CN105213330B - A kind of SC 69124 sodium freeze-dried preparation and preparation method thereof - Google Patents

Abstract

The present invention relates to a kind of injection SC 69124 sodium pharmaceutical composition of stabilization, which specifically includes main ingredient Parecoxib Sodium, freeze drying protectant glycine, the lyophilisation additives tert-butyl alcohol, pH adjusting agent disodium hydrogen phosphate and phosphoric acid.The production technology of the present invention is feasible, and stable and controllable for quality, skin irritatin is small, it is ingenious in lyophilized technique to control time, temperature, vacuum degree, the multinomial key parameter such as the speed of heating and cooling provides rationally effective preparation prescription and preparation process scheme, it is easy to accomplish industrialization for clinical application.

Description

A kind of SC 69124 sodium freeze-dried preparation and preparation method thereof

Technical field

The invention belongs to technical field of medicine, more particularly to a kind of SC 69124 sodium freeze-dried preparation and its preparation side Method.

Background technology

Parecoxib Sodium, entitled N- [[4- (5- methyl -3- phenyl -4- isoxazolyls) phenyl] sulfonyl] propionamide of chemistry Sodium salt, molecular formula C19H17N2O4SNa, molecular weight 392.41.Indication is the short for postoperative pain, and specification is 20mg or 40mg (in terms of SC 69124).

Parecoxib Sodium is a kind of highly selective Cyclooxygenase-2 Inhibitor, belongs to the former times dry goods town in anti-arthritic Pain medicine, the short available for postoperative pain.Parecoxib Sodium is rapid-action and analgesic activity is lasting.SC 69124 40mg's The effect of analgesic effect and intramuscular injection ketorolac 60mg or intravenous 30mg is similar.SC 69124 has COX-2 the selectivity of height, right COX-1 only has faint selectivity, therefore with preferable safety, gastrointestinal ulceration incidence is substantially less than traditional NSAIDs.For SC 69124 as global first injection cox 2 inhibitor, analgesia effect is good, is provided simultaneously with inhibiting super quick, root Except the unique advantage of pain, agree with analgesia new model, push analgesia new concept, meet clinical demand, be expected to become postoperative basis Medication makes more patients enjoy painless surgical operation, is more preferably selected so as to be provided for Postoperative Analgesia After.

Parecoxib Sodium is easily hydrolyzed to Valdecoxib, and dissolves poor in Valdecoxib water, and injection is made and brings It is difficult.And pro-drug of the Parecoxib Sodium as Valdecoxib, there is higher solubility, in order to avoid it is fast in aqueous solution Speed is converted into Valdecoxib, and Parecoxib Sodium is mainly made into lyophilized preparation.In drug production process, injection SC 69124 Sodium freeze-dried preparation need to strictly control moisture, avoid causing significantly hydrolyzing, influence product stability.

It is well known that Parecoxib Sodium drug administration by injection effective dose is low, when drug concentration is low, formability can be brought Problem, it will usually it is considered needing to add excipient, and this can increase preparation difficulty and cost, while be more likely to bring safety hidden Suffer from.The present inventor has found in experimental study, Parecoxib Sodium and common freeze drying protectant, such as mannitol, there is with 5 taboos.In addition, Parecoxib Sodium is susceptible to hydrolysis, water-content indicator will be an important factor for influencing its stability.

In the prior art, the appearance forming of Parecoxib Sodium and the problems such as higher water content are the difficulties in preparation production Point.Since main ingredient dosage is small, concentration is low, and the rigidity of freeze-drying prods sublimation stage is relatively low, if drying temperature is excessively high, solid matrix Rigidity is not enough to maintain honeycomb structure, and the solid content matrix of walls in hole will collapse；And temperature is too low, water content is higher, Influence product stability.Therefore it finds in suitable preparation prescription and technique, especially lyophilized technique to temperature, vacuum degree and liter The control of the key factors such as cooling rate is to solve prior art key of problems.

Invention content

The present invention provides a kind of prescription of the lyophilized preparation of novel Parecoxib Sodium, and the freeze-drying work for passing through improvement Skill solves problems in the prior art.SC 69124 sodium freeze-dried preparation appearance produced by the present invention is good, water content It is low, increase it and deposit the stability of Tibetan and application.

A kind of SC 69124 sodium pharmaceutical composition of the injection of stabilization provided by the invention, includes SC 69124 Sodium, disodium hydrogen phosphate, freeze drying protectant, lyophilisation additives, pH adjusting agent；It is characterized in that, freeze drying protectant is selected from glycine, Lyophilisation additives are selected from the tert-butyl alcohol.

