CN106420599A - Preparation method of citric acid caffeine injection - Google Patents
Preparation method of citric acid caffeine injection Download PDFInfo
- Publication number
- CN106420599A CN106420599A CN201610758467.1A CN201610758467A CN106420599A CN 106420599 A CN106420599 A CN 106420599A CN 201610758467 A CN201610758467 A CN 201610758467A CN 106420599 A CN106420599 A CN 106420599A
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- CN
- China
- Prior art keywords
- injection
- recipe quantity
- liquid
- preparation
- caffeine citrate
- Prior art date
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- NGWSAUQBWVWFCU-UHFFFAOYSA-N CCNC(C)(C)C(C)C Chemical compound CCNC(C)(C)C(C)C NGWSAUQBWVWFCU-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
Abstract
The invention provides a preparation method of a citric acid caffeine injection. The preparation method comprises the step of adding citric acid caffeine and sodium hydroxide into water for injection, so as to obtain the injection. By virtue of the preparation method, the quality of the medicine is improved, and meanwhile, the production cost is lowered.
Description
Technical field
The present invention relates to pharmaceutical preparations technology field, in particular it relates to the preparation side of a kind of caffeine citrate parenteral solution
Method.
Background technology
Caffeine citrate parenteral solution by the application of U.S. EUROHLTH INTL SARL company, obtains FDA in 1999 the earliest
Approval listing, thereafter, European Union, Japan also list in succession, and caffeine citrate parenteral solution is primary for treating premature neonate
Apnea.American-European by as the choice drug rescuing apnea neonatorum.
In prior art, patent CN104586755A provides composition and the preparation side of a kind of caffeine citrate parenteral solution
Method, is prepared from by dosing, decarbonization filtering, embedding, the damp and hot conventional method such as degerming.
Domestic at present not yet have the other citric acid of injection stage and caffeine raw material, therefore, before preparing injection, two kinds
Bulk drug needs to refine respectively so that it is all can reach to inject rank, then just can feed intake use, adds production process and becomes
This.
Content of the invention
General, prepare parenteral solution without the other bulk drug of injection stage, need first bulk drug to be refined into injection stage
Other medicine just can feed intake, current domestic citric acid and caffeine, all without injection rank, it is therefore desirable to could throw after refining respectively
Material uses, and time and effort consuming adds processing step and production cost.
We find under study for action simultaneously, the caffeine citrate parenteral solution prepared by prior art, following three impurity
Content substantially increases, and especially impurity 1 increases to 0.171%, and impurity substantially exceeds standard, after being placed 2 months, and this type of impurity content
Also in sustainable growth, this, by affecting the quality of preparation and long-time stability, brings hidden danger to clinical application.
Impurity 1 (caffeidine)
Impurity 2 (CAS No.7597-60-6)
Impurity 3 4-[N-methyl-N-(N-amino-carbonyl) amino]-1-methylimidazole-5-carboxylic acid sodium
Therefore, it is an object of the invention to the defect overcoming prior art to exist, and a kind of new citric acid coffee is provided
Preparation method because of parenteral solution.
The present invention is achieved through the following technical solutions：
1. add appropriate water for injection to be prepared as injection caffeine citrate 20mg, NaOH 1.7mg.
2. the preparation method of a kind of caffeine citrate parenteral solution is provided
1. the caffeine citrate of the recipe quantity water for injection (60～80 DEG C) of recipe quantity 50～60% is dissolved；
2. press liquid weight/volume percent and add 0.05% needle-use activated carbon, stir, decarbonization filtering.
3. add after the water for injection again NaOH of recipe quantity being added recipe quantity 30% dissolves, make the pH of liquid
In the range of 4.7～5.0, liquid is stirred at room temperature 15 minutes；
4. mend and inject water to about full dose；
5. liquid is clear and bright to liquid with the essence filter of 0.45 μm of millipore filter, check pH value, clarity, content, qualified after, warp
0.22 μm of millipore filter end-filtration, is sub-packed in specification 10ml ampoule, sealing by fusing after nitrogen filling.
6. sterilizing eventually (116 DEG C, sterilizing in 40 minutes), leak detection, cooling back light inspection, labeling, packaging, product inspection.
