CN1748702A - Newly packed naloxone hydrochloride injection and its producing method - Google Patents
Newly packed naloxone hydrochloride injection and its producing method Download PDFInfo
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- CN1748702A CN1748702A CN 200510080479 CN200510080479A CN1748702A CN 1748702 A CN1748702 A CN 1748702A CN 200510080479 CN200510080479 CN 200510080479 CN 200510080479 A CN200510080479 A CN 200510080479A CN 1748702 A CN1748702 A CN 1748702A
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Abstract
The process of producing naloxone hydrochloride injection in new package includes the following steps: preparing naloxone hydrochloride injection intermediate; bacteria-free filtering the intermediate to obtain filtrate; bacteria-free packing the filtrate in Schering bottle; and sterilizing with flowing steam. While bacteria-free filtering, the insoluble particles in the medicine liquid are also eliminated, and this can greatly reduce the phlebitis attacking probability. The product is safe and reliable.
Description
Technical field
The present invention relates to medicinal liquid injection and production method thereof, more particularly, relate to a kind of naloxone hydrochloride injection and production method thereof of new packing.
Background technology
Naloxone hydrochloride is antipyretic-antalgic and non_steroidal anti_inflammatory drug, and is oral invalid, at present must drug administration by injection.Naloxone hydrochloride injection is the widest opiate receptor antagonistic of present clinical practice, is mainly used in: (1) rescue narcosis analgesic acute poisoning, and the respiration inhibition of this class medicine of antagonism, and patient is revived; (2) residual action of antagonism narcosis analgesic, neonate are influenced by narcosis analgesic in its parent and cause respiration inhibition, available this product antagonism; (3) rescue acute alcoholism: quiet notes naloxone 0.4～0.6mg can make the patient clear-headed; (4) be the narcosis analgesic addict to doubting, quiet notes 0.2～0.4mg can excite withdrawal symptom, and diagnostic value is arranged; (5) the short effect of waking up can activate physiological awakening system by the cholinergic effect and make patient clear-headed, is used for that general anesthesia wakens and shock and some coma patient.
The naloxone hydrochloride injection of clinical practice at present all adopts the ampoule bottle packing, and this exists three insurmountable problems:
(1) the rate height that fractures: the rate that fractures in pouring process is up to 10%;
(2) material is of poor quality: international ampoule glass material is international neutral I class glass (being domestic usually said first class material), and the material of domestic ampoule glass is domestic neutral density glass (a usually said second class material), and the chemical stability of second class material and heat stability and to bear the ability of violent variations in temperature all poor than the first class material easily produce " flake " phenomenon when splendid attire strong acid, strong basicity medicinal liquid.Because the pH value of naloxone hydrochloride injection is 3.0-4.0, require packing timber mass-energy acidproof and not with medicinal liquid generation chemical reaction, the second class material not too adapts to this requirement;
(3) fragility: though (a) ratio of present domestic employing easy cut ampule bottle increases, medical personnel have report when being scratched still by the ampoule bottle fragment; (b) report is arranged during patient's clasticity phlebothrombosis, even dead report is arranged, have data to show, during 1 ampoule bottle breaking, what be inhaled into can reach more than 20,000 greater than the microgranule more than 0.5 micron; (c) pharmaceutical factory, traffic unit and the three parts of the Pharmacy department pain in the neck all especially of the fragmentation in the transportation.
In order to overcome the above-mentioned defective of ampoule bottle, the Beijing KaiYin Bioisystech Co., Ltd complies with international vial main development tendency, adopt the control cillin bottle to replace ampoule bottle, prepared the naloxone hydrochloride injection of new packing, and developed new corresponding with it production method.
Summary of the invention
The invention provides a kind of naloxone hydrochloride injection production method of new packing, it comprises the steps:
(1) prepares the middle product of naloxone hydrochloride injection;
(2) product in the middle of the above-mentioned naloxone hydrochloride injection are carried out aseptic filtration, obtain filtrate;
(3) with above-mentioned filtrate sterile filling in cillin bottle.
(4) products in circulation steam sterilization that embedding is good.
In above-mentioned method, the described aseptic filtration of step (2) is preferably finished less than the filter of 0.22 μ m by the aperture.
In above-mentioned method, the described aseptic filtration of step (2) is preferably carried out in hundred grades of clean level zones.
