CN108743569A - Salbutamol sulfate aerosol inhalation solution and preparation method thereof - Google Patents
Salbutamol sulfate aerosol inhalation solution and preparation method thereof Download PDFInfo
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- CN108743569A CN108743569A CN201810983772.XA CN201810983772A CN108743569A CN 108743569 A CN108743569 A CN 108743569A CN 201810983772 A CN201810983772 A CN 201810983772A CN 108743569 A CN108743569 A CN 108743569A
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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
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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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- 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
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- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention belongs to pharmaceutical technology fields, and in particular to salbutamol sulfate aerosol inhalation solution and preparation method thereof.The salbutamol sulfate aerosol inhalation solution includes salbutamol sulfate, sodium gluconate and pH adjusting agent.Salbutamol sulfate aerosol inhalation solution provided by the invention has excellent stability, related content of material is few, ingredient is simple, and without containing auxiliary materials such as preservative, stabilizer, antioxidant, osmotic pressure regulator, complexing of metal ion agent (natrium adetate), the risk of clinical application is reduced, drug safety is improved, its preparation process is simple simultaneously, without high-temperature sterilization, low energy consumption, reduces the cost of large-scale production.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to salbutamol sulfate aerosol inhalation solution and preparation method thereof.
Background technology
Salbutamol sulfate (Salbutamol sulfate), also known as albuterol are a kind of branch with high selectivity
Tracheal smooth muscle beta-2-adrenoreceptor agonists, for relaxation bronchial smooth muscle, contact bronchial muscular spasm has
Specific activity, is a kind of safe and effective suppressing panting calming medicine.Clinically it is usually used in treating all kinds of airway obstructions, as bronchus is roared
Asthma, chronic obstructive pulmonary disease, the bronchial spasm of asthmatic tracheitis and emphysema patient.The molecular formula of salbutamol sulfate
For (C13H21NO3)2.H2SO4, structural formula is as follows：
Currently, having occurred the salbutamol sulfate of several formulations form on the market, wherein the sulphur of inhalation solution form
Sour salbutamol can directly reach diseased region, and effect is direct, rapid-action, can effectively avoid oral medication caused by liver
First pass effect substantially increases bioavilability, and drug dose used is fewer than systemic administration amount, avoids or reduces Formulations for systemic administration
Issuable side effect.But as solution, salbutamol sulfate stability is poor, the structure and pharmacology of catabolite
Property is unclear, affects the safety of medication.Therefore, how to improve its stability is that those skilled in the art thirst for chasing after always
The target asked.
And in order to make solution show preferable long-time stability, it will usually preservative, stabilizer, anti-oxidant be added
The auxiliary materials such as agent, osmotic pressure regulator, complexing of metal ion agent (natrium adetate), the addition of above-mentioned auxiliary material play raising sulfuric acid
The effect of salbutamol aerosol inhalation solution stability, but the addition of many auxiliary materials affects the quality of product, increases and faces
The risk of bed medication, while supported if even if data in the experiment of above-mentioned auxiliary material study on the stability are added by 12 months, stablizing effect
Still there is space to be hoisted.
Therefore, it is necessary to which it is molten to provide the low salbutamol sulfate Neulized inhalation of a kind of excellent in stability, related substances content
Liquid and preparation method thereof.
Invention content
The present invention is intended to provide a kind of salbutamol sulfate aerosol inhalation solution and preparation method thereof, the salbutamol sulfate
Inhalation solution excellent in stability compared with the existing technology, related content of material is few, prepares simple.
In order to achieve the above object, the present invention uses following technical scheme：Salbutamol sulfate aerosol inhalation solution, every institute
Stating 1000ml salbutamol sulfate aerosol inhalation solutions includes：
Preferably, include per the 1000ml salbutamol sulfates aerosol inhalation solution：
Preferably, include per the 1000ml salbutamol sulfates aerosol inhalation solution：
Preferably, the pH adjusting agent is selected from sulfuric acid, hydrochloric acid, acetic acid, citric acid-sodium citrate, Acetic acid-sodium acetate and vinegar
One or more of acid-ammonium acetate.
