CN105213330A - A kind of Parecoxib sodium freeze-dried preparation and preparation method thereof - Google Patents
A kind of Parecoxib sodium freeze-dried preparation and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a kind of stable injection Parecoxib sodium pharmaceutical composition, this pharmaceutical composition specifically comprises principal agent Parecoxib Sodium, freeze drying protectant glycine, the lyophilisation additives tert-butyl alcohol, pH adjusting agent sodium hydrogen phosphate and phosphoric acid.Production technology of the present invention is feasible, stable and controllable for quality, and skin irritation is little, ingeniously in freeze-dry process control the time well, temperature, vacuum, the multinomial key parameter such as the speed of heating and cooling, for clinical application provides rationally effective preparation prescription and preparation process scheme, is easy to realize industrialization.
Description
Technical field
The invention belongs to technical field of medicine, relate to a kind of Parecoxib sodium freeze-dried preparation and preparation method thereof particularly.
Background technology
Parecoxib Sodium, chemistry N-[[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonyl] propionamide sodium salt by name, molecular formula C19H17N2O4SNa, molecular weight 392.41.Indication is the short term therapy for postoperative pain, and specification is 20mg or 40mg (in Parecoxib).
Parecoxib Sodium is a kind of Cyclooxygenase-2 Inhibitor of high selectivity, belongs to the former times dry goods analgesic in anti-arthritic, can be used for the short term therapy of postoperative pain.Parecoxib Sodium is rapid-action and analgesic activity is lasting.The effect of the analgesic effect of Parecoxib 40mg and intramuscular injection ketorolac 60mg or quiet note 30mg is similar.Parecoxib has the selectivity of height to COX-2, and only have faint selectivity to COX-1, therefore have good safety, its gastrointestinal ulceration incidence rate is significantly lower than traditional NSAIDs.Parecoxib is penetrated with cox 2 inhibitor as global first injection, analgesia effect is good, possess simultaneously and suppress super quick, eradicate the unique advantage of pain, agree with pentazocine pattern, promote pentazocine theory, meet clinical demand, be expected to become postoperative basic medication, make more patient enjoy painless surgical operation, thus more preferably select for Postoperative Analgesia After provides.
Parecoxib Sodium is easily hydrolyzed to Valdecoxib, and dissolves poor in Valdecoxib water, makes injection and brings difficulty.And Parecoxib Sodium is as the prodrug of Valdecoxib, have higher solubility, in order to avoid it is converted into Valdecoxib rapidly in aqueous, Parecoxib Sodium is mainly made into lyophilized formulations.In drug production process, injection Parecoxib sodium freeze-dried preparation strictly need control moisture, avoids causing obvious hydrolysis, affects product stability.
As everyone knows, Parecoxib Sodium drug administration by injection effective dose is low, when drug level is low time, can bring formability problems, and usually can be considered to needs to add excipient, and this can increase preparation difficulty and cost, more may bring potential safety hazard simultaneously.The present inventor finds in experimental study, and Parecoxib Sodium and conventional freeze drying protectant, such as mannitol, also exists incompatibility.In addition, Parecoxib Sodium is easy to hydrolysis, and water-content indicator will be the key factor affecting its stability.
In the prior art, the appearance forming of Parecoxib Sodium and problem is during preparation is produced the difficult point such as water content is higher.Because principal agent dosage is little, concentration is low, and the rigidity of freeze-drying prods sublimation stage is lower, if baking temperature is too high, the rigidity of solid matrix is not enough to maintain alveolate texture, and the solid content matrix of walls in hole will be subsided; And temperature is too low, water content is higher, affects product stability.Therefore find suitable preparation prescription and technique, especially in freeze-dry process to temperature, the key factor such as vacuum and warming and cooling rate control, be solve prior art in-problem key.
Summary of the invention
The invention provides a kind of prescription of lyophilized formulations of Parecoxib Sodium of novelty, and the freeze-dry process by improveing, solve the problems existed in prior art.The Parecoxib sodium freeze-dried preparation outward appearance that the present invention obtains is good, and water content is low, increases it and deposits the stability of hiding and applying.
The Parecoxib sodium pharmaceutical composition of a kind of stable injection provided by the invention, includes Parecoxib Sodium, sodium hydrogen phosphate, freeze drying protectant, lyophilisation additives, pH adjusting agent; It is characterized in that, freeze drying protectant is selected from glycine, and lyophilisation additives is selected from the tert-butyl alcohol.