In above-mentioned method, the described sterile filling of step (3) preferably carries out in hundred grades of clean level zones.
In above-mentioned method, the inner surface of the described cillin bottle of step (3) is preferably hydrophobic.
In above-mentioned method, the described flowing steam of step (4) is preferably 100 ℃ of sterilizations 30 minutes.
On the other hand, the present invention also provides a kind of naloxone hydrochloride injection of new packing, and it is produced by following method:
(1) prepares the middle product of naloxone hydrochloride injection;
(2) product in the middle of the above-mentioned naloxone hydrochloride injection are carried out aseptic filtration, obtain filtrate;
(3) with above-mentioned filtrate sterile filling in cillin bottle.
(4) products in circulation steam sterilization that embedding is good.
Aforesaid naloxone hydrochloride injection, the described aseptic filtration of step (2) is preferably finished less than the filter of 0.22 μ m by the aperture.
Aforesaid naloxone hydrochloride injection, the described aseptic filtration of step (2) preferably carry out in hundred grades of clean level zones.
Aforesaid naloxone hydrochloride injection, the described sterile filling of step (3) preferably carry out in hundred grades of clean level zones.
Aforesaid naloxone hydrochloride injection, the inner surface of the described cillin bottle of step (3) is preferably hydrophobic.
Aforesaid naloxone hydrochloride injection, the described flowing steam of step (4) is preferably 100 ℃, sterilizes 30 minutes.
Aforementioned production method is through a filtration sterilization, the process of a flowing steam sterilization, remove the above microorganism of 0.22 μ m in the medicinal liquid with filtering method earlier, kill microorganism below the 0.22 μ m by flowing steam sterilization again, and, in filtration sterilization, can remove the particulate matter in the medicinal liquid, greatly reduce phlebitic occurrence probability.
In addition, the naloxone hydrochloride injection of new packing of the present invention has overcome the shortcoming of ampoule bottle, and this is the naloxone hydrochloride injection of domestic first Zhi Caiyong cillin bottle packing, has following advantage:
(1) production is more reliable, adopts full-automatic import canning line, and the cillin bottle packing can be avoided antibacterial and debris contamination; In addition, the internal control quality standard is higher, can more effective control pyrogen and endotoxin;
(2) use is safer, adopt the international neutral I class glass of representing the glass material developing direction, possess characteristics such as transparent, heat-resisting, acid and alkali-resistance, intensity be big, overcome easily " flake " phenomenon of ampoule bottle, not only can avoid the broken injury of glass medical personnel, and can avoid the clasticity phlebothrombosis;
(3) transportation is more convenient, and cracky not stores, convenient transportation;
(4) simple to operate, reduced operating procedure, to race against time for rescue, clinical practice is more convenient;
(5) with nontoxic inert material the bottle inner surface is handled in the cillin bottle, formed surface hydrophobic, the sodium ion amount of separating out is obviously reduced; Simultaneously, the medicinal liquid residual quantity only accounts for 0.02～0.1%, is 1% of ampoule bottle residual quantity, makes therapeutic dose more accurate; In addition, cillin bottle adopts coated plug, and acidproof, alkaline-resisting, inert is extremely strong, does not react with any chemical compound, has guaranteed stability of drug; And mechanical performance strengthens, and reduces the chip incidence rate.
The specific embodiment
Further explain the present invention with embodiment below, but protection scope of the present invention is not limited to these embodiment.
In the present invention, the method for preparing the middle product of naloxone hydrochloride injection is well-known in the art, need not here to give unnecessary details.
In the present invention, the method for product in the middle of the naloxone hydrochloride injection being carried out aseptic filtration is well-known in the art, as long as the aperture of the pharmaceutical purpose filter that uses need not to give unnecessary details less than 0.22 μ m here.
In the present invention, be well-known in the art with the filtrate sterile filling to the method in the cillin bottle, need not here to give unnecessary details.
In the present invention, the method for the products in circulation steam sterilization that embedding is good is well-known in the art, need not here to give unnecessary details.
Embodiment 1
Present embodiment has carried out the finished product stability check to the naloxone hydrochloride injection according to method preparation of the present invention.
According to Chinese Pharmacopoeia version in 2000 two appendix XIX C " medicine stability test guideline ", and, stability test high spot reviews project is decided to be: appearance luster, content, pH value, clarity and related substance in conjunction with this product quality standard.
