A urea 13 C] reagent and a method for preparing the same

Abstract

The present application relates to a kind of urea[ 13 C] reagent, by weight parts, urea[ 13 C] reagent includes urea[ 13 C] 10-75 parts;Citric acid 800-2500 parts;Mannitol 500-3000 parts;And flavoring agent 20-50 parts;Flavoring agent includes at least one of stevioside, sucralose, neotame and thaumatin.The present application reduces the amount of mannitol, without the need for a large amount of mannitol, to meet the quality requirements of product, reduce the risk of patients using drug, product appearance and content are stable and no impurities in normal temperature storage environment, product can be continuously maintained for 6 months in high temperature and high humidity environment.

Description

Technical Field

[0001] This invention relates to the field of medical chemical reagent technology, specifically to a urea [ 13 C] Reagents and their preparation methods. Background Technology

[0002] Helicobacter pylori is a spiral-shaped, microaerophilic, Gram-negative bacillus with extremely demanding growth requirements. It was first successfully isolated from gastric mucosal biopsy tissue of a patient with chronic active gastritis in 1983 and is currently the only known microorganism capable of surviving in the human stomach. Helicobacter pylori infection includes gastritis, peptic ulcers, and gastric lymphoma caused by Helicobacter pylori infection. A poor prognosis for Helicobacter pylori infection is gastric cancer. There are many methods for detecting Helicobacter pylori infection, such as biopsy, isolation and culture of Helicobacter pylori, rapid urease test, urea breath test, urinary ammonia excretion test, serological tests, and polymerase chain reaction (PCR). Currently, the urea breath test is widely used clinically, but its detection reagents have problems in practical application, such as uneven product content and slow dissolution. Summary of the Invention

[0003] Therefore, it is necessary to provide a urea product with uniform content and rapid dissolution. 13 C] Reagents and their preparation methods.

[0004] To achieve the above objectives, the present invention provides a technical solution:

[0005] A type of urea [ 13 C] reagent, by weight, the urea [ 13 C] Reagents include:

[0006]

[0007] The flavoring agent includes at least one of steviol glycosides, sucralose, neotame, and sematase.

[0008] The present invention also provides a urea as described above. 13 C] The preparation method of the reagent includes the following steps:

[0009] The urea [ 13 C], the citric acid, the mannitol, and the flavoring agent are pulverized and sieved separately to obtain urea. 13 C] Powder, citric acid powder, mannitol powder, flavoring agent powder;

[0010] The urea [ 13 C] powder, the citric acid powder, the mannitol powder, and the flavoring agent powder are added to the mixing hopper of the hopper mixer and mixed evenly to obtain a mixture.

[0011] The mixture is dispensed into bottles or polyester film bags according to a predetermined amount to obtain the urea. 13 C] reagent.

[0012] Preferably, the urea [ 13 The specific steps for adding the powder, the citric acid powder, the mannitol powder, and the flavoring agent powder into the mixing hopper of the hopper mixer and mixing them evenly to obtain the mixture include:

[0013] The urea [ 13 C] powder, 15%-100% of the mannitol powder, and the flavoring agent powder are added to the mixing hopper of the hopper mixer and stirred until evenly mixed to complete the first premixing and obtain the first premix;

[0014] Add 50%-85% mannitol to the first premix and stir again until homogeneous to complete the second premixing, thus obtaining the second premix.

[0015] Add the remaining mannitol and citric acid to the second premix and continue stirring until the mixture is homogeneous to obtain the final mixture.

[0016] Preferably, the urea [ 13 C] powder, 15%-100% of the mannitol powder, and the flavoring agent powder are added to the mixing hopper of the hopper mixer and stirred until evenly mixed to complete the first premixing and obtain the first premixed material. In this step, the stirring speed is 10-15 rpm.

[0017] Preferably, in the step of adding 50%-85% mannitol to the first premix and stirring again to mix evenly to complete the second premix and obtain the second premix, the stirring speed is 10-15 rpm.

[0018] Preferably, in the step of adding the remaining mannitol and citric acid to the second premix and continuing to stir and mix evenly to obtain a mixture, the stirring speed is 10-15 rpm.