Glycine be the present inventor by a large amount of experiment grope preferred freeze drying protectant, with main ingredient SC 69124 There is no incompatibility between sodium, even if putting together, the impurity such as related substance index will not be caused to rise.Different from sweet Reveal alcohol, after the present invention uses glycine as freeze drying protectant, SC 69124 sodium molecule can form net together with glycine skeleton Shape skeleton structure can hold its shape after dry, and color is basically unchanged, and solubility is fine.

The present inventor is found surprisingly that during experiment is groped and adds in the appropriate tert-butyl alcohol, freezes again with water formation cosolvent It is dry, it can cause freeze-drying prods that there is good appearance and formability.Analyzing the reason of this is pleasantly surprised may be：The tert-butyl alcohol Unique physicochemical property, such as solidification point height, high volatility can dissolve each other with water arbitrary proportion, it is made to have ideal freeze-drying The characteristic of additive.Specifically, the solvent of the tert-butyl alcohol can change the crystallization of solute from acicular crystal is formed in freezing process Mode, conducive to distillation；And after a small amount of tert-butyl alcohol is added to the water to form tertiary butanol and water cosolvent, the knot of water can be changed Crystalline state, forms acicular crystal in freezing process, has the surface area of bigger, while after ice crystal distillation, leave tubular conduit, Greatly reduce flow of water vapor resistance, rate of sublimation significantly improves, therefore the tert-butyl alcohol can be used to accelerate in freeze-drying Mass transport process.

Further, the disodium hydrogen phosphate described in prescription of the present invention may be selected from Anhydrous Disodium Phosphate, disodium hydrogen phosphate One kind in heptahydrate or disodium hydrogen phosphate dodecahydrate.The usage ratio of disodium hydrogen phosphate is about 1mol phosphoric acid hydrogen two Sodium accordingly uses 190~220g of SC 69124；PH adjusting agent is according to solution ph, uses phosphoric acid or sodium hydroxide solution To adjust.

SC 69124 sodium freeze-dried preparation made of the present invention is mainly that 20mg/ branch and 40mg/ prop up both specifications.When being made During the SC 69124 sodium freeze-dried preparation of 20mg/ branch, formula composition is as follows：

Parecoxib Sodium 0.43g,

Disodium hydrogen phosphate 0.072g,

Glycine 0.2g,

Tert-butyl alcohol 0.1g,

Between 0.3M phosphorus acid for adjusting pH is 8.15~8.25,

It injects water to liquid total volume 20ml.

When the SC 69124 sodium freeze-dried preparation that 40mg/ branch is made, formula composition is as follows：

Parecoxib Sodium 0.85g,

Disodium hydrogen phosphate 0.15g,

Glycine 0.4g,

Tert-butyl alcohol 0.2g,

Between 0.3M phosphorus acid for adjusting pH is 8.15~8.25,

It injects water to liquid total volume 40ml.

The single-dose preparations filling amount of lyophilized preparation prepared by the present invention is 1ml or 2ml.

Another object of the present invention is also to provide a kind of method for preparing aforementioned pharmaceutical compositions, is comprised the following steps：

（1）Auxiliary material disodium hydrogen phosphate, glycine and the tert-butyl alcohol are dissolved with 90% water for injection, in a constant temperature Degree is lower to add in main ingredient Parecoxib Sodium, between adjusting pH to 8.15~8.25 with 0.3M phosphoric acid solutions, moisturizing to full dose, and 0.2um Polyethersulfone membranes filter, filling in 7ml cillin bottles；

（2）The pre-freeze stage：Above-mentioned SC 69124 sodium freeze-dried preparation midbody solution using the rate of 20 DEG C/h is cooled down, is made It obtains sample temperature and is down to -40 DEG C~-50 DEG C, keep the temperature 4h, shelf temperature is risen to -30 DEG C, keeps 2~3h；

（3）Sublimation stage：Vacuum pump is opened to vacuumize, before case vacuum degree less than after 200Pa, adjust baffle temperature to- 15~-20 DEG C, vacuum pressure is maintained in 80~220Pa, 2~3h of holding；Then, shelf temperature is down to -30~-35 DEG C, protected Hold 1~2h；Shelf temperature is increased -5~0 DEG C again, maintains vacuum pressure in 80~220Pa, 5~10h of holding to water stain line It disappears；

（4）The parsing-desiccation stage 1：Shelf temperature is warmed to room temperature 20 DEG C, keeps 2h, and plate layer temperature is down to 0 DEG C, is kept 2h；

（5）The parsing-desiccation stage 2：Shelf temperature rises to 45 DEG C, keeps 4h, closes vacuum pump；

（6）By obtained sample outlet, lid is rolled to get SC 69124 sodium freeze-dried preparation.