Accelerated test
Get three batches of (lot numbers: 031001,031002,031003) each about 600 bottles of naloxone hydrochloride injection of development, press commercially available back, put 40 ℃ ± 2 ℃, investigate 6 months in relative humidity 75% ± 5% incubator, respectively 1,2,3, the sampling in June, investigate by stability test high spot reviews project, with data and 0 month data relatively, investigate and the results are shown in Table 1 and table 2.
Accelerated test result shows: through quickening test in 6 months, the every index of two specification samples does not have significant change, and all in the scope of quality standard regulation, sample quality is stable.
Table 1 accelerated test is investigated result (1ml: 0.4mg)
| Time (moon) | Lot number | The investigation project | ||||
| Appearance luster | Content (%) | PH value | Related substance | Clarity | ||
| 0 1 2 | 031001 031002 031003 031001 031002 031003 031001 031002 031003 | Achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity | 100.0 99.9 99.8 99.0 99.9 100.0 99.2 99.7 99.1 | 3.24 3.22 3.23 3.25 3.24 3.22 3.24 3.20 3.23 | Up to specification up to specification | Up to specification up to specification |
| 3 6 | 031001 031002 031003 031001 031002 031003 | Achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity | 98.7 98.8 99.0 98.5 98.3 98.3 | 3.23 3.25 3.24 3.26 3.25 3.24 | Up to specification up to specification | Up to specification up to specification |
Table 2 accelerated test is investigated result (2ml: 2mg)
| Time (moon) | Lot number | The investigation project | ||||
| Appearance luster | Content (%) | PH value | Related substance | Clarity | ||
| 0 1 2 3 6 | 031001 031002 031003 031001 031002 031003 031001 031002 031003 031001 031002 031003 031001 031002 031003 | Achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity | 99.8 100.0 99.8 99.5 99.7 99.7 99.9 99.5 99.8 99.4 99.8 99.5 99.0 99.1 99.4 | 3.21 3.23 3.23 3.20 3.21 3.24 3.22 3.21 3.20 3.23 3.24 3.21 3.21 3.20 3.19 | Up to specification up to specification up to specification up to specification | Up to specification up to specification up to specification up to specification |
Long term test
Get three batches of (lot numbers: 031001,031002,031003) each about 1000 bottles of naloxone hydrochloride injection of development, press commercially available back, (25 ℃ ± 2 ℃ and relative humidity 60% ± 10%) preserved at ambient temperature, respectively sampling in 3,6,9,12,18,24,36 months, investigate by stability test high spot reviews project, carry out aseptic and endotoxin simultaneously and investigate, with data and 0 month data relatively, investigation the results are shown in Table 3 and table 4.
Long-term test results shows: through test in long-term 18 months, the every index of two specification samples did not have significant change, and all in the scope of quality standard regulation, sample quality is stable.
Table 3 long term test is investigated result (1ml: 0.4mg)
| Time (moon) | Lot number | The investigation project | ||||||
| Appearance luster | Content (%) | PH value | Related substance | Clarity | Aseptic | Endotoxin | ||
| 0 3 6 9 12 | 031001 031002 031003 031001 031002 031003 031001 031002 031003 031001 031002 031003 031001 031002 031003 | Achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity | 100.0 99.9 99.8 99.6 99.0 99.2 98.9 99.3 99.1 98.3 98.7 98.8 98.7 98.1 98.2 | 3.24 3.22 3.23 3.22 3.21 3.23 3.23 3.20 3.22 3.25 3.23 3.22 3.30 3.25 3.23 | Up to specification up to specification up to specification up to specification | Up to specification up to specification up to specification up to specification | Up to specification up to specification up to specification up to specification | Up to specification up to specification up to specification up to specification |
| 18 | 031001 031002 031003 | Achromatism and clarity achromatism and clarity achromatism and clarity | 98.2 98.5 98.7 | 3.29 3.28 3.24 | Up to specification up to specification | Up to specification up to specification | Up to specification up to specification | Up to specification up to specification |
Table 4 long term test is investigated result (2ml: 2mg)
| Time (moon) | Lot number | The investigation project | ||||||
| Appearance luster | Content (%) | PH value | Related substance | Clarity | Aseptic | Endotoxin | ||
| 0 3 6 9 12 18 | 031001 031002 031003 031001 031002 031003 031001 031002 031003 031001 031002 031003 031001 031002 031003 031001 031002 031003 | Achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity achromatism and clarity | 99.8 100.0 99.8 99.5 99.5 99.8 99.5 99.4 99.7 98.7 99.2 99.2 99.1 98.7 98.7 98.5 99.3 99.0 | 3.21 3.23 3.23 3.23 3.20 3.19 3.19 3.20 3.19 3.20 3.19 3.21 3.23 3.22 3.23 3.24 3.23 3.20 | Up to specification up to specification | Up to specification up to specification | Up to specification up to specification | Up to specification up to specification |
The stability test conclusion
Accelerated test and long-term test results show that sample quality is stable, and naloxone hydrochloride injection is good with the packaging material compatibility of being adopted.
