CN108158989B - Ambroxol hydrochloride injection composition - Google Patents
Ambroxol hydrochloride injection composition Download PDFInfo
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- CN108158989B CN108158989B CN201810169566.5A CN201810169566A CN108158989B CN 108158989 B CN108158989 B CN 108158989B CN 201810169566 A CN201810169566 A CN 201810169566A CN 108158989 B CN108158989 B CN 108158989B
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- ambroxol hydrochloride
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- meglumine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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Abstract
The invention provides an ambroxol hydrochloride injection composition, wherein each 1000ml of the composition comprises the following components: 7.5g of ambroxol hydrochloride, 2-12g of chlorobutanol, 0.5-3g of meglumine, pH value adjusted to 4.5-5.5 by citric acid and a proper amount of water for injection. The ambroxol hydrochloride injection has the advantages of low content of related substances, high stability and the like.
Description
Technical Field
The invention relates to the field of pharmacy, and in particular relates to an ambroxol hydrochloride injection composition.
Background
Ambroxol hydrochloride (Ambroxol hydrochloride) is a metabolite of bromhexine in a human body, is a mucolytic drug, has stronger action than bromhexine, has a chemical name of trans-4- [ (2-amino-3, 5-dibromo benzyl) amino ] cyclohexanol hydrochloride, and has a structural formula as follows:
the primary research product of ambroxol hydrochloride injection is Musultan of Boringer Invighan, Germany, which contains citric acid and disodium hydrogen phosphate and is protected by nitrogen gas, but the stability problem still exists [ two ambroxol hydrochloride injections are compared in stability, Traine and Shenjinfang, Chinese pharmacist 2006,9 (3), 219- ]. The method reduces the content of relevant substances of the ambroxol hydrochloride injection, improves the stability of the ambroxol hydrochloride injection, further protects the medication safety of patients, and is a technical problem which needs to be solved by technical personnel in the field.
Disclosure of Invention
In the process of developing the ambroxol hydrochloride injection, the applicant finds that the chlorobutanol and the meglumine are matched according to a certain proportion for use, so that the content of related substances of the ambroxol hydrochloride injection is obviously reduced, the stability of the ambroxol hydrochloride injection is improved, and an unexpected technical effect is achieved. Based on the above findings, the inventors have provided an ambroxol hydrochloride injection having a simple process, a low content of related substances, a high stability, and a high safety upon administration, and have completed the present invention.
Specifically, the invention provides an ambroxol hydrochloride injection composition, and each 1000ml of the composition comprises the following components:
7.5g of ambroxol hydrochloride,
2-8g of chlorobutanol is added into the mixture,
0.5-2g of meglumine,
adjusting pH to 4.5-5.5 with citric acid,
proper amount of water for injection.
In the preferable embodiment of the invention, the weight ratio of the chlorobutanol to the meglumine is 4: 1.
In addition, the invention particularly provides the following three ambroxol hydrochloride injection compositions:
1) an ambroxol hydrochloride injection composition, wherein each 1000ml of the composition comprises the following components:
7.5g of ambroxol hydrochloride,
2g of chlorobutanol,
0.5g of meglumine is used,
the pH value of the citric acid is adjusted to 5.0,
proper amount of water for injection.
2) An ambroxol hydrochloride injection composition, wherein each 1000ml of the composition comprises the following components:
7.5g of ambroxol hydrochloride,
4g of chlorobutanol, namely 4g of chlorobutanol,
1g of meglumine, namely 1g of meglumine,
the pH value of the citric acid is adjusted to 5.0,
proper amount of water for injection.
3) An ambroxol hydrochloride injection composition, wherein each 1000ml of the composition comprises the following components:
7.5g of ambroxol hydrochloride,
8g of chlorobutanol is added into the mixture,
2g of meglumine, 2g of which,
the pH value of the citric acid is adjusted to 5.0,
proper amount of water for injection.
On the other hand, the invention also relates to a preparation method of the ambroxol hydrochloride injection, which comprises the following steps:
1) the prescribed amount of ambroxol hydrochloride is weighed and dissolved in 100 times of fresh water for injection by weight.
