CN104414980A - Fosaprepitant dimeglumine composition for injection and preparation method thereof - Google Patents
Fosaprepitant dimeglumine composition for injection and preparation method thereof Download PDFInfo
- Publication number
- CN104414980A CN104414980A CN201310367184.0A CN201310367184A CN104414980A CN 104414980 A CN104414980 A CN 104414980A CN 201310367184 A CN201310367184 A CN 201310367184A CN 104414980 A CN104414980 A CN 104414980A
- Authority
- CN
- China
- Prior art keywords
- fosaprepitant
- injection
- compositions
- stearic acid
- disodium edetate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
The invention relates to a fosaprepitant dimeglumine composition for injection and a preparation method thereof, the pharmaceutical composition is composed of fosaprepitant dimeglumine, 15-polyethylene glycol hydroxystearate and sodium calcium edentate, prescription is simple, technology is simple, and the prepared product has the advantages of stable quality, safety and reliability.
Description
Technical field
The present invention relates to a kind of medicinal composition for injections and preparation technology thereof, particularly a kind of injection fosaprepitant composition and method of making the same, belongs to medical art.
Background technology
Nausea and vomiting reaction (CIVN) that chemotherapeutics is as serious in the multiple antitumor drug such as platinum class, amycin in use can produce, the nausea and vomiting of acute severe may cause patient to take off water and rock-soil coupling, malnutrition, severe patient may hemorrhage because gastrointestinal mucosal damage, infect even dead, thus make patient feel fear to chemotherapy, compliance obviously reduces, affect therapeutic effect, thus antiemetic is the important adjuvant therapy medicaments of antineoplaston.The main chemotherapy antiemetic used clinically is at present 5-HT antagonist, representing medicine is ondansetron, granisetron etc., this kind of medicine is good to acute CIVN effect, ruggedness, but the delayed emesis curative effect occurred the patient of High Dose Cis-platin Chemotherapy is slight, and untoward reaction is more, and needing medication every day, patient dependence is poor.
Fosaprepitant is Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2/neurokinin 1(NK-1) receptor blocking agent, mainly through blocking the effect of brain nausea and vomiting signal function mechanisms play.The English name of fosaprepitant is fosaprepitantdimeglumine, and molecular formula is C
23h
22f
7n
4o
6p2C
7h
17nO
5, structural formula is:
Fosaprepitant is the prodrug of Aprepitant (aprepitant), changes into Aprepitant rapidly in vivo after injection.Aprepitant is used for the treatment of the nausea and vomiting that chemotherapeutics causes, be applicable to and other Bendectin coupling intravenous injections, prevent and treat the emetic anticarcinogen chemotherapy (comprising High-dose Cisplatin Chemotherapy) of medium emetic and heavy dose initial and cause acute of medication and the nausea and vomiting that lags repeatedly.
Chinese Patent Application No. is 201310105381.5 disclose fosaprepitant injection composition and preparation method thereof, this patent prescription contains lactose, disodium edetate and Tween-80, identical with the prescription of the fosaprepitant injection that the Merck & Co., Inc. that U.S. FDA is ratified goes on the market.Chinese Patent Application No. is 201110104922.3 disclose a kind of sterile freeze-drying preparation containing Fosaprepitant and preparation method thereof, containing solubilizing agent, chelating agent, freeze-dried excipient and acidity regulator in this patent prescription, wherein freeze-dried excipient is selected from mannitol, glucose etc., solubilizing agent is selected from Tween-80, Polyethylene Glycol etc., and chelating agent is selected from disodium edetate, triethanolamine etc.
All select disodium edetate as chelating agent in above-mentioned two patents, select Tween-80 as solubilizing agent.But well-known, disodium edetate can become solvable complex to cause the minimizing of calcium with calcium binding, in intravenous formulations, use can cause blood calcium concentration to decline; The solubilizing effect of Tween-80 is better, but to explicitly point out Tween-80 venous toxicity in pharmaceutic adjuvant handbook be medium, therefore should the least possible use or need not in intravenous formulations.Application number is that the patent use lactose of 201310105381.5 is as excipient, but it is well-known, everyone body constitution is different, produce serious lactose intolerance sometimes, and lactose is a kind of adjuvant of animal origin, may the milk suffering from the diseased n animal such as bovine spongiform encephalopathy be come from, for pharmacy particularly drug administration by injection there is potential safety hazard.
Therefore, this area needs to find one and guarantees fosaprepitant steady quality, and evident in efficacy, toxic and side effects is few, and the compositions that technique is simply new and technique, the present invention meets such demand.
Summary of the invention
For the problems referred to above, the invention provides a kind of new injection fosaprepitant composition and method of making the same, and prescription is simple, technique is easy to operation, and the constant product quality prepared is safe and reliable.
