CN109718276B - Compound liquorice oral solution and preparation method thereof - Google Patents

The invention discloses a preparation method of a compound liquorice oral solution, which contains povidone K30, and simultaneously, the invention also discloses a preparation method of the compound liquorice oral solution. Povidone K30 is added into the compound liquorice oral solution, so that the morphine content in the oral solution can be improved, the morphine content is kept stable, and the product quality is more stable; in addition, the compound liquorice oral solution has high yield and less precipitate by adopting specific pressure, filter and sterilization method for many times in the preparation process of the compound liquorice oral solution.

Compound liquorice oral solution and preparation method thereof

Technical Field

The invention relates to the field of medicines, in particular to a compound liquorice oral solution and a preparation method thereof.

Background

The compound liquorice oral liquid is collected from the 2010 edition of Chinese pharmacopoeia, the medicine is derived from a compound liquorice mixture, and due to the toxicity problem of antimony potassium tartrate in the mixture, the compound liquorice mixture is renamed to the compound liquorice oral liquid in 7 months and 1 days in 2004, the prescription is changed into liquorice fluid extract, compound camphor tincture and guaifenesin, wherein the liquorice fluid extract is a protective expectorant; the compound camphor tincture is an antitussive; guaifenesin is a expectorant and antitussive agent and has a certain antiseptic effect. Research shows that the prescription after adjustment combines camphor, opium tincture, benzoic acid and star anise oil to prepare the compound camphor tincture, simultaneously the dosage is increased, guaifenesin is newly added, and the cough relieving and phlegm eliminating effects are really better than those of the original prescription; although the prescription increases the content of the dependency-causing substances, the potential for generating physical dependency is small, and the clinical application is safe.

In recent years, the company continuously perfects a quality management system, and implements product quality management to each link of product production and even after sale. The product quality is improved by continuously and deeply researching the product process and the product quality. We not only set up strict internal control standards, but also participated in the establishment of national drug standards. The compound liquorice oral solution produced by our company accounts for more than 30% of the market share, and is accepted by the masses, so that the preparation process of the compound liquorice oral solution is continuously perfected, and the quality of the product is improved, which is significant.

Disclosure of Invention

The invention aims to provide a compound liquorice oral solution with high stability and a preparation method thereof. By improving the preparation process of the compound liquorice oral solution and optimally controlling the stability conditions of the compound liquorice oral solution, the quality and the stability of the product are improved, and the improvement of the curative effect is achieved.

Morphine (17-methyl-4, 5 alpha-epoxy-7, 8-didehydro morphinan-3, 6 alpha-diol) can inhibit the cough center and produce the cough relieving effect, is one of the main components of the compound liquorice oral solution, and the change of the morphine is one of the main factors influencing the stability of the compound liquorice oral solution, so that the research on the improvement of the morphine content and the stability of the compound liquorice oral solution is preferably carried out in the application, and the quality of the product is further improved.

In one aspect, the invention provides a compound liquorice oral solution, and the applicant finds in practice that the content of morphine in the product can be improved and the content of morphine can be kept stable by adding povidone K30 in the compound liquorice oral solution.

Optionally, the concentration of the povidone K30 is 2-4 mg/mL, and preferably, the concentration of the povidone K30 is 3 mg/mL.

On the other hand, the invention provides a preparation method of the compound liquorice oral solution, which comprises the following steps:

1) putting povidone K30 and guaiacol glyceryl ether into boiling water in a preparation tank, starting a stirring paddle, adjusting the rotating speed to 276 rpm, and stirring for 1 hour;

2) filtering the povidone K30 and the guaiacol glycerin solution dissolved in the step 1) by a lint bag under a first pressure condition, and adding the filtered solution into a finished product tank to obtain a first solution;

3) pumping glycerol into a preparation tank under a second pressure condition, heating, cooling, filtering by a flannelette bag, and adding into the first solution obtained in the step 2) to obtain a second solution;

4) filtering the standing licorice fluid extract diluent by a PA rod under a third pressure condition, and adding the filtered licorice fluid extract diluent into the second solution obtained in the step 3) to obtain a third solution;

preferably, the standing time of the liquorice fluid extract diluent is more than 48 hours, but not more than 120 hours;

5) pumping the compound camphor tincture into the third solution obtained in the step 4) to obtain a fourth solution;

6) pumping boiled and cooled purified water into the fourth solution in the step 5), fixing the volume to the full volume, and stirring to obtain the compound liquorice oral solution; informing QA to sample and send to the top and bottom of the tank; and after the semi-finished product is qualified in test, the filling procedure checks and accepts the prepared volume, and then the semi-finished product is supplied for filling.

