CN116270562A - Method for preparing stable solution of 2-amino-3, 5-dibromobenzyl amine derivative for inhalation - Google Patents
Method for preparing stable solution of 2-amino-3, 5-dibromobenzyl amine derivative for inhalation Download PDFInfo
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- CN116270562A CN116270562A CN202211694770.1A CN202211694770A CN116270562A CN 116270562 A CN116270562 A CN 116270562A CN 202211694770 A CN202211694770 A CN 202211694770A CN 116270562 A CN116270562 A CN 116270562A
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61P11/02—Nasal agents, e.g. decongestants
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Abstract
The invention discloses a method for preparing a stable solution of 2-amino-3, 5-dibromobenzyl amine derivatives for inhalation. The stable solution of 2-amino-3, 5-dibromobenzyl amine derivative for inhalation has a pH value of 3.0 and comprises the following components: 2g of bromhexine hydrochloride, 1g of DL-tartaric acid, 0.1-0.5g of L-serine and 1000mL of water for injection. The method comprises the following steps: 1) Bromhexine hydrochloride and L-serine are mixed and ground to obtain a mixture of bromhexine hydrochloride and L-serine; 2) Adding DL-tartaric acid into 90% of water for injection under stirring, dissolving, adding the mixture of bromhexine hydrochloride and L-serine, stirring to dissolve completely, adjusting pH to 3 with sodium hydroxide, and adding water for injection to full amount; 3) Filtering and filling. The invention can improve the stability of bromhexine hydrochloride solution without adding a large amount of stabilizer by adopting a trace amount of L-serine as an auxiliary agent, and the L-serine is an amino acid beneficial to human bodies, so that the risk is avoided, and the medication safety is ensured.
Description
The application is a divisional application with the application number of 202210269898.7, the application date of 2022, 3 and 18, and the invention and the creation name of 'a stable bromhexine hydrochloride solution for inhalation and a preparation method thereof'.
Technical Field
The invention belongs to the field of medicines, and particularly relates to a method for preparing a stable solution of a 2-amino-3, 5-dibromobenzyl amine derivative for inhalation.
Background
Bromhexine hydrochloride for inhalation developed by SANOFI company is first marketed in Belgium at 1990, 9 and 30, under the trade name of
The specification is 0.2% (40 ml, 100ml, 250 ml), and the indications are acute bronchitis, tracheobronchitis, chronic bronchitis, chronic obstructive bronchopulmonary disease, bronchiectasis, acute sinusitis, and chronic sinusitis.
Bromhexine hydrochloride english name: bromhexinehydrochloride, chemical formula:
slightly soluble in methanol, slightly soluble in ethanol, and slightly soluble in water. Not hygroscopic and light stable, but when exposed to aqueous solutions, produce decomposition products.
The Chinese patent application CN104306329A discloses bromhexine hydrochloride injection with higher stability, auxiliary materials comprise tartaric acid, stabilizing agents (mannitol, xylitol and sorbitol) and the like, and the technical scheme has the defects that the auxiliary materials of the injection are large in dosage, for example, the dosage of bromhexine hydrochloride serving as a main medicine is 1-4g, the adding amount of the stabilizing agents reaches 40-60g, and the problem of medication safety to a certain extent exists.
Therefore, the preparation of bromhexine hydrochloride solution for inhalation with simple prescription composition, low stabilizer content and high stability is an urgent problem to be solved in the field.
Disclosure of Invention
The object of the present invention is to provide a process for preparing a stable solution of 2-amino-3, 5-dibromobenzyl amine derivatives for inhalation.
