CN1626081A - Ropivacaine freeze-dried powder and injection preparation in use for injection and preparation method - Google Patents
Ropivacaine freeze-dried powder and injection preparation in use for injection and preparation method Download PDFInfo
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- CN1626081A CN1626081A CN 200310117329 CN200310117329A CN1626081A CN 1626081 A CN1626081 A CN 1626081A CN 200310117329 CN200310117329 CN 200310117329 CN 200310117329 A CN200310117329 A CN 200310117329A CN 1626081 A CN1626081 A CN 1626081A
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Abstract
A freeze-dried injection of ropivacaine is prepared from the ropivacaine methanesulfonate (or hydrochloride), diluent chosen from mannitol, lactose, sodium chloride, dextran, glucose, glycine, hydrolytic gelatin and povidone, isotonic regulator and pH regulator through dissolving them in the water for injection, stirring, cooling, adding the water for injection, adding activated carbon, adsorption, filtering for removing carbon, fitlering by millipore filter and freeze drying.
Description
Technical field
The present invention relates to a kind of pharmaceutical preparation, specifically is ropivacaine lyophilized injectable powder and preparation method.
Background technology
Ropivacaine (ropivacaine) is a New-type long-acting local anesthetics of amide derivatives of Astra Pharma Inc.'s listing in 1996, China's existing Ropivacaine HCL injection import of in December, 1998.Its pharmacological characteristics is that cardiac toxicity is lower, and the sensation retardance separates more obvious with the motion retardance, the vasoconstriction effect is arranged, and therefore need not to add epinephrine again, and the uterus placental blood flow is not had obvious influence.The ropivacaine of low concentration can effectively block the sensory nerve transmission and very little to the nervus motorius influence, and therefore, this medicine is particularly useful for postoperative analgesia and obstetrical analgesia.From the clinical practice of ropivacaine in recent years both at home and abroad, neonate has good tolerability to this medical instrument, and is lighter to puerpera's nervus motorius retardance.The spontaneous labor rate is higher, the obvious reduction of apparatus practise midwifery rate etc.Ropivacaine is adapted to surgical operation anesthesia, epidural anesthesia, comprises cesarotomy, the control of field block acute pain, continues epidural infusion or intermittent single medication, as postoperative or labor pains, field block.On November 2nd, 2000, FDA ratified the new indication of this medicine, can be used for surgical operation, postoperative pain control and 72 hours local anesthesia of birth process.
The preparation of ropivacaine has only dosage form of injection at present, and the poor stability of injection is thermo-labile, easily freezes, and stores and transport all inconvenient.Therefore we develop the lyophilized injectable powder of ropivacaine, have solved the defective that the ropivacaine injection exists, and are important replenishing of ropivacaine preparation.
Summary of the invention
The purpose of this invention is to provide a kind of ropivacaine lyophilized injectable powder.It has the following advantages: 1, can avoid ropivacaine rotten because of hyperpyrexia decomposes, 2, the product quality of gained is loose, dissolve the original characteristic of recovery medicinal liquid rapidly after adding water, 3, water content is low, and drying is carried out in a vacuum simultaneously, so be difficult for oxidation, good stability, the long term store that helps product, 4, opportunities for contamination reduces relatively in the production process, so the particle matter in the product lacks than additive method.
The present invention adds water by ropivacaine and additives and makes obtained by freeze drying behind the solution.The consumption that wherein prepares the water of solution is 2-100 a times of solid weight, and preferred 4-25 doubly.Preparation technology is: the water for injection that adds 40～50 ℃ in the preparation container is an amount of, adds ropivacaine and additives, stirs and makes dissolving fully, after the cooling, adds the injection water again to capacity, adds active carbon, absorption, decarbonization filtering; Gained filtrate is continued with 0.22 μ m filtering with microporous membrane, packing, lyophilization.The vacuum lyophilization condition:
1) pre-freeze: the medicine that branch is installed is put into and is carried out pre-freeze on the freeze drying box internal partition, and products temperature drops to-45 ℃, keeps promptly can carrying out sublimation drying after 2 hours.
2) sublimation drying: the vacuum in the drying baker reaches 13.33Pa (0.1mmHg) when following, closes fridge, slowly heats by the heating system under the dividing plate, and temperature is controlled at below-20 ℃, and the sublimation drying time is 12 hours.