Glycine be the present inventor through a large amount of tests grope preferred freeze drying protectant, there is not incompatibility between itself and principal agent Parecoxib Sodium, even if put together, the impurity indexs such as related substance also can not be caused to rise.Be different from mannitol, the present invention uses glycine as after freeze drying protectant, and Parecoxib sodium molecule can form mesh skeleton structure together with glycine skeleton, can hold its shape after drying, and color is substantially constant, and solubility is fine.
The present inventor gropes in process in test, and unexpected discovery adds the appropriate tert-butyl alcohol, forms cosolvent lyophilizing again, freeze-drying prods can be made to have good outward appearance and formability with water.The reason analyzing this unexpected pleasant surprise may be: the physicochemical property of tert-butyl alcohol uniqueness, and as freezing point is high, high volatility, can dissolve each other with water arbitrary proportion, the characteristic of the lyophilisation additives that to have made it possess desirable.Particularly, the solvent of the tert-butyl alcohol, from forming acicular crystal in freezing process, can change the crystallization mode of solute, be beneficial to distillation; And after a small amount of tert-butyl alcohol is added to the water formation tertiary butanol and water cosolvent, the crystalline state of water can be changed, acicular crystal is formed in freezing process, there is larger surface area, after ice crystal distillation simultaneously, leave tubular conduit, flow of water vapor resistance is reduced greatly, rate of sublimation significantly improves, and the tert-butyl alcohol therefore can be adopted to accelerate the mass transport process in lyophilization.
Further, the sodium hydrogen phosphate described in prescription of the present invention can be selected from disodium hydrogen phosphate,anhydrous, the one in sodium phosphate dibasic heptahydrate or sodium hydrogen phosphate dodecahydrate.The usage ratio of sodium hydrogen phosphate is approximately 1mol sodium hydrogen phosphate and uses Parecoxib 190 ~ 220g accordingly; PH adjusting agent is according to solution ph, uses phosphoric acid or sodium hydroxide solution to regulate.
The Parecoxib sodium freeze-dried preparation that the present invention makes mainly 20mg/ props up and props up this two kinds of specifications with 40mg/.When making the Parecoxib sodium freeze-dried preparation that 20mg/ props up, its formula is composed as follows:
Parecoxib Sodium 0.43g,
Disodium hydrogen phosphate 0.072g,
Glycine 0.2g,
Tert-butyl alcohol 0.1g,
0.3M phosphorus acid for adjusting pH is between 8.15 ~ 8.25,
Inject water to dosing cumulative volume 20ml.
When making the Parecoxib sodium freeze-dried preparation that 40mg/ props up, its formula is composed as follows:
Parecoxib Sodium 0.85g,
Disodium hydrogen phosphate 0.15g,
Glycine 0.4g,
Tert-butyl alcohol 0.2g,
0.3M phosphorus acid for adjusting pH is between 8.15 ~ 8.25,
Inject water to dosing cumulative volume 40ml.
The single-dose preparations fill amount of the lyophilized formulations prepared by the present invention is 1ml or 2ml.
Another object of the present invention also provides a kind of method preparing aforementioned pharmaceutical compositions, comprises following steps:
(1) dissolve adjuvant disodium hydrogen phosphate with 90% water for injection, glycine and the tert-butyl alcohol, add principal agent Parecoxib Sodium at a certain temperature, regulate between pH to 8.15 ~ 8.25 with 0.3M phosphoric acid solution, moisturizing is to full dose, and 0.2um polyethersulfone membranes filters, and fill is in 7ml cillin bottle;
(2) in the pre-freeze stage: adopt the speed of 20 DEG C/h to lower the temperature above-mentioned Parecoxib sodium freeze-dried preparation midbody solution, make sample temperature be down to-40 DEG C ~-50 DEG C, insulation 4h, rises to-30 DEG C by shelf temperature, keeps 2 ~ 3h;
(3) sublimation stage: open vacuum pump evacuation, until front case low vacuum after 200Pa, regulates baffle temperature to-15 ~-20 DEG C, maintains vacuum pressure at 80 ~ 220Pa, keep 2 ~ 3h; Then, shelf temperature is down to-30 ~-35 DEG C, keeps 1 ~ 2h; Again shelf temperature is raised-5 ~ 0 DEG C, maintain vacuum pressure at 80 ~ 220Pa, keep 5 ~ 10h to water stain heading line off;
(4) in the parsing-desiccation stage 1: shelf temperature rises to room temperature 20 DEG C, keep 2h, flaggy temperature is down to 0 DEG C, keep 2h;
(5) in the parsing-desiccation stage 2: shelf temperature rises to 45 DEG C, keep 4h, close vacuum pump;
(6) sample outlet will be obtained, roll lid, obtain Parecoxib sodium freeze-dried preparation.