[0019] Preferably, the stirring speed is 10-15 rpm.

[0020] Preferably, after the second premixing is completed, the urea in the second premix [ 13 The mass ratio of C to mannitol ranges from 1:(2 to 15).

[0021] Preferably, the urea [ 13 C] The mannitol and the flavoring agent are sieved through a screen with a mesh size of 80 to 100 mesh.

[0022] Preferably, the citric acid is sieved using a screen with a mesh size of 60 to 80 mesh.

[0023] The beneficial effects of this invention are:

[0024] This invention reduces the amount of mannitol required, meeting product quality requirements without the need for large amounts of mannitol, thus reducing the risk to patients using the drug. The product remains stable in appearance and content at room temperature without producing impurities, and maintains stability for up to 6 months in high temperature and high humidity environments.

[0025] This invention mixes all the prescription components to prepare a single dosage form, which can be taken in one dose, making it convenient for patients and medical staff. The direct mixing and dispensing process eliminates the use of solvents, resulting in no loss during production and effectively reducing product costs. The multiple premixing steps of this invention effectively ensure the uniformity of the product mixture, thereby ensuring the accuracy of the dosage. Detailed Implementation

[0026] To better illustrate the purpose, technical solution, and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0027] In the embodiments, unless otherwise specified, the experimental methods used are conventional methods, and the materials and reagents used are commercially available unless otherwise specified.

[0028] A type of urea [ 13 C] Reagent, by weight, urea [ 13 C] Reagents include:

[0029]

[0030] Flavoring agents include at least one of steviol glycosides, sucralose, neotame, and sematase.

[0031] The present invention also provides a urea as described above. 13 C] The preparation method of the reagent includes the following steps:

[0032] Urea [ 13 C], citric acid, mannitol, and flavoring agent are pulverized and sieved separately to obtain urea. 13 C] Powder, citric acid powder, mannitol powder, flavoring agent powder;

[0033] Urea [ 13 C] Powder, citric acid powder, mannitol powder, and flavoring agent powder are added to the mixing hopper of the hopper mixer and mixed evenly to obtain a mixture.

[0034] The mixture is dispensed into bottles or polyester film bags according to the predetermined packaging quantity to obtain urea. 13C] reagent.

[0035] In some embodiments, urea [ 13 The specific steps for adding powdered citric acid, mannitol, and flavoring agent into the mixing hopper of a hopper mixer and mixing them evenly to obtain a mixture include:

[0036] Urea [ 13 C] powder, 15%-100% mannitol powder, and flavoring agent powder are added to the mixing hopper of the hopper mixer and stirred until evenly mixed to complete the first premix and obtain the first premix.

[0037] Add 50%-85% mannitol to the first premix and stir again until homogeneous to complete the second premix and obtain the second premix.

[0038] Add the remaining mannitol and citric acid to the second premix and continue stirring until the mixture is homogeneous to obtain the final mixture.

[0039] The purpose of adding mannitol is to improve granulation and prevent clumping, thereby maintaining stable product quality.

[0040] In some embodiments, when urea [ 13 In the step of adding powder, 15%-100% mannitol powder, and flavoring agent powder into the mixing hopper of the hopper mixer and stirring to mix evenly to complete the first premixing and obtain the first premix, the stirring speed is 10-15 rpm and the stirring speed is 350-900 r, more preferably 450-750 r.

[0041] In some embodiments, in the step of adding 50%-85% mannitol to the first premix and stirring again to mix evenly to complete the second premix and obtain the second premix, the stirring speed is 10-15 rpm and the stirring speed is 350-900 r, more preferably 450-750 r.

[0042] In some embodiments, in the step of adding the remaining mannitol and citric acid to the second premix and continuing to stir and mix evenly to obtain a mixture, the stirring speed is 10-15 rpm and the stirring speed is 350-900 r, more preferably 450-750 r.

[0043] In some embodiments, the stirring speed is 10-15 rpm, and the stirring revolutions are 350-900 r, more preferably 450-750 r.