Embodiment 2
Present embodiment is to checking according to the particulate matter number in the naloxone hydrochloride injection of method preparation of the present invention.
After testing, in naloxone hydrochloride injection, contain the above microgranule of 10 μ m below 50, contain the above microgranule of 25 μ m below 5.
" regulation of Chinese pharmacopoeia, the standard of particulate matter must not be crossed 6000 for each test sample container contains the above microgranule of 10 μ m, contains the above microgranule of 25 μ m and must not cross 600 according to version in 2005.
As seen, be less than according to particulate matter digital display work in the naloxone hydrochloride injection of method of the present invention preparation that " regulation of Chinese pharmacopoeia, product quality obviously are better than " the regulation of Chinese pharmacopoeia.
Claims (7)
1. the production method of the naloxone hydrochloride injection of a new packing, it comprises the steps:
(1) prepares the middle product of naloxone hydrochloride injection;
(2) product in the middle of the above-mentioned naloxone hydrochloride injection are carried out aseptic filtration, obtain filtrate;
(3) with above-mentioned filtrate sterile filling in cillin bottle;
(4) products in circulation steam sterilization that embedding is good.
2. the method for claim 1 is characterized in that, the described aseptic filtration of step (2) is to finish less than the filter of 0.22 μ m by the aperture.
3. the method for claim 1 is characterized in that, the described aseptic filtration of step (2) is to carry out in hundred grades of clean level zones.
4. the method for claim 1 is characterized in that, the described sterile filling of step (3) is to carry out in hundred grades of clean level zones.
5. the method for claim 1 is characterized in that, the inner surface of the described cillin bottle of step (3) is hydrophobic.
6. the method for claim 1 is characterized in that, the described flowing steam sterilization of step (4) is 100 ℃ of sterilizations 30 minutes.
7. the naloxone hydrochloride injection of producing by each the described method among the claim 1-6.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510080479 CN1748702A (en) | 2005-07-05 | 2005-07-05 | Newly packed naloxone hydrochloride injection and its producing method |
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| CN 200510080479 CN1748702A (en) | 2005-07-05 | 2005-07-05 | Newly packed naloxone hydrochloride injection and its producing method |
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| CN1748702A true CN1748702A (en) | 2006-03-22 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101732313B (en) * | 2008-11-25 | 2012-10-03 | 北京四环制药有限公司 | Medicine composition of naloxone hydrochloride and polyethylene glycol and preparation method thereof |
| WO2021252449A1 (en) * | 2020-06-08 | 2021-12-16 | Harm Reduction Therapeutics, Inc. | Sterilized formulations |
-
2005
- 2005-07-05 CN CN 200510080479 patent/CN1748702A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101732313B (en) * | 2008-11-25 | 2012-10-03 | 北京四环制药有限公司 | Medicine composition of naloxone hydrochloride and polyethylene glycol and preparation method thereof |
| WO2021252449A1 (en) * | 2020-06-08 | 2021-12-16 | Harm Reduction Therapeutics, Inc. | Sterilized formulations |
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Effective date of registration: 20090116 Address after: Beijing economic and Technological Development Zone Rong 6 Jingdong Street Building No. 3, zip code: 100176 Applicant after: Beijing Kawin Technology Co., Ltd. Address before: Beijing economic and Technological Development Zone, Rong Jingdong street, No. 6, zip code: 100176 Applicant before: Beijing Kawin Biotechnology Co., Ltd. |
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Owner name: BEIJING KAIYIN SCIENCE CO., LTD. Free format text: FORMER OWNER: BEIJING KAIYIN BIOISYSTECH CO., LTD. Effective date: 20090116 |
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Open date: 20060322 |