Preferably, particularly first the glycine of recipe quantity and the tert-butyl alcohol and then addition are dissolved with 90% water for injection Appropriate disodium hydrogen phosphate adjusts pH between 8.9~9.1, maintains at 35~40 DEG C of temperature later, rapidly joins Pa Rui Former times cloth sodium is allowed to dissolve rapidly.Because glycine and the tert-butyl alcohol are other than frozen-dried protective and synergistic effect, moreover it is possible to which hydrotropy pa is auspicious Former times cloth sodium, while the solubility of Parecoxib Sodium has much relations with environmental pH, the disodium hydrogen phosphate added in right amount, which is adjusted, to be closed Suitable pH makes it dissolve rapidly between 8.9~9.1, reduces the time of contact of hydrolysis and degradation probability, avoids being formed after hydrolyzing and cut down Ground former times cloth generates infusible precipitate.

The lyophilized technique of Parecoxib Sodium midbody solution is to determine the committed step of finished appearance formability, pass therein Bond parameter.For example, the control temperature of shelf, the factors such as the vacuum degree and the speed of heating and cooling in corresponding operating stage are all It can be affected to the forming appearance of final product.

The novelty of lyophilized technique of the present invention and effectively part are, in sublimation stage, maintain vacuum pressure in 80~220Pa It is constant, -15~-20 DEG C of 2~3h of holding of shelf plate temperature are adjusted, do not continue to heating distillation, but readjustment cooling of turning around is -30 ~-35 DEG C, keep 1~2h.The reason of operation, is, because of distillation for the first time and the small ice that will could not deeply contain inside lyophilized products The brilliant removing that must distil completely, has one to melt phenomenon slightly during gradually heating up, if then taking conventional heating distillation side Formula will so that the water content for leading to finished product is higher from distilling thoroughly for ice crystal, and stability declines.In addition, we surprisingly send out It is existing, in use of the auxiliary using the tert-butyl alcohol as lyophilisation additives simultaneously of the basis of cooling distillation mode, it can cause freeze-drying prods Appearance it is full, without crackle, water content control is in minimum limit.

Therefore, in lyophilized technique of the invention, it is preferable that the step of preparation method（3）In, the vacuum pressure of sublimation stage Maintain 200~220Pa.

Preferably, the step of preparation method（4）With（5）In, the vacuum pressure of resolution phase maintains 140~160Pa.

It is further preferred that in terms of the rate for heating up or cooling down, step（4）In, the heating rate of shelf is 10 DEG C/h, The rate of temperature fall of shelf is 20 DEG C/h；Step（5）In, the heating rate of shelf is 15 DEG C/h.

Compared with prior art, the invention has the advantages that：

1) preparation method of new SC 69124 composition of sodium provided by the present invention, this method is simple and practicable, prepared Injection SC 69124 sodium pharmaceutical composition light is stablized, stability is good.The present invention optimizes preparation work by groping repeatedly Skill is the deciding factor that its preparation stability is significantly better than commercial samples.

2) new SC 69124 composition of sodium provided by the present invention is through amplification production and study on the stability, it was demonstrated that product matter Amount is stablized, and through pharmacology, toxicological test, solution is non-stimulated to blood vessel, no allergic reaction, also without haemolysis, to human body fanout free region.

3) the present inventor gropes by repetition test, has found the crucial ginseng in the lyophilized technique of suitable Parecoxib Sodium Number, such as cooling time and temperature, especially take the vacuum sublimation means for first cooling down and rising again afterwards in the sublimation stage of freeze-drying, into One step improves product quality, improves product appearance, makes it fuller, ease of solubility is more preferable.

4）The present invention be for clinic provide a kind of pharmaceutical composition of the Parecoxib Sodium of injection preparation composition and Preparing process.The present inventor has been surprisingly found that, using glycine as freeze drying protectant, the tert-butyl alcohol is added for freeze-drying by studying for a long period of time Agent, disodium hydrogen phosphate and phosphoric acid as pH adjusting agent and include special process prepare SC 69124 sodium pharmaceutical composition, medicine The pH stability of object is improved, and pharmaceutical preparation is stablized, and dissolubility is good in water, convenient for storing, transporting and carry, with city It sells SC 69124 preparation of sodium to compare with the comparative example of some prior arts, there is more excellent stability, light resistance is good, surely It is qualitative good, not only successfully solve the problems, such as that the stability of Parecoxib Sodium is poor, it is easy to implement, it can be achieved that industrialization, economy effect It is beneficial notable.

Specific embodiment

In the examples below, the present invention will be more specifically explained, it should be appreciated that the following example is intended to illustrate hair It is bright without to the scope of the present invention form any restrictions.

1 every 20 lyophilized preparation of embodiment contains（Specification 20mg）

Prescription is as follows：

Parecoxib Sodium 0.43g,

Disodium hydrogen phosphate 0.072g,

Glycine 0.2g,

Tert-butyl alcohol 0.1g,

Between 0.3M phosphorus acid for adjusting pH is 8.15~8.25,

It injects water to liquid total volume 20ml.

