CN101327193A - Lornoxicam freeze-dried injection and preparation method thereof - Google Patents
Lornoxicam freeze-dried injection and preparation method thereof Download PDFInfo
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- CN101327193A CN101327193A CNA2008101267495A CN200810126749A CN101327193A CN 101327193 A CN101327193 A CN 101327193A CN A2008101267495 A CNA2008101267495 A CN A2008101267495A CN 200810126749 A CN200810126749 A CN 200810126749A CN 101327193 A CN101327193 A CN 101327193A
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Abstract
The invention relates to lomoxicam freeze-dried powder injection and a preparation method thereof. The freeze-dried powder injection comprises omoxicam, mannite, tromethamine, EDTA and pH regulator. The dosage of the mannite is 3.5 to 8.5 g of mannite per gram of lomoxicam, and the dosage of the EDTA is 0.015 to 0.025g of EDTA per gram of lomoxicam. The invention adopts EDTA to replace EDTA-disodium salt and selects the dosages of the mannite and EDTA so that the clarity of the reconstituted obtained freeze-dried powder is greatly improved, and the formability is good; in addition, the invention adopts two pH regulators, in the process, one pH regulator is used to regulate the solution to a pH range, then the other pH regulator is used to regulate the solution to another pH range, and the freeze drying technology is controlled strictly. The prepared freeze-dried powder injection has great improvement of stability and favorable resolubity.
Description
Technical field
The present invention relates to a kind of field of pharmaceutical preparations, more specifically to a kind of Lornoxicam freeze-dried injection and preparation method thereof.
Background technology
Lornoxicam, chemical name is 6-chloro-4-hydroxy-2-methyl-3-(2-pyridine carbamyl amine)-2H-thieno [2,3-e]-1,2-thiazine-1, the 1-dichloride is the thiazide derivant, has stronger analgesia and antiinflammatory action, can be used in the acute and chronic pain that treatment is caused by inflammation, as postoperative pain, arthritis, rheumatism, soft tissue injury etc.After the intramuscular injection, lornoxicam absorbs rapidly and fully, reaches Cmax after 0.4 hour, no first pass effect.When lornoxicam share when old people's successive administration, when hepatic and renal function injure is not serious or with antacid, its pharmacokinetic parameter there was no significant difference.Be applicable to acute moderate postoperative pain and the pain relevant with acute sciatica.In treatment, during severe pain, can be used as taking medicine or succedaneum of opium kind analgesics, and toleration is better than opiates medicine.
China ratifies Nai Keming (China) company import injection lornoxicam (commodity are by name can fill in wind, and specification 8mg/ props up) and lornoxicam sheet (commodity are by name can fill in wind, and specification 8mg/ props up with 4mg/ and props up) June calendar year 2001, does not see that domestic manufacturer produces lornoxicam.
The same with most of NSAID (non-steroidal anti-inflammatory drug), lornoxicam is difficult to water-soluble, it only is 18.5ug/ml that dissolubility in water is about, this class medicinal substances is prepared into external preparation or ophthalmic preparation, especially vein use liquid preparation the time, for avoiding producing the adverse consequences in the medication process, need to adopt suitable method to increase the dissolubility of lornoxicam in water.Contain trometamol as cosolvent in the prescription in the external injection lornoxicam, but because the slow and gained medicinal liquid muddiness of trometamol dissolving lornoxicam process, and trometamol chance sodium chloride precipitates, make the lornoxicam injectable powder that contains trometamol can not be dissolved in sodium chloride injection, before injection, must adopt dedicated solvent (sterilized water for injection) dissolving in advance, carry out intravenous injection with sodium chloride injection or other infusion solutions mix homogeneously again, therefore the application method step is many, increase the chance of clinical microbiological contamination, limited its use.
Lornoxicam is a kind of very insoluble non-steroid class anti-inflammatory activity material (NSAIDs), and it is unsettled in liquid preparation, wherein produce a large amount of by-products by oxidation reaction and hydrolytic rupture, can improve the stability of this liquid preparation by lyophilization, but have very significantly turbidity by the liquid preparation that the lyophilization thing obtains.
WO9809654A discloses a kind of technical scheme that addresses the above problem, and promptly adds the clarity after an amount of EDTA-disodium salt improves the redissolution of lornoxicam dried frozen aquatic products.Yet, well-knownly be, the EDTA disodium salt can with the calcium ion complexation in the blood plasma, cause human calcium's ion to run off, have bigger side effect and potential harm.
CN1208059C discloses the medicine of a kind of lornoxicam and nicotiamide.This medicine can be the solution form, also can be the freeze-dried powder form.Add nicotiamide and not only can improve the dissolubility of salt in water of lornoxicam or lornoxicam, but also can improve the stability of solution.
200510029452.3 Chinese patent application a kind of Lornoxicam composition for injection is disclosed, comprise injection and freeze-dried powder.Said composition contains the lornoxicam of 0.86-4.3 weight portion, pharmaceutically acceptable basic amino acid, and wherein the weight ratio of lornoxicam and basic amino acid is 1: 0.5-20, the present invention also provide corresponding preparation method.Said composition dissolubility in solution is good, and stability is high.Said composition can also directly be mixed with sodium chloride injection clinically, has improved the convenience and the safety of clinical use.
" preparation of injection lornoxicam and stability study " is [referring to " preparation of injection lornoxicam and the stability study " of Fu Guiying etc., China Dispensary, 2005,16 (9): 671-673] be index with content, related substance, pH value, screening index and preparation technology; Investigate the stability of 3 batch samples, the result shows that best prescription is that lornoxicam 4.0g, propylene glycol 4.0g, mannitol 100g, sodium hydroxide 1mol/L are an amount of, with 3 batch samples of this prescription preparation under the commercially available back condition through quicken, the room temperature test that keeps sample investigates steady quality.
