CN113318075B

CN113318075B - Acetylcysteine solution and preparation method thereof

Info

Publication number: CN113318075B
Application number: CN202110706919.2A
Authority: CN
Inventors: 侯曙光; 舒宏; 杨丽; 贺钢民; 周璇
Original assignee: Sichuan Pu Et Pharmaceutical Co ltd
Current assignee: Sichuan Pu Et Pharmaceutical Co ltd
Priority date: 2021-06-24
Filing date: 2021-06-24
Publication date: 2022-09-13
Anticipated expiration: 2041-06-24
Also published as: CN113318075A

Abstract

The invention provides an acetylcysteine solution, wherein the pH value of the solution is 3.0-5.5, and the acetylcysteine solution does not contain an antioxidant or a metal chelating agent. In the solution provided by the invention, the hydrogen sulfide content in the acetylcysteine solution is lower than 50ppm, and the total amount of the impurity E and the impurity C is lower than 1% by means of adjusting the pH value, reducing headspace residual oxygen and the like.

Description

Acetylcysteine solution and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations.

Background

N-acetyl-L-cysteine (NAC) is an N-acetylated derivative of cysteine, mainly breaks a disulfide bond (-S-S) of acid glycoprotein polypeptide in phlegm through a sulfhydryl group in a molecule, and simultaneously can cleave DNA in the phlegm to play a strong sputum dissolving role, so that the sputum is easy to cough out. With the more and more extensive clinical use and research in more than ten years, it is found that acetylcysteine not only has the function of dissolving the oak mucus, but also has stronger antioxidation and the function of promoting the generation of lung surfactant. Many clinical evidences have proved that acetylcysteine has good therapeutic and preventive effects on various respiratory diseases such as chronic obstructive pulmonary disease, bronchial asthma, acute respiratory distress syndrome, pulmonary interstitial fibrosis, etc.

The acetylcysteine solution for inhalation on the market at present is mainly imported from Italian Zabang

The sterilization method in the production process adopts terminal high temperature sterilization of common injection, and has hydrogen sulfide contentHigh, pungent smell, high irritation to mucosa, and poor tolerance to airway sensitive patients such as children and the elderly. Meanwhile, parameters such as oxidation impurity C and sulfhydryl condensation impurity E can be generated during high-temperature damp-heat sterilization.

The fact that the prescription contains the adjuvant edetate disodium is clearly stated in the imported specification of pranopal pamphlet, according to the research and analysis on the situation of using edetate disodium in intravenous administration preparations in the CDE electronic publication, the edetate disodium can cause the blood calcium concentration to be reduced, and the potential safety risk exists when the concentration is too high.

In addition, some prior arts disclose that auxiliary materials such as antioxidant are added to improve the stability of acetylcysteine in the solution, and the use of excessive auxiliary materials also inevitably introduces potential safety hazards.

Disclosure of Invention

In order to solve the deficiencies in the prior art, patent publication No. CN112245412A discloses an acetylcysteine solution containing only a main drug, sodium hydroxide and water, wherein the pH is selected from 6.6-7.3; patent publication No. CN110870855A also provides an acetylcysteine solution containing only a main drug, a pH regulator and water, wherein the pH is 6.0-8.0. The pH value of the liquid medicines of the two patents is higher than 6.0, and oxidation reaction and thioetherification reaction can occur in the standing process to produce impurities C and E. Acetylcysteine also produces hydrogen sulfide when degraded to form E as an impurity.

Impurity E

N, N' -diacetyl L-lanthionine (dinaline salt)

Impurity C

N, N' -diacetyl-L-cystine

The invention provides a novel acetylcysteine solution with simpler components and good stability.

Specifically, the invention provides an acetylcysteine solution, wherein the pH value of the solution is 3.0-5.5, and the acetylcysteine solution does not contain an antioxidant or a metal chelating agent.

Further, when the pH value in the solution is selected from 3.0 to 4.0, the stability is more excellent.

The metal chelator typically comprises edetate, for example disodium edetate which may be selected from those used in existing formulations.

The antioxidants typically include ascorbic acid, sodium bisulfite, L-cysteine, and the like.

Tromethamine is also not included in the solutions of the present invention.

In the container for packaging the solution, the headspace residual oxygen content is less than 3%, which is more favorable for improving the stability of the solution.

The present invention can adopt a conventional method to control the headspace residual oxygen quantity, such as nitrogen filling or other water-insoluble inert gases which can achieve similar effects.

In the solution provided by the invention, the hydrogen sulfide content in the acetylcysteine solution is lower than 50ppm, and the total amount of the impurity E and the impurity C is lower than 1% by means of adjusting the pH value, reducing headspace residual oxygen and the like.

The solution is prepared by aseptic filling process.

Furthermore, the raw materials of the solution provided by the invention are acetylcysteine, a pH regulator and water, the components are simple, and the safety risk caused by excessive auxiliary materials is avoided.

Wherein the pH regulator is selected from alkali such as sodium hydroxide and sodium carbonate, preferably sodium hydroxide is used.

The preferred scheme of the solution of the invention is as follows: the raw materials only contain acetylcysteine, water and a pH regulator.

In the present invention, the solution may be an inhalation preparation, an injection, or the like.

The invention also provides a preparation method of the acetylcysteine solution for inhalation, which comprises the following steps:

(1) mixing and dissolving the raw materials;

(2) adjusting the pH value;

(3) controlling the residual oxygen content in the headspace of the packaging container to be less than 3%, filtering, sterilizing, and aseptically filling.