For achieving the above object, injection fosaprepitant compositions provided by the invention, is made up of fosaprepitant, 15-hydroxy stearic acid macrogol ester, calcium disodium edetate.
Injection fosaprepitant compositions of the present invention, the compositions of per unit preparation is composed of the following components: fosaprepitant 150mg ~ 280mg, 15-hydroxy stearic acid macrogol ester 55mg ~ 120mg, calcium disodium edetate 13mg ~ 30mg.
Preferably, the compositions of per unit preparation is composed of the following components: fosaprepitant 170mg ~ 260mg, 15-hydroxy stearic acid macrogol ester 65mg ~ 110mg, calcium disodium edetate 16mg ~ 27mg.
Preferably, the compositions of per unit preparation is composed of the following components: fosaprepitant 180mg ~ 250mg, 15-hydroxy stearic acid macrogol ester 70mg ~ 105mg, calcium disodium edetate 18mg ~ 26mg.
Preferred, the compositions of per unit preparation is composed of the following components: fosaprepitant 188mg ~ 245.3mg, 15-hydroxy stearic acid macrogol ester 76.7mg ~ 100mg, calcium disodium edetate 18.6mg ~ 24.3mg.
Wherein, the compositions of per unit preparation is composed of the following components: fosaprepitant 150mg, 15-hydroxy stearic acid macrogol ester 55mg, calcium disodium edetate 13mg.
Or the compositions of per unit preparation is composed of the following components: fosaprepitant 170mg, 15-hydroxy stearic acid macrogol ester 65mg, calcium disodium edetate 16mg.
Or the compositions of per unit preparation is composed of the following components: fosaprepitant 180mg, 15-hydroxy stearic acid macrogol ester 70mg, calcium disodium edetate 18mg.
Or the compositions of per unit preparation is composed of the following components: fosaprepitant 188mg, 15-hydroxy stearic acid macrogol ester 76.7mg, calcium disodium edetate 18.6mg.
Or the compositions of per unit preparation is composed of the following components: fosaprepitant 245.3mg, 15-hydroxy stearic acid macrogol ester 100mg, calcium disodium edetate 24.3mg.
Or the compositions of per unit preparation is composed of the following components: fosaprepitant 250mg, 15-hydroxy stearic acid macrogol ester 105mg, calcium disodium edetate 26mg.
Or the compositions of per unit preparation is composed of the following components: fosaprepitant 260mg, 15-hydroxy stearic acid macrogol ester 110mg, calcium disodium edetate 27mg.
Or the compositions of per unit preparation is composed of the following components: fosaprepitant 280mg, 15-hydroxy stearic acid macrogol ester 120mg, calcium disodium edetate 30mg.
Present invention also offers a kind of injection fosaprepitant preparation method of composition, the method comprises the following steps:
(1) dosing: the water for injection injecting preparation total amount 70% in Agitation Tank, the temperature of water for injection controls at 20 ~ 30 DEG C, first add 15-hydroxy stearic acid macrogol ester, the calcium disodium edetate of recipe quantity, the fosaprepitant of recipe quantity is added after making dissolving, stirring makes it to dissolve completely, add to the full amount of water for injection, stir, add the needle-use activated carbon of 0.1% of preparation total amount, stir and leave standstill 20 minutes, with the titanium rod metre filter extremely clarification of filter sizes 1.0 μm, medicinal liquid 0.22 μm of+0.22 μm of filter cartridge is carried out filtration sterilization;
(2) fill, half tamponade;
(3) lyophilization: goods in drying box of freeze dryer in-60 DEG C ~-20 DEG C pre-freezes 2 ~ 4 hours, evacuation in casing, be 9 ~ 13 handkerchiefs in vacuum, temperature is under-20 DEG C ~ 0 DEG C condition dry 10 ~ 20 hours, keep this vacuum condition in 0 DEG C ~ 15 DEG C dryings 5 ~ 10 hours, drying 4 ~ 8 hours under 20 DEG C ~ 30 DEG C conditions, tamponade, outlet;
(4) lid, lamp inspection is rolled.
The injection fosaprepitant prepared by the present invention is had the following advantages:
(1) though do not use any excipient in prescription of the present invention, but prepared product appearance is still full, in white loose block, overcome in prior art and need to add the excipient such as lactose, mannitol to maintain the technology prejudice of product design, eliminate the security risk brought owing to adding the adjuvants such as lactose, safety is better simultaneously;
(2) present invention uses calcium disodium edetate as chelating agent, eliminate the defect that prior art causes blood calcium concentration to decline owing to using disodium edetate, use safer;
(3) the present invention uses 15-hydroxy stearic acid macrogol ester as solubilizing agent, it has higher physiological tolerance and low haemolysis, solubilising power is comparatively strong and viscosity is lower, even if can also painless administration when high concentration, while guaranteeing drug-eluting, improves safety in utilization;
(4) product quality is better.Found by Piglet s colibacillosis checking, adopt injection fosaprepitant prepared by prescription of the present invention and technique, in the clarity and color, moisture and related substance of outward appearance, redissolution speed, solution, be all better than prior art; In addition, with 0.9% sodium chloride injection compatibility after in 24 hours the quality of sample be better than the prior art under the same terms.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail, but not limitation of the present invention, and the equivalent replacement of all any this areas done according to the disclosure of invention, all belongs to protection scope of the present invention.
