WO2022036629A1

WO2022036629A1 - Method for preparing phloroglucinol injection

Info

Publication number: WO2022036629A1
Application number: PCT/CN2020/110237
Authority: WO
Inventors: 刘建明; 肖筱; 邢久东
Original assignee: 江苏康龙医药有限公司
Priority date: 2020-08-20
Filing date: 2020-08-20
Publication date: 2022-02-24

Abstract

A method for preparing a phloroglucinol injection, the method comprising: (1) mixing trimethylphloroglucinol and phloroglucinol according to a mass ratio of 1:9, and crushing same; (2) taking sodium chloride, and adding same to the foregoing mixed and crushed material, so as to obtain material I; (3) taking more sodium chloride, adding same to phloroglucinol, and mixing well to obtain material II; (4) taking water for injection, heating same to 30-40℃, adding the material I, and stirring same such that same dissolves; (5) heating the medicinal solution I and then cooling, and adding 0.1 M hydrochloric acid aqueous solution to obtain a solution II; (6) taking material II, adding same to the medicinal solution II, adding the water for injection so that 1 L solution contains 10 g phloroglucinol and 10 μg trimethylphloroglucinol, stirring same for 30-40 minutes, adjusting the pH value to 4.5 by using 0.1 M hydrochloric acid, filtering same, filling, and sterilizing, so as to obtain a phloroglucinol injection.

Description

A kind of preparation method of phloroglucinol injection

technical field

The invention relates to the technical field of medicines, in particular to a preparation method of a phloroglucinol injection.

Background technique

Before the last century, phloroglucinol was mainly derived from natural plants. Until the 1950s and 1960s, the pharmaceutical composition of phloroglucinol and trimethylphloroglucinol was widely used in clinical practice as an antispasmodic drug. Subsequently, the variety was introduced in my country, and the clinical practice has been carried out for many years, and the curative effect is accurate.

Phloroglucinol and trimethylphloroglucinol are made into compound preparations, which have obvious antispasmodic effect, rapid action, no atropine-like side effects, very few adverse reactions, and good tolerance. It is used in urology, gastroenterology, Obstetrics and gynecology has been widely used in clinical practice, and has become the drug of choice for the treatment of spastic pain, which is safe and effective.

Currently listed phloroglucinol dosage forms include tablets, injections, etc., and its active ingredients are phloroglucinol and trimethylphloroglucinol. Phloroglucinol injection has been included in the British Pharmacopoeia. However, due to data protection and other reasons, the content and preparation method of the trimethylphloroglucinol crude drug have not been reported in the literature.

In the prior art, in order to control the pH value and osmotic pressure of the injection, acid-base and sodium chloride are often added to adjust the liquid during temporary filling.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is to provide a preparation method of phloroglucinol injection, so that the method is convenient to operate and is beneficial to ensure the quality of medicines.

In order to solve the above-mentioned technical problems, the present invention proposes the following technical solutions:

A preparation method of phloroglucinol injection, characterized in that the method comprises the following steps:

(1) trimethylphloroglucinol and phloroglucinol are mixed in a mass ratio of 1:9, pulverized to obtain mixed pulverized material, for subsequent use;

(2) get sodium chloride, add described mixed pulverized material, mix homogeneously, obtain material one, for subsequent use; The mass ratio of described sodium chloride and mixed pulverized material is 30:1;

(3) take another sodium chloride, add phloroglucinol, mix homogeneously, obtain material two, for subsequent use; in this step, the mass ratio of sodium chloride and phloroglucinol is 200:495;

(4) take water for injection, heat to 30-40 ℃, add material one, stir to dissolve, and obtain liquid medicine one; the ratio of material one to water for injection is: every 10g of material one corresponds to 2.0-2.5L water for injection;

(5) medicinal liquid one is heated to 80-85 ℃, cooled to 30-35 ℃, add the hydrochloric acid aqueous solution of 0.1M, stir 15-30min, obtain medicinal liquid two; The ratio of described medicinal liquid one and hydrochloric acid aqueous solution is: Add 0.4-0.5mL of aqueous hydrochloric acid to each 1L of medicinal solution;

(6) get material 2, add it to medicinal liquid 2, add water for injection, make every 1L solution contain 10g phloroglucinol, 10 μg trimethylphloroglucinol, stir for 30-40min; adjust pH with 0.1M hydrochloric acid value to 4.5, filter, fill;

(7) Sterilize and get it.