2) Weighing trichloro-tert-butanol and meglumine according to the prescription amount, dissolving in water for injection with the weight of 50 times, adding activated carbon with the solvent amount of 0.05 percent, stirring for 15 minutes at 60 ℃, filtering to remove carbon, and filtering by using a 0.22 mu m filter membrane.
3) Adding the treated trichloro-tert-butyl alcohol and meglumine solution into the ambroxol hydrochloride solution, adding water for injection to full volume, stirring uniformly, adjusting the pH to 4.5-5.5 by using citric acid, adding 0.01% of needle activated carbon, preserving the temperature at 60 ℃ for 20 minutes, filtering, finely filtering by using a 0.22 mu m filter membrane, filling the filtrate into an ampoule, sealing, sterilizing at 121 ℃ for 20 minutes, performing light inspection, and packaging to obtain the ambroxol hydrochloride injection.
Experiments show that the ambroxol hydrochloride injection has low content of related substances, high stability and high safety of patients taking the medicine.
Detailed Description
The detailed description of the invention is merely intended to further illustrate or describe the invention and should not be construed as limiting the invention in any way.
Example 1: the ambroxol hydrochloride injection of the invention
The ambroxol hydrochloride injection (1000 pieces) comprises the following components in percentage by weight:
7.5g of ambroxol hydrochloride,
2g of chlorobutanol,
0.5g of meglumine is used,
adjusting the pH value of the solution to 4.5-5.5 by citric acid,
the water for injection is added to 1000 ml.
The preparation process of the ambroxol hydrochloride injection (1000 capsules) comprises the following steps:
1) the prescribed amount of ambroxol hydrochloride is weighed and dissolved in 100 times of fresh water for injection by weight.
2) Weighing trichloro-tert-butanol and meglumine according to the prescription amount, dissolving in water for injection with the weight of 50 times, adding activated carbon with the solvent amount of 0.05 percent, stirring for 15 minutes at 60 ℃, filtering to remove carbon, and filtering by using a 0.22 mu m filter membrane.
3) Adding the treated trichloro-tert-butyl alcohol and meglumine solution into the ambroxol hydrochloride solution, adding water for injection to full volume, stirring uniformly, adjusting the pH to 4.5-5.5 by using citric acid, adding 0.01% of needle activated carbon, preserving the temperature at 60 ℃ for 20 minutes, filtering, finely filtering by using a 0.22 mu m filter membrane, filling the filtrate into an ampoule, sealing, sterilizing at 121 ℃ for 20 minutes, performing light inspection, and packaging to obtain the ambroxol hydrochloride injection.
Example 2: the ambroxol hydrochloride injection of the invention
The ambroxol hydrochloride injection (1000 pieces) comprises the following components in percentage by weight:
7.5g of ambroxol hydrochloride,
4g of chlorobutanol, namely 4g of chlorobutanol,
1g of meglumine, namely 1g of meglumine,
adjusting the pH value of the solution to 4.5-5.5 by citric acid,
the water for injection is added to 1000 ml.
The preparation process of the ambroxol hydrochloride injection (1000 capsules) comprises the following steps: the same as in example 1.
Example 3: the ambroxol hydrochloride injection of the invention
The ambroxol hydrochloride injection (1000 pieces) comprises the following components in percentage by weight:
7.5g of ambroxol hydrochloride,
8g of chlorobutanol is added into the mixture,
2g of meglumine, 2g of which,
adjusting the pH value of the solution to 4.5-5.5 by citric acid,
the water for injection is added to 1000 ml.
The preparation process of the ambroxol hydrochloride injection (1000 capsules) comprises the following steps: the same as in example 1.
Example 4 (comparative example): ambroxol hydrochloride injection
The ambroxol hydrochloride injection (1000 pieces) comprises the following components in percentage by weight:
7.5g of ambroxol hydrochloride,
adjusting the pH value of the solution to 4.5-5.5 by citric acid,
the water for injection is added to 1000 ml.