The inventor is when research Lornoxicam composition for injection and preparation method thereof, preparation and stability study in conjunction with disclosed prescription of WO9809654A and injection lornoxicam " preparation method of [referring to " preparation of injection lornoxicam and the stability study " of Fu Guiying etc.; China Dispensary; 2005; 16 (9): 671-673] prepares Lornoxicam freeze-dried injection; find that its dried frozen aquatic products solubility is bad; solution appearance muddiness before freezing, the clarity of lyophilized injectable powder is bad, and the mouldability of its injectable powder is also not ideal.The inventor improves its prescription and technology, prepared the dried frozen aquatic products solubility good, freeze before solution appearance clarify, the clarity of lyophilized injectable powder is good, the injection lornoxicam of good stability, thereby finished the present invention.
In view of this, special proposition the present invention.
Summary of the invention
The object of the present invention is to provide a kind of Lornoxicam freeze-dried injection.Lornoxicam freeze-dried injection good forming ability provided by the present invention, the dried frozen aquatic products solubility is good, solution appearance clarification before freezing, the clarity of lyophilized injectable powder is good, has good stability.
For achieving the above object, the present invention adopts following technical scheme:
A kind of Lornoxicam freeze-dried injection, comprise lornoxicam, mannitol and tromethane, it is characterized in that described lyophilized injectable powder also comprises EDTA, the consumption of described mannitol is 3.5～8.5 gram/gram lornoxicams, and the consumption of described EDTA is 0.015～0.025 gram/gram lornoxicam.
Lornoxicam is a kind of very insoluble non-steroid class anti-inflammatory activity material (NSAIDs), and it is unsettled in liquid preparation, wherein produce a large amount of by-products by oxidation reaction and hydrolytic rupture, can improve the stability of this liquid preparation by lyophilization, but have very significantly turbidity by the liquid preparation that the lyophilization thing obtains.W09809654A discloses a kind of disodium salt that adds a small amount of EDTA and has avoided solution muddiness by the preparation of cryodesiccated lornoxicam.The inventor finds when the prescription of research Lornoxicam freeze-dried injection, because the consumption of the disodium salt of EDTA is very little in the disclosed prescription of W09809654A, be 0.00625-0.01 milligram/milligram lornoxicam, clarity after the dried frozen aquatic products of prepared Lornoxicam freeze-dried injection redissolves is bad, can not solve the clarity problem after the lornoxicam dried frozen aquatic products redissolves well.The inventor screens its prescription again, the unexpected discovery when adopting EDTA to replace the EDTA-disodium salt, and the clarity after its dried frozen aquatic products redissolution is good.For a person skilled in the art, EDTA and EDTA-disodium salt have closely similar character, and adopting EDTA to obtain better clarity why than the EDTA-disodium salt, the inventor is also in the reason of attempting to seek wherein, but do not find proper explanations so far.
Yet well-knownly be, EDTA is the same with the EDTA-disodium salt, can with blood plasma in the calcium ion complexation, cause human calcium's ion to run off, there are bigger side effect and potential harm, therefore, the strict control of the used in amounts of EDTA, when its consumption is excessive, can there be bigger side effect and potential harm; When consumption is too small, the solubility of lornoxicam dried frozen aquatic products is not had the effect of raising.The inventor finds through a large amount of tests, when the consumption of EDTA is 0.015～0.025 gram/gram lornoxicam, solution clarification before prepared Lornoxicam freeze-dried injection not only freezes, its dried frozen aquatic products solubility is good, and human body is not existed side effect and potential harm.
In addition, the kind of filler and consumption have bigger influence to the mouldability of lyophilized injectable powder.[Cheng Jianming such as Cheng Jianming, Guo Meng. the freeze drying process research [J] of bitter a kind of reed mentioned in ancient books injectable powder. Chinese herbal medicine, 2005,36 (2): 210] in research process, inquired into the influence of different filleies and consumption thereof to the freeze-dried powder mouldability to bitter a kind of reed mentioned in ancient books injectable powder freeze-dry process.Be that the powder pin insufficient formability and the solution time of excipient is long wherein, and be that the lyophilisation additives product is easy to that molding, outward appearance are evenly loose, solution time is the shortest with HP-β-CD with lactose and mannitol.[Tang Lan such as Tang Lan, Liu Li, Xu Desheng. join attached blue or green freeze-dried powder Study on Forming [J]. Chinese patent medicine, 2005,27 (5): 512] to joining in the attached blue or green freeze-dry process research process, screened single usefulness of different additive and compatibility use influence to the lyophilizing effect, the result shows at drug level identical, under the also identical situation of additive amount, four kinds of additives of except that mannitol other all can not make this powder pin molding, and the excipient that compatibility uses has only 5% mannitol and 5%HP-β-CD can make the said preparation basic forming, but outward appearance is not as single the effective of mannitol of using; Also drug level and mannitol consumption are screened simultaneously, the result shows solid content amount＞8% o'clock, and the goods formability is better, and concentration is that 6% o'clock lyophilizing liquid is long-pending little, thickness is suitable, is beneficial to lyophilizing, and mannitol
Formed product was effective in 8% o'clock, considered to determine that finally the mannitol consumption is 10% from saving cost and few additivated angle.Yu Yuhong [Yu Yuhong. the screening of Radix Et Rhizoma Rhei freeze-dried powder molding proppant. academic nd Annual Meeting collection [C] .2000 of the 11 Chinese medicine of Sichuan Province's Chinese medicine association, 12:32] proppant in the Radix Et Rhizoma Rhei lyophilized injectable powder preparation process is screened, the result shows the prescription that lactose is arranged, its mouldability and water solublity are all not so good, when having only mannitol, though mouldability is good, and is poorly soluble, so chosen the mixing formula of manna alcohol and glucose; For further determining the consumption and the ratio of optimum proppant, the ratio of glucose and mannitol is screened, show being at 1: 3 that prescription mouldability, color and luster, the water solublity of ratio is all better; The ratio that proppant is accounted for total solid is screened simultaneously, optimum condition be proppant account for total solid 46%～60%.As seen, the kind of filler and consumption have bigger influence to the mouldability of freeze-dried powder.The inventor is on the basis of the disclosed prescription of WO9809654A, consumption to excipient mannitol screens, find when the consumption of mannitol is 3.5～8.5 gram/gram lornoxicams, the good forming ability of Lornoxicam freeze-dried injection, and from saving cost and few additivated angle consideration, the present invention can obtain better effect than WO9809654A.