In the application, the glycerol and the purified water are subjected to sterilization treatment, and the sterilization treatment method comprises heating and boiling, so that the phenomenon of precipitates generated by direct sterilization of the compound liquorice oral solution is reduced.

Optionally, none of the first pressure, the second pressure, and the third pressure exceeds 0.35 MPa.

Optionally, the mass ratio of the povidone K30 to the guaifenesin in step 1) is 2: 3 to 10.

Optionally, the glycerin in the step 3) accounts for 6-16% of the total volume of the compound liquorice oral solution. The addition of the glycerol plays the roles of a thickening agent and a flavoring agent, and ensures that the product prepared by the invention has less precipitate.

Optionally, in the step 4), the licorice fluid extract diluent accounts for 45-55% of the total volume of the compound licorice oral solution, and preferably, the licorice fluid extract diluent accounts for 50% of the total volume of the compound licorice oral solution.

Optionally, the compound camphor tincture in the step 5) accounts for 20-30% of the total volume of the compound liquorice oral solution.

Optionally, the licorice fluid extract diluent is prepared by the following method: adding anhydrous sodium sulfite into boiling water, and stirring until the sodium sulfite is completely dissolved; sucking Glycyrrhrizae radix fluid extract into a dilution tank in vacuum according to the prescription amount, then putting anhydrous sodium sulfite solution, pulvis Talci, and heavy magnesium carbonate into the dilution tank, and adding boiled and cooled purified water; adjusting the pH value to 8.0-9.0 by using a concentrated ammonia solution, and uniformly stirring to obtain a licorice fluid extract diluent; standing the diluted liquid of the licorice fluid extract for later use. Wherein, the stability of solution has been guaranteed to anhydrous sodium sulfite, and the talcum powder plays homodisperse's effect, is held back when filtering moreover and forms good filter residue layer (filter bridge) in order to prevent that fine oil drips and impurity from passing through on the filter media, makes the finished product clear, therefore the talcum powder has played the effect of helping filtering again to the clarity of product has been guaranteed.

Further optionally, the glycyrrhiza extract accounts for 10-18% of the total volume of the compound glycyrrhiza oral solution; the concentration of the anhydrous sodium sulfite solution is 2-4 mg/mL; the concentration of the talcum powder is 0.6-1.2 mg/mL; the concentration of the heavy magnesium carbonate is 1-2 mg/mL.

Compared with the prior art, the technical scheme of the invention has the following advantages:

(1) povidone K30 is added into the compound liquorice oral solution, so that the morphine content in the oral solution can be improved, the morphine content is kept stable, and the product quality is more stable;

(2) the compound liquorice oral solution prepared by the invention has high yield and less precipitate by adopting specific pressure, filter and sterilization methods for many times in the preparation process.

Drawings

FIG. 1 is a flow chart of the process for preparing a dilution liquid of a licorice fluid extract according to the present invention;

FIG. 2 is a flow chart of the preparation method of the compound licorice oral solution of the present invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The experimental procedures described in the following examples are conventional unless otherwise specified, and the reagents and materials are commercially available without further specification.

Example 1:

1) preparation of licorice fluid extract diluent

Purified water (about 1000L) was added to the sugar dissolving pan, heated to boiling, 15kg of anhydrous sodium sulfite was poured into the sugar dissolving pan, and the stirring paddle was turned on and stirred for 10 minutes until the sodium sulfite was completely dissolved.