Preparation method：

（1）The glycine of recipe quantity and the tert-butyl alcohol first are dissolved with 90% water for injection, is subsequently added into ten hydrogen phosphate dihydrates two Sodium so that pH maintains 35~40 DEG C of temperature, rapidly join the Parecoxib Sodium of recipe quantity, be allowed to later between 8.9~9.1 Rapid dissolving, between adjusting pH to 8.15~8.25 with 0.3M phosphoric acid solutions, moisturizing to full dose, the filtering of 0.2um polyethersulfone membranes, It is filling in 7ml cillin bottles；

（2）The pre-freeze stage：Above-mentioned SC 69124 sodium freeze-dried preparation midbody solution using the rate of 20 DEG C/h is cooled down, is made It obtains sample temperature and is down to -40 DEG C~-50 DEG C, keep the temperature 4h, shelf temperature is risen to -30 DEG C, keeps 2~3h；

（3）Sublimation stage：Vacuum pump is opened to vacuumize, before case vacuum degree less than after 200Pa, adjust baffle temperature to- 15~-20 DEG C, vacuum pressure is maintained in 200~220Pa, 2~3h of holding；Then, shelf temperature is down to -30~-35 DEG C, protected Hold 1~2h；Shelf temperature is increased -5~0 DEG C again, maintains vacuum pressure in 200~220Pa, 5~10h of holding to water stain line It disappears；

（4）The parsing-desiccation stage 1：Vacuum pressure is maintained in 140~160Pa, shelf temperature is warmed to room temperature 20 DEG C, heating Rate is 10 DEG C/h, keeps 2h, plate layer temperature is down to 0 DEG C, rate of temperature fall is 20 DEG C/h, keeps 2h；

（5）The parsing-desiccation stage 2：Vacuum pressure is maintained shelf temperature to be risen to 45 DEG C, heating rate in 140~160Pa For 15 DEG C/h, 4h is kept, closes vacuum pump；

（6）By obtained sample outlet, lid is rolled to get SC 69124 sodium freeze-dried preparation.

2 every 20 lyophilized preparations of embodiment contain（Specification 40mg）

Parecoxib Sodium 0.85g,

Disodium hydrogen phosphate 0.15g,

Glycine 0.4g,

Tert-butyl alcohol 0.2g,

Between 0.3M phosphorus acid for adjusting pH is 8.15~8.25,

It injects water to liquid total volume 40ml.

Preparation method：

（1）The glycine of recipe quantity and the tert-butyl alcohol first are dissolved with 90% water for injection, is subsequently added into ten hydrogen phosphate dihydrates two Sodium so that pH maintains 35~40 DEG C of temperature, rapidly join the Parecoxib Sodium of recipe quantity, be allowed to later between 8.9~9.1 Rapid dissolving, between adjusting pH to 8.15~8.25 with 0.3M phosphoric acid solutions, moisturizing to full dose, the filtering of 0.2um polyethersulfone membranes, It is filling in 7ml cillin bottles；

（2）The pre-freeze stage：Above-mentioned SC 69124 sodium freeze-dried preparation midbody solution using the rate of 20 DEG C/h is cooled down, is made It obtains sample temperature and is down to -40 DEG C~-50 DEG C, keep the temperature 4h, shelf temperature is risen to -30 DEG C, keeps 2~3h；

（3）Sublimation stage：Vacuum pump is opened to vacuumize, before case vacuum degree less than after 200Pa, adjust baffle temperature to- 15~-20 DEG C, vacuum pressure is maintained in 200~220Pa, 2~3h of holding；Then, shelf temperature is down to -30~-35 DEG C, protected Hold 1~2h；Shelf temperature is increased -5~0 DEG C again, maintains vacuum pressure in 200~220Pa, 5~10h of holding to water stain line It disappears；

（4）The parsing-desiccation stage 1：Vacuum pressure is maintained in 140~160Pa, shelf temperature is warmed to room temperature 20 DEG C, heating Rate is 10 DEG C/h, keeps 2h, plate layer temperature is down to 0 DEG C, rate of temperature fall is 20 DEG C/h, keeps 2h；

（5）The parsing-desiccation stage 2：Vacuum pressure is maintained shelf temperature to be risen to 45 DEG C, heating rate in 140~160Pa For 15 DEG C/h, 4h is kept, closes vacuum pump；

（6）By obtained sample outlet, lid is rolled to get SC 69124 sodium freeze-dried preparation.

