so that the drug effect is reduced and the drug resistance is caused. The domestic common technology is to salify sultamicin into sultamicin tosilate by using p-toluenesulfonic acid, the stability of the medicine is slightly improved, but the medicine still needs to be refrigerated and stored, and the p-toluenesulfonic acid is easy to form genotoxic impurities and is not good for the safety of the medicine.
Disclosure of Invention
Accordingly, it is necessary to provide a sultamicin granule preparation having good stability and good safety in use.
In addition, a preparation method of the sultamicin granular preparation is also provided.
The granular preparation of the sultamicin comprises the following components in percentage by mass: 5 to 8 percent of sultamicin, 80 to 90 percent of sweetening agent, 1.0 to 2.5 percent of ion regulator and 0.5 to 13.0 percent of essence.
In one embodiment, the sweetener is selected from at least one of sucrose, sucralose, xylitol, stevioside, aspartame, sorbitol, and mannitol.
In one embodiment, the ionic modifier is selected from at least one of disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and disodium edetate.
In one embodiment, the essence is selected from at least one of cherry-flavored powdered essence, apple-flavored powdered essence, strawberry-flavored powdered essence, and grape-flavored powdered essence.
In one embodiment, the sultamicin granule preparation comprises the following components in percentage by mass: 6.58% of sultamicin, 85.14% of sweetener, 2.14% of ion regulator and 6.14% of essence.
A preparation method of a sultamicin granular preparation comprises the following steps:
weighing the following raw materials in percentage by mass: 5 to 8 percent of sultamicin, 80 to 90 percent of sweetening agent, 1.0 to 2.5 percent of ion regulator and 0.5 to 13.0 percent of essence; and
mixing and granulating the sultamicin, the sweetening agent, the ion regulator and the essence to obtain the sultamicin granular preparation.
In one embodiment, the step of mixing and granulating the sultamicin, the sweetener, the ionic modifier and the essence comprises:
mixing the sweetening agent, the ion regulator and the wetting agent, granulating, and drying to obtain a dry material;
and mixing the dry material with the sultamicin and the essence to obtain the sultamicin granular preparation.
In one embodiment, the wetting agent is ethanol, isopropanol, or water.
In one embodiment, the drying temperature is 60 ℃ to 80 ℃, and the drying is carried out until the mass percentage of the residual solvent is not higher than 0.5% and the mass percentage of the moisture is not higher than 1.0%.
In one embodiment, the step of granulating the sweetener, the ionic modifier and the wetting agent by mixing them comprises: premixing the sweetening agent and the ion regulator for 3-10 min, adding the wetting agent, and performing wet granulation for 1-5 min.
The sultamicin granular preparation comprises sultamicin, a sweetening agent, an ion regulator and essence, and the ratio of the substances is adjusted, so that the substances are matched with each other, the stability of the sultamicin granular preparation is improved, the sultamicin granular preparation can be stored at normal temperature, and the degradation rate is lower under the conditions of high humidity and non-low temperature. And all substances in the sultamicin granular preparation have no toxicity, so that the use safety of the sultamicin granular preparation is improved. Therefore, the sultamicin granular preparation has good stability and better use safety.
Drawings
Fig. 1 is a process flow diagram of a preparation method of sultamicin particles according to an embodiment.
Detailed Description
In order that the invention may be more fully understood, reference will now be made to the following description taken in conjunction with the accompanying drawings. The detailed description sets forth the preferred embodiments of the invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
One embodiment of a particulate formulation of sultamicin, comprising: sultamicin, a sweetening agent, an ion regulator and essence. Wherein the mass percent of the sultamicin is 5-8%. Specifically, the sultamicin granular preparation comprises the following components in percentage by mass: 5 to 8 percent of sultamicin, 80 to 90 percent of sweetening agent, 1.0 to 2.5 percent of ion regulator and 0.5 to 13.0 percent of essence.