[0044] In some embodiments, after the second premixing is completed, the urea in the second premix [ 13 The mass ratio of C to mannitol ranges from 1:(2 to 15).

[0045] In some embodiments, urea [ 13 C], mannitol, and flavoring agents are sieved using a screen size of 80-100 mesh.

[0046] In some embodiments, the sieve size for citric acid is 60-80 mesh.

[0047] Example 1

[0048] Citrate acid is pulverized and passed through an 80-mesh sieve, and the fine powder is kept for later use. Urea [13C], mannitol, and flavoring agent are pulverized and passed through a 100-mesh sieve for later use.

[0049] Take urea [ 13 Add 10 parts of C, 150 parts of mannitol, and 25 parts of flavoring agent to a mixer and mix at 15 rpm for 40 minutes. Add 850 parts of mannitol to the mixture from the previous step and continue mixing at 15 rpm for 30 minutes. Finally, add 2500 parts of citric acid and mix at 10 rpm for a total of 50 minutes.

[0050] Example 2

[0051] Citrate acid is pulverized and passed through an 80-mesh sieve, and the fine powder is kept for later use. Urea [13C], mannitol, and flavoring agent are pulverized and passed through a 100-mesh sieve for later use.

[0052] Take urea [ 13 Add 25 parts of C, 375 parts of mannitol, and 25 parts of flavoring agent to a mixer and mix at 15 rpm for 40 minutes. Add 1500 parts of mannitol to the mixture from the previous step and continue mixing at 15 rpm for 30 minutes. Finally, add 1125 parts of mannitol and 2500 parts of citric acid and mix at 10 rpm for a total of 50 minutes.

[0053] Example 3

[0054] Citrate acid is pulverized and passed through a 60-mesh sieve, and the fine powder is kept for later use. Urea [13C], mannitol, and flavoring agent are pulverized and passed through an 80-mesh sieve for later use.

[0055] Take urea [ 13 Add 45 parts of C, 450 parts of mannitol, and 50 parts of flavoring agent to a mixer and mix at 15 rpm for 40 minutes. Then add 550 parts of mannitol and 1500 parts of citric acid to the mixture from the previous step and mix at 15 rpm for a total of 50 minutes.

[0056] Example 4

[0057] Citrate acid is pulverized and passed through a 60-mesh sieve, and the fine powder is kept for later use. Urea [13C], mannitol, and flavoring agent are pulverized and passed through an 80-mesh sieve for later use.

[0058] Take urea [ 13 Add 50 parts of C, 500 parts of mannitol, and 45 parts of flavoring agent to a mixer and mix at 15 rpm for 40 minutes. Add 1500 parts of citric acid to the mixture from the previous step and mix at 15 rpm for a total of 40 minutes.

[0059] Example 5

[0060] Citrate acid is pulverized through a 60-mesh sieve, and the fine powder is kept for later use.

[0061] Urea [ 13 C] Mannitol and flavoring agent are pulverized and passed through an 80-mesh sieve for later use.

[0062] Take urea [ 13 Add 50 parts of C, 500 parts of mannitol, and 40 parts of flavoring agent to a mixer and mix at 15 rpm for 30 minutes. Then add 300 parts of mannitol and 1000 parts of citric acid to the mixture from the previous step and mix at 15 rpm for a total of 40 minutes.

[0063] Example 6

[0064] Citrate acid is pulverized and passed through a 60-mesh sieve, and the fine powder is kept for later use. Urea [13C], mannitol, and flavoring agent are pulverized and passed through an 80-mesh sieve for later use.

[0065] Take urea [ 13 Add 75 parts of C, 500 parts of mannitol, and 45 parts of flavoring agent to a mixer and mix at 15 rpm for 30 minutes. Then add 800 parts of citric acid to the mixture from the previous step and mix at 15 rpm for a total of 40 minutes.

[0066] Comparative Example 1

[0067] Citrate acid is pulverized and passed through a 60-mesh sieve, and the fine powder is kept for later use. Urea [13C], mannitol, and flavoring agent are pulverized and passed through an 80-mesh sieve for later use.

