CN101167722A - Ketorolac tromethamine freezing-dried power injection and preparation method thereof - Google Patents
Ketorolac tromethamine freezing-dried power injection and preparation method thereof Download PDFInfo
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- CN101167722A CN101167722A CNA2007101131772A CN200710113177A CN101167722A CN 101167722 A CN101167722 A CN 101167722A CN A2007101131772 A CNA2007101131772 A CN A2007101131772A CN 200710113177 A CN200710113177 A CN 200710113177A CN 101167722 A CN101167722 A CN 101167722A
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- injection
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- ketorolac tromethamine
- lyophilized injectable
- injectable powder
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Abstract
Ketorolac trimethylol aminomethane is nonsteroidal analgesic-antiphlogistic for oral administration and injection with strong function of easing pain, which is mainly used for easing moderate and serious postoperative pain, acute nephrocolic concerned with injury, visceralgia concerned with cancer, and anti local inflammation. The invention provides a freeze dried of Ketorolac trimethylol aminomethane and preparation method. The stability of the main drug is greatly improved, the shortcoming of slow effect of oral administration is overcome, and moreover, the instability of main drug and the practical preparing techniue is overcome.
Description
Affiliated field
The present invention relates to new pharmaceutical preparation, particularly ketorolac tromethamine freezing-dried power injection preparation and preparation method thereof.
Background technology
Ketorolac tromethamine (Ketorolac Tromethamine) is the minaline derivant of Syntex company exploitation, ketorolac tromethamine be a kind of can the administration of oral injectable again have powerful pain-stopping effect novel non-steroidal analgesia, an anti-inflammatory agent, be mainly used in and alleviate moderate to serious postoperative pain, the acute kidney angor relevant with the visceral pain of related to cancer etc. with wound, foreign data studies show that this medical instrument have the analgesic activity produce effects soon, longer duration, action intensity to morphine, Pethidine is similar but biggest advantage does not have addiction exactly; And can be used for partial inflammation, have analgesia, antiinflammation.
Used clinically ketorolac tromethamine mainly contains oral administration and injecting and administering preparations at present, as capsule, injection etc.Show according to up-to-date result of study, the Peroral solid dosage form administering mode is slower on drug absorption, and needs most the mode of easing pain fast for patient acute, serious pain, and the selection of administering mode is just particularly important, the oral way administration just has a lot of inconveniences, and it is slow mainly to show as onset.
At present used injection mainly contains external kind, quality better but price is higher, and that home-made injection quality less stable, technology are difficult to control, clarity is bad etc., and brings very big potential safety hazard to clinical application.
Summary of the invention
The invention provides a kind of ketorolac tromethamine injection freeze-dried powder pharmaceutical formulation.Freeze-dried powder is the Powdered injection that is prepared under the environment of vacuum and low temperature, single is very stable a kind of preparation with regard to its pharmaceutical preparation character, the freeze-dried powder dosage form is minimum to the influence of the character unstable factor of principal agent ketorolac tromethamine, the existence that the principal agent ketorolac tromethamine is can be in preparation stable, convenient storage for a long time.Solved injection formulation principal agent unsettled difficult problem in liquid.
Especially it should be noted that in the Workshop Production of reality, if (main prescription is: the principal agent ketorolac tromethamine when adopting the preparation prescription of external injection and technology, dehydrated alcohol, sodium chloride, mannitol (can not add), sodium hydroxide, water for injection), when when laboratory carries out lab scale, various quality index can both reach the prescription of regulation substantially, but it is but very undesirable when actual Workshop Production, may be because home-made ampoule bottle quality does not reach external quality and other technological factor, extremely should produce white point in actual workshop during big produce and make clarity defective, bring very big difficulty to actual production.Solve on the Dan Congqi preparation technology, cost is too high, difficulty is too big.The present invention is prepared into the freeze-dried powder dosage form to ketorolac tromethamine and can addresses these problems effectively, compares ketorolac tromethamine freeze-dried powder injection clarity with injection and is improved, and satisfies the requirement of Workshop Production technology.
Another object of the present invention makes things convenient for clinical application exactly in addition, overcomes the slow drawback of oral administration onset, can play analgesic activity apace, is specially adapted to acute pain patient medication.
Technical scheme provided by the present invention is as follows:
Ketorolac tromethamine 0.1～10%
Excipient 0.1～30%
Antioxidant 0.01～2%
The pH value regulator is an amount of
Water for injection adds to 2000ml
Wherein excipient is mannitol, sorbitol, dextran, glucose, lactose, sodium chloride is a kind of or its mixture; Antioxidant is sodium thiosulfate, sodium sulfite, sodium pyrosulfite, sodium sulfite, vitamin C is a kind of or its mixture; The pH value regulator is a kind of or its mixture of sodium hydroxide, sodium bicarbonate or sodium carbonate.