Among the present invention, preferred, the consumption of described mannitol is 4.5～7 gram/gram lornoxicams, and the consumption of described EDTA is 0.018～0.025 gram/gram lornoxicam.
Preferred, the consumption of described mannitol is 5.81 gram/gram lornoxicams, and the consumption of described EDTA is 0.023 gram/gram lornoxicam.
Among the present invention, described pH regulator agent is two kinds of pH regulator agent, is sodium hydroxide solution and hydrochloric acid solution, preferred 0.5mol/L sodium hydroxide solution and 0.5mol/L hydrochloric acid solution.
In further studying, the inventor in conjunction with " preparation of injection lornoxicam and stability study " [referring to " preparation of injection lornoxicam and the stability study " of Fu Guiying etc., China Dispensary, 2005,16 (9): 671-673] disclosed technology is prepared into Lornoxicam freeze-dried injection with the disclosed prescription of WO98/09654 with it, found that when adopting a kind of pH regulator agent once pH value to be transferred to required scope, dissolved though lornoxicam is temporary, and solution also can keep clarification within a certain period of time, but As time goes on, it is muddy that its solution becomes again, being changed significantly of pH value, its lyophilized injectable powder stable bad.Among the present invention, adopt two kinds of pH regulator agent, it is a kind of sodium hydroxide solution that is, another kind is a hydrochloric acid solution, in preparation process, use a kind of pH regulator agent that solution is transferred to a pH value scope earlier, the another kind of pH regulator agent of reuse is transferred to another pH value scope with solution, and the stability of lyophilized injectable powder significantly improves like this.When adopting 0.5mol/L sodium hydroxide solution and 0.5mol/L hydrochloric acid solution, effect is significantly better than the sodium hydroxide solution and the hydrochloric acid solution of other concentration.
Another object of the present invention is to provide a kind of preparation method of Lornoxicam freeze-dried injection, it is characterized in that, described preparation method comprises the steps:
1) gets mannitol, tromethane and EDTA and put in the Agitation Tank, add water for injection to 80% amount of preparation, add lornoxicam again;
2) treat that lornoxicam adds after, regulate pH value to 10.5-11.5 with sodium hydroxide solution while stirring, the reuse hydrochloric acid solution is regulated pH value to 8.5-9.5, clear and bright solution;
3) in clear and bright solution, add active carbon, filter, in filtrate, add adding to the full amount of water for injection, get solution;
4) solution with the step 3) gained filters, and divides to be filled in the cillin bottle, jumps a queue, and puts into freeze dryer and carries out lyophilization.
The present invention replaces the EDTA-disodium salt with EDTA on the basis of the disclosed prescription of WO98/09654, and in conjunction with " preparation of injection lornoxicam and stability study " [referring to " preparation of injection lornoxicam and the stability study " of Fu Guiying etc., China Dispensary, 2005,16 (9): 671-673] disclosed technology, its technology is improved, be specially in the preparation method and regulate pH value to 11.0 with sodium hydroxide solution earlier, the reuse hydrochloric acid solution is regulated pH value to 9.0, lornoxicam can be dissolved in the water fully, the outward appearance of solution clarification before promptly freezing, the solubility of dried frozen aquatic products is significantly improved, and its stability is significantly improved.
In the above-mentioned preparation method, the solution temperature when adding lornoxicam in the step 1) in the Agitation Tank is controlled between 2-6 ℃.Lornoxicam is a kind of very insoluble non-steroid class anti-inflammatory activity material (NSAIDs), and it is unsettled in liquid preparation, wherein produces a large amount of by-products by oxidation reaction and hydrolytic rupture.Want to solve the stable problem of Lornoxicam freeze-dried injection, not only need rationally to set prescription,, more need precisely to control producing each stage process parameter at the unsettled a plurality of factors of lornoxicam.The present invention is directed to lornoxicam unsettled characteristics in liquid preparation, in process for preparation, make a stable cryogenic solution environmental earlier, guaranteed lornoxicam stablizing from be formulated into the whole process of fill.
In the above-mentioned preparation method, being filtered into described in the step 3) adds the active carbon stirring and adsorbing after 30 minutes, with 0.45 μ m filtering with microporous membrane; Being filtered into described in the step 4) with 0.22 μ m filtering with microporous membrane.
In the above-mentioned preparation method, step 2) sodium hydroxide solution described in is the 0.5mol/L sodium hydroxide solution, and described hydrochloric acid solution is the 0.5mol/L hydrochloric acid solution; Active carbon described in the step 3) is 0.05% medicinal carbon.
Preferred manufacturing procedure is: get mannitol, tromethane and EDTA and put in the Agitation Tank, add injection water to 80% amount of preparation, cooling and insulation add lornoxicam between 2-6 ℃; Regulating pH value to 11.0 with the 0.5mol/L sodium hydroxide solution while stirring makes it be dissolved into clear and bright solution fully; Reuse 0.5mol/L hydrochloric acid solution is regulated pH value to 9.0, medicinal carbon stirring and adsorbing with 0.05% 30 minutes, through 0.45 μ m filtering with microporous membrane carbon removal, add and add to the full amount of water for injection, solution filters through 0.22 μ m microporous filter membrane again, divide to be filled in the injection cillin bottle, the false add plug is put into freeze dryer and is carried out lyophilization.