Preferably, steps (1)-(6) all need to be carried out under the protection of nitrogen.

Preferably, in step (5), the time it takes for the Chinese medicinal solution to be heated to 80-85°C is less than 30min, and the time it takes to cool down from 80-85°C to 30-35°C is less than 30min.

Preferably, the stirring time in step (5) is 20 min.

Preferably, the sterilization condition in step (7) is sterilization at 121° C. for 15 minutes.

The phloroglucinol injection prepared by the method of the invention has stable product quality and few impurities.

The beneficial technical effect of the present invention is mainly reflected in the following aspects:

(1) The adjuvant sodium chloride used to adjust the osmotic pressure is mixed with the two main materials and then prepared, which can effectively reduce the impurity content in the finished product.

(2) Adding the aqueous hydrochloric acid solution, the auxiliary material for adjusting pH, into the solution step by step, can effectively reduce the impurity content in the finished product.

(3) When dissolving the mixture containing trimethylphloroglucinol, the temperature is raised and lowered in a short time, which is beneficial to reduce the impurity content in the finished product.

The beneficial effects of the present invention can be demonstrated by the following series of tests.

Test Example 1 The effect of sodium chloride addition on the content of impurities in the finished product

1.1 Materials

1.1.1 Injection of the present invention: self-made according to the method of Example 3.

1.1.2 Comparative injection 1: with reference to Example 3, it was prepared according to the following method.

(1) The formulation recipe quantity of each raw and auxiliary material is the same as that in Example 3.

(2) The mixed pulverized product is directly used as material one, and the sodium chloride of recipe quantity is all added to the remaining phloroglucinol as material two (referring to the step (3) of embodiment 3).

(3) The total amount of water for injection in liquid medicine 1 is the same as that in Example 3 (see step (4) of Example 3).

(4) The remaining operations are the same as those in Example 3.

1.2 Methods The impurity content in each injection was determined by high performance liquid chromatography

Chromatographic conditions Use octadecyl silane bond and silica gel as filler (Waters SPHERISORB 5μm, 250mm*4.0mm or equivalent chromatographic column); use potassium dihydrogen phosphate solution (1.36g/L potassium dihydrogen phosphate solution, Phosphoric acid was adjusted to pH 3.0) as mobile phase A, and acetonitrile was used as mobile phase B; linear gradient elution was performed in Table 1 below.

Table 1

Determination method Take the injection as the test solution; another precise amount of 1ml of the injection is diluted with acetonitrile-mobile phase A (1:9) to make 100ml, shake well, as the control solution. Take 20 μL of the control solution and inject it into the liquid chromatograph, and adjust the detection sensitivity so that the height of the chromatographic peak of the main component is about 10%-25% of the full scale of the recorder. Precisely measure 10 μL of each of the test solution and the reference solution and inject them into the liquid chromatograph, record the chromatogram, if there is an impurity peak in the chromatogram of the test solution, after deducting the solvent peak, take the phloroglucinol peak as a reference, calculate each The relative retention time of impurities is calculated by calculating the impurity content in the test solution by the ratio of the sum of the peak areas of the impurities to the main peak area of the control solution.

1.3 Results

The test results are shown in Table 2: before the sterilization, the impurity content in the injection of the present invention and the comparative injection 1 is roughly equal; but after high-temperature sterilization, the impurity content in the comparative injection 1 rises significantly, and the results show that this The sodium chloride addition method in the technical solution of the invention is beneficial to reduce the impurity content in the finished product.