Beneficial effect
Compared with prior art, the present invention has following beneficial effect：
1. the present invention feeds intake with the double salt caffeine citrate that citric acid and caffeine are made, and decreases relative substance, special
The impurity 1～3 producing when being not to prepare by prior art substantially reduces, and substantially increases quality and the stability of injection.
2. caffeine citrate is disposably directly fed intake by the present invention, and changing in existing production technology needs citric acid
The step refining respectively with caffeine, operation is simple, and saves operation and production cost.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in detail.Following example will assist in the technology of this area
Personnel are further appreciated by the present invention, but do not limit the present invention in any form.It should be pointed out that, the ordinary skill to this area
For personnel, without departing from the inventive concept of the premise, some deformation can also be made and improve.These broadly fall into the present invention
Protection domain.
Embodiment 1
Prescription：
Preparation method：
1. the citric acid monohydrate of the recipe quantity water for injection (60～80 DEG C) of recipe quantity 50～60% is dissolved；Add
Enter the caffeine of recipe quantity, stir；
2. press liquid weight/volume percent and add 0.05% needle-use activated carbon, stir, decarbonization filtering；
3. stir after the water for injection again sodium citrate dihydrate of recipe quantity being added recipe quantity 20% dissolves and add
Enter, make the pH of liquid in the range of 4.5～5.0；
4. mend and inject water to about full dose；
5. liquid is clear and bright to liquid with the essence filter of 0.45 μm of millipore filter, check pH value, clarity, content, qualified after, warp
0.22 μm of millipore filter end-filtration, is sub-packed in specification 10ml ampoule, sealing by fusing after nitrogen filling.
6. sterilizing eventually (121 DEG C, sterilizing in 15 minutes), leak detection, cooling back light inspection, labeling, packaging, product inspection.
Embodiment 2
Prescription：
Caffeine citrate 40.0g
NaOH 22.6g
Inject water to 2.0L
Make 2000
Preparation method：
1. the caffeine citrate of the recipe quantity water for injection (60～80 DEG C) of recipe quantity 50～60% is dissolved；
2. press liquid weight/volume percent and add 0.05% needle-use activated carbon, stir, decarbonization filtering；
Stirring after dissolving in the water for injection that 3. NaOH of recipe quantity add recipe quantity 30% again adds, and makes liquid
PH in the range of 4.7～5.0；
4. mend and inject water to about full dose；
5. liquid is clear and bright to liquid with the essence filter of 0.45 μm of millipore filter, check pH value, clarity, content, qualified after, warp
0.22 μm of millipore filter end-filtration, is sub-packed in specification 10ml ampoule, sealing by fusing after nitrogen filling；
6. sterilizing eventually (121 DEG C, sterilizing in 15 minutes), leak detection, cooling back light inspection, labeling, packaging, product inspection.
Embodiment 3
Prescription：
Caffeine citrate 1.0Kg
NaOH 565.0g
Water for injection 50.0L
Make 50000
Preparation method：
1. the caffeine citrate of the recipe quantity water for injection (60～80 DEG C) of recipe quantity 50～60% is dissolved；
2. press liquid weight/volume percent and add 0.05% needle-use activated carbon, stir, decarbonization filtering；
Stirring after dissolving in the water for injection that 3. NaOH of recipe quantity add recipe quantity 30% again adds, and makes liquid
PH in the range of 4.7～5.0；
4. mend and inject water to about full dose；
5. liquid is clear and bright to liquid with the essence filter of 0.45 μm of millipore filter, check pH value, clarity, content, qualified after, warp
0.22 μm of millipore filter end-filtration, is sub-packed in specification 10ml ampoule, sealing by fusing after nitrogen filling；
6. sterilizing eventually (121 DEG C, sterilizing in 15 minutes), leak detection, cooling back light inspection, labeling, packaging, product inspection.
Embodiment 4
Table 1 embodiment 1 and embodiment the 2nd, embodiment 3 quality versus
By table 1, all high than embodiment the 2nd, embodiment 3 by the impurity before and after embodiment 1 sterilizing prepared by prior art, explanation
The quality of the pharmaceutical preparations prepared by the present invention is significantly improved compared with prior art.
