A method for preparing a stable solution of 2-amino-3,5-dibromobenzylamine derivative for inhalation

Abstract

The present invention discloses a method for preparing a stable solution of 2-amino-3,5-dibromobenzylamine derivative for inhalation. The stable solution of 2-amino-3,5-dibromobenzylamine derivative for inhalation has a pH value of 3.0 and its composition is as follows: 2 g of bromhexine hydrochloride, 1 g of DL-tartaric acid, 0.1-0.5 g of L-serine, and the injection water is added to 1000 mL. The method comprises: 1) mixing bromhexine hydrochloride and L-serine and grinding them to obtain a mixture of bromhexine hydrochloride and L-serine; 2) taking 90% of the injection water, adding DL-tartaric acid under stirring, after dissolution, adding the mixture of bromhexine hydrochloride and L-serine and stirring until completely dissolved, adjusting the pH to 3 with sodium hydroxide, and making up the injection water to the full volume; 3) filtering and filling. The present invention does not need to add a large amount of stabilizers. Using a trace amount of L-serine as an auxiliary agent can improve the stability of the bromhexine hydrochloride solution. L-serine is an amino acid beneficial to the human body and will not bring risks, ensuring the safety of drug use.

Description

[0001] This application is a divisional application of the application with the application number 202210269898.7, the application date of March 18, 2022, and the invention creation name of "A Stable Bromhexine Hydrochloride Solution for Inhalation and Its Preparation Method". Technical Field

[0002] The present invention belongs to the field of medicine, and specifically relates to a method for preparing a stable solution of 2-amino-3,5-dibromobenzylamine derivatives for inhalation. Background Art

[0003] Bromhexine Hydrochloride for Inhalation developed by SANOFI was first launched in Belgium on September 30, 1990, under the trade name with specifications of 0.2% (40 ml, 100 ml, 250 ml), and indications for acute bronchitis, tracheobronchitis, chronic bronchitis, chronic obstructive bronchopulmonary disease, bronchiectasis, acute sinusitis, and chronic sinusitis.

[0004] The English name of Bromhexine Hydrochloride: Bromhexine Hydrochloride, chemical formula:

[0005]

[0006] It is slightly soluble in methanol, slightly soluble in ethanol, and very slightly soluble in water. It is not hygroscopic and is stable to light, but when it is exposed to an aqueous solution, decomposition products will be produced.

[0007] Chinese Patent Application CN104306329A discloses a Bromhexine Hydrochloride injection with relatively high stability, and its excipients include tartaric acid and stabilizers (mannitol, xylitol, and sorbitol), etc. The disadvantage of this technical solution is that the dosage of the excipients in the injection is relatively large. For example, the dosage of the main drug Bromhexine Hydrochloride is 1 - 4 g, and the addition amount of the stabilizer reaches 40 - 60 g, there are certain problems with the safety of medication.

[0008] Therefore, it is an urgent problem to be solved in the field to prepare a Bromhexine Hydrochloride solution for inhalation with a simple prescription composition, a low content of stabilizer, and high stability. Summary of the Invention

[0009] The purpose of the present invention is to provide a method for preparing a stable solution of 2-amino-3,5-dibromobenzylamine derivatives for inhalation.

[0010] The stable solution of 2-amino-3,5-dibromobenzylamine derivatives for inhalation has a pH value of 3.0, and its composition is:

[0011] Bromhexine Hydrochloride 2 g

[0012] DL-Tartaric Acid 1 g

[0013] 0.1 - 0.5 g of L-serine,

[0014] q.s. to 1000 mL with water for injection,

[0015] More specifically, the composition of the ambroxol hydrochloride solution for inhalation is as follows:

[0016] (1) 2 g of ambroxol hydrochloride

[0017] 1 g of DL-tartaric acid

[0018] 0.1 g of L-serine,

[0019] q.s. to 1000 mL with water for injection,

[0020] (2) 2 g of ambroxol hydrochloride

[0021] 1 g of DL-tartaric acid

[0022] 0.2 g of L-serine,

[0023] q.s. to 1000 mL with water for injection,

[0024] (3) 2 g of ambroxol hydrochloride

[0025] 1 g of DL-tartaric acid

[0026] 0.3 g of L-serine,

[0027] q.s. to 1000 mL with water for injection,

[0028] (4) 2 g of ambroxol hydrochloride

[0029] 1 g of DL-tartaric acid

[0030] 0.4 g of L-serine,

[0031] q.s. to 1000 mL with water for injection.