Table 2 Influence of sodium chloride addition method on impurity content in finished products

Test Example 2 The influence of the addition method of hydrochloric acid aqueous solution on the content of impurities in the finished product

2.1 Materials

2.1.1 Injection of the present invention: self-made according to the method of Example 3.

2.1.2 Comparative injection 2: with reference to Example 3, it was prepared according to the following method.

(2) There is no operation of adding the aqueous hydrochloric acid solution in step (5) (that is, the aqueous hydrochloric acid solution is added at one time in step (6)).

(3) The remaining operations are the same as those in Example 3.

2.2 Method Refer to the method of 1.2 above.

2.3 Results

The test results are shown in Table 3: before sterilization, the impurity contents in the injection of the present invention and the comparative injection 2 are approximately equal; but after high-temperature sterilization, the impurity content in the comparative injection 2 is significantly increased. The results show that the hydrochloric acid addition method in the technical solution of the present invention is beneficial to reduce the impurity content in the finished product.

Table 3 The influence of the addition method of hydrochloric acid aqueous solution on the content of impurities in the finished product

Test Example 3 The effect of rapid heating and cooling process on the content of impurities in the finished product

3.1 Materials

3.1.1 Injection of the present invention: self-made according to the method of Example 3.

3.1.2 Comparative injection 3: with reference to Example 3, it was prepared according to the following method.

(2) There is no heating operation in step (5), that is, the temperature of the medicinal solution is always maintained at 30-40°C.

(3) The remaining operations are the same as those in Example 3.

3.2 Method Refer to the method of 1.2 above.

3.3 Results

The test results are shown in Table 4: before sterilization, the impurity content in the comparative injection 3 was higher than that in the injection of the present invention; after high-temperature sterilization, the impurity content in the comparative injection 3 was significantly increased. The results show that the rapid heating and cooling process in the technical solution of the present invention is beneficial to reduce the impurity content in the finished product.

Table 4 Influence of rapid heating and cooling process on impurity content in finished products

In order to better illustrate the technical solution, the present invention will be further described below with reference to specific embodiments, but the protection scope required by the present invention is not limited to the following examples.

detailed description

Example 1

Preparation of Phloroglucinol Injection

(5) the medicinal liquid is heated up to 80-85°C, cooled to 30-35°C (the time spent warming up to 80-85°C is less than 30min, and the time spent cooling from 80-85°C to 30-35°C is less than 30min), add the hydrochloric acid aqueous solution of 0.1M, stir 15min, obtain medicinal liquid two; The ratio of described medicinal liquid one and hydrochloric acid aqueous solution is: every 1L medicinal liquid adds hydrochloric acid aqueous solution 0.4mL;

(6) get material two, join in medicinal liquid two, add water for injection, make every 1L solution contain 10g phloroglucinol, 10 μg trimethylphloroglucinol, stir 30min; Adjust pH value to 0.1M hydrochloric acid to 4.5, filtration, filling;

(7) Sterilize at 121°C for 15 minutes, and then obtain.

Steps (1)-(6) all need to be carried out under the protection of nitrogen.

Determination of impurity content in finished products

Content determination method: refer to 1.2 above.

The content determination results are shown in Table 5.

Table 5 Impurity content in finished product

Example 2

Preparation of Phloroglucinol Injection

(5) the medicinal liquid is heated up to 80-85°C, cooled to 30-35°C (the time spent warming up to 80-85°C is less than 30min, and the time spent cooling from 80-85°C to 30-35°C is less than 30min), add the hydrochloric acid aqueous solution of 0.1M, stir 30min, obtain medicinal solution two; The ratio of described medicinal solution one and hydrochloric acid aqueous solution is: every 1L medicinal solution adds hydrochloric acid aqueous solution 0.5mL;

(6) get material two, join in medicinal liquid two, add water for injection, make every 1L solution contain 10g phloroglucinol, 10 μg trimethylphloroglucinol, stir 40min; Adjust pH value with 0.1M hydrochloric acid to 4.5, filtration, filling;

(7) Sterilize at 121°C for 15 minutes, and then obtain.