1 the present inventor of test example gropes to study about lyophilized technique

It was found that, in order to keep SC 69124 sodium freeze-dried preparation well-tended appearance, sublimation stage and parsing-desiccation rank The drying time of section, temperature, warming and cooling rate are even more important.Usually not parsing-desiccation stage 1 or dry in the prior art Time is too short.Since content is low, SC 69124 sodium freeze-dried preparation collapses lyophilized preparation.Temperature is low, and the porous honeycomb of layer is lyophilized Cavernous structure is because residual moisture causes to collapse, therefore resolution phase drying temperature should not be increased to 45 DEG C, but parsing-desiccation The water content that end article can be caused if temperature is low is high, and stability declines.

The factors such as our preparations to specification 20mg and 40mg, lyophilized technique pressure, temperature are investigated, as a result such as Under：

Table 1 illustrates to increase with the increase of sublimation stage pressure, drying time, and energy consumption also increases, due to hypotony meeting Product surface is caused to boil, appearance is bad, while refrigeration oil may bring system into, and system pressure is caused to change, and consider, Select drying pressures of the 80~220Pa as sublimation stage, preferably 200~220Pa.

Table 2 illustrates, in the case where parsing-desiccation temperature keeps 5h for 45 DEG C, no matter pressure is much, even if water content is closed Lattice, lyophilized preparation can all have crackle generation, therefore still need to adjustment lyophilized technique, and parsing-desiccation temperature is adjusted to 35 DEG C.

Table 3 illustrates that after the temperature in adjustment parsing-desiccation stage, the appearance of freeze-dried products makes moderate progress, this is because freezing Drying agent content is low, and collapse temperature is low, poor rigidity, if drying temperature is excessively high, due to still having a small amount of residual moisture to cause in product Porous honeycomb cavernous structure collapses.In 200~220Pa, still there is crackle generation relative to low-pressure, this is because dry Pressure is higher, and water content can increase, and product rigidity that the moisture in product is higher when leading to dry is insufficient.When pressure is less than 160Pa When can obtain the freeze-dried products containing less crackle.Accordingly, it is believed that, the lyophilized preparation of more low water content, carries in order to obtain High product stability, it is necessary to parsing-desiccation temperature be improved, still, still need to adjusting process before this so that water content is reduced to Again with 45 DEG C of parsing-desiccations after to a certain degree.

Table 4 illustrates after increasing the parsing-desiccation stage 1, though follow-up dry reaches 45 DEG C of equal flawlesses of freeze-dried products, and with Drying pressure decline, water content also declines.

It is long-standing outer to solve the prior art for the parsing-desiccation process for increasing heating cooling of the invention See problem.Optimised process can make water content be down to 1% or even 0.5% hereinafter, and reducing compared with the prior art total time, saving Cost.Finally, we also examine the redissolution speed under optimum condition, redissolve clarity, high-temperature stability etc., find related object Matter content is low, good stability, and the redissolution time is short, solution clarification.

Comparative example 1 is tested according to the ingredient proportion of CN201310395684.5 embodiments 1

Parecoxib Sodium 40g in terms of SC 69124

Disodium hydrogen phosphate 6.54g

Sodium dihydrogen phosphate 0.46g

Phosphoric acid/Sodium hydroxide q.s.

Water for injection adds to 2L.

Preparation process includes：

1) 90% water for injection of recipe quantity is taken, first the disodium hydrogen phosphate of recipe quantity is added in and sodium dihydrogen phosphate is stirred to molten Solution, it is spare；

2) 1 is taken）Middle solution adds in 0.1mol/L phosphoric acid or sodium hydrate aqueous solution, adjusts pH to 8.1；

3) under the conditions of 25 DEG C, by 2）The Parecoxib Sodium of recipe quantity is added in solution, stirring is complete to dissolving；

4) 3 are taken）Solution adds in 0.1% needle charcoal of the amount of solution, after stirring completely, places 15 minutes, filters, filling It penetrates with water to full dose, measure liquid initial pH value；

5) 4 are taken）Solution adds in 0.1mol/L phosphoric acid or sodium hydrate aqueous solution, adjusts pH value range 7.5 ~ 8.5；

6) it is qualified to visible foreign matters using 0.45 μm and 0.22 μm of miillpore filter refined filtration；

7) Quality control of intermediates：Detect SC 69124 sodium content, pH values, it is seen that the detection projects such as foreign matter；

8) it according to intermediates content, adjusts loading amount and confirms loading amount range, carry out filling, half tamponade；

9) sample that will have been dispensed is fitted into freeze dryer, and sample is refrigerated to -50~-40 DEG C, keep temperature freezing 2~ 3 hours, 2~12pa is evacuated to after freezing, is slowly heated uniformly to -5~0 DEG C, then stops heating, keeps temperature drying 10 ~20 hours, then 30~40 DEG C were warming up in 10~20 hours, then stop heating, heat preservation and dryness 2~3 hours, tamponade goes out Case；

10) by obtained sample outlet, lid is rolled to get SC 69124 sodium pharmaceutical composition.