The stable solution of 2-amino-3, 5-dibromobenzyl amine derivative for inhalation has a pH value of 3.0 and comprises the following components:
bromhexine hydrochloride 2g
DL-tartaric acid 1g
L-serine 0.1-0.5g,
the water for injection was added to 1000mL,
more specifically, the composition of the bromhexine hydrochloride solution for inhalation is as follows:
(1) Bromhexine hydrochloride 2g
DL-tartaric acid 1g
0.1g of L-serine,
the water for injection was added to 1000mL,
(2) Bromhexine hydrochloride 2g
DL-tartaric acid 1g
0.2g of L-serine,
the water for injection was added to 1000mL,
(3) Bromhexine hydrochloride 2g
DL-tartaric acid 1g
0.3g of L-serine,
the water for injection was added to 1000mL,
(4) Bromhexine hydrochloride 2g
DL-tartaric acid 1g
0.4g of L-serine,
water for injection was added to 1000mL.
The method for preparing the stable 2-amino-3, 5-dibromobenzyl amine derivative solution for inhalation comprises the following steps:
1) Bromhexine hydrochloride and L-serine are mixed and ground to obtain a mixture of bromhexine hydrochloride and L-serine;
2) Adding DL-tartaric acid into 90% of water for injection under stirring, dissolving, adding the mixture of bromhexine hydrochloride and L-serine, stirring to dissolve completely, adjusting pH to 3 with sodium hydroxide, and adding water for injection to full amount;
3) Filtering and filling:
and (3) uniformly stirring the liquid medicine after constant volume, filtering the liquid medicine by a 0.22 mu m polyether sulfone filter membrane, filling nitrogen, and sealing by melting to obtain the traditional Chinese medicine.
The invention can improve the stability of bromhexine hydrochloride solution without adding a large amount of stabilizer by adopting a trace amount of L-serine as an auxiliary agent, and the L-serine is an amino acid beneficial to human bodies, so that the risk is avoided, and the medication safety is ensured.
Detailed Description
The following detailed description of the invention is provided in connection with the accompanying drawings that are presented to illustrate the invention and not to limit the scope thereof. The examples provided below are intended as guidelines for further modifications by one of ordinary skill in the art and are not to be construed as limiting the invention in any way.
The experimental methods in the following examples, unless otherwise specified, are conventional methods, and are carried out according to techniques or conditions described in the literature in the field or according to the product specifications. Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
Example 1,
Prescription:
bromhexine hydrochloride 2g
DL-tartaric acid 1g
0.1g of L-serine,
the water for injection was added to 1000mL,
the preparation method comprises the following steps:
1) Bromhexine hydrochloride and L-serine are mixed and ground to obtain a mixture of bromhexine hydrochloride and L-serine;
2) Adding DL-tartaric acid into 90% of water for injection under stirring, dissolving, adding the mixture of bromhexine hydrochloride and L-serine, stirring to dissolve completely, adjusting pH to 3 with sodium hydroxide, and adding water for injection to full amount;
3) Filtering and filling:
and (3) uniformly stirring the liquid medicine after constant volume, filtering the liquid medicine by a 0.22 mu m polyether sulfone filter membrane, filling nitrogen, and sealing by melting to obtain the traditional Chinese medicine.
EXAMPLE 2,
Bromhexine hydrochloride 2g
DL-tartaric acid 1g
0.2g of L-serine,
the water for injection was added to 1000mL,
the preparation method comprises the following steps:
1) Bromhexine hydrochloride and L-serine are mixed and ground to obtain a mixture of bromhexine hydrochloride and L-serine;
2) Adding DL-tartaric acid into 90% of water for injection under stirring, dissolving, adding the mixture of bromhexine hydrochloride and L-serine, stirring to dissolve completely, adjusting pH to 3 with sodium hydroxide, and adding water for injection to full amount;
3) Filtering and filling:
and (3) uniformly stirring the liquid medicine after constant volume, filtering the liquid medicine by a 0.22 mu m polyether sulfone filter membrane, filling nitrogen, and sealing by melting to obtain the traditional Chinese medicine.