3) dry again: the drying stage temperature is controlled at 20 ℃ again, and be 12 hours drying time again.
Described ropivacaine is treatment effective dose ropivacaine and officinal salt thereof, preferred Ropivacaine HCL and s-ropivacaine mesylate.
Described additives comprise diluent, isoosmotic adjusting agent, pH regulator agent etc.
Described diluent is selected from mannitol, lactose, sodium chloride, dextran, glucose, glycine, gelatin hydrolysate, polyvidone etc., preferred mannitol.Diluent accounts for the 10%-90% of prescription gross weight in the present invention, preferred 40%-60%.Also can not add diluent among the present invention, but the outward appearance that adds behind the diluent is more even, fine and smooth, pure white, dissolubility is better again.
Described isoosmotic adjusting agent is selected from sodium chloride, glucose, mannitol, lactose etc.The consumption of isoosmotic adjusting agent oozes or the slightly high suitable consumption that oozes for medicinal liquid being adjusted to body fluid etc.
Described pH regulator agent is selected from hydrochloric acid, sodium hydroxide etc.PH regulator agent consumption is can the pH regulator of solution is extremely near neutral, as pH4.0-7.0.
Content assaying method of the present invention is for shining high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000).
Chromatographic condition and system suitability test are filler (4.6 * 250mm, 5 μ m) with octadecylsilane chemically bonded silica; Acetonitrile～0.1mol/L ammonium sulfate (25: 75, regulate pH value to 4.0 with 20% phosphoric acid liquid) is a mobile phase; The detection wavelength is 215nm.Number of theoretical plate calculates by the s-ropivacaine mesylate peak should be not less than 5000.
The algoscopy precision takes by weighing this product and makes the solution that contains 90 μ g among every 1ml approximately with the mobile phase dissolved dilution in right amount, shakes up, as need testing solution; The s-ropivacaine mesylate reference substance that is dried to constant weight of learning from else's experience 105 ℃ is an amount of, makes the solution that contains 90 μ g among every 1ml approximately with the mobile phase dissolved dilution, in contrast product solution.Get each 20 μ l of need testing solution and reference substance solution and inject chromatograph of liquid, the record chromatogram is pressed external standard method with calculated by peak area, promptly.
Following examples are used for further specifying the present invention, rather than limitation of the scope of the invention.
Embodiment 1
Prescription: s-ropivacaine mesylate 84.5g
Mannitol 84.5g
Water for injection adds to 2000ml
Make 1000 altogether
Method for making: take by weighing recipe quantity mannitol, add 1900ml water for injection, stirring makes molten entirely.Add the recipe quantity s-ropivacaine mesylate then, gradation progressively adds, and the limit edged stirs.Add the back and continue heating (80 ℃) stirring 20 minutes, make molten entirely.Control medicinal liquid pH value is 4.0～6.0, adds water for injection to 2000ml.With 0.1% (w/v) active carbon, 50 ℃ adsorbed decarbonization filtering 15 minutes down; Gained filtrate continues with 0.22 μ m filtering with microporous membrane the clear and bright filtrate of gained to be carried out the inspection of semifinished product.The semi-finished product medicinal liquid that is up to the standards is carried out fill.Every fill 2ml.Lyophilization as follows.Seal, roll lid then.Preserve after product inspection is qualified.
The vacuum lyophilization condition:
1) pre-freeze: the medicine that branch is installed is put into and is carried out pre-freeze on the freeze drying box internal partition, and products temperature drops to-45 ℃, keeps promptly can carrying out sublimation drying after 2 hours.
2) sublimation drying: the vacuum in the drying baker reaches 13.33Pa (0.1mmHg) when following, closes fridge, slowly heats by the heating system under the dividing plate, and temperature is controlled at below-20 ℃, and the sublimation drying time is 12 hours.
3) dry again: the drying stage temperature is controlled at 20 ℃ again, and be 12 hours drying time again, and loss on drying should meet the Chinese Pharmacopoeia regulation.
One in above-mentioned sample added under the injection water 10ml dissolving room temperature place, observed the dissolving situation and measured content, the results are shown in Table 1 in 0,4,8,24 hour.