Sucking 500L of Glycyrrhrizae radix fluid extract into a dilution tank under vacuum, directly adding 15kg of anhydrous sodium sulfite solution, 4kg of talcum powder and 8kg of heavy magnesium carbonate into the dilution tank, adding boiled and cooled purified water, diluting to 2500L, adjusting pH with concentrated ammonia solution, starting a stirring paddle, stirring for 1 hour, testing with pH test paper, and adjusting pH to 8.5 to obtain Glycyrrhrizae radix fluid extract diluent. And (5) informing QA to sample and performing bacteria detection.

Standing the diluted liquid of the licorice fluid extract for more than 48 hours but not more than 120 hours, and performing pressure filtration for standby.

2) Preparation of compound licorice oral solution

Adding purified water (about 200L) into a preparation tank, heating and boiling, adding 15kg of povidone K30 and 40kg of guaiacol glyceryl ether into the preparation tank, starting a stirring paddle, stirring at 276 rpm for 1 hour, and filtering by a flannelette bag to enter a finished product tank; sucking 550L of glycerol into the preparation tank by using a pneumatic diaphragm pump, heating, cooling, filtering by using a flannelette bag, and feeding into a finished product tank; and (3) performing pressure filtration on the diluted liquid of the liquorice fluid extract after standing for 50 hours by using a 15-micron PA rod, and then putting the diluted liquid into a finished product tank. The pressure of the above solution added with polyvidone K30, guaifenesin solution, glycerol and Glycyrrhrizae radix fluid extract diluent should not exceed 0.35 Mpa.

1250L of compound camphor tincture was then pumped into the finishing tank (note: compound camphor tincture is an anesthetic, two-person rechecking had to be strictly performed, QA oversees production on site, and signs on original records).

And finally, adding purified water into the sugar dissolving pot, boiling, cooling by a condenser, pumping into a finished product tank, metering the volume to 5000L, and stirring for 1 hour. And informing QA to sample and send to the top and bottom of the tank respectively. And after the semi-finished product is qualified in test, the filling procedure checks and accepts the prepared volume, and then the semi-finished product is supplied for filling.

Comparative example 1:

1) preparation of licorice fluid extract diluent

Purified water (about 1000L) was added to the sugar dissolving pan, heated to boiling, 15kg of anhydrous sodium sulfite was poured into the sugar dissolving pan, and the stirring paddle was turned on and stirred for 10 minutes until the sodium sulfite was completely dissolved.

Sucking 500L of Glycyrrhrizae radix fluid extract into a dilution tank under vacuum, directly adding 15kg of anhydrous sodium sulfite solution, 4kg of talcum powder and 8kg of heavy magnesium carbonate into the dilution tank, adding boiled and cooled purified water, diluting to 2500L, adjusting pH with concentrated ammonia solution, starting a stirring paddle, stirring for 1 hour, testing with pH test paper, and adjusting pH to 8.5 to obtain Glycyrrhrizae radix fluid extract diluent. And (5) informing QA to sample and performing bacteria detection.

Standing the diluted liquid of the licorice fluid extract for more than 48 hours but not more than 120 hours, and performing pressure filtration for standby.

2) Preparation of compound licorice oral solution

Adding purified water (about 200L) into a preparation tank, heating and boiling, adding 40kg of guaiacol glyceryl ether into the preparation tank, starting a stirring paddle, stirring at 276 rpm for 1 hour, and filtering by a flannelette bag into a finished product tank; sucking 550L of glycerol into the preparation tank by using a pneumatic diaphragm pump, heating, cooling, filtering by using a flannelette bag, and feeding into a finished product tank; and (3) performing pressure filtration on the diluted liquid of the liquorice fluid extract after standing for 50 hours by using a 15-micron PA rod, and then putting the diluted liquid into a finished product tank. The pressure of the above solution added with polyvidone K30, guaifenesin solution, glycerol and Glycyrrhrizae radix fluid extract diluent should not exceed 0.35 Mpa.

1250L of compound camphor tincture was then pumped into the finishing tank (note: compound camphor tincture is an anesthetic, two-person rechecking had to be strictly performed, QA oversees production on site, and signs on original records).