Preferably, after the glycine particularly first dissolving recipe quantity with 90% water for injection and the tert-butyl alcohol, then add appropriate disodium hydrogen phosphate and regulate pH between 8.9 ~ 9.1, afterwards at holding temperature 35 ~ 40 DEG C, add Parecoxib Sodium fast, make it rapid dissolving.Because glycine and the tert-butyl alcohol are except frozen-dried protective and potentiation; can also hydrotropy Parecoxib Sodium; simultaneously the dissolubility of Parecoxib Sodium and environmental pH have much relations; the sodium hydrogen phosphate added in right amount regulates suitable pH between 8.9 ~ 9.1; it is made to dissolve rapidly; decrease time of contact and the degraded probability of hydrolysis, form Valdecoxib after avoiding being hydrolyzed, produce infusible precipitate.
The freeze-dry process of Parecoxib Sodium midbody solution is the committed step determining finished appearance formability, key parameter wherein.Such as, the control temperature of shelf, the vacuum in corresponding operating stage, and to heat up and the factor such as speed of cooling all can bring impact to the shaping outward appearance of final product.
The novelty of freeze-dry process of the present invention and effectively part be, at sublimation stage, maintain vacuum pressure constant at 80 ~ 220Pa, shelf plate temperature-15 ~-20 DEG C is regulated to keep 2 ~ 3h, no longer continue the distillation that heats up, but readjustment cooling of turning around is at-30 ~-35 DEG C, keeps 1 ~ 2h.The reason of this operation is, the removing because the tiny ice crystal that lyophilized products inside contains deeply also could not must distil by first time distillation completely, in the process progressively heated up, have one slightly to melt phenomenon, if then take conventional ramp produces distillation mode, ice crystal will be made can not to distil thoroughly, cause the water content of finished product higher, stability declines.In addition, we surprisingly find, in the auxiliary use using the tert-butyl alcohol as lyophilisation additives simultaneously of the basis of cooling distillation mode, the outward appearance of freeze-drying prods can be made full, and do not have crackle, water content control is in Min..
Therefore, in freeze-dry process of the present invention, preferably, in the step (3) of preparation method, the vacuum pressure of sublimation stage maintains 200 ~ 220Pa.
Preferably, in the step (4) of preparation method and (5), the vacuum pressure of resolution phase maintains 140 ~ 160Pa.
Further preferably, in the speed heated up or lower the temperature, in step (4), the heating rate of shelf is 10 DEG C/h, and the rate of temperature fall of shelf is 20 DEG C/h; In step (5), the heating rate of shelf is 15 DEG C/h.
Compared with prior art, tool of the present invention has the following advantages:
1) preparation method of new Parecoxib composition of sodium provided by the present invention, the method is simple, and prepared injection Parecoxib sodium pharmaceutical composition is stablized light, good stability.The present invention, through repeatedly groping, optimizes preparation process, is the deciding factor that its preparation stability is significantly better than commercial samples.
2) new Parecoxib composition of sodium provided by the present invention is produced and study on the stability through amplifying, and prove constant product quality, through pharmacology, toxicological test, solution is non-stimulated to blood vessel, without anaphylaxis, also without haemolysis, to human body fanout free region.
3) the present inventor gropes through repetition test, have found the key parameter in the freeze-dry process of applicable Parecoxib Sodium, such as cooling time and temperature, especially the vacuum sublimation means of first lowering the temperature and rising again afterwards are taken at the sublimation stage of lyophilizing, further increase product quality, improve product appearance, make it fuller, ease of solubility is better.
4) the present invention is clinical the preparation composition and the preparing process that provide a kind of pharmaceutical composition of Parecoxib Sodium of injection.The present inventor is through studying for a long period of time, unexpected discovery, take glycine as freeze drying protectant, the tert-butyl alcohol is lyophilisation additives, sodium hydrogen phosphate and phosphoric acid are as pH adjusting agent, and comprise Parecoxib sodium pharmaceutical composition prepared by special process, the pH stability of medicine is improved, pharmaceutical preparation is stablized, in water, dissolubility is good, be convenient to storage, transport and carry, compare with the comparative example of some prior aries with commercially available Parecoxib preparation of sodium, there is more excellent stability, light resistance is good, good stability, not only successfully solve the problem of the poor stability of Parecoxib Sodium, easy to implement, industrialization can be realized, remarkable in economical benefits.