Prescription described in prescription, according to following preparation technology:
The ketorolac tromethamine, excipient, antioxidant that takes by weighing recipe quantity adds in the water for injection of an amount of (water for injection of about 40% recipe quantity) and stirs, add the injection active carbon again, the addition of active carbon is 0.02% (g/v) approximately, is incubated 15 minutes, filtering decarbonization.
Add water for injection to full dose, stir, regulate pH value to 7.0～8.0, through the filtering with microporous membrane of 0.45 μ m and 0.22 μ m, filtrate is canned after tested in cillin bottle successively for obtain solution, the about 2ml of every Bottle ﹠ Can dress, and the false add plug is put into freeze drying box.
Lyophilizing: empty van pre-freeze is put into goods then to about 0 ℃ in advance, and products temperature was reduced to-45 ℃～-60 ℃ pre-freezes of pact 7～10 hours; The open cold condenser is reduced to below-60 ℃ temperature then, begins to be evacuated to about 30Pa; Progressively improve temperature then to-15 ℃, vacuum drying 20～40 hours slowly heats up; Improve once more about shelf temperature to 30 ℃, kept 2～4 hours, vacuum maintains 5～10Pa, finishes the outlet of jumping a queue entirely until the qualified lyophilizing of moisture.
Roll aluminium lid, check, packing, promptly.
Because ketorolac tromethamine is the freeze-dried powder dosage form in the present invention, all with the injection form administration, this has just overcome the shortcoming that the oral administration bioavailability is not high, curative effect is not high during the actual clinical administration; Simultaneously make that also stability of formulation improves greatly, the activity of principal agent is able to maximum reservation, prolong the holding time of medicine preparation greatly, prolonged the effect duration of pharmaceutical preparation effectively, and farthest overcome the bad technology difficult problem of clarity in the injection.
The present invention is stable through influence factor's test card phaneroplasm amount, reaches the processing quality requirement of big production fully.
The specific embodiment
Embodiment 1
The injection ketorolac tromethamine freezes the preparation in powder
Ketorolac tromethamine 10g
Mannitol 40g
Sodium chloride 4g
Sodium thiosulfate 1g
Sodium hydroxide is an amount of
Water for injection adds to 2000ml
Preparation technology:
(1) ketorolac tromethamine, mannitol, sodium chloride, sodium thiosulfate that the takes by weighing recipe quantity water for injection that adds an amount of (water for injection of about 40% recipe quantity) stirs, add the injection active carbon again, the addition of active carbon is 0.02% (g/v) approximately, be incubated 15 minutes, filtering decarbonization.
(2) add water for injection to full dose, stir, regulate pH value to 7.5 with the 1ml/L sodium hydroxide for preparing in advance.Through the filtering with microporous membrane of 0.45 μ m and 0.22 μ m, filtrate is canned after tested in cillin bottle successively for obtain solution, the about 2ml of every Bottle ﹠ Can dress, and the false add plug is put into freeze drying box.
(3) lyophilizing: empty van pre-freeze is put into goods then to about 0 ℃ in advance, and products temperature was reduced to-45 ℃～-60 ℃ pre-freezes of pact 7～10 hours; The open cold condenser is reduced to below-60 ℃ temperature then, begins to be evacuated to about 30Pa; Progressively improve temperature then to-15 ℃, vacuum drying 20～40 hours slowly heats up; Improve once more about shelf temperature to 30 ℃, kept 2～4 hours, vacuum maintains 5～10Pa, finishes the outlet of jumping a queue entirely until the qualified lyophilizing of moisture.
(4) roll aluminium lid, check, packing, promptly.
Embodiment 2
The injection ketorolac tromethamine freezes the preparation in powder
Ketorolac tromethamine 20g
Mannitol 60g
Sodium chloride 5g
Sodium thiosulfate 3g
Sodium hydroxide is an amount of
Water for injection adds to 2000ml
Preparation technology:
(1) ketorolac tromethamine, mannitol, sodium chloride, sodium thiosulfate that the takes by weighing recipe quantity water for injection that adds an amount of (water for injection of about 40% recipe quantity) stirs, add the injection active carbon again, the addition of active carbon is 0.02% (g/v) approximately, be incubated 15 minutes, filtering decarbonization.
(2) add water for injection to full dose, stir, regulate pH value to 7.6 with the 1ml/L sodium hydroxide for preparing in advance.Through the filtering with microporous membrane of 0.45 μ m and 0.22 μ m, filtrate is canned after tested in cillin bottle successively for obtain solution, the about 2ml of every Bottle ﹠ Can dress, and the false add plug is put into freeze drying box.
