CN106692124A - Acetylcysteine pharmaceutical composition and preparation method thereof - Google Patents
Acetylcysteine pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN106692124A CN106692124A CN201510430616.7A CN201510430616A CN106692124A CN 106692124 A CN106692124 A CN 106692124A CN 201510430616 A CN201510430616 A CN 201510430616A CN 106692124 A CN106692124 A CN 106692124A
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Abstract
The invention aims to provide a more stable acetylcysteine pharmaceutical composition and a preparation method thereof. The acetylcysteine pharmaceutical composition comprises acetylcysteine and medically acceptable excipients, and the aqueous solution of the composition has a pH value of 7.0-7.5.
Description
Technical field
The invention belongs to pharmaceutical field, in particular to more stable acetylcysteine
Pharmaceutical composition and preparation method thereof.
Background technology
Acetylcysteine is white crystalline powder, the foul smell for having similar garlic, sour, is had
Draw moist, 101~107 DEG C of fusing point is readily soluble in water or ethanol.Molecular weight is 163.2, point
Minor is C5H8NO3S, No. CAS is 616-81-1, and with the following chemical structure.
In November, 2004, Cumberland Pharmaceuticals companies have listed second in the U.S.
Acyl cysteine parenteral solution " Acetadote " (NDA 021539), it is to prevent or mitigate
The Standard dose of potential hepatic lesion caused by paracetamol is excessive.Paracetamol is to be permitted
Many prescription class analgesic drug products and OTC class analgesic drug product and flu, fever therapy medicine
Usual component, overtreatment (consumption per day is more than 4000mg) can cause serious even lethal
Hepatic lesion.
However, being oxidized easily and dropping when acetylcysteine is in the solution and exposed to air
Solution.According to the quality standard that BP versions in 2013 are recorded, what mucolyticum acid degradation was produced
Known impurities mainly have 4, respectively：Impurity A：Cys, impurity B：L-
Cystine, impurity C：N ' N- diacetyl cystines, impurity D：The Guang ammonia of N ' S- diacetyl half
Acid.Molecular structural formula is respectively as shown in following formula I~IV.
Wherein, the main generations of being degraded because of oxidation of impurity C, impurity B and impurity D are received
High temperature and pH value are influenceed and produce, and impurity A is produced by the disulfide bonds of impurity B,
The two can mutually be converted under certain condition.
Oxygen in known air or in the aqueous solution has great shadow to the stability of acetylcysteine
Ring, for example, applying for artificial Kanboland Medical Products Inc. (U.S.), international Shen
Please number be PCT/U2006/020681, within Chinese territory Application No. 20111016526.5 and
The patent for authorizing is obtained by " using de aerated water during preparation solution, and by using nitrogen displacement
Oxygen makes to minimize the exposure of air, makes the solution by 0.2 μm of sterilising filter, will
Product is fitted into phial or ampoule, and exposed to the headroom with nitrogen displacement so that its
The oxygen of minimum " in process for preparation and was stored avoiding mucolyticum aqueous acid
It is oxidized in journey, so as to improve the stability of acetylcysteine water-soluble pharmaceutical compositions.
And, the patent also avoids acetylcysteine water soluble drug using filtration sterilization
Composition carries out the main ingredient degraded risk that high-temperature sterilization is brought when for injection, maximum
Degree improves the stability of acetylcysteine water-soluble pharmaceutical compositions.
In addition, United States Patent (USP) 5807884 discloses using chelating agent EDTA to improve acetyl
High response of the cysteine in syrup formulation, United States Patent (USP) 6114387 is disclosed
The application of EDTA stabilization acetylcysteines in solid dosage forms.The Guang of acetyl half of in the market
The propylhomoserin aqueous solution, such as trade name Mucolyticum aqueous acid, also by ethylenediamine tetra-acetic acid
Disodium salt improves the stability of medicine.EDTA is widely used chelating agent, generally quilt
Referred to as ethylenediamine tetra-acetic acid, its molecular weight is 282.24.
Existing document has also carried out relevant report, example to the pH value of mucolyticum aqueous acid
Such as specify it in the Acetylcysteine Injection quality standards that BP versions in 2013 are recorded
PH value range is 6.5~7.5, FDA approvalsSpecification requires its pH value model
It is 6.0~7.5 to enclose, the A of Patent No. CN 102266316 that U.S. Cumberland company applies at it
6~8 are refer in the patent specification of (international application no is PCT/U2006/020691)
PH value range, and stability when pH value is 6.8 is tested in embodiment.However,
So far, not disclosed technical literature is to mucolyticum aqueous acid correlation combiner
The pH value of thing carries out careful research.