Wherein, the mass percentage of the sultamicin can be 5%, 5.5%, 6%, 6.58%, 7%, 7.5% or 8%. In one embodiment, the mass percentage of sultamicin is 6.58%.
The sweetener is at least one selected from sucrose, sucralose, xylitol, stevioside, aspartame, sorbitol and mannitol. Further preferably, the sweetener is selected from at least one of sucralose and xylitol. In the sultamicin granule preparation, the mass percentage of the sweetener can be 80%, 82%, 82.28%, 84%, 84.56%, 85%, 86%, 86.72%, 86.99%, 87%, 87.2%, 87.6%, 87.8%, 88% or 90%. In one embodiment, the sweetener is 85% by weight. The sweetening agent can adjust the sweet taste of the sultamicin granular preparation and improve the taste and mouthfeel of the sultamicin granular preparation.
The ion regulator is at least one selected from disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate and disodium edetate. Preferably, the ionic modifier is selected from one or both of disodium hydrogen phosphate and sodium dihydrogen phosphate. In the sultamicin granule preparation, the mass percentage of the ion regulator is 2.5%, 2.4%, 2.36%, 2.3%, 2.2%, 2.14%, 2.15%, 2.13%, 2.0%, 1.8%, 1.65%, 1.5%, 1.2% or 1.0%. In one embodiment, the mass percent of the ionic modifier is 2.0%. The ion regulator is added into the sultamicin granular preparation, so that the stability of the sultamicin granular preparation can be improved, the sultamicin granular preparation can be stored and placed at normal temperature, and the validity period of the product is prolonged.
The essence is at least one selected from cherry-flavor powder essence, apple-flavor powder essence, strawberry-flavor powder essence and grape-flavor powder essence. The essence can regulate taste. Preferably, the essence is cherry-flavored powdered essence or strawberry-flavored powdered essence. In the sultamicin granular preparation, the mass percent of the essence is 0.5%, 1%, 3%, 3.35%, 3.66%, 3.82%, 4.30%, 6%, 6.70%, 7.20%, 8.94%, 10%, 12% or 13%. In one embodiment, the essence is 6.0% by mass.
Further preferably, the sultamicin granule preparation comprises the following components in percentage by mass: 6.58% of sultamicin, 85.14% of sweetener, 2.14% of ion regulator and 6.14% of essence.
In actual production, the sultamicin granule preparation can be set to contain 0.25g of sultamicin per bag. It is understood that the types of the sultamicin granular preparation can be set to be other types.
In the traditional technology, how to avoid the degradation of sultamicin into ampicillin in the preparation process is introduced, but the stability problem is still not solved, the preparation in the process is placed under the humidity of 75% for 10 days, and the ampicillin content of the preparation in the process still degrades to 9.4%.
The sultamicin granular preparation at least has the following advantages:
(1) the sultamicin granular preparation has the advantages that the stability of the sultamicin granular preparation is obviously improved by adjusting the proportion of all substances, the sultamicin granular preparation can be stored at normal temperature, and the degradation rate is low.
(2) All substances in the sultamicin granular preparation have no toxicity, so that the use safety of the sultamicin granular preparation is improved.
(3) The ion regulator is added into the sultamicin granular preparation, so that the stability of the sultamicin granular preparation can be improved, and the degradation rate of the sultamicin granular preparation is lower under the conditions of high humidity and non-low temperature.
(4) The sweetening agent and the essence in the sultamicin granular preparation can adjust the taste and the flavor of the sultamicin granular preparation, and are easy to take by the old and children. And the types of the essences are adjusted, so that the sultamicin granular preparation has different tastes, and the requirements of most people on different tastes are met.
Referring to fig. 1, a method for preparing a sultamicin granule formulation according to an embodiment is a method for preparing a sultamicin granule formulation according to the above embodiment, and includes the following steps:
step S110: weighing the following raw materials in percentage by mass: 5 to 8 percent of sultamicin, 80 to 90 percent of sweetening agent, 1.0 to 2.5 percent of ion regulator and 0.5 to 13.0 percent of essence.