EXAMPLE 3,
Bromhexine hydrochloride 2g
DL-tartaric acid 1g
0.3g of L-serine,
the water for injection was added to 1000mL,
the preparation method comprises the following steps:
1) Bromhexine hydrochloride and L-serine are mixed and ground to obtain a mixture of bromhexine hydrochloride and L-serine;
2) Adding DL-tartaric acid into 90% of water for injection under stirring, dissolving, adding the mixture of bromhexine hydrochloride and L-serine, stirring to dissolve completely, adjusting pH to 3 with sodium hydroxide, and adding water for injection to full amount;
3) Filtering and filling:
and (3) uniformly stirring the liquid medicine after constant volume, filtering the liquid medicine by a 0.22 mu m polyether sulfone filter membrane, filling nitrogen, and sealing by melting to obtain the traditional Chinese medicine.
EXAMPLE 4,
Bromhexine hydrochloride 2g
DL-tartaric acid 1g
0.4g of L-serine,
water for injection was added to 1000mL.
The preparation method comprises the following steps:
1) Bromhexine hydrochloride and L-serine are mixed and ground to obtain a mixture of bromhexine hydrochloride and L-serine;
2) Adding DL-tartaric acid into 90% of water for injection under stirring, dissolving, adding the mixture of bromhexine hydrochloride and L-serine, stirring to dissolve completely, adjusting pH to 3 with sodium hydroxide, and adding water for injection to full amount;
3) Filtering and filling:
and (3) uniformly stirring the liquid medicine after constant volume, filtering the liquid medicine by a 0.22 mu m polyether sulfone filter membrane, filling nitrogen, and sealing by melting to obtain the traditional Chinese medicine.
Comparative example 1,
(1) Bromhexine hydrochloride 2g
DL-tartaric acid 1g
The water for injection was added to 1000mL,
preparation method
1) Adding DL-tartaric acid into 90% of water for injection under stirring, dissolving, adding bromhexine hydrochloride, stirring to dissolve completely, adjusting pH to 3 with sodium hydroxide, and adding water for injection to full amount;
2) Filtering and filling:
and (3) uniformly stirring the liquid medicine after constant volume, filtering the liquid medicine by a 0.22 mu m polyether sulfone filter membrane, filling nitrogen, and sealing by melting to obtain the traditional Chinese medicine.
The prepared sample was analyzed and tested as follows:
and (3) respectively placing the sealed samples under the condition of illumination of 5000lx, and detecting the content, related substances and the like in 30 days, wherein the detection results are as follows:
related substances
The experimental results show that: the addition of a trace amount of L-serine is advantageous for improving the stability (especially the light stability) of bromhexine hydrochloride solution, and when the mass ratio of L-serine to bromhexine hydrochloride is 0.1:1 (example 2), the light stability of the obtained solution is the best.
The present invention is described in detail above. It will be apparent to those skilled in the art that the present invention can be practiced in a wide range of equivalent parameters, concentrations, and conditions without departing from the spirit and scope of the invention and without undue experimentation. While the invention has been described with respect to specific embodiments, it will be appreciated that the invention may be further modified. In general, this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains.
Claims (5)
1. A process for preparing a stable solution of 2-amino-3, 5-dibromobenzyl amine derivatives for inhalation having a pH of 3.0 comprising:
bromhexine hydrochloride 2g
DL-tartaric acid 1g
L-serine 0.1-0.5g,
the water for injection was added to 1000mL,
the method comprises the following steps: 1) Bromhexine hydrochloride and L-serine are mixed and ground to obtain a mixture of bromhexine hydrochloride and L-serine;
2) Adding DL-tartaric acid into 90% of water for injection under stirring, dissolving, adding the mixture of bromhexine hydrochloride and L-serine, stirring to dissolve completely, adjusting pH to 3 with sodium hydroxide, and adding water for injection to full amount;
3) Filtering and filling:
and (3) uniformly stirring the liquid medicine after constant volume, filtering the liquid medicine by a 0.22 mu m polyether sulfone filter membrane, filling nitrogen, and sealing by melting to obtain the traditional Chinese medicine.