Each embodiment prescription:
Preparation injection fosaprepitant 1000 bottles, the weight of each embodiment Raw is as shown in the table: (unit: g)
Embodiment 1:
Preparation technology: the water for injection injecting 2100ml in Agitation Tank, water for injection temperature is within the scope of 20 DEG C ~ 30 DEG C, first add 15-hydroxy stearic acid macrogol ester 55g, calcium disodium edetate 13g, fosaprepitant 150g is added after making dissolving, stirring makes it to dissolve completely, pH to 8.0 is regulated with 1mol/L hydrochloric acid solution or 1mol/L sodium hydroxide solution, inject water to 3000ml, stir, add the needle-use activated carbon of preparation total amount 0.1%, stir and leave standstill 20 minutes, medicinal liquid 0.22 μm of+0.22 μm of filter cartridge is carried out filtration sterilization; Fill, half tamponade; Goods are in-20 DEG C of pre-freezes 4 hours in drying box of freeze dryer, and evacuation in casing is 9 ~ 13 handkerchiefs in vacuum, temperature is under-20 DEG C ~ 0 DEG C condition dry 10 hours, keeps this vacuum condition in 0 DEG C ~ 15 DEG C dryings 5 hours, under 20 DEG C of conditions dry 7 hours, tamponade, outlet; Roll lid, lamp inspection, obtain injection fosaprepitant.
Embodiment 2:
Preparation technology: the water for injection injecting 2500ml in Agitation Tank, water for injection temperature is within the scope of 20 DEG C ~ 30 DEG C, first add 15-hydroxy stearic acid macrogol ester 65g, calcium disodium edetate 16g, fosaprepitant 170g is added after making dissolving, stirring makes it to dissolve completely, pH to 8.2 is regulated with 1mol/L hydrochloric acid solution or 1mol/L sodium hydroxide solution, inject water to 3000ml, stir, add the needle-use activated carbon of preparation total amount 0.1%, stir and leave standstill 20 minutes, medicinal liquid 0.22 μm of+0.22 μm of filter cartridge is carried out filtration sterilization; Fill, half tamponade; Goods are in-30 DEG C of pre-freezes 4 hours in drying box of freeze dryer, and evacuation in casing is 9 ~ 13 handkerchiefs in vacuum, temperature is under-20 DEG C ~ 0 DEG C condition dry 13 hours, keeps this vacuum condition in 0 DEG C ~ 15 DEG C dryings 6 hours, under 25 DEG C of conditions dry 5 hours, tamponade, outlet; Roll lid, lamp inspection, obtain injection fosaprepitant.
Embodiment 3:
Preparation technology: the water for injection injecting 2500ml in Agitation Tank, water for injection temperature is within the scope of 20 DEG C ~ 30 DEG C, first add 15-hydroxy stearic acid macrogol ester 70g, calcium disodium edetate 18g, fosaprepitant 180g is added after making dissolving, stirring makes it to dissolve completely, pH to 8.2 is regulated with 1mol/L hydrochloric acid solution or 1mol/L sodium hydroxide solution, inject water to 3000ml, stir, add the needle-use activated carbon of preparation total amount 0.1%, stir and leave standstill 20 minutes, medicinal liquid 0.22 μm of+0.22 μm of filter cartridge is carried out filtration sterilization; Fill, half tamponade; Goods are in-30 DEG C of pre-freezes 3 hours in drying box of freeze dryer, and evacuation in casing is 9 ~ 13 handkerchiefs in vacuum, temperature is under-20 DEG C ~ 0 DEG C condition dry 14 hours, keeps this vacuum condition in 0 DEG C ~ 15 DEG C dryings 7 hours, under 25 DEG C of conditions dry 5 hours, tamponade, outlet; Roll lid, lamp inspection, obtain injection fosaprepitant.