Filtering to remove bacteria, and removing bacteria in liquid or air by physical retention method to achieve aseptic purpose. The apparatus used is a filter with a tiny pore size. Commonly used bacteria filters are membrane filters (0.45 μm and 0.22 μm pore size), ceramic filters, asbestos filters (i.e., Seitz filters), sintered glass filters, and the like.

The invention also provides the application of the solution in preparing a mucolytic agent.

The invention also provides the application of the solution in preparing a medicine for treating difficult expectoration.

The method reduces the pH value of the liquid medicine, reduces the headspace residual oxygen, adopts sterilization filtration and aseptic production, finally avoids the use of a damp-heat sterilization process, avoids the use of disodium edetate, has low content of hydrogen sulfide, has low content of impurities E and C, and obviously improves the safety.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are 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.

Example 1

Dissolving acetylcysteine in water, adding sodium hydroxide to adjust pH to 5.5, aseptically filling, and controlling residual oxygen content in the headspace of the ampoule bottle to be 2.0% to obtain acetylcysteine solution.

Example 2

Dissolving acetylcysteine in water, adding sodium hydroxide to adjust pH to 4.5, aseptically filling, and controlling residual oxygen content in the headspace of the ampoule bottle to be 2.0% to obtain acetylcysteine solution.

Example 3

Dissolving acetylcysteine in water, adding sodium hydroxide to adjust pH to 4.0, aseptically filling, and controlling residual oxygen content in the headspace of the ampoule bottle to 2.0% to obtain acetylcysteine solution.

Example 4

Dissolving acetylcysteine in water, adding sodium hydroxide to adjust pH to 4.0, aseptically filling, and controlling residual oxygen content in the headspace of the ampoule bottle to 3.0% to obtain acetylcysteine solution.

Example 5

Dissolving acetylcysteine in water, adding sodium hydroxide to adjust pH to 4.0, aseptically filling, and controlling residual oxygen content in the headspace of the ampoule bottle to 1.0% to obtain acetylcysteine solution.

Example 6

Dissolving acetylcysteine in water, adding sodium hydroxide to adjust pH to 3.0, aseptically filling, and controlling residual oxygen content in the headspace of the ampoule bottle to 2.0% to obtain acetylcysteine solution.

Example 7

Dissolving acetylcysteine in water, adding sodium hydroxide to adjust pH to 3.5, aseptically filling, and controlling residual oxygen content in the headspace of the ampoule bottle to 2.0% to obtain acetylcysteine solution.

Comparative experiment:

the following table was used to prepare acetylcysteine solutions for inhalation having different pH values and residual oxygen ratios, and the concentration of hydrogen sulfide was determined by titration method and the substance related to the drug solution was determined by HPLC method.

TABLE 1 sample information Table

Sample number	pH value	Head space residual oxygen amount	Edetate disodium (mg/ml)
				1	6.8	3.0％	1.0
2	6.5	2.0％	0
				3	6.5	1.0％	0
4	6.0	2.0％	0
				5	6.0	1.0％	0
6	5.5	2.0％	0
				7	5.0	2.0％	0
8	4.0	2.0％	0
				9	3.5	2.0％	0
10	3.0	2.0％	0
				11	4.0	3.0％	0
12	4.0	1.0％	0

Note: sample No. 1, imported product of Zabang Italy, trade name

The results of the related contents are shown in the following table through HPLC detection:

TABLE 20 month data

TABLE 3 acceleration of 12 month data

Sample number	Hydrogen sulfide content (ppm)	Impurity E%	Impurity C
				1	158	0.60	1.02
2	98	0.38	0.82
				3	102	0.36	0.88
4	35	0.28	0.62
				5	43	0.25	0.68
6	10	0.10	0.48
				7	7	0.08	0.39
8	6	0.06	0.09
				9	5	0.05	0.11
10	4	0.07	0.13
				11	5	0.08	0.11
12	3	0.06	0.10

The results in the table show that, in an aseptic process, when the pH value of the liquid medicine is reduced, the headspace residual oxygen amount is reduced, the hydrogen sulfide content can be reduced under the condition of not using disodium edetate or other antioxidants, and an accelerated experiment shows that compared with the prior art, the method can better ensure the stability of the solution and obviously reduce the impurity content.

Although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.

Claims

1. An acetylcysteine inhalation formulation, comprising: the pH value of the solution is 3.0-5.5, and the raw materials are acetylcysteine, a pH regulator and water; the headspace residual oxygen content in the container encapsulating the solution was less than 3%.

2. An acetylcysteine inhalation formulation according to claim 1, characterized by: the pH value of the solution is selected from 3.0-4.5.

3. The acetylcysteine inhalation formulation of claim 1, wherein: the headspace residual oxygen content is less than 2%.

4. An acetylcysteine inhalation formulation according to claim 1, characterized by: the hydrogen sulfide content in the solution is less than 50 ppm; the total amount of the impurities E and C is less than 1 percent.

5. An acetylcysteine inhalation formulation according to claim 1, characterized by: the pH regulator is selected from sodium hydroxide and sodium carbonate.

6. A process for the preparation of an acetylcysteine inhalation formulation according to any one of claims 1-5, characterized in that: it comprises the following contents:

(1) mixing and dissolving the raw materials;

(2) adjusting the pH value;

(3) controlling the content of residual oxygen in the headspace of the packaging container to be less than 3%, filtering, sterilizing and aseptically filling.

7. Use of a formulation according to any one of claims 1 to 5 in the preparation of a mucolytic agent.

8. Use of a formulation according to any one of claims 1 to 5 in the manufacture of a medicament for the treatment of dyspnea.