Outward appearance and content after table 1 injection ropivacaine dissolves again
| ????0h | ????4h | ????8h | ????24h | |
| Outward appearance | Dissolving is rapid, achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity |
| Content | ????100.0％ | ????99.2％ | ????98.1％ | ????98.5％ |
Embodiment 2
Prescription: s-ropivacaine mesylate 22.5g
Mannitol 22.5g
Water for injection adds to 2000ml
Make 1000 altogether
Method for making: take by weighing recipe quantity mannitol, add 1900ml water for injection, stirring makes molten entirely.Add the recipe quantity s-ropivacaine mesylate then, gradation progressively adds, and the limit edged stirs.Add the back and continue heating (80 ℃) stirring 20 minutes, make molten entirely.Control medicinal liquid pH value is 5.0～7.0, adds water for injection to 2000ml.With 0.1% (w/v) active carbon, 50 ℃ adsorbed decarbonization filtering 15 minutes down; Gained filtrate continues with 0.22 μ m filtering with microporous membrane the clear and bright filtrate of gained to be carried out the inspection of semifinished product.The semi-finished product medicinal liquid that is up to the standards is carried out fill.Every fill 2ml.Lyophilization as follows.Seal, roll lid then.Preserve after product inspection is qualified.
The vacuum lyophilization condition is with embodiment 1.
One in above-mentioned sample added under the injection water 10ml dissolving room temperature place, observed the dissolving situation and measured content, the results are shown in Table 2 in 0,4,8,24 hour.
Outward appearance and content after table 2 injection ropivacaine dissolves again
| ??0h | ????4h | ????8h | ????24h | |
| Outward appearance | Dissolving is rapid, achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity |
| Content | ??100.0％ | ????100.1％ | ????99.2％ | ????99.4％ |
Embodiment 3
Prescription: Ropivacaine HCL 75g
Mannitol 75g
Water for injection adds to 2000ml
Make 1000 altogether
Method for making: take by weighing recipe quantity mannitol, add 1900ml water for injection, stirring makes molten entirely.Add the recipe quantity Ropivacaine HCL then, gradation progressively adds, and the limit edged stirs.Add the back and continue heating (80 ℃) stirring 20 minutes, make molten entirely.Control medicinal liquid pH value is 4.0～6.0, adds water for injection to 2000ml.With 0.1% (w/v) active carbon, 50 ℃ adsorbed decarbonization filtering 15 minutes down; Gained filtrate continues with 0.22 μ m filtering with microporous membrane the clear and bright filtrate of gained to be carried out the inspection of semifinished product.The semi-finished product medicinal liquid that is up to the standards is carried out fill.Every fill 2ml.Lyophilization as follows.Seal, roll lid then.Preserve after product inspection is qualified.
The vacuum lyophilization condition is with embodiment 1.
One in above-mentioned sample added under the injection water 10ml dissolving room temperature place, observed the dissolving situation and measured content, the results are shown in Table 3 in 0,4,8,24 hour.
Outward appearance and content after table 3 injection ropivacaine dissolves again
| ?0h | ????4h | ????8h | ????24h | |
| Outward appearance | Dissolving is rapid, achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity |
| Content | ?100.0％ | ????99.1％ | ????99.3％ | ????98.0％ |
Embodiment 4
Prescription: Ropivacaine HCL 20g
Mannitol 20g
Water for injection adds to 1000ml
Make 1000 altogether
Method for making: take by weighing recipe quantity mannitol, add 900ml water for injection, stirring makes molten entirely.Add the recipe quantity Ropivacaine HCL then, gradation progressively adds, and the limit edged stirs.Add the back and continue heating (80 ℃) stirring 20 minutes, make molten entirely.Control medicinal liquid pH value is 6.0～7.0, adds water for injection to 1000ml.With 0.1% (w/v) active carbon, 50 ℃ adsorbed decarbonization filtering 15 minutes down; Gained filtrate continues with 0.22 μ m filtering with microporous membrane the clear and bright filtrate of gained to be carried out the inspection of semifinished product.The semi-finished product medicinal liquid that is up to the standards is carried out fill.Every fill 1ml.Lyophilization as follows.Seal, roll lid then.Preserve after product inspection is qualified.
The vacuum lyophilization condition is with embodiment 1.
One in above-mentioned sample added under the injection water 10ml dissolving room temperature place, observed the dissolving situation and measured content, the results are shown in Table 4 in 0,4,8,24 hour.