Detailed description of the invention
In the examples below, more specifically will explain the present invention, but should be understood that the following example is intended to the present invention is described and does not form any restriction to scope of the present invention.
every 20 lyophilized formulations of embodiment 1 contain (specification 20mg)
Prescription is as follows:
Parecoxib Sodium 0.43g,
Disodium hydrogen phosphate 0.072g,
Glycine 0.2g,
Tert-butyl alcohol 0.1g,
0.3M phosphorus acid for adjusting pH is between 8.15 ~ 8.25,
Inject water to dosing cumulative volume 20ml.
Preparation method:
(1) glycine and the tert-butyl alcohol of recipe quantity is first dissolved with 90% water for injection, then disodium hydrogen phosphate is added, make pH between 8.9 ~ 9.1, holding temperature 35 ~ 40 DEG C, adds the Parecoxib Sodium of recipe quantity fast afterwards, makes it rapid dissolving, regulate between pH to 8.15 ~ 8.25 with 0.3M phosphoric acid solution, moisturizing is to full dose, and 0.2um polyethersulfone membranes filters, and fill is in 7ml cillin bottle;
(2) in the pre-freeze stage: adopt the speed of 20 DEG C/h to lower the temperature above-mentioned Parecoxib sodium freeze-dried preparation midbody solution, make sample temperature be down to-40 DEG C ~-50 DEG C, insulation 4h, rises to-30 DEG C by shelf temperature, keeps 2 ~ 3h;
(3) sublimation stage: open vacuum pump evacuation, until front case low vacuum after 200Pa, regulates baffle temperature to-15 ~-20 DEG C, maintains vacuum pressure at 200 ~ 220Pa, keep 2 ~ 3h; Then, shelf temperature is down to-30 ~-35 DEG C, keeps 1 ~ 2h; Again shelf temperature is raised-5 ~ 0 DEG C, maintain vacuum pressure at 200 ~ 220Pa, keep 5 ~ 10h to water stain heading line off;
(4) the parsing-desiccation stage 1: maintain vacuum pressure at 140 ~ 160Pa, shelf temperature is risen to room temperature 20 DEG C, heating rate is 10 DEG C/h, and keep 2h, flaggy temperature is down to 0 DEG C, and rate of temperature fall is 20 DEG C/h, keeps 2h;
(5) the parsing-desiccation stage 2: maintain vacuum pressure at 140 ~ 160Pa, shelf temperature is risen to 45 DEG C, heating rate is 15 DEG C/h, keeps 4h, closes vacuum pump;
(6) sample outlet will be obtained, roll lid, obtain Parecoxib sodium freeze-dried preparation.
every 20 lyophilized formulations of embodiment 2 contain (specification 40mg)
Parecoxib Sodium 0.85g,
Disodium hydrogen phosphate 0.15g,
Glycine 0.4g,
Tert-butyl alcohol 0.2g,
0.3M phosphorus acid for adjusting pH is between 8.15 ~ 8.25,
Inject water to dosing cumulative volume 40ml.
Preparation method:
(1) glycine and the tert-butyl alcohol of recipe quantity is first dissolved with 90% water for injection, then disodium hydrogen phosphate is added, make pH between 8.9 ~ 9.1, holding temperature 35 ~ 40 DEG C, adds the Parecoxib Sodium of recipe quantity fast afterwards, makes it rapid dissolving, regulate between pH to 8.15 ~ 8.25 with 0.3M phosphoric acid solution, moisturizing is to full dose, and 0.2um polyethersulfone membranes filters, and fill is in 7ml cillin bottle;
(2) in the pre-freeze stage: adopt the speed of 20 DEG C/h to lower the temperature above-mentioned Parecoxib sodium freeze-dried preparation midbody solution, make sample temperature be down to-40 DEG C ~-50 DEG C, insulation 4h, rises to-30 DEG C by shelf temperature, keeps 2 ~ 3h;
(3) sublimation stage: open vacuum pump evacuation, until front case low vacuum after 200Pa, regulates baffle temperature to-15 ~-20 DEG C, maintains vacuum pressure at 200 ~ 220Pa, keep 2 ~ 3h; Then, shelf temperature is down to-30 ~-35 DEG C, keeps 1 ~ 2h; Again shelf temperature is raised-5 ~ 0 DEG C, maintain vacuum pressure at 200 ~ 220Pa, keep 5 ~ 10h to water stain heading line off;
(4) the parsing-desiccation stage 1: maintain vacuum pressure at 140 ~ 160Pa, shelf temperature is risen to room temperature 20 DEG C, heating rate is 10 DEG C/h, and keep 2h, flaggy temperature is down to 0 DEG C, and rate of temperature fall is 20 DEG C/h, keeps 2h;
(5) the parsing-desiccation stage 2: maintain vacuum pressure at 140 ~ 160Pa, shelf temperature is risen to 45 DEG C, heating rate is 15 DEG C/h, keeps 4h, closes vacuum pump;
(6) sample outlet will be obtained, roll lid, obtain Parecoxib sodium freeze-dried preparation.