Preferably, the pH adjusting agent is selected from sulfuric acid.
The present invention realizes that the key point of said effect is to add sodium gluconate, and inventor is it was unexpectedly observed that grape
The addition of sodium saccharate plays the role of stabilizer, is investigated through stability test, the results show that salbutamol sulfate mist of the present invention
Change inhalation solution storage-stable 24 months, pH, related content of material are without significant change.It can be real for sodium gluconate is added
The principle of existing said effect, not yet clear, inventor speculates to may be the effect because sodium gluconate acts as pH adjusting agent,
And sodium gluconate itself has the function of complexation of metal ions, therefore just embody can increase salbutamol sulfate atomization inhale
Enter the characteristic of stability of solution.
In addition, way conventional in existing salbutamol sulfate preparation process is that nitrogen is filled in water for injection, a side
Face will strictly control water temperature, on the other hand not be resistant to high-temperature sterilization.If but cannot pass through high-temperature sterilization requirement, i.e., can not protect
Demonstrate,prove sterile requirement.And inventor it was unexpectedly observed that due to sodium gluconate addition, while the pH for controlling inhalation solution exists
When 3.5~4.0,60~80 DEG C of 10~15min of sterilizing can reach sterility requirements, needs not move through 121 DEG C of high-temperature sterilization, saves
Energy consumption, while ensure that the quality safety of drug, achieve unexpected technique effect.
The present invention also provides a kind of methods preparing the salbutamol sulfate aerosol inhalation solution, including following step
Suddenly：
A 80% water for injection) is added in preparing tank, is filled with nitrogen, salbutamol sulfate and sodium gluconate is added,
Stirring and dissolving；
B pH to 3.0~5.0, constant volume, successively through 0.45 μm of coarse filtration, 0.22 μm of refined filtration) are adjusted with pH adjusting agent；
C after) detection is qualified, embedding, 60~80 DEG C of 10~15min of sterilizing to get.
Preferably, the step C) in sterilising temp be 65 DEG C, sterilization time 15min.
Preferably, the step B) in adjust pH to 3.5~4.0.
Preferably, the step B) in adjust pH to 3.5.
The present invention has the following advantages：
Salbutamol sulfate aerosol inhalation solution provided by the invention has excellent stability, and related content of material is few,
Ingredient is simple, and without containing preservative, stabilizer, antioxidant, osmotic pressure regulator, complexing of metal ion agent (edetic acid(EDTA) two
Sodium) etc. auxiliary materials, reduce the risk of clinical application, improve drug safety, while its preparation process is simple, goes out without high temperature
Bacterium, low energy consumption, reduces the cost of large-scale production.
Specific implementation mode
The specific implementation mode of form by the following examples makees further specifically the above of the present invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following embodiment.
Embodiment 1, salbutamol sulfate aerosol inhalation solution
| Component | Dosage |
| Salbutamol sulfate | 5g |
| Sodium gluconate | 0.2g |
| Sulfuric acid | Adjust pH to 3.5 |
| Water for injection | Add to 1000ml |
Embodiment 2, salbutamol sulfate aerosol inhalation solution
| Component | Dosage |
| Salbutamol sulfate | 3g |
| Sodium gluconate | 0.1g |
| Sulfuric acid | Adjust pH to 3.8 |
| Water for injection | Add to 1000ml |
Embodiment 3, salbutamol sulfate aerosol inhalation solution
| Component | Dosage |
| Salbutamol sulfate | 5g |
| Sodium gluconate | 0.5g |
| Sulfuric acid | Adjust pH to 4.0 |
| Water for injection | Add to 1000ml |
Preparation method：
A 80% water for injection) is added in preparing tank, is filled with nitrogen, salbutamol sulfate and sodium gluconate is added,
Stirring and dissolving；
B pH, constant volume, successively through 0.45 μm of coarse filtration, 0.22 μm of refined filtration) are adjusted with pH adjusting agent；
C after) detection is qualified, embedding, 65 DEG C of sterilizing 15min to get.
Comparative example 1, salbutamol sulfate aerosol inhalation solution
Difference lies in be added without sodium gluconate, remaining is same as Example 1 to comparative example 1 with embodiment 1.