In the above-mentioned preparation method, described lyophilization is divided into pre-freeze, distillation and secondary distillation three phases, pre-freeze stage: the temperature inside the box is reduced to-35 ℃ to-45 ℃, kept 3-5 hour; Sublimation stage: when the temperature of condenser reached below-40 ℃, to the whole system evacuation, pressure was arranged between the 8-25 handkerchief, and temperature slowly rises to 1-3 ℃, keeps 15-19 hour; Secondary sublimation stage: temperature is risen to 20-30 ℃, kept 5-15 hour.
In the above-mentioned preparation method, it is 10-45 hour that temperature rises to 1-3 ℃ of used time, and it is 5-12 hour that temperature rises to 20-30 ℃ of used time.
Preferably, the pre-freeze stage of the present invention is reduced to the temperature inside the box-45 ℃; Sublimation stage rises to 2 ℃ with temperature; The secondary sublimation stage rises to 25 ℃ with temperature.
Process conditions in the inventive method play crucial effects to the quality that guarantees product.Particularly the control of pre-freeze, the temperature and time when distilling has effectively improved the crystalline state of crude drug and the aeration of manufactured goods.Simultaneously steam can be appeared smoothly, make the full not atrophy of profile of product, and color and luster homogeneous, fully dry, and kept medicine good stable and porous.Manufactured goods can recover the preceding state of lyophilizing rapidly after adding water.
In addition, the present invention is directed to lornoxicam unsettled characteristics in liquid preparation, in process for preparation, make stable alkalescence and cryogenic solution environmental earlier, add lornoxicam again, guaranteed lornoxicam stablizing from be formulated into the whole process of fill.Ensuing freeze-drying process, adopt distinctive low-temperature quick-freezing, sublimation drying stage by stage heats up, the freeze drying process of parsing-desiccation under the lower temperature, the lyophilizing of gained lornoxicam is shaped good, invariant color, obtained the good crystal formation of the more conventional lyophilizing crystallization of stability, water content is low, and favourable stable transportation and storage have thoroughly solved the stable problem of Lornoxicam freeze-dried injection.In a word, the present invention has improved the stability of Lornoxicam freeze-dried injection in preparation process greatly, and the Lornoxicam freeze-dried injection impurity (its related substances) of preparation gained is lower, and the quality stable homogeneous is stored and transport convenient.Preparation technology of the present invention is simple, convenient feasible, good reproducibility is easy to realize industrialized great production, and freeze-drying time is short, percent defective (variable color) is low, lamp inspection inspection rejects difficulty is low, saves manpower, short production cycle, lower percent defective and lower human cost, production cost is reduced significantly, can produce considerable economic and social benefit.
Specifically, preparation method of the present invention comprises the steps:
1. the cleaning of cillin bottle, sterilization
Bottle (low Pyrex control injection bottle) is removed through outer package, bottle is put into the wash bottle transfer dish, power-on, bottle is reached in the bottle washer, be delivered to Drying tunnel with 50 ℃～60 ℃ purified water, water for injection after cleaning cleaning, through the preheating zone drying, the 350 ℃ of sterilizations in high-temperature region, sterilization in 15 minutes, the low-temperature space cooling, it is standby to enter the fill chamber.
2. the cleaning of butyl rubber bung, sterilization
Plug is put into rubber cork rinsing machine, extremely clean with the water for injection rinsing; Move in the efficient plug sterilizing oven of clamshell doors, carry out 120 ℃, 2 hours drying, sterilization, cooling, it is standby to enter the fill chamber.
3. the cleaning of plastic-aluminum composite cover, sterilization
Aluminium-plastic cap is removed through outer package, and after being conveyed into the aluminium-plastic cap cleaning machine and cleaning, baking is 120 minutes in 120 ℃ of baking ovens, and cooling is standby.
4. precision takes by weighing mannitol, tromethane and EDTA and puts in the Agitation Tank, adds water for injection to 80% amount of preparation, and cooling also insulation adds lornoxicam between 2-6 ℃; After treating that lornoxicam adds, regulate pH value to 10.5-11.5 with the sodium hydroxide solution of 0.5mol/l while stirring, the hydrochloric acid solution of reuse 0.5mol/l is regulated pH value to 8.5-9.5, gets clear and bright solution; The medicinal carbon stirring and adsorbing of adding 0.05% in clear and bright solution 30 minutes, through the carbon removal of 0.45um filtering with microporous membrane, filtrate is in pipeline input dilute preparing tank, add to the full amount of water for injection, fully stir and made the solution mix homogeneously in 20 minutes, the solution for preparing carries out the end-filtration degerming through the microporous filter membrane of 0.22um, filtrate is fed through in the basin standby through pipeline, quality inspection personnel extracts solution, carry out clarity, content, pH value, bacterial endotoxin mensuration, filtrate after qualified changes canned over to, and is standby.
5. fill
The operator will detect qualified solution and insert, and adjust loading amount and false add plug quality by detecting intermediate amounts, and fill is in low Pyrex control injection bottle, every loading amount of self check in 15 minutes and false add plug quality situation respectively.
6. lyophilization
The fill certified products are put into material disc in time put on the dividing plate of freeze drying box, divide three phases to carry out lyophilization, the pre-freeze stage: the temperature inside the box to be reduced to-35 ℃ to-45 ℃, kept 3-5 hour; Sublimation stage: when the temperature of condenser reached below-40 ℃, to the whole system evacuation, pressure was arranged between the 8-25 handkerchief, and temperature slowly rises to 1-3 ℃, keeps 15-19 hour; Secondary sublimation stage: temperature is risen to 20-30 ℃, kept 5-15 hour; Press full plug then, outlet.