test example 1 the present inventor about freeze-dry process grope research
Find in experiment, in order to keep Parecoxib sodium freeze-dried preparation well-tended appearance, the drying time in sublimation stage and parsing-desiccation stage, temperature, warming and cooling rate is even more important.Usually there is no the parsing-desiccation stage 1 in prior art, or drying time is too short.Lyophilized formulations due to content low, Parecoxib sodium freeze-dried preparation subsides.Temperature is low, and the porous honeycomb cavernous structure of lyophilizing layer is because residual moisture causes subsiding, and therefore resolution phase baking temperature should not be increased to 45 DEG C, but the low words of parsing-desiccation temperature can cause the water content of end article high, and stability declines.
We are to the preparation of specification 20mg and 40mg, freeze-dry process pressure, and the factors such as temperature are investigated, and result is as follows:
Table 1 illustrates the increase along with sublimation stage pressure, drying time increases, power consumption also increases, because hypotony can cause product surface to seethe with excitement, outward appearance is bad, and refrigeration oil may bring system into simultaneously, system pressure is caused to change, consider, select 80 ~ 220Pa as the drying pressure of sublimation stage, preferably 200 ~ 220Pa.
Table 2 illustrates, is 45 DEG C in parsing-desiccation temperature, and when keeping 5h, no matter pressure is much, even if water content is qualified, lyophilized formulations all can have crackle to produce, and therefore still needs to adjust freeze-dry process, parsing-desiccation temperature is adjusted to 35 DEG C.
Table 3 illustrates, after the temperature in adjustment parsing-desiccation stage, the outward appearance of freeze-dried products makes moderate progress, this is because lyophilized formulations content is low, collapse temperature is low, poor rigidity, if baking temperature is too high, porous honeycomb cavernous structure is caused to subside owing to still having a small amount of residual moisture in goods.When 200 ~ 220Pa, still have crackle to produce relative to low-pressure, this is because drying pressure is higher, and water content can increase, and goods rigidity that the moisture in goods is higher when causing drying is not enough.The freeze-dried products containing less crackle can be obtained when pressure is less than 160Pa.Accordingly, we think, in order to obtain the lyophilized formulations of more low water content, improving product stability, parsing-desiccation temperature must be improved, but, still need adjusting process that water content is reduced to a certain degree before this and use 45 DEG C of parsing-desiccations again.
After table 4 illustrates and increases the parsing-desiccation stage 1, even if follow-up drying reaches 45 DEG C of equal flawlesses of freeze-dried products, and along with drying pressure decline, water content also declines.
The parsing-desiccation process adding the cooling that heats up of the invention, solves the long-standing outward appearance difficult problem of prior art.Optimised process can make water content be down to 1% even less than 0.5%, and total time comparatively prior art reduce, saved cost.Finally, we also examine the redissolution speed under optimum condition, redissolution clarity, and high-temperature stability etc. find that its related substances is low, good stability, and the time of redissolving is short, and solution is clarified.
comparative example 1 is tested according to the ingredient proportion of CN201310395684.5 embodiment 1
Parecoxib Sodium is in Parecoxib 40g
Sodium hydrogen phosphate 6.54g
Sodium dihydrogen phosphate 0.46g
Phosphoric acid/Sodium hydroxide q. s
Water for injection adds to 2L.