The content of the invention
Although the water-soluble pharmaceutical compositions containing acetylcysteine are in the model that pH value is 6~8
Enclose interior kept stable good, but inventor by system in-depth study, it is unexpected
It was found that：When its pH value is strict controlled in the range of 7.0~7.5, (being in production technology can
Control) when, the stability of composition is better, and the impurity of generation is less, and quality is more
Stabilization.This safety applications to the pharmaceutical composition clinically is of great importance.
Specifically, the present invention provides following technical scheme.
(1) acetylcysteine pharmaceutical composition, comprising acetylcysteine and medically may be used
The auxiliary material of receiving, it is characterised in that the pH value of composition solution is 7.0~7.5, enters one
Step is preferably 7.2；
(2) the acetylcysteine pharmaceutical composition as described in (1), wherein, medically
Acceptable auxiliary material includes pH adjusting agent, water for injection etc.；
(3) the acetylcysteine pharmaceutical composition as described in (1) or (2), wherein,
Chelating agent is also included, amount of chelant is 0~0.0005g/ml；
(4) the acetylcysteine pharmaceutical composition as described in (1) to (3), wherein,
Chelating agent is selected from EDTA and its pharmaceutical salts, citric acid, butanedioic acid, tartaric acid, EDTA
Be edetic acid(EDTA) (ethylenediamine tetra-acetic acid), the pharmaceutical salts of EDTA include mosatil, according to
Ground acid disodium, edetate sodium etc.；
(5) the acetylcysteine pharmaceutical composition as described in (1) to (4), wherein,
Chelating agent is mosatil；
(6) the acetylcysteine pharmaceutical composition as described in (1) to (5), wherein,
Amount of chelant is preferably 0, i.e., without chelating agent；
(7) the acetylcysteine pharmaceutical composition as described in (1) to (6), wherein,
PH adjusting agent is selected from NaOH, potassium hydroxide, calcium hydroxide, magnesium hydroxide, bicarbonate
1 kind in sodium, saleratus, sodium carbonate, ammoniacal liquor, disodium hydrogen phosphate, dipotassium hydrogen phosphate
Or two or more, preferably NaOH；
(8) preparation method of acetylcysteine pharmaceutical composition, comprises the following steps：
In the state of whole filling with inert gas, by (A) acetylcysteine or the Guang of (B) acetyl half
Propylhomoserin and chelating agent are added in the water for injection of removing oxygen, and stirring dissolves it, then
The pH value of solution is adjusted using pH adjusting agent, the water for injection of addition removing oxygen is carried out
Constant volume, is filtered using 0.2 μm of filter afterwards, after packing, in filling inertia in bottle
Gas, is sealed.
Above-mentioned inert gas can be for nitrogen, rare gas etc., but preferably nitrogen, further
It is preferred that the nitrogen of 99.999% purity and the above.
According to the present invention it is possible to obtain following excellent technique effect：And prior art (1)
Compare, the stability of acetylcysteine pharmaceutical composition of the pH value in the range of 7.0~7.5
More good, the impurity of generation is less, and quality is more stablized；(2) acetyl is significantly improved
Security of the cysteine pharmaceutical composition in clinical practice.
Specific embodiment
According to table 1 and prescription listed by table 2, to liquid dispensing container, the advance inflated with nitrogen deoxygenation of pipeline,
And in the state of being maintained under liquid level and continuing inflated with nitrogen, by acetylcysteine, Ca-EDTA
Sodium is added into the water for injection through inflated with nitrogen deoxidation treatment for about preparing total amount 60%, stirring
Dissolve it, 20% sodium hydroxide solution that addition is prepared with deoxidation water for injection is adjusted
PH value, plus deoxidation treatment water for injection to full dose, stir and evenly mix, liquid utilize 0.2 μm
Filter filtered, the dosage propped up with 10ml/ is sub-packed in the 10ml ampoules of pre- inflated with nitrogen
In bottle, obtained final product after nitrogen charging sealing.