7. roll lid
The operator inserts the good semi-finished product of lyophilizing and carries out gland, observes at any time to prick to cover situation, chooses defective work, certified products is put into the handing-over bucket put to the handing-over window.
8. lamp inspection
The operator inserts to roll and builds semi-finished product, chooses to detect defective works such as rolling lid scratches, distortion, spray bottle tomography, atrophy, and certified products are put to the handing-over window.
9. labeling, packing and warehouse-in
Qualified semi-finished product are inserted, carry out labeling and packing after audit semi-finished product, label, packing box are errorless, packaged finished product is warehousing after passing after testing.
Compared with prior art, the present invention has following advantage:
(1) the present invention adopts the EDTA-disodium salt in the disclosed prescription of EDTA replacement WO98/09654, and the consumption of EDTA and mannitol screened, the clarity after prepared dried frozen aquatic products redissolves has obtained tangible improvement, and clarity is good, the good forming ability of lyophilized injectable powder, favorable solubility;
(2) in the Lornoxicam freeze-dried injection prescription provided by the present invention, adopt two kinds of pH regulator agent, it is a kind of sodium hydroxide solution that is, another kind is a hydrochloric acid solution, in preparation process, use a kind of pH regulator agent that solution is transferred to a pH value scope earlier, the another kind of pH regulator agent of reuse is transferred to another pH value scope with solution, and the stability of lyophilized injectable powder significantly improves like this;
(3) among the present invention, the consumption of EDTA has been carried out strict control, solution clarification before prepared Lornoxicam freeze-dried injection not only freezes, its dried frozen aquatic products solubility is good, and human body is not existed side effect and potential harm;
(4) preparation method technology provided by the present invention is simple, and the preceding solution appearance of freezing of prepared Lornoxicam freeze-dried injection is clarified, and the solubility of dried frozen aquatic products is good, and clarity meets the requirements, and its stability obviously is better than prior art.
The specific embodiment
Below be the specific embodiment of the present invention, described embodiment is in order to further describe the present invention, rather than restriction the present invention.
Embodiment 1
(1) prescription:
Lornoxicam 8.6g
Mannitol 50.0g
Tromethane 12.0g
EDTA 0.2g
Activated carbon 1.0g
Water for injection 2000ml
0.5mol/l sodium hydroxide solution an amount of (pH regulator agent)
0.5mol/l hydrochloric acid solution an amount of (pH regulator agent)
Make 1000 bottles
(2) preparation technology:
1) get mannitol, tromethane and EDTA and put in the Agitation Tank, add water for injection to 80% amount of preparation, add lornoxicam again, the solution temperature when adding lornoxicam in the Agitation Tank is controlled at 4 ℃;
2) treat that lornoxicam adds after, regulate pH value to 10.5 with sodium hydroxide solution while stirring, the reuse hydrochloric acid solution is regulated pH value to 8.5, clear and bright solution;
3) add active carbon in clear and bright solution, stirring and adsorbing with filtering, added adding to the full amount of water for injection after 30 minutes in filtrate, get solution;
4) solution with the step 3) gained filters, and divides to be filled in the cillin bottle, jumps a queue, and puts into freeze dryer and carries out lyophilization, and wherein lyophilization is divided into pre-freeze, distillation and secondary distillation three phases, pre-freeze stage: the temperature inside the box is reduced to-35 ℃, kept 3 hours; Sublimation stage: when the temperature of condenser reached below-40 ℃, to the whole system evacuation, pressure was arranged between 8 handkerchiefs, and temperature slowly rises to 1 ℃, keeps 15 hours; Secondary sublimation stage: temperature is risen to 20 ℃, kept 5 hours.
Embodiment 2
(1) prescription:
Lornoxicam 8.6g
Mannitol 30.1g
Tromethane 12.0g
EDTA 0.129g
Activated carbon 1.0g
Water for injection 2000ml
0.5mol/l sodium hydroxide solution an amount of (pH regulator agent)
0.5mol/l hydrochloric acid solution an amount of (pH regulator agent)
Make 1000 bottles
(2) preparation technology:
1) get mannitol, tromethane and EDTA and put in the Agitation Tank, add water for injection to 80% amount of preparation, add lornoxicam again, the solution temperature when adding lornoxicam in the Agitation Tank is controlled at 2 ℃;
2) treat that lornoxicam adds after, regulate pH value to 11.5 with sodium hydroxide solution while stirring, the reuse hydrochloric acid solution is regulated pH value to 9.5, clear and bright solution;
3) in clear and bright solution, add active carbon, filter, in filtrate, add adding to the full amount of water for injection, get solution;
4) solution with the step 3) gained filters, and divides to be filled in the cillin bottle, jumps a queue, and puts into freeze dryer and carries out lyophilization, and wherein lyophilization is divided into pre-freeze, distillation and secondary distillation three phases, pre-freeze stage: the temperature inside the box is reduced to-45 ℃, kept 5 hours; Sublimation stage: when the temperature of condenser reached below-40 ℃, to the whole system evacuation, pressure was arranged between 25 handkerchiefs, and temperature slowly rises to 3 ℃, keeps 19 hours; Secondary sublimation stage: temperature is risen to 30 ℃, kept 15 hours.