Embodiment 4:
Preparation technology: the water for injection injecting 2800ml in Agitation Tank, water for injection temperature is within the scope of 20 DEG C ~ 30 DEG C, first add 15-hydroxy stearic acid macrogol ester 76.7g, calcium disodium edetate 18.6g, fosaprepitant 188g is added after making dissolving, stirring makes it to dissolve completely, pH to 8.3 is regulated with 1mol/L hydrochloric acid solution or 1mol/L sodium hydroxide solution, inject water to 3000ml, stir, add the needle-use activated carbon of preparation total amount 0.1%, stir and leave standstill 20 minutes, medicinal liquid 0.22 μm of+0.22 μm of filter cartridge is carried out filtration sterilization, fill, half tamponade, goods are in-40 DEG C of pre-freezes 3 hours in drying box of freeze dryer, and evacuation in casing is 9 ~ 13 handkerchiefs in vacuum, temperature is under-20 DEG C ~ 0 DEG C condition dry 15 hours, keeps this vacuum condition in 0 DEG C ~ 15 DEG C dryings 8 hours, under 25 DEG C of conditions dry 6 hours, tamponade, outlet, roll lid, lamp inspection, obtain injection fosaprepitant.
Embodiment 5:
Preparation technology: the water for injection injecting 2800ml in Agitation Tank, water for injection temperature is within the scope of 20 DEG C ~ 30 DEG C, first add 15-hydroxy stearic acid macrogol ester 100g, calcium disodium edetate 24.3g, fosaprepitant 245.3g is added after making dissolving, stirring makes it to dissolve completely, pH to 8.3 is regulated with 1mol/L hydrochloric acid solution or 1mol/L sodium hydroxide solution, inject water to 3900ml, stir, add the needle-use activated carbon of preparation total amount 0.1%, stir and leave standstill 20 minutes, medicinal liquid 0.22 μm of+0.22 μm of filter cartridge is carried out filtration sterilization, fill, half tamponade, goods are in-40 DEG C of pre-freezes 3 hours in drying box of freeze dryer, and evacuation in casing is 9 ~ 13 handkerchiefs in vacuum, temperature is under-20 DEG C ~ 0 DEG C condition dry 15 hours, keeps this vacuum condition in 0 DEG C ~ 15 DEG C dryings 5 hours, under 25 DEG C of conditions dry 6 hours, tamponade, outlet, roll lid, lamp inspection, obtain injection fosaprepitant.
Embodiment 6:
Preparation technology: the water for injection injecting 3200ml in Agitation Tank, water for injection temperature is within the scope of 20 DEG C ~ 30 DEG C, first add 15-hydroxy stearic acid macrogol ester 105g, calcium disodium edetate 26g, fosaprepitant 250g is added after making dissolving, stirring makes it to dissolve completely, pH to 8.4 is regulated with 1mol/L hydrochloric acid solution or 1mol/L sodium hydroxide solution, inject water to 3900ml, stir, add the needle-use activated carbon of preparation total amount 0.1%, stir and leave standstill 20 minutes, medicinal liquid 0.22 μm of+0.22 μm of filter cartridge is carried out filtration sterilization; Fill, half tamponade; Goods are in-50 DEG C of pre-freezes 3 hours in drying box of freeze dryer, and evacuation in casing is 9 ~ 13 handkerchiefs in vacuum, temperature is under-20 DEG C ~ 0 DEG C condition dry 17 hours, keeps this vacuum condition in 0 DEG C ~ 15 DEG C dryings 7 hours, under 30 DEG C of conditions dry 4 hours, tamponade, outlet; Roll lid, lamp inspection, obtain injection fosaprepitant.
Embodiment 7:
Preparation technology: the water for injection injecting 3200ml in Agitation Tank, water for injection temperature is within the scope of 20 DEG C ~ 30 DEG C, first add 15-hydroxy stearic acid macrogol ester 110g, calcium disodium edetate 27g, fosaprepitant 260g is added after making dissolving, stirring makes it to dissolve completely, pH to 8.4 is regulated with 1mol/L hydrochloric acid solution or 1mol/L sodium hydroxide solution, inject water to 3900ml, stir, add the needle-use activated carbon of preparation total amount 0.1%, stir and leave standstill 20 minutes, medicinal liquid 0.22 μm of+0.22 μm of filter cartridge is carried out filtration sterilization; Fill, half tamponade; Goods are in-50 DEG C of pre-freezes 2 hours in drying box of freeze dryer, and evacuation in casing is 9 ~ 13 handkerchiefs in vacuum, temperature is under-20 DEG C ~ 0 DEG C condition dry 17 hours, keeps this vacuum condition in 0 DEG C ~ 15 DEG C dryings 7 hours, under 30 DEG C of conditions dry 4 hours, tamponade, outlet; Roll lid, lamp inspection, obtain injection fosaprepitant.