Comparative example 2 is tested according to the ingredient proportion of CN201310412213.0 embodiments 1

The formula composition of SC 69124 sodium pharmaceutical composition described in every 1000 is：

Parecoxib Sodium 40g in terms of SC 69124

Disodium hydrogen phosphate 8g

Mosatil 0.4g

Sodium hydroxide q.s.

Water for injection adds to 2L.

Preparation process includes：

1) 80% water for injection of recipe quantity is taken, first the disodium hydrogen phosphate of recipe quantity is added in and mosatil is stirred to molten Solution, it is spare；

2) 1 is taken）Middle solution adds in 0.1mol/L sodium hydrate aqueous solutions, adjusts pH to 7.5；

3) by 2）The Parecoxib Sodium of recipe quantity is added in solution, stirring is complete to dissolving；

4) 3 are taken）Solution adds in 0.1% needle charcoal of the amount of solution, after stirring completely, places 20 minutes, filters, filling It penetrates with water to full dose, measure liquid initial pH value；

5) 4 are taken）Solution adds in 0.1mol/L sodium hydrate aqueous solutions, adjusts pH value range 7.5~8.0；

6) it is qualified to visible foreign matters using 0.45 μm and 0.22 μm of miillpore filter refined filtration；

7) Quality control of intermediates：Detect SC 69124 sodium content, pH value, it is seen that the detection projects such as foreign matter；

8) it according to intermediates content, adjusts loading amount and confirms loading amount range, carry out filling, half tamponade；

9) sample that will have been dispensed is fitted into freeze dryer, and sample is refrigerated to -50~-40 DEG C, keep temperature freezing 3~ 4 hours, 2~8pa is evacuated to after freezing, is slowly heated uniformly to 0~5 DEG C, then stops heating up, holding temperature drying 10~ 20 hours, then 20~25 DEG C were warming up in 10~20 hours, then stop heating, heat preservation and dryness 4~5 hours, tamponade goes out Case；

10) by obtained sample outlet, lid is rolled to get SC 69124 sodium pharmaceutical composition.

2 embodiment of the present invention of test example is compared with the lyophilized technique and effect of comparative example

The external forming of SC 69124 sodium freeze-dried preparation and internal soundness are heavily dependent on the quality of lyophilized technique. Our Parecoxib Sodiums as obtained by by prescription dispensing of the present invention use different lyophilized techniques with the midbody solution after liquid The freeze-drying prods of gained are prepared, investigate its indices.We are from moisture, appearance, redissolve speed, redissolve clarity and carry out pair Than.

Moisture takes this product to be measured according to Chinese Pharmacopoeia latest edition aquametry.

Dissolution time takes 3 bottles of sample, every bottle plus 0.9% sodium chloride solution, and 20mg specifications add 1mL, and 40mg specifications add 2mL is gently shaked, and the time is redissolved in observation.

The clarity of solution takes the solution under dissolution time item that should clarify, such as aobvious muddiness, compared with No. 1 turbidity standard, It must not be denseer.

Test example 3 is by Examples 1 and 2, SC 69124 sodium freeze-dried preparation made from comparative example 1 and 2, to it at 60 DEG C and Thimble test in 90 days is compared

Upper table is it is found that in thimble test of the embodiment of the present invention 1 and 2 in 60 DEG C and 90 days, hence it is evident that due to right Ratio 1 and 2.

Test example 4 matches charging sequence during liquid

For the preparation prescription of the present invention, main ingredient Parecoxib Sodium, freeze drying protectant glycine, lyophilisation additives uncle are shared Butanol, disodium hydrogen phosphate and phosphoric acid conditioning agent need to add, influence of the different charging sequence to main ingredient solution rate.

Charging sequence 1：Water for injection is first dissolved into Parecoxib Sodium, adds the glycine of recipe quantity, the tert-butyl alcohol and phosphorus Sour disodium hydrogen.

Phenomenon is：Main ingredient does not dissolve, after adding in disodium hydrogen phosphate and glycine, the tert-butyl alcohol, slow mechanism dissolved.

Charging sequence 2：The disodium hydrogen phosphate of recipe quantity and Parecoxib Sodium are added in water for injection simultaneously, added in Glycine and the tert-butyl alcohol.

Phenomenon is：Solid starts not dissolving, with slow mechanism dissolved after stirring.

Charging sequence 3：The glycine of recipe quantity and the tert-butyl alcohol first are dissolved with 90% water for injection, is subsequently added into Shi Ershui Disodium hydrogen phosphate so that pH maintains 35-40 DEG C of temperature later between 8.9-9.1, rapidly joins the SC 69124 of recipe quantity Sodium is allowed to dissolve rapidly.

Phenomenon is：Main ingredient quickly dissolves, and solution is clarified after dissolving.