[0068] Take urea [ 13 C] 75 parts, mannitol 500 parts, flavoring agent 50 parts, add to a mixer and mix at 15 rpm for 30 min; add 300 parts mannitol and 1500 parts citric acid to the mixture from the previous step and mix at 10 rpm for a total of 50 min.

[0069] Comparative Example 2

[0070] Citrate acid is pulverized and passed through a 60-mesh sieve, and the fine powder is kept for later use. Urea [13C], mannitol, and flavoring agent are pulverized and passed through an 80-mesh sieve for later use.

[0071] Take urea [13 C] 75 parts, mannitol 500 parts, flavoring agent 125 parts, add to a mixer and mix at 15 rpm for 30 min; add 250 parts mannitol and 2000 parts citric acid to the mixture from the previous step and mix at 10 rpm for a total of 50 min.

[0072] The amounts of each component used in Examples 1-6 and Comparative Examples 1-2 are shown in Table 1.

[0073] Table 1. Dosage of each component in Examples 1-6 and Comparative Examples 1-2

[0074]

[0075]

[0076] The samples obtained in Examples 1-6 and Comparative Examples 1-2 were placed in high temperature and high humidity (40℃, 75%RH) and normal temperature (30℃, 65%RH) environments to investigate their quality stability and were compared with the control formulation samples. The results of the initial state of the samples are shown in Table 2. The results of placing the samples in high temperature and high humidity and normal temperature environments for 6 months are shown in Tables 3 and 4.

[0077] Table 2. Test results of samples in their initial placement state.

[0078]

[0079] Table 3. Test results of samples stored for 6 months (40℃, 75% RH)

[0080] prescription Appearance content biuret Total impurities Melting time Example 1 White powder 98.1％ Not detected Not detected ≤10s Example 2 White powder 99.3％ Not detected Not detected ≤25s Example 3 White powder 100.1％ Not detected Not detected ≤10s Example 4 White powder 98.8％ Not detected Not detected ≤10s Example 5 White powder 99.1％ Not detected Not detected ≤10s Example 6 White powder 99.7％ Not detected Not detected ≤10s Comparative Example 1 off-white powder 95.9％ 0.07％ 4.88％ ≤15s Comparative Example 2 Moisture absorption and clumping 95.7％ 0.07％ 2.97％ >5min

[0081] Table 4. Test results of samples stored for 6 months (30℃, 65% RH)

[0082]

[0083] As shown in Tables 2, 3 and 4, the samples obtained in Examples 1 to 6 are stable in appearance and content without producing impurities in a normal temperature storage environment, and the products can maintain the stability of 6 Rs in a high temperature and high humidity environment.

[0084] Furthermore, due to the interaction between citric acid and sucralose in Comparative Example 1, when the mass ratio of citric acid to sucralose is ≤30:1, it will lead to urea […]. 13 C] The reagent sample undergoes an appearance change (from white powder to off-white powder), and the smaller the proportion, the shorter the change time.

[0085] In Comparative Example 2, aspartame will be used as a flavoring agent. Aspartame and the organic acid citric acid will form a complex, which will enhance hygroscopicity and lead to clumping.

[0086] It should be noted that the specific parameters or reagents in the above embodiments are specific or preferred embodiments under the concept of the present invention, and not limitations thereof; those skilled in the art can make adaptive adjustments within the concept and protection scope of the present invention.

Claims

1. A type of urea [ 13 C] reagent, characterized in that, The urea [ 13 C] The preparation method of the reagent includes the following steps: Citrate acid is pulverized through an 80-mesh sieve, and the fine powder is kept for later use. Urea [ 13 C] Mannitol and flavoring agent are pulverized and passed through a 100-mesh sieve for later use. The flavoring agent is composed of 10 parts sucralose, 10 parts neotame and 5 parts sematose. Take urea [ 13 Add 10 parts of C, 150 parts of mannitol, and 25 parts of flavoring agent to a mixer and mix at 15 rpm for 40 minutes. Add 850 parts of mannitol to the mixture obtained in the previous step and continue mixing at 15 rpm for 30 minutes. Finally, add 2500 parts of citric acid and mix at 10 rpm for a total of 50 minutes.