(3) lyophilizing: empty van pre-freeze is put into goods then to about 0 ℃ in advance, and products temperature was reduced to-45 ℃～-60 ℃ pre-freezes of pact 7～10 hours; The open cold condenser is reduced to below-60 ℃ temperature then, begins to be evacuated to about 30Pa; Progressively improve temperature then to-15 ℃, vacuum drying 20～40 hours slowly heats up; Improve once more about shelf temperature to 30 ℃, kept 2～4 hours, vacuum maintains 5～10Pa, finishes the outlet of jumping a queue entirely until the qualified lyophilizing of moisture.
(4) roll aluminium lid, check, packing, promptly.
Embodiment 3
The preparation of injection ketorolac tromethamine lyophilized powder
Ketorolac tromethamine 30g
Mannitol 70g
Sodium sulfite 6g
Sodium hydroxide is an amount of
Water for injection adds to 2000ml
Preparation technology:
(1) ketorolac tromethamine, mannitol, sodium sulfite that the takes by weighing recipe quantity water for injection that adds an amount of (water for injection of about 40% recipe quantity) stirs, add the injection active carbon again, the addition of active carbon is 0.02% (g/v) approximately, is incubated 15 minutes, filtering decarbonization.
(2) add water for injection to full dose, stir, regulate pH value to 7.5 with the 1ml/L sodium hydroxide for preparing in advance.Through the filtering with microporous membrane of 0.45 μ m and 0.22 μ m, filtrate is canned after tested in cillin bottle successively for obtain solution, the about 2ml of every Bottle ﹠ Can dress, and the false add plug is put into freeze drying box.
(3) lyophilizing: empty van pre-freeze is put into goods then to about 0 ℃ in advance, and products temperature was reduced to-45 ℃～-60 ℃ pre-freezes of pact 7～10 hours; The open cold condenser is reduced to below-60 ℃ temperature then, begins to be evacuated to about 30Pa; Progressively improve temperature then to-15 ℃, vacuum drying 20～40 hours slowly heats up; Improve once more about shelf temperature to 30 ℃, kept 2～4 hours, vacuum maintains 5～10Pa, finishes the outlet of jumping a queue entirely until the qualified lyophilizing of moisture.
(4) roll aluminium lid, check, packing, promptly.
Embodiment 4
Influence factor's test
After the formulation and technology of employing embodiment 1 is prepared into finished product, remove outer package, the ketorolac tromethamine freezing-dried power injection agent that is up to the standards entirely of learning from else's experience place respectively strong illumination (4500 ± 5000LX), placed 10 days under high temperature (60 ℃) condition, in the 10th o'clock sky sampling and measuring, and with 0 day data relatively, result of the test sees Table 1 and table 2.
Table 1 high temperature (60 ℃) result of the test
| Time (%) | Appearance character | PH value | Clarity | Content (%) | Related substance |
| 0 day 10 days | The slightly micro-yellow in off-white color block off-white color block surface | 7.487.47 | Up to specification | 99.42 99.49 | 0.24 0.26 |
Table 2 illumination (4500 ± 5000LX) result of the tests
| Time (%) | Appearance character | PH value | Clarity | Content (%) | Related substance |
| 0 day 10 days | The slightly micro-yellow in off-white color block off-white color block surface | 7.487.49 | Up to specification | 99.4299.38 | 0.23 0.25 |
The reference substance factors influencing is the result show, the injection sample is basicly stable to heat, illumination, high temperature (60 ℃), high light (investigate 10 days under 4500 ± 5000LX) conditions, the sample character is that the slightly micro-yellow in off-white color block surface, related substance slightly raise, but still in prescribed limit.Every index has no significant change.
Illustrate that according to above experimental result this formulation and technology adopts common low Pyrex control Carbenicllin bottle, lucifuge, storage gets final product in the cool.
Claims (8)
1. a freeze-dried powder injection is characterized in that prescription mainly contains: ketorolac tromethamine, excipient, antioxidant and pH value regulator.
2. lyophilized injectable powder as claimed in claim 1 is characterized in that described excipient is one or more in mannitol, sorbitol, dextran, glucose, lactose, the sodium chloride.
3. lyophilized injectable powder as claimed in claim 1 is characterized in that described antioxidant is one or more in sodium thiosulfate, sodium sulfite, sodium pyrosulfite, sodium sulfite, the vitamin C.
4. lyophilized injectable powder as claimed in claim 3 is characterized in that described antioxidant selects sodium thiosulfate for use.
5. lyophilized injectable powder as claimed in claim 1 is characterized in that the described composition amount of respectively writing out a prescription is that principal agent ketorolac tromethamine 0.1～10%, excipient 0.1～30%, antioxidant 0.01～2%, water for injection add to 2000ml.