[0032] The method for preparing a stable solution of 2-amino-3,5-dibromobenzylamine derivative for inhalation provided by the present invention includes the following steps:

[0033] 1) Mix ambroxol hydrochloride and L-serine and grind to obtain a mixture of ambroxol hydrochloride and L-serine;

[0034] 2) Take 90% of water for injection, add DL-tartaric acid under stirring, dissolve it, then add the mixture of ambroxol hydrochloride and L-serine and stir until completely dissolved, adjust the pH to 3 with sodium hydroxide, and make up the volume to the full amount with water for injection;

[0035] 3) Filter and fill:

[0036] After the liquid medicine is fixed in volume, it is stirred evenly, filtered through a 0.22 μm polyethersulfone filter membrane, filled, nitrogen-filled, and heat-sealed to obtain the product.

[0037] The present invention does not need to add a large amount of stabilizers. Using a small amount of L-serine as an auxiliary agent can improve the stability of the bromhexine hydrochloride solution. L-serine is an amino acid beneficial to the human body and will not bring risks, ensuring the safety of medication. Specific embodiments

[0038] The present invention will be further described in detail below in conjunction with specific embodiments. The examples given are only for clarifying the present invention, rather than limiting the scope of the present invention. The following examples can be used as a guide for those of ordinary skill in the art to make further improvements and do not limit the present invention in any way.

[0039] The experimental methods in the following examples are all conventional methods unless otherwise specified, and are carried out according to the techniques or conditions described in the literature in this field or according to the product instructions. The materials, reagents, etc. used in the following examples can be obtained from commercial channels unless otherwise specified.

[0040] Example 1

[0041] Prescription:

[0042] Bromhexine hydrochloride 2 g

[0043] DL-tartaric acid 1 g

[0044] L-serine 0.1 g

[0045] Water for injection is added to 1000 mL

[0046] Preparation method:

[0047] 1) Mix bromhexine hydrochloride and L-serine and grind them to obtain a mixture of bromhexine hydrochloride and L-serine;

[0048] 2) Take 90% of the water for injection, add DL-tartaric acid under stirring, dissolve it, then add the mixture of bromhexine hydrochloride and L-serine and stir until completely dissolved. Adjust the pH to 3 with sodium hydroxide and make up the volume with water for injection to the full volume;

[0049] 3) Filtration and filling:

[0050] After the liquid medicine is fixed in volume, it is stirred evenly, filtered through a 0.22 μm polyethersulfone filter membrane, filled, nitrogen-filled, and heat-sealed to obtain the product.

[0051] Example 2

[0052] Bromhexine hydrochloride 2 g

[0053] 1 g of DL-tartaric acid

[0054] 0.2 g of L-serine,

[0055] Add water for injection to make up to 1000 mL,

[0056] Preparation method:

[0057] 1) Grind the bromhexine hydrochloride and L-serine after mixing to obtain a mixture of bromhexine hydrochloride and L-serine;

[0058] 2) Take 90% of the water for injection, add DL-tartaric acid under stirring, after dissolution, add the mixture of bromhexine hydrochloride and L-serine and stir until completely dissolved, adjust the pH to 3 with sodium hydroxide, and make up the volume with water for injection to the full volume;

[0059] 3) Filter and fill:

[0060] After making up the volume, stir the liquid medicine evenly, filter through a 0.22 μm polyethersulfone filter membrane, fill, charge with nitrogen, and seal by fusion to obtain.