Wherein, the mass percentage of the sultamicin can be 5%, 5.5%, 6%, 6.58%, 7%, 7.5% or 8%. In one embodiment, the mass percentage of sultamicin is 6.58%.
The sweetener is at least one selected from sucrose, sucralose, xylitol, stevioside, aspartame, sorbitol and mannitol. Further preferably, the sweetener is selected from at least one of sucralose and xylitol. In the sultamicin granule preparation, the mass percentage of the sweetener can be 80%, 82%, 82.28%, 84%, 84.56%, 85%, 86%, 86.72%, 86.99%, 87%, 87.2%, 87.6%, 87.8%, 88% or 90%. In one embodiment, the sweetener is 85% by weight. The sweetening agent can adjust the sweet taste of the sultamicin granular preparation and improve the taste and mouthfeel of the sultamicin granular preparation.
The ion regulator is at least one selected from disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate and disodium edetate. Preferably, the ionic modifier is selected from one or both of disodium hydrogen phosphate and sodium dihydrogen phosphate. In the sultamicin granule preparation, the mass percentage of the ion regulator is 2.5%, 2.4%, 2.36%, 2.3%, 2.2%, 2.14%, 2.15%, 2.13%, 2.0%, 1.8%, 1.65%, 1.5%, 1.2% or 1.0%. In one embodiment, the mass percent of the ionic modifier is 2.0%. The ion regulator is added into the sultamicin granular preparation, so that the stability of the sultamicin granular preparation can be improved, the sultamicin granular preparation can be stored and placed at normal temperature, and the validity period of the product is prolonged.
The essence is at least one selected from cherry-flavor powder essence, apple-flavor powder essence, strawberry-flavor powder essence and grape-flavor powder essence. The essence can regulate taste. Preferably, the essence is cherry-flavored powdered essence or strawberry-flavored powdered essence. In the sultamicin granular preparation, the mass percent of the essence is 0.5%, 1%, 3%, 3.35%, 3.66%, 3.82%, 4.30%, 6%, 6.70%, 7.20%, 8.94%, 10%, 12% or 13%. In one embodiment, the essence is 6.0% by mass.
Further preferably, the sultamicin granule preparation comprises the following components in percentage by mass: 6.58% of sultamicin, 85.14% of sweetener, 2.14% of ion regulator and 6.14% of essence.
Step S120: the sultamicin, the sweetener, the ion regulator and the essence are respectively crushed and then sieved by a sieve of 60 meshes to 80 meshes.
Further, the mesh number of the sieve is 60 meshes.
Step S130: mixing sultamicin, a sweetening agent, an ion regulator and essence, and granulating to obtain the sultamicin granular preparation.
Specifically, step S130 includes steps S132 to S134:
step S132: mixing the sweetening agent, the ion regulator and the wetting agent, granulating, and drying to obtain a dry material.
Wherein the wetting agent is ethanol, isopropanol or water. Preferably, the wetting agent is isopropanol. The wetting agent can wet and bond the sweetener and the ion regulator, and is convenient for granulation. The mass of the wetting agent is 50-90% of that of the sultamicin. For example, the wetting agent is added in a mass of 50%, 60%, 65%, 70%, 75%, 80%, 85% or 90% of the mass of sultamicin.
Specifically, the step of mixing and granulating the sweetener, the ionic modifier and the wetting agent is performed in a wet granulator. The step of mixing and granulating the sweetening agent, the ion regulator and the wetting agent comprises the following steps: the sweetening agent and the ion regulator are firstly put into a wet granulator and premixed for 3min to 10min, and then the wetting agent is added to granulate for 1min to 5 min. In one embodiment, the wetting agent is added by a peristaltic pump.