Comparative example 2, salbutamol sulfate aerosol inhalation solution
Difference lies in substitute sodium gluconate, remaining and 1 phase of embodiment with natrium adetate for comparative example 2 and embodiment 1
Together.
Comparative example 3, salbutamol sulfate aerosol inhalation solution
Difference lies in step B described in preparation method with embodiment 1 for comparative example 3) adjust pH to 4.5, remaining and implementation
Example 1 is identical.
Comparative example 4, salbutamol sulfate aerosol inhalation solution
Difference lies in step B described in preparation method with embodiment 1 for comparative example 4) adjust pH to 3.2, remaining and implementation
Example 1 is identical.
Test example one, quality evaluation
Salbutamol sulfate aerosol inhalation solution prepared by Example 1~3 and comparative example 1~2, according to Chinese Pharmacopoeia
Detection method in relation to substance in two salbutamol sulfates of version in 2015 detects related matter percentage, pH etc., detection knot
Fruit is as shown in table 1 below.
1 testing result of table
| Group | Shape | PH value | Content (%) | Related substance (%) |
| Embodiment 1 | Colorless clear liquid | 3.5 | 101.5 | 0.02 |
| Embodiment 2 | Colorless clear liquid | 3.8 | 99.8 | 0.04 |
| Embodiment 3 | Colorless clear liquid | 4.0 | 100.5 | 0.03 |
| Comparative example 1 | Colorless clear liquid | 3.5 | 99.6 | 0.02 |
| Comparative example 2 | Colorless clear liquid | 3.5 | 98.4 | 0.04 |
By upper table 1 it is found that the salbutamol sulfate aerosol inhalation solution index of correlation of the preparation of the embodiment of the present invention 1~3 is equal
Meet quality standard.
Test example two, stability test
Salbutamol sulfate aerosol inhalation solution prepared by Example 1~3 and comparative example 1~2,40 DEG C,
It is stored under conditions of RH75% 12 months, 24 months, according to detection side in Chinese Pharmacopoeia two salbutamol sulfates of version in 2015
Method, detects the variation in relation to indexs such as matter percentages, and testing result is as shown in table 2 below.
2 estimation of stability result of table
By upper table 2 it is found that the salbutamol sulfate aerosol inhalation solution of the preparation of the embodiment of the present invention 1~3 is with excellent
Stability is still clarified after being stored 24 months under conditions of 40 DEG C, RH75%, is become without apparent in relation to content of material and content
Change.
Compared with Example 1, comparative example 1 is added without sodium gluconate, the salbutamol sulfate aerosol inhalation solution of preparation
After storing 12 months under the same conditions, related content of material is increased significantly to 0.13%, and stability is poor；And it is added according to ground
Acid disodium, after the salbutamol sulfate aerosol inhalation solution of preparation stores 24 months under the same conditions, the content in relation to substance
Also risen.This explanation, the addition of sodium gluconate can significantly improve the stabilization of salbutamol sulfate aerosol inhalation solution
Property.
Test example three, sterilization determination
Take different batches Examples 1 to 3 and comparative example 1~4 prepare salbutamol sulfate aerosol inhalation solution at
Product carry out bacterium inspection, and it is as shown in table 3 below that bacterium examines result.
3 bacterium of table examines result
If from 1~2 test result of comparative example it is found that being added without sodium gluconate, can not be reached at all through 65 DEG C of sterilizing 15min
It requires to sterilizing, while can be seen that from 3~4 test result of comparative example, also need to ensure the pH of solution after sodium gluconate is added
It can be examined by bacterium in the range of maintaining 3.5~4.0.
The above-described embodiments merely illustrate the principles and effects of the present invention, and is not intended to limit the present invention.It is any ripe
The personage for knowing this technology can all carry out modifications and changes to above-described embodiment without violating the spirit and scope of the present invention.Cause
This, institute is complete without departing from the spirit and technical ideas disclosed in the present invention by those of ordinary skill in the art such as
At all equivalent modifications or change, should by the present invention claim be covered.