Preparation technology comprises:
1) get recipe quantity 90% water for injection, the sodium hydrogen phosphate and the sodium dihydrogen phosphate that first add recipe quantity are stirred to dissolving, for subsequent use;
2) 1 is got) middle solution, add 0.1mol/L phosphoric acid or sodium hydrate aqueous solution, adjust pH to 8.1;
3) under 25 DEG C of conditions, by 2) add the Parecoxib Sodium of recipe quantity in solution, be stirred to and dissolve completely;
4) 3 are got) solution, add 0.1% pin charcoal of this amount of solution, stir completely, place 15 minutes, filter, add to the full amount of water for injection, measure medicinal liquid original ph;
5) 4 are got) solution, add 0.1mol/L phosphoric acid or sodium hydrate aqueous solution, adjust pH scope 7.5 ~ 8.5;
6) adopt 0.45 μm and 0.22 μm of microporous filter membrane fine straining qualified to visible foreign matters;
7) Quality control of intermediates: detect Parecoxib sodium content, pH value, the test items such as visible foreign matters;
8) according to intermediates content, regulate loading amount, and confirm loading amount scope, carry out fill, half tamponade;
9) by point sample installed, load in freeze dryer, sample is refrigerated to-50 ~-40 DEG C, keep temperature freezing 2 ~ 3 hours, be evacuated to 2 ~ 12pa after freezing, slow homogeneous heating, to-5 ~ 0 DEG C, then stops heating up, keep temperature drying 10 ~ 20 hours, in 10 ~ 20 hours, be warming up to 30 ~ 40 DEG C again, then stop heating up, heat preservation and dryness 2 ~ 3 hours, tamponade, outlet;
10) sample outlet will be obtained, roll lid, obtain Parecoxib sodium pharmaceutical composition.
comparative example 2 is tested according to the ingredient proportion of CN201310412213.0 embodiment 1
The formula of the Parecoxib sodium pharmaceutical composition described in every 1000 consists of:
Parecoxib Sodium is in Parecoxib 40g
Sodium hydrogen phosphate 8g
Calcium disodium edetate 0.4g
Sodium hydroxide q. s
Water for injection adds to 2L.
Preparation technology comprises:
1) get recipe quantity 80% water for injection, the sodium hydrogen phosphate and the calcium disodium edetate that first add recipe quantity are stirred to dissolving, for subsequent use;
2) 1 is got) middle solution, add 0.1mol/L sodium hydrate aqueous solution, adjust pH to 7.5;
3) by 2) add the Parecoxib Sodium of recipe quantity in solution, be stirred to and dissolve completely;
4) 3 are got) solution, add 0.1% pin charcoal of this amount of solution, stir completely, place 20 minutes, filter, add to the full amount of water for injection, measure medicinal liquid original ph;
5) 4 are got) solution, add 0.1mol/L sodium hydrate aqueous solution, adjust pH scope 7.5 ~ 8.0;
6) adopt 0.45 μm and 0.22 μm of microporous filter membrane fine straining qualified to visible foreign matters;
7) Quality control of intermediates: detect Parecoxib sodium content, pH value, the test items such as visible foreign matters;
8) according to intermediates content, regulate loading amount, and confirm loading amount scope, carry out fill, half tamponade;
9) by point sample installed, load in freeze dryer, sample is refrigerated to-50 ~-40 DEG C, keep temperature freezing 3 ~ 4 hours, be evacuated to 2 ~ 8pa after freezing, slow homogeneous heating to 0 ~ 5 DEG C, then stop heating up, keep temperature drying 10 ~ 20 hours, in 10 ~ 20 hours, be warming up to 20 ~ 25 DEG C again, then stop heating up, heat preservation and dryness 4 ~ 5 hours, tamponade, outlet;
10) sample outlet will be obtained, roll lid, obtain Parecoxib sodium pharmaceutical composition.
the freeze-dry process of test example 2 embodiment of the present invention and comparative example and effectiveness comparison
The external shaping of Parecoxib sodium freeze-dried preparation and internal soundness depend on the quality of freeze-dry process to a great extent.We, by adopting different freeze-dry process to prepare the freeze-drying prods of gained the midbody solution after the Parecoxib Sodium dosing of prescription batching gained of the present invention, investigate its indices.We are from moisture, outward appearance, redissolution speed, and clarity of redissolving contrasts.
Moisture, gets this product and measures according to Chinese Pharmacopoeia latest edition aquametry.
Dissolution time, sample thief 3 bottles, every bottle adds 0.9% sodium chloride solution, 20mg specification add 1mL, 40mg specification add 2mL, jolt gently, observe the redissolution time.
The clarity of solution, the solution got under dissolution time item should be clarified, and as aobvious muddiness, compares with No. 1 turbidity standard, must not be denseer.
test example 3 is by embodiment 1 and 2, and the Parecoxib sodium freeze-dried preparation that comparative example 1 and 2 is obtained, compares its thimble test at 60 DEG C and in 90 days
Upper table is known, in the thimble test of the embodiment of the present invention 1 and 2 at 60 DEG C and in 90 days, obviously due to comparative example 1 and 2.
charging sequence during test example 4 dosing
For preparation prescription of the present invention, total principal agent Parecoxib Sodium, freeze drying protectant glycine, the lyophilisation additives tert-butyl alcohol, sodium hydrogen phosphate and phosphoric acid regulator need to add, and different charging sequence is on the impact of principal agent dissolution velocity.