5 embodiment of the present invention of test example and the influence factor comparative studies of commercial product

2 gained sample of embodiment and commercially available product are compared, are respectively placed in the illumination of 4500 ± 500Lx, 60 ± 2 DEG C High temperature, 10 days in 92.5% high humidity insulating box, respectively at 0 day, 10 days to its character, pH value and related substance is checked and city It sells sample to compare, as a result see the table below.

6 vascular stimulation tests of test example

Hemolytic test：The lyophilized preparation of the 40mg specifications of embodiment 2 is added in into 0.9% sodium chloride solution 2mL, dissolving shakes up, It is added in 2% rabbit erythrocyte suspension, 6h is observed continuously, haemolysis occurs in each Guan Junwei.

Sensitivity test：The lyophilized preparation of the 40mg specifications of embodiment 2 is added in into 0.9% sodium chloride solution 2mL, dissolving is shaken It is even, the test of sensitivity response is carried out to the auricular vein of cavy, after exciting administration twice, does not observe and searches, roll up, erect The sensitization phenomenons such as hair, expiratory dyspnea, death, show the freeze-drying parenteral solution of the present invention does not have sensitization to animal subject object.

Vascular stimulation tests：The lyophilized preparation of the 40mg specifications of embodiment 2 is added in into 0.9% sodium chloride solution 2mL, needle Rabbit auricular vein is injected, Histopathology the result shows that：Ear's normal configuration exists, Mild edema, ear vein Tube wall is intact, has no downright bad, and blood engorgement in tube chamber has no thrombus, the intact nothing of vascular endothelial cell comes off.Compared to solvent group Ear vein pathomorphology change it is similar, have no the reaction of notable blood vessel irritation.

The foregoing is merely illustrative of the preferred embodiments of the present invention, is not limited to the substantial technological content of the present invention, The substantial technological content of the present invention is broadly to be defined in the right of application to summarize, and any technology that other people complete is real Body or method, if with the right of application defined in it is identical, also or a kind of equivalent change, will be by It is considered as and is covered by among present claims range.

Claims (7)

1. a kind of preparation method of the SC 69124 sodium pharmaceutical composition of the injection of stabilization, which is characterized in that comprising as follows Step：

(1) auxiliary material disodium hydrogen phosphate, glycine and the tert-butyl alcohol are dissolved with 90% water for injection, at a certain temperature Main ingredient Parecoxib Sodium is added in, between adjusting pH to 8.15~8.25 with 0.3M phosphoric acid solutions, moisturizing to full dose, 0.2um polyethers Sulfone membrane filtration, it is filling in 7ml cillin bottles；

(2) the pre-freeze stage：Above-mentioned SC 69124 sodium freeze-dried preparation midbody solution is cooled down using the rate of 20 DEG C/h, be down to- 40 DEG C~-50 DEG C, 4h is kept the temperature, then shelf temperature is risen to -30 DEG C, keep 2~3h；

(3) sublimation stage：It opens vacuum pump to vacuumize, case vacuum degree adjusts baffle temperature -15~-20 less than 200Pa before treating Between DEG C, vacuum pressure is maintained in 80~220Pa, holding 2-3h；Then, it between shelf temperature being dropped to -30~-35 DEG C, protects Hold 1~2h；Shelf temperature is increased at -5~0 DEG C again, maintains vacuum pressure in 80~220Pa, keeps 5~10h until water Stain heading line off；

(4) the parsing-desiccation stage 1：Shelf temperature is warmed to room temperature 20 DEG C, keeps 2h, and plate layer temperature is down to 0 DEG C, keeps 2h；

(5) the parsing-desiccation stage 2：Shelf temperature rises to 45 DEG C, keeps 4h, closes vacuum pump；

(6) by obtained sample outlet, lid is rolled to get SC 69124 sodium freeze-dried preparation.

2. preparation method according to claim 1, which is characterized in that in step (1), particularly first with 90% injection Water come dissolve the glycine of recipe quantity and the tert-butyl alcohol and then add in disodium hydrogen phosphate so that pH 8.9~9.1 it Between, it maintains at 35~40 DEG C of temperature, rapidly joins Parecoxib Sodium, be allowed to dissolve rapidly.

3. preparation method according to claim 1, which is characterized in that in step (3), the vacuum pressure of sublimation stage maintains In 200~220Pa.

4. preparation method according to claim 1, which is characterized in that in step (4) and (5), the parsing-desiccation stage it is true Pneumatics power maintains 140~160Pa.

5. preparation method according to claim 1, which is characterized in that in step (4), the heating rate of shelf for 10 DEG C/ H, 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.