And finally, adding purified water into the sugar dissolving pot, boiling, cooling by a condenser, pumping into a finished product tank, metering the volume to 5000L, and stirring for 1 hour. And informing QA to sample and send to the top and bottom of the tank respectively. And after the semi-finished product is qualified in test, the filling procedure checks and accepts the prepared volume, and then the semi-finished product is supplied for filling.

The compound licorice oral solutions prepared in example 1 and comparative example 1 were left for 3 months, 6 months, and 9 months, and the morphine content in the oral solutions was measured, respectively. The results are shown in the data in table 1: (1) the content of morphine in the compound liquorice oral solution in the example 1 (added with povidone K30) is higher than that in the comparative example 1 (added with povidone K30); (2) with the increase of the storage time, the morphine content in the example 1 is still maintained at a higher level, and the content fluctuation is smaller, while the morphine content in the comparative example 1 is in a descending trend with the increase of the storage time, and the content fluctuation amplitude is larger, so that the addition of the povidone K30 in the compound liquorice oral solution can improve the morphine content in the oral solution and maintain the morphine content stable, so that the product quality is more stable.

TABLE 1 Effect of different storage times on morphine content

The foregoing detailed description of the preferred embodiments of the invention has been presented. It should be understood that numerous modifications and variations could be devised by those skilled in the art in light of the present teachings without departing from the inventive concepts. Therefore, the technical solutions available to those skilled in the art through logic analysis, reasoning and limited experiments based on the prior art according to the concept of the present invention should be within the scope of protection defined by the claims.

1. The preparation method of the compound liquorice oral solution is characterized by comprising the following steps:

1) putting povidone K30 and guaiacol glycerin ether into boiling water in a preparation tank, starting a stirring paddle, adjusting the rotating speed to 276 rpm, and stirring for 1 hour, wherein the mass ratio of the povidone K30 to the guaiacol glycerin ether is 2: 3-10;

2) filtering the povidone K30 and the guaiacol glycerin solution dissolved in the step 1) by using a flannelette bag under a first pressure condition, and adding the filtered povidone K30 and the dissolved guaiacol glycerin solution into a finished product tank to obtain a first solution, wherein the mass ratio of the povidone K30 to the guaiacol glycerin ether is 2: 3-10, wherein the first pressure is not more than 0.35 MPa;

3) pumping glycerol into a preparation tank under a second pressure condition, heating, cooling, filtering by using a flannelette bag, and adding the cooled solution into the first solution obtained in the step 2) to obtain a second solution, wherein the compound camphor tincture accounts for 20-30% of the total volume of the compound liquorice oral solution, the glycerol accounts for 6-16% of the total volume of the compound liquorice oral solution, and the second pressure is not more than 0.35 MPa;

4) filtering the standing licorice fluid extract diluent by a PA rod and adding the filtered licorice fluid extract diluent into the second solution obtained in the step 3) under a third pressure condition to obtain a third solution, wherein the licorice fluid extract diluent accounts for 45-55% of the total volume of the compound licorice oral solution, and the third pressure is not more than 0.35 MPa;

5) pumping compound camphor tincture into the third solution obtained in the step 4) to obtain a fourth solution, wherein the compound camphor tincture accounts for 20-30% of the total volume of the compound liquorice oral solution;

wherein the liquorice fluid extract diluent is prepared by adopting the following method: adding anhydrous sodium sulfite into boiling water, and stirring until the sodium sulfite is completely dissolved; sucking Glycyrrhrizae radix fluid extract into a dilution tank in vacuum according to the prescription amount, then putting anhydrous sodium sulfite solution, pulvis Talci, and heavy magnesium carbonate into the dilution tank, and adding boiled and cooled purified water; adjusting the pH value to 8.0-9.0 by using a concentrated ammonia solution, and uniformly stirring to obtain a licorice fluid extract diluent; standing the licorice fluid extract diluent for later use; the compound liquorice oral solution comprises 10-18% of liquorice extract, 2-4 mg/mL of anhydrous sodium sulfite solution, 0.6-1.2 mg/mL of talcum powder and 1-2 mg/mL of heavy magnesium carbonate.