Embodiment 8:
Preparation technology: the water for injection injecting 3500ml in Agitation Tank, water for injection temperature is within the scope of 20 DEG C ~ 30 DEG C, first add 15-hydroxy stearic acid macrogol ester 120g, calcium disodium edetate 30g, fosaprepitant 280g is added after making dissolving, stirring makes it to dissolve completely, pH to 8.6 is regulated with 1mol/L hydrochloric acid solution or 1mol/L sodium hydroxide solution, inject water to 3900ml, stir, add the needle-use activated carbon of preparation total amount 0.1%, stir and leave standstill 20 minutes, medicinal liquid 0.22 μm of+0.22 μm of filter cartridge is carried out filtration sterilization; Fill, half tamponade; Goods are in-60 DEG C of pre-freezes 2 hours in drying box of freeze dryer, and evacuation in casing is 9 ~ 13 handkerchiefs in vacuum, temperature is under-20 DEG C ~ 0 DEG C condition dry 20 hours, keeps this vacuum condition in 0 DEG C ~ 15 DEG C dryings 10 hours, under 20 DEG C of conditions dry 8 hours, tamponade, outlet; Roll lid, lamp inspection, obtain injection fosaprepitant.
Comparative formulation 1: injection fosaprepitant commercially available product, trade name: EMEND, specification: 115mg, manufacturer: Merck & Co., Inc.
Comparative formulation 2: be that the prescription of 201110104922.3 embodiments 4 and technique prepare Comparative formulation 2, specification: 150mg according to Chinese Patent Application No..
Test example 1 quality research is tested
Get sample and Comparative formulation 1, each 20 of Comparative formulation 2 sample of the embodiment of the present invention 2,4,5,7 preparation, respectively high temperature (40 DEG C, RH75%), illumination (4500lx, 25 DEG C) place 10 days under condition, carry out the mensuration of outward appearance, redissolution speed, the clarity of solution and color, moisture, related substance respectively at sampling in the 0th day, 5 days, 10 days, result of the test is as shown in table 1.
Table 1 embodiment of the present invention and Comparative formulation quality comparation
Result shows, 0 day time, the outward appearance of product prepared by the embodiment of the present invention and Comparative formulation 2 sample is full, and in white loose block, solution is colourless clear liquid, but Comparative formulation 1 sample is off-white color, and solution is faint yellow; The moisture of embodiment of the present invention preparing product, principal degradation impurity Aprepitant amount and total impurities amount are all starkly lower than Comparative formulation 1 and Comparative formulation 2, and speed of redissolving is obviously faster than Comparative formulation 1 and Comparative formulation 2 sample.
Place after 10 days under high temperature (40 DEG C, RH75%) condition, product prepared by the embodiment of the present invention and Comparative formulation 2 sample substantially unchanged in outward appearance, clarity, but the redissolution speed of Comparative formulation 2 sample is obviously slack-off; Comparative formulation 1 sample appearance generation significant change, becomes off-white color atrophy block from the off-white color block that loosens, and speed of redissolving is obviously slack-off, and solution is faint yellow, and the color of sample when being deeper than 0 day; Product prepared by the embodiment of the present invention and Comparative formulation 1,2 increase all to some extent in moisture, principal degradation impurity Aprepitant amount and total impurities amount three indexs, but embodiment of the present invention sample is starkly lower than Comparative formulation 1,2 sample.
At illumination condition (4500lx, 25 DEG C) under place after 10 days, product prepared by the embodiment of the present invention and Comparative formulation 2 sample are in outward appearance, redissolution speed, clarity aspect has no significant change, and Comparative formulation 1 sample appearance generation significant change, become off-white color atrophy block from the off-white color block that loosens, redissolution slows, and solution colour is slightly deepened; Product prepared by the embodiment of the present invention is compared with Comparative formulation 1,2 sample, and moisture, principal degradation impurity Aprepitant amount and total impurities amount all slowly increase, but is starkly lower than Comparative formulation 1,2 sample.
As can be seen from the above results, embodiment of the present invention sample outward appearance, redissolve speed, the clarity of solution and color, moisture, Aprepitant amount and total impurities amount aspect are all better than Comparative formulation 1, Comparative formulation 2 sample, product quality and stability better.
Test example 2 compatibility mechanism
The usage and dosage that injection fosaprepitant description according to FDA approval specifies, respectively the embodiment of the present invention 2,4,5,7 sample and Comparative formulation 1,2 sample 0.9% sodium chloride injection are mixed with the solution that Fosaprepitant concentration is 1mg/ml, investigate its after compatibility when ambient temperatare sets to 0 h, 12h, 24h the situation of change of character, content and related substance.Result of the test sees the following form.