[0061] Example 3,

[0062] 2 g of bromhexine hydrochloride

[0063] 1 g of DL-tartaric acid

[0064] 0.3 g of L-serine,

[0065] Add water for injection to make up to 1000 mL,

[0066] Preparation method:

[0067] 1) Grind the bromhexine hydrochloride and L-serine after mixing to obtain a mixture of bromhexine hydrochloride and L-serine;

[0068] 2) Take 90% of the water for injection, add DL-tartaric acid under stirring, after dissolution, add the mixture of bromhexine hydrochloride and L-serine and stir until completely dissolved, adjust the pH to 3 with sodium hydroxide, and make up the volume with water for injection to the full volume;

[0069] 3) Filter and fill:

[0070] After making up the volume, stir the liquid medicine evenly, filter through a 0.22 μm polyethersulfone filter membrane, fill, charge with nitrogen, and seal by fusion to obtain.

[0071] Example 4,

[0072] 2 g of bromhexine hydrochloride

[0073] 1 g of DL-tartaric acid

[0074] 0.4 g of L-serine,

[0075] Add water for injection to make up to 1000 mL.

[0076] Preparation method:

[0077] 1) Grind bromhexine hydrochloride and L-serine after mixing to obtain a mixture of bromhexine hydrochloride and L-serine;

[0078] 2) Take 90% of water for injection, add DL-tartaric acid under stirring, after dissolution, add the mixture of bromhexine hydrochloride and L-serine and stir until completely dissolved, adjust the pH to 3 with sodium hydroxide, and make up the volume with water for injection to the full volume;

[0079] 3) Filter and fill:

[0080] After volume fixation, stir the liquid medicine evenly, filter through a 0.22 μm polyethersulfone filter membrane, fill, charge with nitrogen, and seal by melting to obtain the product.

[0081] Comparative Example 1

[0082] (1) 2 g of bromhexine hydrochloride

[0083] 1 g of DL-tartaric acid

[0084] Add water for injection to make up to 1000 mL,

[0085] Preparation method

[0086] 1) Take 90% of water for injection, add DL-tartaric acid under stirring, after dissolution, add bromhexine hydrochloride and stir until completely dissolved, adjust the pH to 3 with sodium hydroxide, and make up the volume with water for injection to the full volume;

[0087] 2) Filter and fill:

[0088] After volume fixation, stir the liquid medicine evenly, filter through a 0.22 μm polyethersulfone filter membrane, fill, charge with nitrogen, and seal by melting to obtain the product.

[0089] Analyze and detect the prepared samples, and the results are as follows:

[0090]

[0091] Place the samples after sealing by melting under the condition of 5000 lx of light for 30 days to detect the content, related substances and other items, and the detection results are as follows:

[0092]

[0093]

[0094] Related substances

[0095]

[0096]

[0097] The experimental results show that: adding a trace amount of L-serine is beneficial to improving the stability of the bromhexine hydrochloride solution (especially the light stability). When the mass ratio of L-serine to bromhexine hydrochloride is 0.1:1 (Example 2), the obtained solution has the best light stability.

[0098] The present invention has been described in detail above. For those skilled in the art, without departing from the gist and scope of the present invention and without unnecessary experiments, the present invention can be implemented within a relatively wide range under equivalent parameters, concentrations and conditions. Although specific embodiments of the present invention are given, it should be understood that the present invention can be further improved. In short, according to the principle of the present invention, this application intends to cover any changes, uses or improvements of the present invention, including changes made by using conventional techniques known in the art that are outside the scope disclosed in this application.

Claims

1. A method for preparing a stable solution of 2-amino-3,5-dibromobenzylamine derivative for inhalation, wherein the stable solution of 2-amino-3,5-dibromobenzylamine derivative for inhalation has a pH value of 3.0 and its composition is as follows: 2 g of bromhexine hydrochloride 1 g of DL-tartaric acid 0.2 g of L-serine, q.s. to 1000 mL with water for injection, The method comprises the following steps: 1) Mix bromhexine hydrochloride and L-serine and grind them to obtain a mixture of bromhexine hydrochloride and L-serine; 2) Take 90% of water for injection, add DL-tartaric acid under stirring, dissolve it, then add the mixture of bromhexine hydrochloride and L-serine and stir until completely dissolved, adjust the pH to 3 with sodium hydroxide, and make up the volume with water for injection to the full volume; 3) Filter and fill: After volume fixation, stir the liquid medicine evenly, filter it through a 0.22 μm polyethersulfone filter membrane, fill it, charge it with nitrogen, and seal it by fusion to obtain the product.

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