Charging sequence 1: first water for injection is dissolved Parecoxib Sodium, then the glycine adding recipe quantity, the tert-butyl alcohol and sodium hydrogen phosphate.
Phenomenon is: principal agent does not dissolve, and after adding sodium hydrogen phosphate and glycine, the tert-butyl alcohol, slowly dissolves.
Charging sequence 2: the sodium hydrogen phosphate of recipe quantity and Parecoxib Sodium are simultaneously joined in water for injection, is adding glycine and the tert-butyl alcohol.
Phenomenon is: solid starts not dissolve, and slowly dissolves along with after stirring.
Charging sequence 3: the glycine and the tert-butyl alcohol that first dissolve recipe quantity with 90% water for injection, then add disodium hydrogen phosphate, make pH between 8.9-9.1, afterwards holding temperature 35-40 DEG C, add the Parecoxib Sodium of recipe quantity fast, make it rapid dissolving.
Phenomenon is: principal agent rapid solution, solution clarification after dissolving.
influence factor's comparative study of test example 5 embodiment of the present invention and commercially available prod
Embodiment 2 gained sample and commercially available product are compared, be placed in the illumination of 4500 ± 500Lx respectively, the high temperature of 60 ± 2 DEG C, in 92.5% high humidity calorstat 10 days, respectively at 0 day, 10 days its character, pH value and related substance checked and to compare with commercial samples, the results are shown in following table.
test example 6 vascular stimulation tests
Hemolytic test: the lyophilized formulations of the 40mg specification of embodiment 2 is added 0.9% sodium chloride solution 2mL, and dissolving shakes up, join in 2% rabbit erythrocyte suspension, Continuous Observation 6h, there is haemolysis in each Guan Junwei.
Sensitivity test: the lyophilized formulations of the 40mg specification of embodiment 2 is added 0.9% sodium chloride solution 2mL, dissolving shakes up, the auricular vein of Cavia porcellus is carried out to the test of sensitivity response, after exciting administration through twice, all do not observe and search, rolling up, perpendicular hair, dyspnea, death waits sensitization phenomenon, shows that lyophilizing injection of the present invention does not have sensitization to animal subject thing.
Vascular stimulation tests: the lyophilized formulations of the 40mg specification of embodiment 2 is added 0.9% sodium chloride solution 2mL, inject for rabbit auricular vein, its histopathology result shows: ear's normal configuration exists, Mild edema, ear vein tube wall is intact, and have no downright bad, tube chamber inner blood fills, have no thrombosis, the intact nothing of vascular endothelial cell comes off.Similar compared to the ear vein pathomorphology change of solvent group, have no the reaction of remarkable blood vessel irritation.
The foregoing is only preferred embodiment of the present invention, and be not used to limit substantial technological content of the present invention, substantial technological content of the present invention is that the right being broadly defined in application gathers, any technology entities that other people complete or method, if with application right define identical, also or a kind of change of equivalence, be all covered by being regarded as among this right.
Claims (10)
1. a Parecoxib sodium pharmaceutical composition for stable injection, include Parecoxib Sodium, sodium hydrogen phosphate, freeze drying protectant, lyophilisation additives, pH adjusting agent, it is characterized in that, freeze drying protectant is selected from glycine, and lyophilisation additives is selected from the tert-butyl alcohol.
2. pharmaceutical composition according to claim 1, is characterized in that, described sodium hydrogen phosphate can be selected from disodium hydrogen phosphate,anhydrous, the one in sodium phosphate dibasic heptahydrate or sodium hydrogen phosphate dodecahydrate; PH adjusting agent is according to solution ph, uses phosphoric acid or sodium hydroxide solution to regulate.
3. pharmaceutical composition according to claim 1 and 2, is characterized in that, the formula making the Parecoxib sodium freeze-dried preparation (specification 20mg/ props up) of 20 is composed as follows:
Parecoxib Sodium 0.43g,
Disodium hydrogen phosphate 0.072g,
Glycine 0.2g,
Tert-butyl alcohol 0.1g,
0.3M phosphorus acid for adjusting pH between 8.15 ~ 8.25,
Inject water to dosing cumulative volume 20ml.
4. pharmaceutical composition according to claim 1 and 2, is characterized in that, the formula making the Parecoxib sodium freeze-dried preparation (specification 40mg/ props up) of 20 is composed as follows:
Parecoxib Sodium 0.85g,
Disodium hydrogen phosphate 0.15g,
Glycine 0.4g,
Tert-butyl alcohol 0.2g,
0.3M phosphorus acid for adjusting pH between 8.15 ~ 8.25,
Inject water to dosing cumulative volume 40ml.