Embodiment 3
(1) prescription:
Lornoxicam 8.6g
Mannitol 73.1g
Tromethane 12.0g
EDTA 0.215g
Activated carbon 1.0g
Water for injection 2000ml
0.5mol/l sodium hydroxide solution an amount of (pH regulator agent)
0.5mol/l hydrochloric acid solution an amount of (pH regulator agent)
Make 1000 bottles
(2) preparation technology:
1) get mannitol, tromethane and EDTA and put in the Agitation Tank, add water for injection to 80% amount of preparation, add lornoxicam again, the solution temperature when adding lornoxicam in the Agitation Tank is controlled at 6 ℃;
2) treat that lornoxicam adds after, regulate pH value to 11 with sodium hydroxide solution while stirring, the reuse hydrochloric acid solution is regulated pH value to 9.0, clear and bright solution;
3) in clear and bright solution, add active carbon, filter, in filtrate, add adding to the full amount of water for injection, get solution;
4) solution with the step 3) gained filters, and divides to be filled in the cillin bottle, jumps a queue, and puts into freeze dryer and carries out lyophilization, and wherein lyophilization is divided into pre-freeze, distillation and secondary distillation three phases, pre-freeze stage: the temperature inside the box is reduced to-40 ℃, kept 4 hours; Sublimation stage: when the temperature of condenser reached below-40 ℃, to the whole system evacuation, pressure was arranged between 20 handkerchiefs, and temperature slowly rises to 2 ℃, keeps 18 hours; Secondary sublimation stage: temperature is risen to 25 ℃, kept 10 hours.
Embodiment 4
(1) prescription:
Lornoxicam 8.6g
Mannitol 38.7g
Tromethane 12.0g
EDTA 0.155g
Activated carbon 1.0g
Water for injection 2000ml
0.5mol/l sodium hydroxide solution an amount of (pH regulator agent)
0.5mol/l hydrochloric acid solution an amount of (pH regulator agent)
Make 1000 bottles
(2) preparation technology:
1) get mannitol, tromethane and EDTA and put in the Agitation Tank, add water for injection to 80% amount of preparation, add lornoxicam again, the solution temperature when adding lornoxicam in the Agitation Tank is controlled at 5 ℃;
2) treat that lornoxicam adds after, regulate pH value to 10.8 with sodium hydroxide solution while stirring, the reuse hydrochloric acid solution is regulated pH value to 8.7, clear and bright solution;
3) in clear and bright solution, add active carbon, filter, in filtrate, add adding to the full amount of water for injection, get solution;
4) solution with the step 3) gained filters, and divides to be filled in the cillin bottle, jumps a queue, and puts into freeze dryer and carries out lyophilization, and wherein lyophilization is divided into pre-freeze, distillation and secondary distillation three phases, pre-freeze stage: the temperature inside the box is reduced to-38 ℃, kept 3.5 hours; Sublimation stage: when the temperature of condenser reached below-40 ℃, to the whole system evacuation, pressure was arranged between 15 handkerchiefs, and temperature slowly rises to 1.5 ℃, keeps 18 hours; Secondary sublimation stage: temperature is risen to 23 ℃, kept 8 hours.
Embodiment 5
(1) prescription:
Lornoxicam 8.6g
Mannitol 60.2g
Tromethane 12.0g
EDTA 0.21g
Activated carbon 1.0g
Water for injection 2000ml
0.5mol/l sodium hydroxide solution an amount of (pH regulator agent)
0.5mol/l hydrochloric acid solution an amount of (pH regulator agent)
Make 1000 bottles
(2) preparation technology:
1) get mannitol, tromethane and EDTA and put in the Agitation Tank, add water for injection to 80% amount of preparation, add lornoxicam again, the solution temperature when adding lornoxicam in the Agitation Tank is controlled at 3 ℃;
2) treat that lornoxicam adds after, regulate pH value to 10.7 with sodium hydroxide solution while stirring, the reuse hydrochloric acid solution is regulated pH value to 8.9, clear and bright solution;
3) in clear and bright solution, add active carbon, filter, in filtrate, add adding to the full amount of water for injection, get solution;
4) solution with the step 3) gained filters, and divides to be filled in the cillin bottle, jumps a queue, and puts into freeze dryer and carries out lyophilization, and wherein lyophilization is divided into pre-freeze, distillation and secondary distillation three phases, pre-freeze stage: the temperature inside the box is reduced to-39 ℃, kept 4.5 hours; Sublimation stage: when the temperature of condenser reached below-40 ℃, to the whole system evacuation, pressure was arranged between 18 handkerchiefs, and temperature slowly rises to 2.5 ℃, keeps 16 hours; Secondary sublimation stage: temperature is risen to 26 ℃, kept 13 hours.
[comparative example] stability test relatively
Formulation and technology according to the embodiment of the invention 1 prepares 3 batch samples (080101,080102,080103), again according to " preparation of injection lornoxicam and stability study " [referring to " preparation of injection lornoxicam and the stability study " of Fu Guiying etc., China Dispensary, 2005,16 (9): 671-673] formulation and technology prepares 3 batch samples (080104,080105,080106), will carry out influence factor's test, accelerated test and room temperature reserved sample observing respectively by 6 prepared batch samples of above-mentioned two kinds of methods.
(1) influence factor's test (strong illumination and hot test)
From the prepared sample of above-mentioned two kinds of formulation and technologies, respectively take out one, removing outer package is placed in the surface plate, under (4500 ± 500) Lx illuminance, place 60 ℃ of calorstats to place 10d respectively, respectively at 5d, 10d sampling and measuring, and with 0d result relatively, investigate the indexs such as character, clarity, pH value, related substance and content of the prepared sample of above-mentioned two kinds of formulation and technologies respectively, the result sees table 1 and table 2 for details.
Table 1, exposure experiments to light result
(annotate: A and B are respectively according to the embodiment of the invention 1 and " preparation of injection lornoxicam and stability study " [referring to " preparation of injection lornoxicam and the stability study " of Fu Guiying etc. in the table, China Dispensary, the injection lornoxicam of method preparation 2005,16 (9): 671-673].)