2. A type of urea [ 13 The preparation method of reagent C] is characterized in that, The preparation method includes the following steps: Citrate acid is pulverized through an 80-mesh sieve, and the fine powder is kept for later use. Urea [ 13 C] Mannitol and flavoring agent are pulverized and passed through a 100-mesh sieve for later use. The flavoring agent is composed of 10 parts sucralose, 10 parts neotame and 5 parts sematose. Take urea [ 13 Add 10 parts of C, 150 parts of mannitol, and 25 parts of flavoring agent to a mixer and mix at 15 rpm for 40 minutes. Add 850 parts of mannitol to the mixture obtained in the previous step and continue mixing at 15 rpm for 30 minutes. Finally, add 2500 parts of citric acid and mix at 10 rpm for a total of 50 minutes.

3. A type of urea [ 13 C] reagent, characterized in that, The urea [ 13 C] The preparation method of the reagent includes the following steps: Citrate acid is pulverized through an 80-mesh sieve, and the fine powder is kept for later use. Urea [ 13 C] Mannitol and flavoring agent are pulverized and passed through a 100-mesh sieve for later use. The flavoring agent is composed of 10 parts steviol glycosides, 10 parts sucralose, and 5 parts neotame. Take urea [ 13 Add 25 parts of C, 375 parts of mannitol, and 25 parts of flavoring agent to a mixer and mix at 15 rpm for 40 minutes. Add 1500 parts of mannitol to the mixture obtained in the previous step and continue mixing at 15 rpm for 30 minutes. Finally, add 1125 parts mannitol and 2500 parts citric acid and mix at 10 rpm for 50 minutes.

4. A type of urea [ 13 The preparation method of reagent C] is characterized in that, The preparation method includes the following steps: Citrate acid is pulverized through an 80-mesh sieve, and the fine powder is kept for later use. Urea [ 13 C] Mannitol and flavoring agent are pulverized and passed through a 100-mesh sieve for later use. The flavoring agent is composed of 10 parts steviol glycosides, 10 parts sucralose, and 5 parts neotame. Take urea [ 13 Add 25 parts of C, 375 parts of mannitol, and 25 parts of flavoring agent to a mixer and mix at 15 rpm for 40 minutes. Add 1500 parts of mannitol to the mixture obtained in the previous step and continue mixing at 15 rpm for 30 minutes. Finally, add 1125 parts mannitol and 2500 parts citric acid and mix at 10 rpm for 50 minutes.

5. A type of urea [ 13 C] reagent, characterized in that, The urea [ 13 C] The preparation method of the reagent includes the following steps: Citrate acid is pulverized through a 60-mesh sieve, and the fine powder is kept for later use. Urea [ 13 C] Mannitol and flavoring agent are pulverized and passed through an 80-mesh sieve for later use. The flavoring agent is composed of 20 parts steviol glycosides and 30 parts sucralose. Take urea [ 13 Add 45 parts of C, 450 parts of mannitol, and 50 parts of flavoring agent to a mixer and mix at 15 rpm for 40 minutes. Add 550 parts mannitol and 1500 parts citric acid to the mixture obtained in the previous step and mix at 15 rpm for 50 minutes.

6. A type of urea [ 13 The preparation method of reagent C] is characterized in that, The preparation method includes the following steps: Citrate acid is pulverized through a 60-mesh sieve, and the fine powder is kept for later use. Urea [ 13 C] Mannitol and flavoring agent are pulverized and passed through an 80-mesh sieve for later use. The flavoring agent is composed of 20 parts steviol glycosides and 30 parts sucralose. Take urea [ 13 Add 45 parts of C, 450 parts of mannitol, and 50 parts of flavoring agent to a mixer and mix at 15 rpm for 40 minutes. Add 550 parts mannitol and 1500 parts citric acid to the mixture obtained in the previous step and mix at 15 rpm for 50 minutes.