In step S132, the drying temperature is 60 ℃ to 80 ℃. Drying until the mass percent of the residual solvent is not higher than 0.5 percent and the mass percent of the water is not higher than 1.0 percent. In one embodiment, the step of drying is performed in an oven. Because the sultamicin is sensitive to moisture and can be decomposed into ampicillin and sulbactam under the action of moisture, and the bioavailability of the sultamicin can be reduced due to the fact that the sultamicin is degraded before entering the body, drying is needed after wet granulation, and the moisture or residual solvent in dry materials is controlled to reach the standard.
Specifically, after the drying process, a sieving process is also included. The mesh number of the sieve is 40-60 meshes. Further, the mesh number of the sieve is 60 meshes.
Step S134: and mixing the dry material with sultamicin and essence to obtain the sultamicin granular preparation.
Specifically, in step S134, the mixing time is 10min to 20 min. After step S134, a sieving step is also included. The mesh number of the sieve is 40-60 meshes. Further, the mesh number of the sieve is 40 meshes.
In the actual production, after the step S130, bagging the sultamicin granular preparation according to the specified mass to obtain the sultamicin granular preparation with the content of the sultamicin of 0.25 g/bag. It can be understood that the specification of the sultamicin granule preparation can be adjusted according to actual conditions.
The preparation method of the sultamicin granular preparation at least has the following advantages:
(1) the preparation method of the sultamicin granular preparation can prepare the sultamicin granules which have good taste, are suitable for children to take, and have uniform content and good stability. The method has the obvious advantages that the ion regulator is introduced into the prescription, the storage stability is improved, the sultamicin granule preparation can be stored at normal temperature, the moisture is strictly controlled in the preparation process, the problem that the sultamicin is degraded when meeting water is avoided, and the sultamicin granule preparation with higher quality is prepared.
(2) The preparation method of the sultamicin granular preparation is simple and is easy for industrial production.
The following are specific examples:
example 1
The components and the mixture ratio of the sultamicin granule preparation of the embodiment are shown in the following table 1:
TABLE 1
Figure BDA0002354671480000091
The preparation process of the sultamicin granule preparation of the embodiment is specifically as follows:
(1) the sultamicin, the sweetener, the ion regulator and the powder essence are respectively crushed and sieved by a 60-mesh sieve.
(2) According to the mixture ratio in the table 1, 330.5g of sucralose, 1.45g of sodium dihydrogen phosphate and 6.65g of disodium hydrogen phosphate are weighed and placed in a wet granulator to be premixed for 6 minutes. Adding 20g of wetting agent isopropanol at constant speed by using a peristaltic pump, and granulating for 5 minutes.
(3) And (3) transferring the wet granules obtained in the step (2) into an oven, drying at 60 ℃, controlling the residual solvent of the isopropanol to be 0.23%, and then sieving by a 60-mesh sieve to obtain a dry material.
(4) And (4) adding the dried material obtained in the step (3) into a mixer, weighing 25.01g of the crushed and sieved sultamicin and 16.34g of the strawberry-flavor powder essence, adding into the mixer, mixing for 18 minutes, and sieving by a 40-mesh sieve to obtain the sultamicin granular preparation.
(5) And (4) packaging and bagging the sultamicin granular preparation obtained in the step (4) by using a PET/Al/PE composite film according to 3.79 g/bag to obtain 0.25 g/bag of sultamicin granular preparation.
The sultamicin granular preparation prepared by the embodiment has uniform granules, grape flavor, sweet taste, content of 99.42 percent, extremely low related substances and excellent stability.
Example 2
The components and the mixture ratio of the sultamicin granule preparation of the embodiment are shown in the following table 2:
TABLE 2
Figure BDA0002354671480000101
The preparation process of the sultamicin granular preparation of the present example is similar to that of the sultamicin granular preparation of example 1, except that: in the step (2), 15g of water is used as a wetting agent; in the step (3), the moisture content after drying is controlled to be 0.36%.
The sultamicin granular preparation prepared by the embodiment has uniform granules, strawberry flavor, sweet taste, content of 99.78%, extremely low related substances and excellent stability.