2. The method according to claim 1, characterized in that: the stable solution of 2-amino-3, 5-dibromobenzyl amine derivative for inhalation has a pH value of 3.0 and comprises the following components:
bromhexine hydrochloride 2g
DL-tartaric acid 1g
0.2g of L-serine,
water for injection was added to 1000mL.
3. The method according to claim 1, characterized in that: the stable solution of 2-amino-3, 5-dibromobenzyl amine derivative for inhalation has a pH value of 3.0 and comprises the following components:
bromhexine hydrochloride 2g
DL-tartaric acid 1g
0.1g of L-serine,
water for injection was added to 1000mL.
4. The method according to claim 1, characterized in that: the stable solution of 2-amino-3, 5-dibromobenzyl amine derivative for inhalation has a pH value of 3.0 and comprises the following components:
bromhexine hydrochloride 2g
DL-tartaric acid 1g
0.3g of L-serine,
water for injection was added to 1000mL.
5. The method according to claim 1, characterized in that: the stable solution of 2-amino-3, 5-dibromobenzyl amine derivative for inhalation has a pH value of 3.0 and comprises the following components:
bromhexine hydrochloride 2g
DL-tartaric acid 1g
0.4g of L-serine,
water for injection was added to 1000mL.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211694770.1A CN116270562A (en) | 2022-03-18 | 2022-03-18 | Method for preparing stable solution of 2-amino-3, 5-dibromobenzyl amine derivative for inhalation |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210269898.7A CN114557983B (en) | 2022-03-18 | 2022-03-18 | Stable bromhexine hydrochloride solution for inhalation and preparation method thereof |
| CN202211694770.1A CN116270562A (en) | 2022-03-18 | 2022-03-18 | Method for preparing stable solution of 2-amino-3, 5-dibromobenzyl amine derivative for inhalation |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210269898.7A Division CN114557983B (en) | 2022-03-18 | 2022-03-18 | Stable bromhexine hydrochloride solution for inhalation and preparation method thereof |
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| CN202211694770.1A Pending CN116270562A (en) | 2022-03-18 | 2022-03-18 | Method for preparing stable solution of 2-amino-3, 5-dibromobenzyl amine derivative for inhalation |
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| IT1314184B1 (en) * | 1999-08-12 | 2002-12-06 | Nicox Sa | PHARMACEUTICAL COMPOSITIONS FOR THE THERAPY OF STRESS-OXIDATIVE CONDITIONS |
| CN1259041C (en) * | 2004-02-05 | 2006-06-14 | 马小歧 | Bromhexine Hydrochloride aseptic freeze-drying formulation for injection and its preparation method |
| JP4911274B2 (en) * | 2004-05-11 | 2012-04-04 | 大正製薬株式会社 | Stabilized solid formulation |
| CN100417381C (en) * | 2006-02-09 | 2008-09-10 | 西安力邦医药科技有限责任公司 | Nicorandil freeze-drying powder preparation method |
| CN101627993B (en) * | 2009-08-03 | 2011-12-07 | 上海华源药业（宁夏）沙赛制药有限公司 | Liquid preparation containing fifteen compound amino acids and preparation method thereof |
| CN105456187A (en) * | 2016-01-07 | 2016-04-06 | 河北仁合益康药业有限公司 | Bromhexine hydrochloride solution composition for inhalation and preparation method thereof |
| CN109833293B (en) * | 2019-02-25 | 2021-12-21 | 浙江长典药物技术开发有限公司 | Preparation method of doxofylline injection |
| CN112089688A (en) * | 2020-10-30 | 2020-12-18 | 康普药业股份有限公司 | Stable ambroxol hydrochloride injection and preparation method thereof |
| CN112891300B (en) * | 2021-01-28 | 2022-03-15 | 朗天药业(湖北)有限公司 | Ambroxol hydrochloride injection and preparation method thereof |
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