Table 2,60 ℃ of hot test results
(annotate: A and B are respectively according to the embodiment of the invention 1 and " preparation of injection lornoxicam and stability study " [referring to " preparation of injection lornoxicam and the stability study " of Fu Guiying etc. in the table, China Dispensary, the injection lornoxicam of method preparation 2005,16 (9): 671-673].)
(2) accelerated test
It is to place 6mo under 75% condition that 6 batch samples (080101,080102,080103,080104,080105,080106) of simulation listing packing are placed 40 ℃, relative humidity, the sampling and measuring respectively respectively at 1,2,3, during 6mo, and during with 0mo sample data relatively, the result sees table 3 for details.
Table 3, accelerated test result
| Lot number | Time (mo) | Outward appearance | Clarity | pH | Related substance (%) | Content (%) |
| 080101 | 0 | Yellow loose block | Up to specification | 8.68 | 0.51 | 103.1 |
| 1 | Yellow loose block | Up to specification | 8.60 | 0.58 | 103.5 | |
| 2 | Yellow loose block | Up to specification | 8.64 | 0.56 | 102.9 | |
| 3 | Yellow loose block | Up to specification | 8.61 | 0.60 | 103.2 | |
| 6 | Yellow loose block | Up to specification | 8.67 | 0.56 | 102.8 | |
| 080102 | 0 | Yellow loose block | Up to specification | 8.75 | 0.61 | 101.7 |
| 1 | Yellow loose block | Up to specification | 8.80 | 0.60 | 101.6 | |
| 2 | Yellow loose block | Up to specification | 8.74 | 0.65 | 101.0 | |
| 3 | Yellow loose block | Up to specification | 8.81 | 0.68 | 102.2 | |
| 6 | Yellow loose block | Up to specification | 8.79 | 0.66 | 101.3 | |
| 080103 | 0 | Yellow loose block | Up to specification | 8.67 | 0.67 | 99.8 |
| 1 | Yellow loose block | Up to specification | 8.71 | 0.68 | 99.7 | |
| 2 | Yellow loose block | Up to specification | 8.66 | 0.63 | 99.5 | |
| 3 | Yellow loose block | Up to specification | 8.73 | 0.65 | 99.3 | |
| 6 | Yellow loose block | Up to specification | 8.70 | 0.62 | 99.2 | |
| 080104 | 0 | Yellow loose block | Up to specification | 8.98 | 0.49 | 104.1 |
| 1 | Yellow loose block | Up to specification | 8.96 | 0.48 | 103.9 | |
| 2 | Yellow loose block | Up to specification | 8.97 | 0.46 | 103.7 | |
| 3 | Yellow loose block | Up to specification | 8.95 | 0.47 | 103.8 | |
| 6 | Yellow loose block | Up to specification | 8.98 | 0.48 | 103.9 | |
| 080105 | 0 | Yellow loose block | Up to specification | 8.97 | 0.48 | 104.2 |
| 1 | Yellow loose block | Up to specification | 8.96 | 0.46 | 104.1 | |
| 2 | Yellow loose block | Up to specification | 8.95 | 0.47 | 104.0 | |
| 3 | Yellow loose block | Up to specification | 8.96 | 0.49 | 103.8 | |
| 6 | Yellow loose block | Up to specification | 8.94 | 0.50 | 103.9 | |
| 080106 | 0 | Yellow loose block | Up to specification | 8.98 | 0.47 | 103.8 |
| 1 | Yellow loose block | Up to specification | 8.96 | 0.48 | 103.7 | |
| 2 | Yellow loose block | Up to specification | 8.97 | 0.49 | 104.1 | |
| 3 | Yellow loose block | Up to specification | 8.95 | 0.50 | 103.6 | |
| 6 | Yellow loose block | Up to specification | 8.96 | 0.48 | 104.0 |
(2) the room temperature test that keeps sample
With 6 batch samples (080101,080102,080103,080104,080105,080106) of simulation listing packing place 3,6,9 at ambient temperature, period sampling measuring behind the 12mo, and during with 0mo sample data relatively, the result sees table 4 for details.
Table 4, the room temperature result of the test that keeps sample
| Lot number | Time (mo) | Outward appearance | Clarity | pH | Related substance (%) | Content (%) |
| 080101 | 0 | Yellow loose block | Up to specification | 8.68 | 0.51 | 103.1 |
| 3 | Yellow loose block | Up to specification | 8.71 | 0.55 | 103.0 | |
| 6 | Yellow loose block | Up to specification | 8.65 | 0.58 | 103.4 | |
| 9 | Yellow loose block | Up to specification | 8.73 | 0.60 | 102.9 | |
| 12 | Yellow loose block | Up to specification | 8.70 | 0.61 | 102.6 | |
| 080102 | 0 | Yellow loose block | Up to specification | 8.75 | 0.61 | 101.7 |
| 3 | Yellow loose block | Up to specification | 8.76 | 0.63 | 101.3 | |
| 6 | Yellow loose block | Up to specification | 8.75 | 0.64 | 101.5 | |
| 9 | Yellow loose block | Up to specification | 8.83 | 0.67 | 101.0 | |
| 12 | Yellow loose block | Up to specification | 8.81 | 0.69 | 100.6 | |
| 080103 | 0 | Yellow loose block | Up to specification | 8.67 | 0.67 | 99.8 |
| 3 | Yellow loose block | Up to specification | 8.63 | 0.67 | 99.6 | |
| 6 | Yellow loose block | Up to specification | 8.69 | 0.73 | 99.1 |
| 9 | Yellow loose block | Up to specification | 8.70 | 0.72 | 99.5 | |
| 12 | Yellow loose block | Up to specification | 8.71 | 0.75 | 98.4 | |
| 080104 | 0 | Yellow loose block | Up to specification | 8.98 | 0.49 | 104.2 |
| 3 | Yellow loose block | Up to specification | 8.97 | 0.46 | 104.1 | |
| 6 | Yellow loose block | Up to specification | 8.95 | 0.47 | 103.9 | |
| 9 | Yellow loose block | Up to specification | 8.96 | 0.45 | 103.8 | |
| 12 | Yellow loose block | Up to specification | 8.96 | 0.48 | 103.7 | |
| 080105 | 0 | Yellow loose block | Up to specification | 8.97 | 0.45 | 104.3 |
| 3 | Yellow loose block | Up to specification | 8.95 | 0.43 | 104.5 | |
| 6 | Yellow loose block | Up to specification | 8.96 | 0.46 | 104.2 | |
| 9 | Yellow loose block | Up to specification | 8.97 | 0.47 | 103.9 | |
| 12 | Yellow loose block | Up to specification | 8.98 | 0.48 | 103.8 | |
| 080106 | 0 | Yellow loose block | Up to specification | 8.97 | 0.49 | 103.9 |
| 3 | Yellow loose block | Up to specification | 8.96 | 0.46 | 104.0 | |
| 6 | Yellow loose block | Up to specification | 8.97 | 0.48 | 104.1 | |
| 9 | Yellow loose block | Up to specification | 8.98 | 0.47 | 103.8 | |
| 12 | Yellow loose block | Up to specification | 8.95 | 0.45 | 104.2 |
As can be seen from the above table, product of the present invention is better than the stability of the product of prior art.