Example 3
The components and the mixture ratio of the sultamicin granule preparation of the embodiment are shown in the following table 3:
TABLE 3
Figure BDA0002354671480000102
The preparation process of the sultamicin granular preparation of the present example is similar to that of the sultamicin granular preparation of example 1, except that: in the step (2), 25g of ethanol is used as a wetting agent; in the step (3), the ethanol content after drying is controlled to be 0.18%.
The sultamicin granular preparation prepared by the embodiment has uniform granules, cherry flavor, sweet taste, content of 99.35 percent, extremely low related substances and excellent stability.
Example 4
The components and the mixture ratio of the sultamicin granule preparation of the embodiment are shown in the following table 4:
TABLE 4
Figure BDA0002354671480000111
The preparation process of the sultamicin granular preparation of the present example is similar to that of the sultamicin granular preparation of example 1, except that: in the step (2), 20g of isopropanol is used as a wetting agent; in the step (3), the isopropyl alcohol was controlled to 0.15% after drying.
The sultamicin granular preparation prepared by the sultamicin granular preparation has uniform granules, apple flavor, sweet taste, content of 98.97 percent, extremely low related substances and excellent stability.
Example 5
The components and the mixture ratio of the sultamicin granule preparation of the embodiment are shown in the following table 5:
TABLE 5
Figure BDA0002354671480000112
The preparation process of the sultamicin granular preparation of the present example is similar to that of the sultamicin granular preparation of example 1, except that: in the step (2), 20g of ethanol is used as a wetting agent; in the step (3), ethanol is controlled to be 0.23% after drying.
The sultamicin granular preparation prepared by the sultamicin granular preparation has uniform granules, strawberry flavor, slightly sweet taste, 99.56% of content, extremely low content of related substances and excellent stability.
Example 6
The components and the mixture ratio of the sultamicin granule preparation of the embodiment are shown in the following table 6:
TABLE 6
Figure BDA0002354671480000121
The preparation process of the sultamicin granular preparation of the present example is similar to that of the sultamicin granular preparation of example 1, except that: in the step (2), 20g of ethanol is used as a wetting agent; in the step (3), ethanol is controlled to be 0.23% after drying.
The sultamicin granular preparation prepared by the sultamicin granular preparation has uniform granules, cherry taste, sweet taste, 99.33% content of related substances and excellent stability.
Example 7
The components and the mixture ratio of the sultamicin granule preparation of the embodiment are shown in the following table 7:
TABLE 7
Figure BDA0002354671480000122
The preparation process of the sultamicin granular preparation in this embodiment is the same as the preparation process of the sultamicin granular preparation in embodiment 1, and is not described herein again.
Example 8
The components and the mixture ratio of the sultamicin granule preparation of the embodiment are shown in the following table 8:
TABLE 8
Figure BDA0002354671480000131
The preparation process of the sultamicin granular preparation in this embodiment is the same as the preparation process of the sultamicin granular preparation in embodiment 1, and is not described herein again.
Example 9
The components and the mixture ratio of the sultamicin granule preparation of the embodiment are shown in the following table 9:
TABLE 9
Figure BDA0002354671480000132
The preparation process of the sultamicin granular preparation in this embodiment is the same as the preparation process of the sultamicin granular preparation in embodiment 1, and is not described herein again.
Comparative example 1
The components and proportions of the sultamicin granule formulation of comparative example 1 are shown in table 10 below:
watch 10
Figure BDA0002354671480000133
Figure BDA0002354671480000141
The preparation process of the sultamicin granule formulation of comparative example 1 is specifically as follows:
(1) the sultamicin, the sweetener and the powder essence are respectively crushed and sieved by a 60-mesh sieve.
(2) 341.85g of sucrose was weighed out in the proportions shown in Table 7, and was placed in a wet granulator and premixed for 6 minutes. Adding 20g of wetting agent isopropanol at constant speed by using a peristaltic pump, and granulating for 5 minutes.