The embodiment prescription of table 1 is constituted
| Prescription | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Embodiment 7 | Embodiment 8 |
| Acetylcysteine (kg) | 1 | 2 | 2 | 2 | 2 | 2 | 2 | 2 |
| Mosatil (g) | 5 | 4 | 0 | 0 | 0 | 3 | 3 | 3 |
| Regulation pH value | 7.2 | 7.2 | 7.0 | 7.2 | 7.5 | 7.0 | 7.2 | 7.5 |
| With liquid cumulative volume (L) | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
The comparative example prescription of table 2 is constituted
Example and comparative example quadrat sampling product everywhere, respectively by British Pharmacopoeia versions in 2009 and
The Acetylcysteine Injection quality standard methods that version in 2013 is recorded are detected, and
Placed 6 months under the conditions of 40 DEG C, sampled respectively at 3, June and detected, detection method reference
The Acetylcysteine Injection mass that British Pharmacopoeia versions in 2009 and version in 2013 are recorded
Standard method, detects hydrogen sulfide and relative substance CYSTINE, the Guang ammonia of L- half in sample respectively
The quality index such as acid, N ' N- diacetyl cystine, N ' S- diacetyl cysteines, as a result joins
It is shown in Table 3~table 5.
Relevant substance detecting method is as follows：All solution all should face uses brand-new.Precision measures this
Product, plus flowing phase dilution is made the solution containing acetylcysteine 2mg in every 1ml, as
Need testing solution；Separately take Cys, CYSTINE, N ' N- diacetyl cystine, N ' S-
Diacetyl cysteine reference substance, it is accurately weighed, plus after the appropriate dissolving of 1mol/L hydrochloric acid solutions,
It is made of flowing phase dilution in every 1ml and contains CYSTINE, Cys, N ' N- bis- respectively
The solution of acetylcystine, N ' S- diacetyl cysteines 10ug, as reference substance solution.
Determined using high performance liquid chromatography (two D of annex V of Chinese Pharmacopoeia version in 2010), with
Octadecylsilane chemically bonded silica is filler, with methyl alcohol -0.02mol/L sodium pentanesulfonates
0.5% ammonium sulfate (1:9, with 2mol/L hydrochloric acid solutions adjust pH value to 2.0) be stream
Dynamic phase, Detection wavelength is 205nm.Precision measures need testing solution and each 20 μ l of reference substance solution,
Liquid chromatograph is injected separately into, chromatogram is recorded, by external standard method with calculated by peak area, other
The above-mentioned main peak of total miscellaneous deduction and above-mentioned impurity are calculated with areas of peak normalization method, are obtained final product.
Content assaying method is as follows：Precision measures this product 2ml, acetic acid 20ml on the rocks, 20~
25 DEG C are titrated to the micro- yellow of solution rapidly with iodine titration solution (0.05mol/L), and at 30 seconds
It is interior colour-fast.Half per the acetyl of 1ml iodine titration solution (0.05mol/L) equivalent to 16.32mg
Cystine (C5H9NO3S)。
Each prescription testing result of table 3
40 DEG C of accelerated stabilities of each prescription of table 4 investigate 3 months testing results
40 DEG C of accelerated stabilities of each prescription of table 5 investigate 6 months testing results
From result above, compared with comparative example (pH value is outside 7.0~7.5 scope),
The stability of acetylcysteine pharmaceutical composition of the pH value in the range of 7.0~7.5 is better
Good, the impurity of generation is less, and quality is more stablized.Wherein, it is steady by the 40 DEG C of acceleration of each prescription
It is qualitative investigate 6 months testing result (table 5) understand, compared with comparative example, the sulphur of embodiment
Change hydrogen, impurity B and other it is total it is miscellaneous significantly reduce, i.e., the long-term stability for preserving is significantly better than
Comparative example, and this safety applications to acetylcysteine pharmaceutical composition clinically has weight
Big meaning.
Claims (10)
1. acetylcysteine pharmaceutical composition, can comprising acetylcysteine and medically connect
The auxiliary material received, it is characterised in that the pH value of composition solution is 7.0~7.5.
2. acetylcysteine pharmaceutical composition according to claim 1, its feature exists
In the pH value of composition solution is 7.2.
3. acetylcysteine pharmaceutical composition according to claim 1 and 2, wherein,
The medically acceptable auxiliary material includes pH adjusting agent, water for injection.
4. acetylcysteine pharmaceutical composition according to claim 3, wherein, also
Comprising chelating agent, amount of chelant is 0~0.0005g/ml.
5. acetylcysteine pharmaceutical composition according to claim 4, wherein, institute
State chelating agent and be selected from EDTA and its pharmaceutical salts, citric acid, butanedioic acid, tartaric acid.
6. the acetylcysteine pharmaceutical composition according to claim 4 or 5, wherein,
The chelating agent is mosatil.
7. the acetylcysteine pharmaceutical composition according to claim 4 or 5, wherein,
The amount of chelant is 0.