6. a kind of SC 69124 sodium pharmaceutical composition of the injection of stabilization, which is characterized in that it is using claim 1 institute The lyophilized preparation that specification made of preparation method is 20mg is stated, it is specific as follows：

Its prescription is,

Parecoxib Sodium 0.43g,

Disodium hydrogen phosphate 0.072g,

Glycine 0.2g,

Tert-butyl alcohol 0.1g,

Between 0.3M phosphorus acid for adjusting pH is 8.15~8.25,

It injects water to liquid total volume 20ml；

Preparation method is as follows,

(1) glycine of recipe quantity and the tert-butyl alcohol first are dissolved with 90% water for injection, are subsequently added into disodium hydrogen phosphate, So that pH between 8.9~9.1, maintains 35~40 DEG C of temperature, rapidly joins the Parecoxib Sodium of recipe quantity, be allowed to rapid later Dissolving, between adjusting pH to 8.15~8.25 with 0.3M phosphoric acid solutions, moisturizing to full dose, 0.2um polyethersulfone membranes filter, filling In 7ml cillin bottles；

(2) the pre-freeze stage：Above-mentioned SC 69124 sodium freeze-dried preparation midbody solution is cooled down using the rate of 20 DEG C/h so that sample Product temperature degree is down to -40 DEG C~-50 DEG C, keeps the temperature 4h, and shelf temperature is risen to -30 DEG C, keeps 2~3h；

(3) sublimation stage：Vacuum pump is opened to vacuumize, after case vacuum degree is less than 200Pa before, adjusting baffle temperature to -15~- 20 DEG C, vacuum pressure is maintained in 200~220Pa, 2~3h of holding；Then, shelf temperature is down to -30~-35 DEG C, keep 1~ 2h；Shelf temperature is increased -5~0 DEG C again, maintains vacuum pressure in 200~220Pa, 5~10h of holding to water stain heading line off；

(4) the parsing-desiccation stage 1：Vacuum pressure is maintained shelf temperature to be warmed to room temperature 20 DEG C, heating rate in 140~160Pa For 10 DEG C/h, 2h is kept, plate layer temperature is down to 0 DEG C, rate of temperature fall is 20 DEG C/h, keeps 2h；

(5) the parsing-desiccation stage 2：Vacuum pressure is maintained shelf temperature to be risen to 45 DEG C, heating rate 15 in 140~160Pa DEG C/h, 4h is kept, closes vacuum pump；

(6) by obtained sample outlet, lid is rolled to get SC 69124 sodium freeze-dried preparation.

7. a kind of SC 69124 sodium pharmaceutical composition of the injection of stabilization, which is characterized in that it is using claim 1 institute The lyophilized preparation that specification made of preparation method is 40mg is stated, it is specific as follows：

Its prescription is,

Parecoxib Sodium 0.85g,

Disodium hydrogen phosphate 0.15g,

Glycine 0.4g,

Tert-butyl alcohol 0.2g,

Between 0.3M phosphorus acid for adjusting pH is 8.15~8.25,

It injects water to liquid total volume 40ml；

Preparation method is,

(1) glycine of recipe quantity and the tert-butyl alcohol first are dissolved with 90% water for injection, are subsequently added into disodium hydrogen phosphate, So that pH between 8.9~9.1, maintains 35~40 DEG C of temperature, rapidly joins the Parecoxib Sodium of recipe quantity, be allowed to rapid later Dissolving, between adjusting pH to 8.15~8.25 with 0.3M phosphoric acid solutions, moisturizing to full dose, 0.2um polyethersulfone membranes filter, filling In 7ml cillin bottles；

(2) the pre-freeze stage：Above-mentioned SC 69124 sodium freeze-dried preparation midbody solution is cooled down using the rate of 20 DEG C/h so that sample Product temperature degree is down to -40 DEG C~-50 DEG C, keeps the temperature 4h, and shelf temperature is risen to -30 DEG C, keeps 2~3h；

(3) sublimation stage：Vacuum pump is opened to vacuumize, after case vacuum degree is less than 200Pa before, adjusting baffle temperature to -15~- 20 DEG C, vacuum pressure is maintained in 200~220Pa, 2~3h of holding；Then, shelf temperature is down to -30~-35 DEG C, keep 1~ 2h；Shelf temperature is increased -5~0 DEG C again, maintains vacuum pressure in 200~220Pa, 5~10h of holding to water stain heading line off；

(4) the parsing-desiccation stage 1：Vacuum pressure is maintained shelf temperature to be warmed to room temperature 20 DEG C, heating rate in 140~160Pa For 10 DEG C/h, 2h is kept, plate layer temperature is down to 0 DEG C, rate of temperature fall is 20 DEG C/h, keeps 2h；

(5) the parsing-desiccation stage 2：Vacuum pressure is maintained shelf temperature to be risen to 45 DEG C, heating rate 15 in 140~160Pa DEG C/h, 4h is kept, closes vacuum pump；

(6) by obtained sample outlet, lid is rolled to get SC 69124 sodium freeze-dried preparation.