(3) And (3) transferring the wet granules obtained in the step (2) into an oven, drying at 60 ℃, controlling the residual solvent of the isopropanol to be 0.29%, and then sieving by a 60-mesh sieve to obtain a dry material.
(4) And (4) adding the dried material obtained in the step (3) into a mixer, weighing 25.94g of the crushed and sieved sultamicin and 26.43g of the grape flavor powder essence, adding into the mixer, mixing for 18 minutes, and sieving by a 40-mesh sieve to obtain the sultamicin granular preparation.
(5) And (5) packaging and bagging the sultamicin granular preparation obtained in the step (4) by using a PET/Al/PE composite film according to 3.83 g/bag to obtain 0.25 g/bag of sultamicin granular preparation.
The sultamicin granules prepared by the embodiment are uniform, have grape flavor and sweet taste, contain 98.42 percent of related substances and are poor in stability.
Comparative example 2
The components and proportions of the sultamicin granule formulation of comparative example 2 are shown in table 11 below:
TABLE 11
Figure BDA0002354671480000142
The preparation process of the sultamicin granule formulation of comparative example 2 is specifically as follows:
(1) the sultamicin, the sweetener, the ion regulator and the powder essence are respectively crushed and sieved by a 60-mesh sieve.
(2) 391.06g of sucrose, 1.42g of potassium dihydrogen phosphate and 6.23g of disodium hydrogen phosphate were weighed out in the proportions shown in Table 8 and placed in a wet granulator and premixed for 6 minutes. 20g of wetting agent water is added at a constant speed by a peristaltic pump, and granulation is carried out for 5 minutes.
(3) And (3) transferring the wet granules obtained in the step (2) into an oven, drying at 60 ℃, controlling the moisture to be 2.36%, and then sieving with a 60-mesh sieve to obtain a dry material.
(4) And (4) adding the dried material obtained in the step (3) into a mixer, weighing 30.43g of the sultamicin and 33.32g of the grape-flavor powder essence which are crushed and sieved, adding into the mixer, mixing for 18 minutes, and sieving by a 40-mesh sieve to obtain the sultamicin granular preparation.
(5) And (4) packaging and bagging the sultamicin granular preparation obtained in the step (4) by using a PET/A1/PE composite film according to 3.80 g/bag to obtain 0.25 g/bag of sultamicin granular preparation.
The sultamicin granules prepared in the comparative example 2 are uniform in granules, have strawberry flavor and sweet taste, are increased by 97.62 percent in content, and are good in stability.
Comparative example 3
The formulation of the sultamicin granule formulation of comparative example 3 is the same as the formulation of the sultamicin granule formulation of example 2.
The preparation of the sultamicin granule formulation of comparative example 3 was performed according to the method of patent CN 102512414A.
The preparation process of the sultamicin granular preparation of comparative example 3 is to obtain the sultamicin granular preparation, which has uneven granules, slight strawberry flavor, bitter taste, 98.23% content, increased related substances and poor stability.
The sultamicin granule formulations prepared in the above examples 1 to 9 and comparative examples 1 to 3 were tested for their contents and substances, and the results are shown in table 12 below.
TABLE 12 measurement data of the related substances and contents of sultamicin granule formulations of the examples
Figure BDA0002354671480000151
Figure BDA0002354671480000161
According to the technical guidelines for chemical drug stability research and the requirements of stability tests of the preparation in Q1A of ICH, the substances and contents are taken as key research items. The relevant results are shown in table 13 and table 14 below, where table 13 is the stability data of the sultamicin granule formulation of each example stored at 5 ℃ ± 3 ℃ for different periods of time, and table 14 is the stability data of the sultamicin granule formulation of each example stored at 30 ℃ ± 2 ℃/65% RH ± 5% RH for different periods of time:
TABLE stability data at 135 ℃. + -. 3 ℃
Figure BDA0002354671480000162
TABLE 1430 deg.C + -2 deg.C/65% RH + -5% RH condition stability data
Figure BDA0002354671480000171
It can be seen from the comparison of the above experimental data that, in the present document, wet granulation is performed on the sweetener and the ion regulator, drying is performed to control moisture, and then the wet granulation is mixed with sultamicin and essence, so that the prepared granular preparation has no obvious change in related substances after being placed at normal temperature and being placed under a high humidity condition for a period of time, and has good stability. In addition, the stability of the sultamicin granular preparation is obviously improved after the ion regulator is added into the prescription, and the preparation product has no obvious increase of related substances when the preparation is placed and stored at normal temperature, so that the transportation and the storage of the product are facilitated, the effective period of the product can be prolonged, and the cost performance of the medicine is improved.