8. acetylcysteine pharmaceutical composition according to claim 3, wherein, institute
State pH adjusting agent and be selected from NaOH, potassium hydroxide, calcium hydroxide, magnesium hydroxide, carbonic acid
In hydrogen sodium, saleratus, sodium carbonate, ammoniacal liquor, disodium hydrogen phosphate, dipotassium hydrogen phosphate 1
Plant or two or more.
9. acetylcysteine pharmaceutical composition according to claim 6, wherein, institute
PH adjusting agent is stated for NaOH.
10. the acetylcysteine pharmaceutical combination any one of the claims 1~9
The preparation method of thing, comprises the following steps：In the state of whole filling with inert gas, by (A)
Acetylcysteine or (B) acetylcysteine and chelating agent are added to the injection of removing oxygen
With in water, stirring dissolves it, and the pH value of solution is then adjusted using pH adjusting agent,
The water for injection of addition removing oxygen carries out constant volume, is carried out using 0.2 μm of filter afterwards
Filtering, after packing, in filling with inert gas in bottle, is sealed.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109875959A (en) * | 2018-12-17 | 2019-06-14 | 武汉兴华智慧医药科技有限公司 | A kind of sucking acetylcysteine solution and preparation method thereof |
| CN110870855A (en) * | 2018-08-30 | 2020-03-10 | 北京盈科瑞创新药物研究有限公司 | Acetylcysteine solution preparation for inhalation and preparation method thereof |
| CN111870591A (en) * | 2020-09-16 | 2020-11-03 | 海南斯达制药有限公司 | Method for controlling hydrogen sulfide content of acetylcysteine solution |
| CN112129844A (en) * | 2019-06-25 | 2020-12-25 | 武汉兴华智慧医药科技有限公司 | Acetylcysteine degradation product and preparation method and application thereof |
| CN112245412A (en) * | 2020-09-28 | 2021-01-22 | 山西国润制药有限公司 | Acetylcysteine solution for inhalation and preparation method and application thereof |
| CN113018444A (en) * | 2020-01-09 | 2021-06-25 | 海南斯达制药有限公司 | Pharmaceutical composition for treating respiratory system diseases and preparation method thereof |
| CN114681397A (en) * | 2020-12-26 | 2022-07-01 | 四川汇宇制药股份有限公司 | Preparation method of acetylcysteine injection |
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| CN1711998A (en) * | 2005-03-30 | 2005-12-28 | 杭州华科生物医药技术有限公司 | Multi-dimensional acetylcysteine solution with stabilized pH near to neutrality and production thereof |
| CN103038356A (en) * | 2010-07-21 | 2013-04-10 | 坎伯兰医药品股份有限公司 | Acetycysteine compositions and methods of use thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1711998A (en) * | 2005-03-30 | 2005-12-28 | 杭州华科生物医药技术有限公司 | Multi-dimensional acetylcysteine solution with stabilized pH near to neutrality and production thereof |
| CN103038356A (en) * | 2010-07-21 | 2013-04-10 | 坎伯兰医药品股份有限公司 | Acetycysteine compositions and methods of use thereof |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110870855A (en) * | 2018-08-30 | 2020-03-10 | 北京盈科瑞创新药物研究有限公司 | Acetylcysteine solution preparation for inhalation and preparation method thereof |
| CN109875959A (en) * | 2018-12-17 | 2019-06-14 | 武汉兴华智慧医药科技有限公司 | A kind of sucking acetylcysteine solution and preparation method thereof |
| CN109875959B (en) * | 2018-12-17 | 2020-07-07 | 武汉兴华智慧医药科技有限公司 | Acetylcysteine solution for inhalation and preparation method thereof |
| CN112129844A (en) * | 2019-06-25 | 2020-12-25 | 武汉兴华智慧医药科技有限公司 | Acetylcysteine degradation product and preparation method and application thereof |
| CN113018444A (en) * | 2020-01-09 | 2021-06-25 | 海南斯达制药有限公司 | Pharmaceutical composition for treating respiratory system diseases and preparation method thereof |
| CN111870591A (en) * | 2020-09-16 | 2020-11-03 | 海南斯达制药有限公司 | Method for controlling hydrogen sulfide content of acetylcysteine solution |
| CN111870591B (en) * | 2020-09-16 | 2022-07-26 | 海南斯达制药有限公司 | Method for controlling hydrogen sulfide content of acetylcysteine solution |
| CN112245412A (en) * | 2020-09-28 | 2021-01-22 | 山西国润制药有限公司 | Acetylcysteine solution for inhalation and preparation method and application thereof |
| CN114681397A (en) * | 2020-12-26 | 2022-07-01 | 四川汇宇制药股份有限公司 | Preparation method of acetylcysteine injection |
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Application publication date: 20170524 |