The preparation process of the ambroxol hydrochloride injection (1000 capsules) comprises the following steps: weighing ambroxol hydrochloride with the prescription amount, dissolving the ambroxol hydrochloride in 100 times of fresh water for injection by weight, adding the water for injection to the full amount, stirring uniformly, adjusting the pH to 4.5-5.5 by using citric acid, adding 0.01% of active carbon for injection, preserving the heat at 60 ℃ for 20 minutes, filtering, finely filtering by using a 0.22 mu m filter membrane, filling the filtrate in an ampoule, sealing, sterilizing at 121 ℃ for 20 minutes, checking by using a lamp, and packaging to obtain the ambroxol hydrochloride injection.
Experimental example stability study of ambroxol hydrochloride injection
Examining the ambroxol hydrochloride injection prepared in the examples 1 to 4, the test results of related substances and the like are shown in tables 1 to 3:
TABLE 1 test results of ambroxol hydrochloride injection (0 day)
TABLE 2 accelerated test results of ambroxol hydrochloride injection (40 ℃. + -. 2 ℃, RH75% + -5%, 6 months)
Accelerated tests show that the related substance content and stability of the ambroxol hydrochloride injection (examples 1-3) are obviously better than those of the comparative example (example 4).
TABLE 3 Long-term stability test results of ambroxol hydrochloride injection (25 ℃. + -. 2 ℃, RH 60%. + -. 10%, 24 months)
Long-term stability studies show that the related substance content and stability of the ambroxol hydrochloride injection (examples 1-3) are obviously better than those of the comparative example (example 4).
Claims (4)
1. An ambroxol hydrochloride injection composition, wherein each 1000ml of the composition comprises the following components:
7.5g of ambroxol hydrochloride,
2-8g of chlorobutanol is added into the mixture,
0.5-2g of meglumine,
adjusting pH to 4.5-5.5 with citric acid,
proper amount of water for injection;
wherein the weight ratio of the chlorobutanol to the meglumine is 4: 1.
2. The ambroxol hydrochloride injection composition according to claim 1, wherein the composition of each 1000ml of the composition is as follows:
7.5g of ambroxol hydrochloride,
2g of chlorobutanol,
0.5g of meglumine is used,
the pH value of the citric acid is adjusted to 5.0,
proper amount of water for injection.
3. The ambroxol hydrochloride injection composition according to claim 1, wherein the composition of each 1000ml of the composition is as follows:
7.5g of ambroxol hydrochloride,
4g of chlorobutanol, namely 4g of chlorobutanol,
1g of meglumine, namely 1g of meglumine,
the pH value of the citric acid is adjusted to 5.0,
proper amount of water for injection.
4. The ambroxol hydrochloride injection composition according to claim 1, wherein the composition of each 1000ml of the composition is as follows:
7.5g of ambroxol hydrochloride,
8g of chlorobutanol is added into the mixture,
2g of meglumine, 2g of which,
the pH value of the citric acid is adjusted to 5.0,
proper amount of water for injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810169566.5A CN108158989B (en) | 2018-03-01 | 2018-03-01 | Ambroxol hydrochloride injection composition |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810169566.5A CN108158989B (en) | 2018-03-01 | 2018-03-01 | Ambroxol hydrochloride injection composition |
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| Publication Number | Publication Date |
|---|---|
| CN108158989A CN108158989A (en) | 2018-06-15 |
| CN108158989B true CN108158989B (en) | 2020-08-28 |
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Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| ES2315123B1 (en) * | 2006-09-25 | 2009-12-30 | Divasa-Farmavic, S.A. | STABLE PHARMACEUTICAL COMPOSITIONS OF TETRACICLINES IN SOLUTION, PROCEDURE FOR OBTAINING AND USES. |
| DK2854768T3 (en) * | 2012-05-30 | 2017-06-12 | Fresenius Kabi Oncology Ltd | PHARMACEUTICAL COMPOSITIONS OF PEMETREXED |
| CN102872462B (en) * | 2012-10-26 | 2013-04-17 | 山东罗欣药业股份有限公司 | Ambroxol hydrochloride composition and preparation thereof |
| CN102920994B (en) * | 2012-11-29 | 2013-11-06 | 罗诚 | Pharmaceutical composition containing animal bone polypeptide |
| CN105326789B (en) * | 2015-12-08 | 2018-06-05 | 青岛正大海尔制药有限公司 | Ambroxol albuterol solution agent |
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