5. prepare a method for the pharmaceutical composition according to any one of claim 1-4, it is characterized in that, comprise following steps:
(1) dissolve adjuvant disodium hydrogen phosphate with 90% water for injection, glycine and the tert-butyl alcohol, add principal agent Parecoxib Sodium at a certain temperature, regulate between pH to 8.15 ~ 8.25 with 0.3M phosphoric acid solution, moisturizing is to full dose, and 0.2um polyethersulfone membranes filters, and fill is in 7ml cillin bottle;
(2) the pre-freeze stage: adopt the speed of 20 DEG C/h to lower the temperature above-mentioned Parecoxib sodium freeze-dried preparation midbody solution, be down to-40 DEG C ~-50 DEG C, insulation 4h, then shelf temperature is risen to-30 DEG C, keep 2 ~ 3h;
(3) sublimation stage: open vacuum pump evacuation, treat that front case low vacuum is in 200Pa, regulates baffle temperature between-15 ~-20 DEG C, maintains vacuum pressure at 80 ~ 220Pa, keeps 2-3h; Then, shelf temperature is dropped between-30 ~-35 DEG C, keep 1 ~ 2h; Again shelf temperature is raised at-5 ~ 0 DEG C, maintain vacuum pressure at 80 ~ 220Pa, keep 5 ~ 10h until water stain heading line off;
(4) in the parsing-desiccation stage 1: shelf temperature rises to room temperature 20 DEG C, keep 2h, flaggy temperature is down to 0 DEG C, keep 2h;
(5) in the parsing-desiccation stage 2: shelf temperature rises to 45 DEG C, keep 4h, close vacuum pump;
(6) sample outlet will be obtained, roll lid, obtain Parecoxib sodium freeze-dried preparation.
6. preparation method according to claim 5, it is characterized in that, in step (1), after the glycine particularly first dissolving recipe quantity with 90% water for injection and the tert-butyl alcohol, add disodium hydrogen phosphate again, make pH between 8.9 ~ 9.1, at holding temperature 35 ~ 40 DEG C, add Parecoxib Sodium fast, make it rapid dissolving.
7. preparation method according to claim 5, is characterized in that, in step (3), the vacuum pressure of sublimation stage maintains 200 ~ 220Pa.
8. preparation method according to claim 5, is characterized in that, in step (4) and (5), the vacuum pressure in parsing-desiccation stage maintains 140 ~ 160Pa.
9. the lyophilized formulations of the Parecoxib Sodium according to claim 1-4, is characterized in that, single-dose preparations fill amount is 1ml or 2ml.
10. preparation method according to claim 5, is characterized in that, in step (4), the heating rate of shelf is 10 DEG C/h, and the rate of temperature fall of shelf is 20 DEG C/h; In step (5), the heating rate of shelf is 15 DEG C/h.
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| CN109985040A (en) * | 2019-05-15 | 2019-07-09 | 南京正大天晴制药有限公司 | A kind of injection Parecoxib Sodium Pharmaceutical composition and preparation method thereof for preemptive analgesia |
| CN111228226A (en) * | 2020-03-06 | 2020-06-05 | 瑞阳制药有限公司 | Freeze-dried preparation of pyrrosia faberi for injection and preparation method thereof |
| CN112791177A (en) * | 2019-10-28 | 2021-05-14 | 深圳翰宇药业股份有限公司 | Somatostatin freeze-dried composition for injection and preparation method thereof |
| CN113456597A (en) * | 2020-03-30 | 2021-10-01 | 石药集团欧意药业有限公司 | Parecoxib sodium for injection and preparation method thereof |
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| CN109985040A (en) * | 2019-05-15 | 2019-07-09 | 南京正大天晴制药有限公司 | A kind of injection Parecoxib Sodium Pharmaceutical composition and preparation method thereof for preemptive analgesia |
| CN112791177A (en) * | 2019-10-28 | 2021-05-14 | 深圳翰宇药业股份有限公司 | Somatostatin freeze-dried composition for injection and preparation method thereof |
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| CN113456597A (en) * | 2020-03-30 | 2021-10-01 | 石药集团欧意药业有限公司 | Parecoxib sodium for injection and preparation method thereof |
| CN113456597B (en) * | 2020-03-30 | 2023-02-14 | 石药集团欧意药业有限公司 | Parecoxib sodium for injection and preparation method thereof |
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