Claims (9)
1. salbutamol sulfate aerosol inhalation solution, which is characterized in that molten per the 1000ml salbutamol sulfates Neulized inhalation
Liquid includes：
2. salbutamol sulfate aerosol inhalation solution as described in claim 1, which is characterized in that husky per the 1000ml sulfuric acid
Butylamine alcohol aerosol inhalation solution includes：
3. salbutamol sulfate aerosol inhalation solution as claimed in claim 2, which is characterized in that husky per the 1000ml sulfuric acid
Butylamine alcohol aerosol inhalation solution includes：
4. the salbutamol sulfate aerosol inhalation solution as described in claims 1 to 3 is any, which is characterized in that the pH is adjusted
Agent is selected from one or more of sulfuric acid, hydrochloric acid, acetic acid, citric acid-sodium citrate, Acetic acid-sodium acetate and acetic acid-ammonium acetate.
5. salbutamol sulfate aerosol inhalation solution as claimed in claim 4, which is characterized in that the pH adjusting agent is selected from sulphur
Acid.
6. the preparation method of the salbutamol sulfate aerosol inhalation solution as described in Claims 1 to 4 is any, which is characterized in that
Include the following steps：
A 80% water for injection) is added in preparing tank, is filled with nitrogen, salbutamol sulfate and sodium gluconate, stirring is added
Dissolving；
B pH to 3.0~5.0, constant volume, successively through 0.45 μm of coarse filtration, 0.22 μm of refined filtration) are adjusted with pH adjusting agent；
C after) detection is qualified, embedding, 60~80 DEG C of 10~15min of sterilizing to get.
7. preparation method as claimed in claim 6, which is characterized in that the step C) in sterilising temp be 65 DEG C, when sterilizing
Between be 15min.
8. preparation method as claimed in claim 6, which is characterized in that the step B) in adjust pH to 3.5~4.0.
9. preparation method as claimed in claim 8, which is characterized in that the step B) in adjust pH to 3.5.
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| CN201810983772.XA CN108743569A (en) | 2018-08-27 | 2018-08-27 | Salbutamol sulfate aerosol inhalation solution and preparation method thereof |
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| CN201810983772.XA CN108743569A (en) | 2018-08-27 | 2018-08-27 | Salbutamol sulfate aerosol inhalation solution and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111658661A (en) * | 2020-06-12 | 2020-09-15 | 深圳大佛药业股份有限公司 | Salbutamol sulfate inhalation preparation and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105832712A (en) * | 2016-05-12 | 2016-08-10 | 河北仁合益康药业有限公司 | Salbutamol sulfate solution composition for inhaling and preparation method thereof |
| CN107126416A (en) * | 2016-02-26 | 2017-09-05 | 上海信谊金朱药业有限公司 | The preparation method of salbutamol sulfate aerosol inhalation solution |
| CN107296803A (en) * | 2017-07-27 | 2017-10-27 | 海南利能康泰制药有限公司 | A kind of suction salbutamol sulfate solution and preparation method thereof |
-
2018
- 2018-08-27 CN CN201810983772.XA patent/CN108743569A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107126416A (en) * | 2016-02-26 | 2017-09-05 | 上海信谊金朱药业有限公司 | The preparation method of salbutamol sulfate aerosol inhalation solution |
| CN105832712A (en) * | 2016-05-12 | 2016-08-10 | 河北仁合益康药业有限公司 | Salbutamol sulfate solution composition for inhaling and preparation method thereof |
| CN107296803A (en) * | 2017-07-27 | 2017-10-27 | 海南利能康泰制药有限公司 | A kind of suction salbutamol sulfate solution and preparation method thereof |
Non-Patent Citations (1)
| Title |
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| 段刚等: "《酶制剂应用技术问答》", 31 May 2014, 中国轻工业出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111658661A (en) * | 2020-06-12 | 2020-09-15 | 深圳大佛药业股份有限公司 | Salbutamol sulfate inhalation preparation and preparation method thereof |
| CN111658661B (en) * | 2020-06-12 | 2021-06-01 | 深圳大佛药业股份有限公司 | Salbutamol sulfate inhalation preparation and preparation method thereof |
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Application publication date: 20181106 |