Table 2 compatibility mechanism result
Result shows: after embodiment 2,4,5,7 sample compatibility, obvious change does not all occur for the character of medicinal liquid and content, and after Comparative formulation 1,2 sample compatibility, medicinal liquid clarity of solution when 24h slightly changes; After compatibility, in medicinal liquid of the present invention, the content of Aprepitant slightly increases, and in Comparative formulation 1,2 sample, the amount of Aprepitant obviously increases.Place in 24h process with 0.9% sodium chloride injection compatibility as can be seen from the test results, the clarity of the embodiment of the present invention 2,4,5,7 sample solution is better, and Aprepitant content and total impurities amount are all well below Comparative formulation 1 and Comparative formulation 2 sample, after inventive samples and 0.9% sodium chloride injection compatibility are described, in 24h, the quality of sample is better than Comparative formulation 1 under the same terms and Comparative formulation 2 sample.
Test example 3 safety testing
By hemolytic and Local irritation study, the safety of injection fosaprepitant compositions prepared by the present invention is verified.
(1) haemolysis and agglutination test
The preparation of 2% red blood cell suspension: get healthy rabbits blood, put into conical flask, stir blood with Glass rod, to remove Fibrinogen, makes into defibrinated blood.Add 0.9% sodium chloride solution about 10 times amount, shake up, per minute 1000 ~ 1500 leave the heart 15 minutes, removing supernatant, and the erythrocyte of precipitation washs 2 ~ 3 times as stated above with 0.9% sodium chloride solution again, to the not aobvious redness of supernatant.The erythrocyte of gained is made the suspension of 2% with 0.9% sodium chloride solution, be for experiment.
The preparation of need testing solution: embodiment 2, embodiment 4, embodiment 5, embodiment 7 sample are mixed with the solution that Fosaprepitant concentration is 1mg/ml, respectively as need testing solution with 0.9% sodium chloride injection.
Get 14, cleaned glass test tube and number, wherein 1, No. 2 pipe is embodiment 2 sample test sample pipe, 3, No. 4 pipes are embodiment 4 sample test sample pipe, and 5, No. 6 pipes are embodiment 5 sample test sample pipe, and 7, No. 8 pipes are embodiment 7 sample test sample pipe, No. 9 pipes are negative control pipe, No. 10 pipes are positive control pipe, and No. 11 pipes are embodiment 2 test sample control tube, and No. 12 pipes are embodiment 4 test sample control tube, No. 13 pipes are embodiment 5 test sample control tube, and No. 14 pipes are embodiment 7 test sample control tube.Add 2% red cell suspension, 0.9% sodium chloride solution, distilled water shown according to the form below successively, after mixing, put immediately in the calorstat of 37 DEG C ± 0.5 DEG C and carry out incubation, after 3 hours, observe haemolysis and aggregation.
Table 3 haemolysis and agglutination test scheme
The haemolysis situation of each pipe of perusal, found that, at once occurs haemolysis after positive control pipe (No. 10 pipes) adds distilled water; 11 ~ No. 14 pipes are colourless clear liquid, and 1 ~ No. 9 pipe erythrocyte sinks, and supernatant achromatism and clarity, manages almost zero difference with 11 ~ No. 14, shows that the embodiment of the present invention 2,4 and embodiment 5,7 sample occur without haemolysis; Reversed 3 times gently by 1 ~ No. 9 pipe, visible red cell evenly scatters, and proves without red blood cell condensation.Result shows: the injection fosaprepitant that the embodiment of the present invention 2,4 and embodiment 5,7 provide to family's rabbit erythrocyte without haemolysis and cause cohesion.
(2) irritation test
Get health, ear edge not damaged rabbit 30, be divided into A, B, C, D, E five groups at random, often organize 6.Wherein, A group: embodiment 2 sample+0.9% sodium chloride injection group, B group: embodiment 4 sample+0.9% sodium chloride injection group, C group: embodiment 5 sample+0.9% sodium chloride injection group, D group: embodiment 7 sample+0.9% sodium chloride injection group, E group: 0.9% sodium chloride injection matched group.To be in the intravenous drip of rabbit ear edge above-mentioned A, B, C, D, E five groups of injection with aseptic manipulation respectively.Through multiple dosing, perusal phenomenon is: when vein slowly instils, animal is without struggle reaction, and medication local has no the symptom such as congested, red and swollen, and blood vessel lines is very clear, and surrounding tissue is without obvious edema.Histopathologic slide's check result is visible: auricular vein is without endothelial denudation, and Endothelial Structure is complete, without thrombosis, also has no other extremely, compares no significant difference with 0.9% sodium chloride injection group.Result shows, injection fosaprepitant compositions of the present invention is to blood vessel nonirritant.