Steps (1)-(6) all need to be carried out under the protection of nitrogen.

Determination of impurity content in finished products

Content determination method: refer to 1.2 above.

The content determination results are shown in Table 6.

Table 6 Impurity content in finished product

Example 3

Preparation of Phloroglucinol Injection

(4) take water for injection, heat to 30-40 ℃, add material one, stir to dissolve, and obtain liquid one; the ratio of material one to water for injection is: every 10g of material one corresponds to 2.0-2.5L water for injection;

(5) the medicinal liquid is heated up to 80-85°C, cooled to 30-35°C (the time spent warming up to 80-85°C is less than 30min, and the time spent cooling from 80-85°C to 30-35°C is less than 30min), add the hydrochloric acid aqueous solution of 0.1M, stir 20min, obtain medicinal liquid two; The ratio of described medicinal liquid one and hydrochloric acid aqueous solution is: every 1L medicinal liquid adds hydrochloric acid aqueous solution 0.45mL;

(6) get material two, join in medicinal liquid two, add water for injection, make every 1L solution contain 10g phloroglucinol, 10 μg trimethylphloroglucinol, stir for 35min; adjust pH value to 0.1M hydrochloric acid to 4.5, filtration, filling;

(7) Sterilize at 121°C for 15 minutes, and then obtain.

Steps (1)-(6) all need to be carried out under the protection of nitrogen.

Obviously, the above-mentioned embodiments are only examples for clearly illustrating the present invention, and are not intended to limit the embodiments. For those of ordinary skill in the art, changes or modifications in other different forms can also be made on the basis of the above description. There is no need and cannot be exhaustive of all implementations here. Any modifications, equivalent replacements and improvements made within the spirit and principle of the present invention shall be included within the protection scope of the claims of the present invention.

Claims

A preparation method of Phloroglucinol injection, characterized in that the method comprises the following steps:

(1) trimethylphloroglucinol and phloroglucinol are mixed in a mass ratio of 1:9, pulverized to obtain mixed pulverized material, for subsequent use;

(2) get sodium chloride, add described mixed pulverized material, mix homogeneously, obtain material one, for subsequent use; the mass ratio of described sodium chloride and mixed pulverized material is 30:1;

(3) take another sodium chloride, add phloroglucinol, mix homogeneously, obtain material two, for subsequent use; in this step, the mass ratio of sodium chloride and phloroglucinol is 200:495;

(4) take water for injection, heat to 30-40 ℃, add material one, stir to dissolve, and obtain liquid one; the ratio of material one to water for injection is: every 10g of material one corresponds to 2.0-2.5L water for injection;

(5) medicinal liquid one is heated to 80-85 ℃, cooled to 30-35 ℃, add the hydrochloric acid aqueous solution of 0.1M, stir 15-30min, obtain medicinal liquid two; The ratio of described medicinal liquid one and hydrochloric acid aqueous solution is: Add 0.4-0.5mL of aqueous hydrochloric acid to each 1L of medicinal solution;

(6) get material 2, add it to medicinal liquid 2, add water for injection, make every 1L solution contain 10g phloroglucinol, 10 μg trimethylphloroglucinol, stir for 30-40min; adjust pH with 0.1M hydrochloric acid value to 4.5, filter, fill;

(7) Sterilize and get it.
The compound method of a kind of phloroglucinol injection according to claim 1, is characterized in that, steps (1)-(6) all need to carry out under the condition of nitrogen filling protection.
The compound method of a kind of phloroglucinol injection according to claim 2, it is characterised in that step (5) Chinese medicinal liquid once warming up to 80-85 DEG C the time spent is less than 30min, cooled from 80-85 DEG C to The time spent at 30-35°C is less than 30min.
The compound method of a kind of phloroglucinol injection according to claim 3, is characterized in that, the time of stirring described in step (5) is 20min.
The method for preparing a phloroglucinol injection according to claim 4, wherein the sterilization condition in step (7) is sterilization at 121°C for 15 minutes.