7. A type of urea [ 13 C] reagent, characterized in that, The urea [ 13 C] The preparation method of the reagent includes the following steps: Citrate acid is pulverized through a 60-mesh sieve, and the fine powder is kept for later use. Urea [ 13 C] Mannitol and flavoring agent are pulverized and passed through an 80-mesh sieve for later use. The flavoring agent is steviol glycoside. Take urea [ 13 Add 50 parts of C, 500 parts of mannitol, and 45 parts of flavoring agent to a mixer and mix at 15 rpm for 40 minutes. Add 1500 parts of citric acid to the mixture obtained in the previous step and mix at 15 rpm for 40 minutes.

8. A type of urea [ 13 The preparation method of reagent C] is characterized in that, The preparation method includes the following steps: Citrate acid is pulverized through a 60-mesh sieve, and the fine powder is kept for later use. Urea [ 13 C] Mannitol and flavoring agent are pulverized and passed through an 80-mesh sieve for later use. The flavoring agent is steviol glycoside. Take urea [ 13 Add 50 parts of C, 500 parts of mannitol, and 45 parts of flavoring agent to a mixer and mix at 15 rpm for 40 minutes. Add 1500 parts of citric acid to the mixture obtained in the previous step and mix at 15 rpm for 40 minutes.

9. A type of urea [ 13 C] reagent, characterized in that, The urea [ 13 C] The preparation method of the reagent includes the following steps: Citrate acid is pulverized through a 60-mesh sieve, and the fine powder is kept for later use. Urea [ 13 C] Mannitol and flavoring agent are pulverized and passed through an 80-mesh sieve for later use. The flavoring agent is composed of 15 parts sucralose and 25 parts steviol glycosides. Take urea [ 13 Add 50 parts of C, 500 parts of mannitol, and 40 parts of flavoring agent to a mixer and mix at 15 rpm for 30 minutes. Add 300 parts mannitol and 1000 parts citric acid to the mixture obtained in the previous step and mix at 15 rpm for a total of 40 minutes.

10. A type of urea [ 13 The preparation method of reagent C] is characterized in that, The preparation method includes the following steps: Citrate acid is pulverized through a 60-mesh sieve, and the fine powder is kept for later use. Urea [ 13 C] Mannitol and flavoring agent are pulverized and passed through an 80-mesh sieve for later use. The flavoring agent is composed of 15 parts sucralose and 25 parts steviol glycosides. Take urea [ 13 Add 50 parts of C, 500 parts of mannitol, and 40 parts of flavoring agent to a mixer and mix at 15 rpm for 30 minutes. Add 300 parts mannitol and 1000 parts citric acid to the mixture obtained in the previous step and mix at 15 rpm for a total of 40 minutes.

11. A type of urea [ 13 C] reagent, characterized in that, The urea [ 13 C] The preparation method of the reagent includes the following steps: Citrate acid is pulverized through a 60-mesh sieve, and the fine powder is kept for later use. Urea [ 13 C] Mannitol and flavoring agent are pulverized and passed through an 80-mesh sieve for later use. The flavoring agent is composed of 15 parts sucralose and 15 parts steviol glycosides. Take urea [ 13 Add 75 parts of C, 500 parts of mannitol, and 30 parts of flavoring agent to a mixer and mix at 15 rpm for 30 minutes. Add 800 parts of citric acid to the mixture obtained in the previous step and mix at 15 rpm for 40 minutes.

12. A type of urea [ 13 The preparation method of reagent C] is characterized in that, The preparation method includes the following steps: Citrate acid is pulverized through a 60-mesh sieve, and the fine powder is kept for later use. Urea [ 13 C] Mannitol and flavoring agent are pulverized and passed through an 80-mesh sieve for later use. The flavoring agent is composed of 15 parts sucralose and 15 parts steviol glycosides. Take urea [ 13 Add 75 parts of C, 500 parts of mannitol, and 30 parts of flavoring agent to a mixer and mix at 15 rpm for 30 minutes. Add 800 parts of citric acid to the mixture obtained in the previous step and mix at 15 rpm for 40 minutes.

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