Embodiment 5
Table 2 embodiment the 2nd, 3 and commercially available product sample quality detection
| Sample | Proterties | PH value | Content | There is related substance (theophylline, theobromine, paraxanthine, total impurities) |
| Embodiment 2 | Colourless clear liquid | 4.83 | 101.3% | 0.0215%, 0.0054%, 0.0103%, 0.0421% |
| Embodiment 3 | Colourless clear liquid | 4.73 | 100.7% | 0.0179%, 0.0044%, 0.0119%, 0.0376% |
| Commercially available product | Colourless clear liquid | 4.70 | 102.1% | 0.0373%, 0.0102%, 0.0178%, 0.0724% |
Embodiment 6
Table 3 caffeine citrate parenteral solution long-term stable experiment result
Result of the test shows：After the injection ambient temperatare of embodiment the 2nd, 3 preparations put 6 months, every Index for examination is without bright
Aobvious change, impurity reduces compared with commercially available product stability, and stability also than more preferably, illustrates injection quality prepared by the present invention
It is improved.
Claims (2)
1. a caffeine citrate parenteral solution, its prescription is, contains in every 1ml parenteral solution：Caffeine citrate 20mg, hydroxide
Sodium 11.3mg.
2. the preparation method of a caffeine citrate parenteral solution, it is characterised in that said method comprising the steps of：
1. by the caffeine citrate of the recipe quantity water for injection of recipe quantity 50～60%（60～80 DEG C）Dissolve；
2. press liquid weight/volume percent and add 0.05% needle-use activated carbon, stir, decarbonization filtering；
Stirring after dissolving in the water for injection that 3. NaOH of recipe quantity add recipe quantity 30% again adds, and makes the pH of liquid
In the range of 4.7～5.0；
4. mend and inject water to about full dose；
5. liquid is clear and bright to liquid with the essence filter of 0.45 μm of millipore filter, check pH value, clarity, content, qualified after, through 0.22
μm millipore filter end-filtration, is sub-packed in specification 10ml ampoule, nitrogen fill after sealing by fusing；
6. sterilizing eventually（121 DEG C, sterilizing in 15 minutes）, leak detection, cooling back light inspection, labeling, packaging, product inspection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610758467.1A CN106420599B (en) | 2016-08-30 | 2016-08-30 | Preparation method of citric acid caffeine injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610758467.1A CN106420599B (en) | 2016-08-30 | 2016-08-30 | Preparation method of citric acid caffeine injection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106420599A true CN106420599A (en) | 2017-02-22 |
| CN106420599B CN106420599B (en) | 2020-01-17 |
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| CN201610758467.1A Active CN106420599B (en) | 2016-08-30 | 2016-08-30 | Preparation method of citric acid caffeine injection |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107233306A (en) * | 2017-07-03 | 2017-10-10 | 华润双鹤利民药业（济南）有限公司 | A kind of caffeine citrate parenteral solution and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104586755A (en) * | 2014-12-30 | 2015-05-06 | 成都苑东药业有限公司 | Caffeine citrate injection pharmaceutical composition and preparation method thereof |
| CN105030716A (en) * | 2015-08-06 | 2015-11-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Caffeine drug combination and preparation method thereof |
| CN105250227A (en) * | 2015-09-30 | 2016-01-20 | 合肥华方医药科技有限公司 | Citric acid caffeine freeze-dried powder and preparation method thereof |
-
2016
- 2016-08-30 CN CN201610758467.1A patent/CN106420599B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104586755A (en) * | 2014-12-30 | 2015-05-06 | 成都苑东药业有限公司 | Caffeine citrate injection pharmaceutical composition and preparation method thereof |
| CN105030716A (en) * | 2015-08-06 | 2015-11-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Caffeine drug combination and preparation method thereof |
| CN105250227A (en) * | 2015-09-30 | 2016-01-20 | 合肥华方医药科技有限公司 | Citric acid caffeine freeze-dried powder and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107233306A (en) * | 2017-07-03 | 2017-10-10 | 华润双鹤利民药业（济南）有限公司 | A kind of caffeine citrate parenteral solution and preparation method thereof |
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| CN106420599B (en) | 2020-01-17 |
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