Therefore, the sultamicin particles prepared by the mixture ratio and the preparation method of the embodiment achieve the purpose of taste masking, so that the taste and the mouthfeel are good, the sultamicin particle preparation can not generate large impurity change, the stability of the product is improved, the storage and the use of a patient are facilitated, the medication safety is improved, and the drug effect change caused by degradation can not occur.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (9)

1. The sultamicin granular preparation is characterized by comprising the following components in percentage by mass: 5-8% of sultamicin, 80-90% of sweetening agent, 1.0-2.5% of ion regulator and 0.5-13.0% of essence, wherein the ion regulator is selected from at least one of disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate and disodium edetate;
the preparation method of the sultamicin granular preparation comprises the following steps:
mixing the sweetening agent, the ion regulator and the wetting agent, granulating, and drying to obtain a dry material, wherein the drying temperature is 60-80 ℃, and the drying is carried out until the mass percent of the residual solvent is not higher than 0.5%, and the mass percent of the water is not higher than 1.0%; and
and mixing the dry material with the sultamicin and the essence to obtain the sultamicin granular preparation.
2. A particulate formulation of sultamicin according to claim 1, wherein the sweetener is selected from at least one of sucrose, xylitol, stevioside, sorbitol and mannitol.
3. A particulate formulation of sultamicin according to claim 1, wherein the flavor is selected from at least one of cherry, apple, strawberry and grape flavored powdered flavors.
4. A particulate preparation of sultamicin according to any one of claims 1 to 3, characterized in that the particulate preparation of sultamicin comprises, in mass percent: 6.58% of sultamicin, 85.14% of sweetener, 2.14% of ion regulator and 6.14% of essence.
5. A preparation method of a sultamicin granular preparation is characterized by comprising the following steps:
weighing the following raw materials in percentage by mass: 5-8% of sultamicin, 80-90% of sweetening agent, 1.0-2.5% of ion regulator and 0.5-13.0% of essence, wherein the ion regulator is selected from at least one of disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate and disodium edetate;
mixing the sweetening agent, the ion regulator and the wetting agent, granulating, and drying to obtain a dry material, wherein the drying temperature is 60-80 ℃, and the drying is carried out until the mass percent of the residual solvent is not higher than 0.5%, and the mass percent of the water is not higher than 1.0%; and
and mixing the dry material with the sultamicin and the essence to obtain the sultamicin granular preparation.
6. The method for preparing a granular preparation of sultamicin according to claim 5, wherein the mass of the wetting agent is 50-90% of the mass of the sultamicin.
7. The method for preparing sultamicin granular formulation according to claim 5, wherein the wetting agent is ethanol, isopropanol or water.
8. The method for preparing a granular preparation of sultamicin according to claim 5, further comprising the step of pulverizing the sultamicin, the sweetener, the ionic modifier and the essence respectively and then sieving the pulverized particles with a 60-80 mesh sieve before the step of mixing and granulating the sweetener, the ionic modifier and the wetting agent.
9. The method for preparing a granular formulation of sultamicin according to claim 5, wherein the step of mixing the sweetener, the ionic modifier and the wetting agent for granulation comprises: premixing the sweetening agent and the ion regulator for 3-10 min, adding the wetting agent, and performing wet granulation for 1-5 min.
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