6. lyophilized injectable powder as claimed in claim 1 is characterized in that described pH value regulator is one or more in sodium hydroxide, sodium bicarbonate or the sodium carbonate.
7. the described lyophilized injectable powder of claim 1 is characterized in that described preparation pH value is 7.0～8.0.
8. the described lyophilized injectable powder of claim 1 is characterized in that its preparation method is as follows:
(1) ketorolac tromethamine, excipient, antioxidant of getting recipe quantity adds in the water for injection of an amount of (water for injection of about 40% recipe quantity) and stirs, and adds the injection active carbon again, is incubated 15 minutes, filtering decarbonization;
(2) add water for injection to full dose, stir, regulate pH value to 7.0～8.0, obtain solution is through filtering with microporous membrane, and filtrate is canned after tested in cillin bottle, and the false add plug is put into freeze drying box;
(3) goods are put into the freeze dryer lyophilizing, products temperature was reduced to-45 ℃～-60 ℃ pre-freezes about 7～10 hours earlier; Temperature is reduced to below-60 ℃ begin evacuation, progressively improve temperature then to-15 ℃, vacuum drying 20～40 hours slowly heats up; Improve shelf temperature to 30 ℃ once more, kept 2～4 hours, vacuum maintains 5～10Pa, finishes the outlet of jumping a queue entirely until the qualified lyophilizing of goods moisture; Roll aluminium lid, promptly.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710113177A CN100593404C (en) | 2007-10-22 | 2007-10-22 | Ketorolac tromethamine freezing-dried power injection and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710113177A CN100593404C (en) | 2007-10-22 | 2007-10-22 | Ketorolac tromethamine freezing-dried power injection and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101167722A true CN101167722A (en) | 2008-04-30 |
| CN100593404C CN100593404C (en) | 2010-03-10 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200710113177A Active CN100593404C (en) | 2007-10-22 | 2007-10-22 | Ketorolac tromethamine freezing-dried power injection and preparation method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107137417A (en) * | 2016-03-01 | 2017-09-08 | 长春诺赛生物科技有限公司 | One kind is used to treat cachectic pharmaceutical composition and its application |
| CN108785258A (en) * | 2017-12-07 | 2018-11-13 | 武汉赛沃医药科技有限公司 | A kind of Plerixafor preparation and preparation method thereof |
| CN113679676A (en) * | 2020-05-19 | 2021-11-23 | 南京海融医药科技股份有限公司 | Pharmaceutical composition of levoketorolac and preparation method thereof |
| CN114159384A (en) * | 2021-02-07 | 2022-03-11 | 南京锐志生物医药有限公司 | Low-irritation ketorolac tromethamine injection with stable chemical properties |
-
2007
- 2007-10-22 CN CN200710113177A patent/CN100593404C/en active Active
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107137417A (en) * | 2016-03-01 | 2017-09-08 | 长春诺赛生物科技有限公司 | One kind is used to treat cachectic pharmaceutical composition and its application |
| CN108785258A (en) * | 2017-12-07 | 2018-11-13 | 武汉赛沃医药科技有限公司 | A kind of Plerixafor preparation and preparation method thereof |
| CN113679676A (en) * | 2020-05-19 | 2021-11-23 | 南京海融医药科技股份有限公司 | Pharmaceutical composition of levoketorolac and preparation method thereof |
| WO2022241983A1 (en) * | 2020-05-19 | 2022-11-24 | 南京海融医药科技股份有限公司 | Levoketorolac pharmaceutical composition and preparation method therefor |
| CN114159384A (en) * | 2021-02-07 | 2022-03-11 | 南京锐志生物医药有限公司 | Low-irritation ketorolac tromethamine injection with stable chemical properties |
| CN114159384B (en) * | 2021-02-07 | 2023-04-07 | 南京锐志生物医药有限公司 | Low-irritation ketorolac tromethamine injection with stable chemical properties |
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| Publication number | Publication date |
|---|---|
| CN100593404C (en) | 2010-03-10 |
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| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Assignee: Shandong Xinshidai Pharmaceutical Industry Co., Ltd. Assignor: Lunan Pharmaceutical Group Co., Ltd. Contract record no.: 2010370000508 Denomination of invention: Ketorolac tromethamine freezing-dried power injection and preparation method thereof Granted publication date: 20100310 License type: Exclusive License Open date: 20080430 Record date: 20100908 |
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| EC01 | Cancellation of recordation of patent licensing contract |
Assignee: Shandong Xinshidai Pharmaceutical Industry Co., Ltd. Assignor: Lunan Pharmaceutical Group Co., Ltd. Contract record no.: 2010370000508 Date of cancellation: 20121226 |
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| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model |