Outward appearance and content after table 4 injection ropivacaine dissolves again
| ????0h | ????4h | ????8h | ????24h | |
| Outward appearance | Dissolving is rapid, achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity |
| Content | ????100.0％ | ????99.9％ | ????99.7％ | ????98.6％ |
Embodiment 5
Prescription: Ropivacaine HCL 75g
Sodium chloride 75
Water for injection adds to 2000ml
Make 1000 altogether
Method for making: take by weighing recipe quantity sodium chloride, add 1900ml water for injection, stirring makes molten entirely.Add the recipe quantity Ropivacaine HCL then, gradation progressively adds, and the limit edged stirs.Add the back and continue heating (80 ℃) stirring 20 minutes, make molten entirely.Control medicinal liquid pH value is 6.0～7.0, adds water for injection to 2000ml.With 0.1% (w/v) active carbon, 50 ℃ adsorbed decarbonization filtering 15 minutes down; Gained filtrate continues with 0.22 μ m filtering with microporous membrane the clear and bright filtrate of gained to be carried out the inspection of semifinished product.The semi-finished product medicinal liquid that is up to the standards is carried out fill.Every fill 1ml.Lyophilization as follows.Seal, roll lid then.Preserve after product inspection is qualified.
The vacuum lyophilization condition is with embodiment 1.
One in above-mentioned sample added under the injection water 10ml dissolving room temperature place, observed the dissolving situation and measured content, the results are shown in Table 5 in 0,4,8,24 hour.
Outward appearance and content after table 5 injection ropivacaine dissolves again
| ????0h | ????4h | ????8h | ????24h | |
| Outward appearance | Dissolving is rapid, achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity |
| Content | ????100.0％ | ????98.9％ | ????99.1％ | ????97.3％ |
Embodiment 6
Prescription: s-ropivacaine mesylate 22.5g
Dextran 22.5
Water for injection adds to 2000ml
Make 1000 altogether
Method for making: take by weighing the recipe quantity dextran, add 1900ml water for injection, stirring makes molten entirely.Add the recipe quantity s-ropivacaine mesylate then, gradation progressively adds, and the limit edged stirs.Add the back and continue heating (80 ℃) stirring 20 minutes, make molten entirely.Control medicinal liquid pH value is 6.0～7.0, adds water for injection to 2000ml.With 0.1% (w/v) active carbon, 50 ℃ adsorbed decarbonization filtering 15 minutes down; Gained filtrate continues with 0.22 μ m filtering with microporous membrane the clear and bright filtrate of gained to be carried out the inspection of semifinished product.The semi-finished product medicinal liquid that is up to the standards is carried out fill.Every fill 1ml.Lyophilization as follows.Seal, roll lid then.Preserve after product inspection is qualified.
The vacuum lyophilization condition is with embodiment 1.
One in above-mentioned sample added under the injection water 10ml dissolving room temperature place, observed the dissolving situation and measured content, the results are shown in Table 6 in 0,4,8,24 hour.
Outward appearance and content after table 6 injection ropivacaine dissolves again
| ????0h | ????4h | ????8h | ????24h | |
| Outward appearance | Dissolving is rapid, achromatism and clarity | Achromatism and clarity | Achromatism and clarity | Achromatism and clarity |
| Content | ????100.0％ | ????99.8％ | ????98.4％ | ????97.5％ |
Claims (10)
1, a kind of freeze-dried composition of ropivacaine, comprising the treatment effective dose the ropivacaine officinal salt and can cryodesiccated additives.
2, pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically useful salt of ropivacaine is selected from s-ropivacaine mesylate and Ropivacaine HCL.
3, pharmaceutical composition as claimed in claim 1 wherein can comprise diluent, isoosmotic adjusting agent, pH regulator agent etc. by cryodesiccated additives.
4, pharmaceutical composition as claimed in claim 3, wherein diluent is selected from mannitol, lactose, sodium chloride, dextran, glucose, glycine, gelatin hydrolysate, polyvidone.
5, pharmaceutical composition as claimed in claim 3, wherein diluent is a mannitol.
6, pharmaceutical composition as claimed in claim 3, wherein diluent accounts for the 10%-90% of prescription gross weight.