Known by above-mentioned result of the test, the injection fosaprepitant compositions adopting prescription of the present invention and technique to prepare, prescription is simple, do not add lactose and make excipient, reduce security risk, use calcium disodium edetate as chelating agent simultaneously, solve the problem that blood calcium concentration reduces, employ safety and solubilizing effect better 15-hydroxy stearic acid macrogol ester as solubilizing agent simultaneously, further ensure the safety of product; Preparation process is easy to operation, and carries out drying by lower temperature, ensure that the quality of product better.Adopt the constant product quality that prescription of the present invention and technique prepare, safe and effective, comparatively prior art tool has made marked progress, and is more suitable for industrialized great production.
Claims (10)
1. an injection fosaprepitant compositions, is characterized in that said composition is made up of fosaprepitant, 15-hydroxy stearic acid macrogol ester, calcium disodium edetate.
2. injection fosaprepitant compositions according to claim 1, it is characterized in that, the compositions of per unit preparation is composed of the following components: fosaprepitant 150mg ~ 280mg, 15-hydroxy stearic acid macrogol ester 55mg ~ 120mg, calcium disodium edetate 13mg ~ 30mg.
3. injection fosaprepitant compositions according to claim 2, it is characterized in that, the compositions of per unit preparation is composed of the following components: fosaprepitant 170mg ~ 260mg, 15-hydroxy stearic acid macrogol ester 65mg ~ 110mg, calcium disodium edetate 16mg ~ 27mg.
4. injection fosaprepitant compositions according to claim 2, it is characterized in that, the compositions of per unit preparation is composed of the following components: fosaprepitant 180mg ~ 250mg, 15-hydroxy stearic acid macrogol ester 70mg ~ 105mg, calcium disodium edetate 18mg ~ 26mg.
5. injection fosaprepitant compositions according to claim 2, it is characterized in that, the compositions of per unit preparation is composed of the following components: fosaprepitant 188mg ~ 245.3mg, 15-hydroxy stearic acid macrogol ester 76.7mg ~ 100mg, calcium disodium edetate 18.6mg ~ 24.3mg.
6. injection fosaprepitant compositions according to claim 2, it is characterized in that, the compositions of per unit preparation is composed of the following components: fosaprepitant 150mg, 15-hydroxy stearic acid macrogol ester 55mg, calcium disodium edetate 13mg.
7. injection fosaprepitant compositions according to claim 2, it is characterized in that, the compositions of per unit preparation is composed of the following components: fosaprepitant 188mg, 15-hydroxy stearic acid macrogol ester 76.7mg, calcium disodium edetate 18.6mg.
8. injection fosaprepitant compositions according to claim 2, it is characterized in that, the compositions of per unit preparation is composed of the following components: fosaprepitant 245.3mg, 15-hydroxy stearic acid macrogol ester 100mg, calcium disodium edetate 24.3mg.
9. injection fosaprepitant compositions according to claim 2, it is characterized in that, the compositions of per unit preparation is composed of the following components: fosaprepitant 280mg, 15-hydroxy stearic acid macrogol ester 120mg, calcium disodium edetate 30mg.
10. the injection fosaprepitant preparation method of composition described in any one of claim 1 ~ 9, it is characterized in that, the method comprises the following steps:
(1) dosing: the water for injection injecting preparation total amount 70% in Agitation Tank, the temperature of water for injection controls at 20 ~ 30 DEG C, first add 15-hydroxy stearic acid macrogol ester, the calcium disodium edetate of recipe quantity, the fosaprepitant of recipe quantity is added after making dissolving, stirring makes it to dissolve completely, add to the full amount of water for injection, stir, add the needle-use activated carbon of preparation total amount 0.1%, stir and leave standstill 20 minutes, with the titanium rod metre filter extremely clarification of filter sizes 1.0 μm, medicinal liquid 0.22 μm of+0.22 μm of filter cartridge is carried out filtration sterilization;
(2) fill, half tamponade;
(3) lyophilization: goods in drying box of freeze dryer in-60 DEG C ~-20 DEG C pre-freezes 2 ~ 4 hours, evacuation in casing, be 9 ~ 13 handkerchiefs in vacuum, temperature is under-20 DEG C ~ 0 DEG C condition dry 10 ~ 20 hours, keep this vacuum condition in 0 DEG C ~ 15 DEG C dryings 5 ~ 10 hours, drying 4 ~ 8 hours under 20 DEG C ~ 30 DEG C conditions, tamponade, outlet;
(4) lid, lamp inspection is rolled.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310367184.0A CN104414980B (en) | 2013-08-22 | 2013-08-22 | A kind of injection fosaprepitant dimeglumine compositionss and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310367184.0A CN104414980B (en) | 2013-08-22 | 2013-08-22 | A kind of injection fosaprepitant dimeglumine compositionss and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104414980A true CN104414980A (en) | 2015-03-18 |