Claims (10)
1, a kind of Lornoxicam freeze-dried injection, comprise lornoxicam, mannitol and tromethane, it is characterized in that, described lyophilized injectable powder also comprises EDTA and pH regulator agent, the consumption of described mannitol is 3.5～8.5 gram/gram lornoxicams, and the consumption of described EDTA is 0.015～0.025 gram/gram lornoxicam.
2, Lornoxicam freeze-dried injection according to claim 1 is characterized in that, the consumption of described mannitol is 4.5～7 gram/gram lornoxicams, and the consumption of described EDTA is 0.018～0.025 gram/gram lornoxicam.
3, Lornoxicam freeze-dried injection according to claim 2 is characterized in that, the consumption of described mannitol is 5.81 gram/gram lornoxicams, and the consumption of described EDTA is 0.023 gram/gram lornoxicam.
4, the preparation method of the described Lornoxicam freeze-dried injection of claim 1 is characterized in that, described preparation method comprises the steps:
1) gets mannitol, tromethane and EDTA and put in the Agitation Tank, add water for injection to 80% amount of preparation, add lornoxicam again;
2) treat that lornoxicam adds after, regulate pH value to 10.5-11.5 with sodium hydroxide solution while stirring, the reuse hydrochloric acid solution is regulated pH value to 8.5-9.5, clear and bright solution;
3) in clear and bright solution, add active carbon, filter, in filtrate, add adding to the full amount of water for injection, get solution;
4) solution with the step 3) gained filters, and divides to be filled in the injection cillin bottle, and the false add plug is put into freeze dryer and carried out lyophilization.
5, the preparation method of Lornoxicam freeze-dried injection according to claim 4 is characterized in that, the solution temperature when adding lornoxicam in the step 1) in the Agitation Tank is controlled between 2-6 ℃.
6, the preparation method of Lornoxicam freeze-dried injection according to claim 5 is characterized in that, being filtered into described in the step 3) adds the active carbon stirring and adsorbing after 30 minutes, with 0.45 μ m filtering with microporous membrane; Being filtered into described in the step 4) with 0.22 μ m filtering with microporous membrane.
7, the preparation method of Lornoxicam freeze-dried injection according to claim 6 is characterized in that step 2) described in sodium hydroxide solution be the 0.5mol/L sodium hydroxide solution, described hydrochloric acid solution is the 0.5mol/L hydrochloric acid solution; Active carbon described in the step 3) is 0.05% medicinal carbon.
8, according to the preparation method of any described Lornoxicam freeze-dried injection of claim 4-7, it is characterized in that, described lyophilization is divided into pre-freeze, distillation and secondary distillation three phases, pre-freeze stage: the temperature inside the box is reduced to-35 ℃ to-45 ℃, kept 3-5 hour; Sublimation stage: when the temperature of condenser reached below-40 ℃, to the whole system evacuation, pressure was arranged between the 8-25 handkerchief, and temperature slowly rises to 1-3 ℃, keeps 15-19 hour; Secondary sublimation stage: temperature is risen to 20-30 ℃, kept 5-15 hour.
9, the preparation method of Lornoxicam freeze-dried injection according to claim 8 is characterized in that, it is 10-45 hour that temperature rises to 1-3 ℃ of used time, and it is 5-12 hour that temperature rises to 20-30 ℃ of used time.
10, the preparation method of Lornoxicam freeze-dried injection according to claim 9 is characterized in that, the pre-freeze stage is reduced to the temperature inside the box-45 ℃; Sublimation stage rises to 2 ℃ with temperature; The secondary sublimation stage rises to 25 ℃ with temperature.
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Address after: 570216 No. 8 factory building, Haikou Free Trade Zone, Nanhai Avenue, Hainan, Haikou Patentee after: HAINAN JINRUI PHARMACEUTICAL Co.,Ltd. Address before: 570216 No. 8 factory building, Haikou Free Trade Zone, Nanhai Avenue, Hainan, Haikou Patentee before: HAINAN JINRUI PHARMACEUTICAL Co.,Ltd. |
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| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A Lornoxicam freeze-dried powder injection and its preparation method Effective date of registration: 20230920 Granted publication date: 20091118 Pledgee: Qingdao Qishun Investment Management Co.,Ltd. Pledgor: HAINAN JINRUI PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980057940 |