7, pharmaceutical composition as claimed in claim 3, wherein diluent accounts for the 40%-60% of prescription gross weight.
8, pharmaceutical composition as claimed in claim 1, its preparation technology is: the water for injection that adds 40～50 ℃ in the preparation container is an amount of, adds ropivacaine and additives, stirring makes dissolving fully, after the cooling, adds the injection water again to capacity, add active carbon, absorption, decarbonization filtering; Gained filtrate is continued with 0.22 μ m filtering with microporous membrane, packing, lyophilization.
9, pharmaceutical composition as claimed in claim 8, the consumption that wherein prepares the water of solution are 2-100 times of solid weight.
10, pharmaceutical composition as claimed in claim 8, the consumption that wherein prepares the water of solution are 4-25 times of solid weight.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200310117329 CN1626081A (en) | 2003-12-10 | 2003-12-10 | Ropivacaine freeze-dried powder and injection preparation in use for injection and preparation method |
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| CN 200310117329 CN1626081A (en) | 2003-12-10 | 2003-12-10 | Ropivacaine freeze-dried powder and injection preparation in use for injection and preparation method |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102038651A (en) * | 2010-12-25 | 2011-05-04 | 山东新时代药业有限公司 | Ropivacaine mesylate freeze-dried powder injection |
| CN102552126A (en) * | 2012-01-20 | 2012-07-11 | 清远嘉博制药有限公司 | High-safety ropivacaine hydrochloride injection and preparation method thereof |
| CN103304471A (en) * | 2013-07-12 | 2013-09-18 | 四川省惠达药业有限公司 | Ropivacaine mesylate compound, preparation process thereof and pharmaceutical composition thereof |
| CN105816432A (en) * | 2016-03-24 | 2016-08-03 | 成都天台山制药有限公司 | Freeze-drying ropivacaine hydrochloride composition for injection and quality control method thereof |
| CN105560195B (en) * | 2016-03-24 | 2019-07-05 | 成都天台山制药有限公司 | Injection is freeze-dried Ropivacaine HCL composition |
| US10821087B2 (en) | 2015-07-24 | 2020-11-03 | Neon Laboratories Limited | Stabilized injectable emulsion of Propofol and Ketamine |
| US11224593B2 (en) | 2015-07-13 | 2022-01-18 | Neon Laboratories Limited | Hyperbaric injection solution of ropivacaine hydrochloride and process for preparation thereof |
-
2003
- 2003-12-10 CN CN 200310117329 patent/CN1626081A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102038651A (en) * | 2010-12-25 | 2011-05-04 | 山东新时代药业有限公司 | Ropivacaine mesylate freeze-dried powder injection |
| CN102038651B (en) * | 2010-12-25 | 2013-04-03 | 山东新时代药业有限公司 | Ropivacaine mesylate freeze-dried powder injection |
| CN102552126A (en) * | 2012-01-20 | 2012-07-11 | 清远嘉博制药有限公司 | High-safety ropivacaine hydrochloride injection and preparation method thereof |
| CN103304471A (en) * | 2013-07-12 | 2013-09-18 | 四川省惠达药业有限公司 | Ropivacaine mesylate compound, preparation process thereof and pharmaceutical composition thereof |
| CN103304471B (en) * | 2013-07-12 | 2015-02-04 | 四川省惠达药业有限公司 | Ropivacaine mesylate compound, preparation process thereof and pharmaceutical composition thereof |
| US11224593B2 (en) | 2015-07-13 | 2022-01-18 | Neon Laboratories Limited | Hyperbaric injection solution of ropivacaine hydrochloride and process for preparation thereof |
| US10821087B2 (en) | 2015-07-24 | 2020-11-03 | Neon Laboratories Limited | Stabilized injectable emulsion of Propofol and Ketamine |
| CN105816432A (en) * | 2016-03-24 | 2016-08-03 | 成都天台山制药有限公司 | Freeze-drying ropivacaine hydrochloride composition for injection and quality control method thereof |
| CN105560195B (en) * | 2016-03-24 | 2019-07-05 | 成都天台山制药有限公司 | Injection is freeze-dried Ropivacaine HCL composition |
| CN105816432B (en) * | 2016-03-24 | 2020-02-07 | 成都天台山制药有限公司 | Freeze-dried ropivacaine hydrochloride composition for injection and quality control method thereof |
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