| CN104414980B CN104414980B (en) | 2017-03-29 |
Family
ID=52965807
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310367184.0A Active CN104414980B (en) | 2013-08-22 | 2013-08-22 | A kind of injection fosaprepitant dimeglumine compositionss and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104414980B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023078171A1 (en) * | 2021-11-02 | 2023-05-11 | 上海博志研新药物技术有限公司 | Fosaprepitant-containing liquid pharmaceutical composition, preparation method therefor, and use thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102166199A (en) * | 2011-04-02 | 2011-08-31 | 武汉希熙生物科技有限公司 | Preparation method of fosaprepitant dimeglumine freeze-dried preparation for injection |
| CN102755296A (en) * | 2011-04-26 | 2012-10-31 | 齐鲁制药有限公司 | Sterile lyophilized preparation containing fosaprepitant, and preparation method thereof |
| CN103156813A (en) * | 2013-03-29 | 2013-06-19 | 山东罗欣药业股份有限公司 | Fosaprepitant dimeglumine injection composition and preparation method thereof |
-
2013
- 2013-08-22 CN CN201310367184.0A patent/CN104414980B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102166199A (en) * | 2011-04-02 | 2011-08-31 | 武汉希熙生物科技有限公司 | Preparation method of fosaprepitant dimeglumine freeze-dried preparation for injection |
| CN102755296A (en) * | 2011-04-26 | 2012-10-31 | 齐鲁制药有限公司 | Sterile lyophilized preparation containing fosaprepitant, and preparation method thereof |
| CN103156813A (en) * | 2013-03-29 | 2013-06-19 | 山东罗欣药业股份有限公司 | Fosaprepitant dimeglumine injection composition and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 易红等: "几种注射用表面活性剂的质量标准及安全性概述", 《中国实验方剂学杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023078171A1 (en) * | 2021-11-02 | 2023-05-11 | 上海博志研新药物技术有限公司 | Fosaprepitant-containing liquid pharmaceutical composition, preparation method therefor, and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104414980B (en) | 2017-03-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102755296B (en) | Sterile lyophilized preparation containing fosaprepitant, and preparation method thereof | |
| CN102512378B (en) | Stable and safe oxiracetam pharmaceutical composition for injection | |
| CN102225063A (en) | Pantoprazole sodium composition for injection | |
| AU2019321089A1 (en) | Liquid bendamustine pharmaceutical compositions | |
| CN102836171B (en) | Solution for surgery and endoscope washing and preparation method thereof | |
| CN104434819B (en) | Aceglutamide for Injection powder-injection pharmaceutical composition and preparation method | |
| CN114632065A (en) | Freeze-dried preparation and preparation method and application thereof | |
| CN110772480B (en) | Bendamustine medicament composition and application thereof | |
| US8445029B2 (en) | Plasma-adapted full electrolyte solution | |
| CN104971049A (en) | Freeze-dried preparation containing fosaprepitant and preparation method of freeze-dried preparation | |
| CN102784382A (en) | Argatroban drug composition and preparation method and application of argatroban drug composition | |
| CN104414980A (en) | Fosaprepitant dimeglumine composition for injection and preparation method thereof | |
| CN103877032B (en) | Vecuronium bromide pharmaceutical composition for injection and preparation method thereof | |
| CN103948602B (en) | Cefoperazone sodium and tazobactam sodium medicinal composition for injection and preparation method thereof | |
| CA3000634C (en) | Novel ophthalmic composition comprising rebamipide and method for preparing the same | |
| CN115990262A (en) | Damp heat sterilized nimodipine composition without ethanol and phosphatide and its preparing method | |
| CN103877582B (en) | Compound glycyrrhizin medicinal composition for injection and preparation method thereof | |
| CN101491495B (en) | Salvianolic acid B magnesium injection, preparation method and use thereof | |
| CN100560068C (en) | The preparation method of Levogyration sulpiride injection and its | |
| CN105769756B (en) | A kind of fumaric acid Sitafloxacin hydrate injection and preparation method thereof | |
| CN103877578B (en) | Pharmaceutical naloxone hydrochloride composition for injection and preparation method of pharmaceutical naloxone hydrochloride composition | |
| CN103054799A (en) | Amiodarone hydrochloride injection emulsion and preparation method thereof | |
| CN108210451B (en) | Stable breviscapine injection and preparation process thereof | |
| CN103768055A (en) | Etomidate composition for injection and preparation method thereof | |
| CN103110592B (en) | Freeze-drying composition for injection and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Address after: 611731 Chengdu province high tech Zone, west of the source road, No. 8, No. Applicant after: CHENGDU EASTON BIOPHARMACEUTICALS CO., LTD. Address before: 611731 Chengdu province high tech Zone, west of the source road, No. 8, No. Applicant before: Chengdu Easton Pharmaceutical Co., Ltd. |
|
| COR | Change of bibliographic data | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |