CN102697724A - Clopidogrel and salt submicron emulsion injection thereof as well as preparation method of same - Google Patents
Clopidogrel and salt submicron emulsion injection thereof as well as preparation method of same Download PDFInfo
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- CN102697724A CN102697724A CN2012101857003A CN201210185700A CN102697724A CN 102697724 A CN102697724 A CN 102697724A CN 2012101857003 A CN2012101857003 A CN 2012101857003A CN 201210185700 A CN201210185700 A CN 201210185700A CN 102697724 A CN102697724 A CN 102697724A
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Abstract
The invention belongs to the technical field of medicine and relates to clopidogrel and salt submicron emulsion injection thereof as well as a preparation method of the clopidogrel and the salt submicron emulsion injection thereof. Particularly, the invention provides clopidogrel, salt submicron emulsion injection including clopidogrel, salt, oil for injection, assistant emulsifier, isoosmotic adjusting agents, pH adjusting agents and water for injection, and a preparation method of the clopidogrel and the salt submicron emulsion injection. 100 mL of the injection comprises clopidogrel, 0.05 g to 0.15 g salt (measured according to clopidogrel), 5 g to 30 g of oil for injection, 0.5 g to 3.4 g of emulsifier, 0 g to 1 g of assistant emulsifier, 2.0 g to 4.0 g of isoosmotic adjusting agents, and 7.0 g to 9.0 g of pH adjusting agents, and 100 mL of water for injection is added. The clopidogrel and the salt submicron emulsion injection thereof, provided by the invention, have the physical chemical property conforming to the requirement of drug for intravenous use and are suitable for clinical application.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of clopidogrel and salt sub-microemulsion injection thereof and preparation method thereof.
Background technology
Clopidogrel (Clopidogrel) is second thienopyridine medicine, is adenosine diphosphate (ADP) (ADP) acceptor inhibitor.Its chemistry (S)-α by name-(2-chlorphenyl)-6, the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H) methyl acetate also.Chemical structural formula is as follows:
Clopidogrel is an anticoagulant; Optionally, irreversibly suppress combining and the activation of the glycoprotein GP II b/ III a complex of the ADP mediation of secondary of adenosine diphosphate (ADP) (ADP) and its platelet receptor, thereby suppress hematoblastic mutual gathering.In addition, clopidogrel can also be blocked the platelet activation amplification that causes after ADP discharges, thereby suppresses the platelet aggregation of other agonist inductions.
Clopidogrel can be used for preventing and treating myocardial infarction, ischemic cerebral thrombosis, the complication that thromboangiitis obliterans and atherosclerosis and thromboembolism cause.Be applied to have in the recent period the patient of apoplexy, myocardial infarction taking place or making a definite diagnosis peripheral arterial disease, can reduce the generation (myocardial infarction, apoplexy and vascular are dead) of atherosclerotic event after the treatment.
Clopidogrel (free alkali attitude) is unfavorable for storage or handles processing for having semisolid (oily) form of high viscosity flow property.Its low-solubility in water makes it be difficult in the industry exploitation becomes medicinal product.At present, can be used in the human body diseases treatment, use its inorganic salt or organic salt form more in order to make clopidogrel.What use in the listing product at present, is its sulfate or mesylate form.
At present, the listing preparation of bisulfate clopidogrel has only oral solid formulation---tablet.Clopidogrel oral onset time is slower, shows time dependence and dose dependent, therefore is inappropriate for the treatment of acute thrombus.Can improve onset time though improve dosage, too high dosage also can increase the side effect of clopidogrel, when improving platelet effects, also will weigh the hemorrhage risk problem of bringing because of high dose.Therefore, press for a kind of dosage form that can quick acting of exploitation, with the treatment situation of reply acute thrombus.Injection is rapid-action with it, the dosage flexible characteristic, has become the first-selected dosage form of research worker.
Yet clopidogrel and salt thereof the dissolubility in aqueous solution is low, has very strong pH dependency.And clopidogrel is unstable in aqueous solution, mainly through the degraded of hydrolysis approach, changes into the carboxylic acid derivates form by ester-formin, and its hydrolytic stability has the pH dependency.Therefore, but its preparation that is prepared into stable injection is had certain difficulty.Still there is not the injection listing of clopidogrel and salt thereof at present both at home and abroad.
Patent US4847265 (applicant: SANOFI SA; French) and EP0281459A1 (applicant: SANOFI SA; France) clopidogrel of mentioning in and the pH value of saline solution thereof all are lower than 2.0; If be used for the human injection, pH value all is lower than the human body tolerance range, and is bigger to patient's zest.
Mention the lyophilized powder of clopidogrel or its salt among the patent WO9717064 (applicant: SANOFI SA, France), but clopidogrel and salt thereof form insoluble aggregation easily when independent lyophilizing, stick on the bottle wall operating difficulties.
Patent WO0010534 is on the basis of patent WO9717064; Add poloxamer 188; Stop clopidogrel and the gathering of salt when lyophilizing thereof; After the aqueous solution lyophilizing with clopidogrel and salt and poloxamer 188, with injection again after specific solvent (polyglycol distearate Solutol HS 15 and phosphate buffer are more than the pH4.0) redissolution.This method clinical practice comparatively bothers.
(applicant: the BeiJing SaiKe Pharmacy Co., Ltd) employing solubilizing agent (Tween 80, polyoxyethylene castor oil etc.) and cosolvent prepare the injection of clopidogrel and salt thereof, pH scope 2.0 ~ 7.0 to Chinese patent 200610103222.1.Used solubilizing agent Tween 80 and polyoxyethylene castor oil large usage quantity can cause haemolysis or anaphylaxis in clinical practice.
Patent WO2008134600 (applicant: Cydex Pharmaceuticals, Inc.) utilize beta-schardinger dextrin-to improve the dissolubility and the stability of bisulfate clopidogrel and salt thereof, be used for drug administration by injection; Patent WO2009133455 (applicant: Cadila Healthcare Limited) adopt Solutol HS 15 to prepare the injection of clopidogrel and salt thereof as solubilizing agent.
Through the document retrieval, do not see the report of relevant clopidogrel and salt sub-microemulsion injection thereof and preparation method thereof at present as yet.Through the early stage each item study of pharmacy, the preparation that the inventor is successful clopidogrel and salt sub-microemulsion injection thereof.On the one hand, it is prepared into intravenous injection, not only can improves its onset time, be used for the acute thrombus treatment, patient's medication of dysphagia is conveniently arranged, and injection also has the dosage flexible characteristic.On the other hand, be made into submicronized emulsion, medicine is distributed in oil phase or the water oil interfacial film, avoid it directly to contact, not only can improve its dissolubility, can also effectively increase its stability with water; Submicronized emulsion can also for the patient with severe symptoms, can not oral route or the oral route patient that can not keep normal energy and fatty acid level, energy that supply is suitable and essential fatty acid; Submicronized emulsion has excellent biological compatibility, low toxicity, low irritant; At present, possessed the condition and the technology of carrying out large-scale production intravenous injection submicronized emulsion.This is undoubtedly to further promotion and promote clopidogrel and the application of salt in clinical has great importance.The bisulfate clopidogrel sub-microemulsion injection of the present invention's exploitation is expected to the substituting selection as oral clopidogrel sheet, is used for the treatment of acute thrombus.
Summary of the invention
The object of the present invention is to provide a kind of clopidogrel and salt sub-microemulsion injection thereof, its each item physicochemical property all meets the intravenous administration requirement, and the long term storage physical and chemical stability is good, is suitable for clinical practice.
Another object of the present invention is to provide the method for preparing of above-mentioned clopidogrel and salt sub-microemulsion injection thereof, this method is safety and stability but also be suitable for suitability for industrialized production not only.
According to first purpose of the present invention, clopidogrel provided by the invention and salt sub-microemulsion injection thereof, in 100 mL injection, it comprises:
| Clopidogrel and salt thereof (in clopidogrel) | 0.05 g~0.15 g |
| Oil for injection | 5 g~30 g |
| Emulsifying agent | 0.5 g~3.4 g |
| Co-emulsifier | 0 g~1 g |
| Isoosmotic adjusting agent | 2.0 g~4.0 g |
| The pH regulator agent | In right amount, be adjusted to 7.0 ~ 9.0 |
| Water for injection | To 100 mL. |
At most preferred clopidogrel of the present invention and salt sub-microemulsion injection thereof, in 100 mL injection, it comprises:
| Clopidogrel and salt thereof (in clopidogrel) | 0.05 g~0.15 g |
| Oil for injection | 10 g~30 g |
| Emulsifying agent | 0.8 g~2.4 g |
| Co-emulsifier | 0.2 g~0.8 g |
| Isoosmotic adjusting agent | 2.0 g~3.0 g |
| The pH regulator agent | In right amount, be adjusted to 7.0 ~ 9.0 |
| Water for injection | To 100 mL. |
Said clopidogrel and salt thereof, salt wherein are selected from sulfate, hydrochlorate, benzene sulfonate, amino acid salts, citrate, maleate, fumarate or other slightly solubility organic salt or inorganic salt, preferably sulfuric acid salt.
Described oil for injection is selected from one or several in mineral oil, vegetable oil, neutral lipoid, sterol derivative, animal oil, the artificial oil; Can be in Semen Maydis oil, soybean oil, safflower oil, olive oil, Oleum Ricini, Oleum Gossypii semen, Oleum Camelliae, Semen Coicis oil, MCT Oil, fish oil, the Oleum Fructus Bruceae one or several, preferred soybean oil, MCT Oil or the mixture of the two.
Described emulsifying agent is selected from one or several in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, hydrogenated soy phosphatidyl choline, hydrogenated yolk lecithin, the synthetic phospholipid, preferably soya lecithin, Ovum Gallus domesticus Flavus lecithin or the mixture of the two.
Described co-emulsifier is selected from one or several in tween, span, the poloxamer, preferred tween, poloxamer or the mixture of the two.
Described tween is selected from one or several among Tween-20, Tween-40, Tween-60, Tween-80, the Tween-85, preferred Tween-80.
Described isoosmotic adjusting agent is selected from glycerol for injection, sodium chloride or the mixture of the two, preferred glycerol for injection.
Described pH regulator agent is selected from one or several in sodium hydroxide, sodium carbonate, the sodium bicarbonate, preferred sodium hydroxide.
Can also comprise antioxidant in the described Emulsion composition, be selected from sodium pyrosulfite, sodium thiosulfate, vitamin C, natural Vitamin E, the ascorbyl palmitate one or several, preferred natural Vitamin E.
The also preferred following prescription of the present invention:
| Clopidogrel and salt thereof (in clopidogrel) | 0.05 g~0.15 g |
| The injection MCT Oil | 2.5 g~10 g |
| The injection soybean oil | 2.5 g~10 g |
| Lecithin | 0.5 g~2.0 g |
| Poloxamer F-68 | 0.2 g~0.5 g |
| Tween 80 | 0.1 g~0.2 g |
| Glycerol for injection | 2.0 g~4.0 g |
| The pH regulator agent | In right amount, be adjusted to 7.0 ~ 9.0 |
| Water for injection | To 100 mL. |
Emulsion of the present invention is O/W type Emulsion, and its mean diameter is in 100 nm ~ 200 nm scopes.
According to another object of the present invention, the present invention provides the method for preparing of clopidogrel and salt sub-microemulsion injection thereof, and this method in turn includes the following steps:
Step 1: clopidogrel and salt thereof are joined in the oil for injection that contains emulsifying agent, be heated to 60 ~ 80 ℃, stirring is dissolved it fully, makes oil phase;
Step 2: co-emulsifier and isoosmotic adjusting agent are joined in the water for injection, be heated to 60 ~ 80 ℃, stirring is dissolved it fully, makes water;
Step 3: under high-speed stirred, oil phase and water are mixed, make colostrum;
Step 4: colostrum is transferred in the high pressure homogenizer, and high pressure homogenize prepares Emulsion;
Step 5: the Emulsion behind step 4 homogenizing is regulated pH value with the pH regulator agent, filter, fill, inflated with nitrogen, sterilization promptly makes clopidogrel and salt sub-microemulsion injection thereof.
Inflated with nitrogen protection in the whole process of preparation.
More specifically, each step of this method is following:
Step 1: clopidogrel and salt thereof are joined in the oil for injection that contains emulsifying agent, be heated to 60 ~ 80 ℃, stirring is dissolved it fully, makes oil phase;
Step 2: co-emulsifier and isoosmotic adjusting agent are joined in the water for injection, be heated to 60 ~ 80 ℃, stirring is dissolved it fully, makes water;
Step 3: under rotating speed 10,000 rpm ~ 17,000 rpm, oil phase and water are mixed, stir 3 times, each 3 min make colostrum;
Step 4: colostrum is transferred in the high pressure homogenizer, 20 ~ 60 ℃ of homogenizing temperatures, with 400 ~ 800 bar homogenization pressure homogenizing;
Step 5: the Emulsion behind step 4 homogenizing is regulated pH value to 7 ~ 9 with the pH regulator agent, cross 0.45 μ m microporous filter membrane, fill, inflated with nitrogen, 121 ℃ of sterilization 15 min promptly make clopidogrel and salt sub-microemulsion injection thereof.
Inflated with nitrogen protection in the whole process of preparation.
Described sterilization method is selected from sterilization of high steam formula or the sterilization of rotary water bath formula, preferred rotary water bath formula sterilization.
The present invention is directed to the characteristics of clopidogrel and salt thereof, make clopidogrel and salt sub-microemulsion injection thereof.Have following beneficial effect: oral clopidogrel tablet onset time is relatively slow, has certain hysteresis quality, is inappropriate for the treatment of acute thrombus; And the patient of dysphagia is arranged for those, like gerontal patient or paralytic, inconvenient its of oral formulations taken; In addition, clopidogrel has strong impulse, bitterness and tart flavour, and mouth and/or gastrointestinal tract often feel hurt when oral.Therefore, it is developed to intravenous formulations, not only can improves its onset time, patient's medication of dysphagia is conveniently arranged, can also avoid effectively and cover its bad smell, and injection also has the dosage flexible characteristic.Clopidogrel and salt thereof the dissolubility in aqueous solution is low, has very strong pH dependency, and unstable in aqueous solution, is easy to degraded.Therefore, be made into submicronized emulsion, medicine is distributed in oil phase or the water oil interfacial film, avoid it directly to contact, not only can improve its dissolubility, can also effectively increase its stability with water; Submicronized emulsion can for the patient with severe symptoms, can not oral route or the oral route patient that can not keep normal energy and fatty acid level, energy that supply is suitable and essential fatty acid; Submicronized emulsion has excellent biological compatibility, low toxicity, low irritant.
The specific embodiment
Below in conjunction with specific embodiment the present invention is done further explain, this enforcement profit only is used to the present invention is described and unrestricted the present invention.
Embodiment 1:
Prescription
| Bisulfate clopidogrel (in clopidogrel) | 0.075 g |
| The injection MCT Oil | 5.0 g |
| The injection soybean oil | 5.0 g |
| Ovum Gallus domesticus Flavus lecithin | 1.2 g |
| Poloxamer F-68 | 0.2 g |
| Tween-80 | 0.2 g |
| Glycerol for injection | 2.5 g |
| Water for injection | To 100 mL |
Method for preparing:
Step 1: the Ovum Gallus domesticus Flavus lecithin of formula ratio is dissolved in injection MCT Oil and the injection soybean oil, adds the bisulfate clopidogrel of formula ratio then, heating in water bath to 60 ~ 80 ℃, and stir it is dissolved fully, make oil phase;
Step 2: glycerol for injection, poloxamer F-68, the Tween-80 of formula ratio are dissolved in the water for injection, heating in water bath to 60 ~ 80 ℃, and stir it is dissolved fully, make water;
Step 3: under the high shear dispersion machine stirs, with rotating speed 16,000 rpm, oil phase and water are mixed, stir 3 times, each 3 min make colostrum;
Step 4: colostrum is transferred in the high pressure homogenizer, and homogenizing temperature is at 30 ~ 50 ℃, with 700 bar homogenization pressure homogenizing 5 times;
Step 5: the Emulsion behind step 4 homogenizing is regulated pH value to 8.0 with 0.1 mol/L sodium hydrate aqueous solution, cross 0.45 μ m microporous filter membrane, fill, inflated with nitrogen, 121 ℃ of rotary water baths 15 min that sterilize promptly make the bisulfate clopidogrel sub-microemulsion injection.
Embodiment 2:
Prescription
| Bisulfate clopidogrel (in clopidogrel) | 0.075 g |
| The injection MCT Oil | 5.0 g |
| The injection soybean oil | 5.0 g |
| Ovum Gallus domesticus Flavus lecithin | 1.2 g |
| Poloxamer F-68 | 0.2 g |
| Tween-80 | 0.2 g |
| Vitamin E | 0.002 g |
| Glycerol for injection | 2.5 g |
| Water for injection | To 100 mL |
Method for preparing:
Step 1: vitamin E, the Ovum Gallus domesticus Flavus lecithin of formula ratio are dissolved in injection MCT Oil and the injection soybean oil; The bisulfate clopidogrel that adds formula ratio then; Heating in water bath to 60 ~ 80 ℃, and stir it is dissolved fully, make oil phase;
Step 2: glycerol for injection, poloxamer F-68, the Tween-80 of formula ratio are dissolved in the water for injection, heating in water bath to 60 ~ 80 ℃, and stir it is dissolved fully, make water;
Step 3: under the high shear dispersion machine stirs, with rotating speed 16,000 rpm, oil phase and water are mixed, stir 3 times, each 3 min make colostrum;
Step 4: colostrum is transferred in the high pressure homogenizer, and homogenizing temperature is at 30 ~ 50 ℃, with 700 bar homogenization pressure homogenizing 5 times;
Step 5: the Emulsion behind step 4 homogenizing is regulated pH value to 8.0 with 0.1 mol/L sodium hydrate aqueous solution, cross 0.45 μ m microporous filter membrane, fill, inflated with nitrogen, 121 ℃ of high pressure steam sterilization 15 min promptly make the bisulfate clopidogrel sub-microemulsion injection.
Embodiment 3:
Prescription
| Bisulfate clopidogrel (in clopidogrel) | 0.075 g |
| The injection MCT Oil | 5.0 g |
| The injection soybean oil | 5.0 g |
| Ovum Gallus domesticus Flavus lecithin | 2.0 g |
| Vitamin E | 0.002 g |
| Glycerol for injection | 2.25 g |
| Water for injection | To 100 mL |
Method for preparing:
Step 1: vitamin E, the Ovum Gallus domesticus Flavus lecithin of formula ratio are dissolved in injection MCT Oil and the injection soybean oil; The bisulfate clopidogrel that adds formula ratio then; Heating in water bath to 60 ~ 80 ℃, and stir it is dissolved fully, make oil phase;
Step 2: the glycerol for injection of formula ratio is dissolved in the water for injection, heating in water bath to 60 ~ 80 ℃, and stir it is dissolved fully, make water;
Step 3: under the high shear dispersion machine stirs, with rotating speed 16,000 rpm, oil phase and water are mixed, stir 3 times, each 3 min make colostrum;
Step 4: colostrum is transferred in the high pressure homogenizer, and homogenizing temperature is at 30 ~ 50 ℃, with 700 bar homogenization pressure homogenizing 5 times;
Step 5: the Emulsion behind step 4 homogenizing is regulated pH value to 8.0 with 0.1 mol/L sodium hydrate aqueous solution, cross 0.45 μ m microporous filter membrane, fill, inflated with nitrogen, 121 ℃ of rotary water baths 15 min that sterilize promptly make the bisulfate clopidogrel sub-microemulsion injection.
Embodiment 4:
Prescription
| Bisulfate clopidogrel (in clopidogrel) | 0.075 g |
| The injection MCT Oil | 7.5 g |
| The injection soybean oil | 7.5 g |
| Ovum Gallus domesticus Flavus lecithin | 1.2 g |
| Poloxamer F-68 | 0.3 g |
| Tween 80 | 0.2 g |
| Glycerol for injection | 2.25 g |
| Water for injection | To 100 mL |
Method for preparing:
With embodiment 1.
Embodiment 5:
Prescription
| Bisulfate clopidogrel (in clopidogrel) | 0.075g |
| The injection MCT Oil | 12.0 g |
| The injection soybean oil | 8.0 g |
| Soybean lecithin | 1.5 g |
| Poloxamer F-68 | 0.2 g |
| Tween -80 | 0.2 g |
| Glycerol for injection | 2.0 g |
| Water for injection | To 100 mL |
Method for preparing:
With embodiment 1.
Embodiment 6:
Prescription
| Bisulfate clopidogrel (in clopidogrel) | 0.075g |
| The injection MCT Oil | 20.0 g |
| The injection soybean oil | 10.0 g |
| Ovum Gallus domesticus Flavus lecithin | 1.5 g |
| Poloxamer F-68 | 0.4 g |
| Tween -80 | 0.2 g |
| Glycerol for injection | 2.0 g |
| Water for injection | To 100 mL |
Method for preparing:
With embodiment 1.
Embodiment 7:
Prescription
| Bisulfate clopidogrel (in clopidogrel) | 0.150 g |
| The injection MCT Oil | 18.0 g |
| The injection soybean oil | 12.0 g |
| Ovum Gallus domesticus Flavus lecithin | 1.5 g |
| Poloxamer F-68 | 0.5 g |
| Tween -80 | 0.3 g |
| Glycerol for injection | 2.25 g |
| Water for injection | To 100 mL |
Method for preparing:
With embodiment 1.
Embodiment 8:
Prescription
| Bisulfate clopidogrel (in clopidogrel) | 0.075 g |
| The injection MCT Oil | 30.0 g |
| Ovum Gallus domesticus Flavus lecithin | 2.0 g |
| Poloxamer F-68 | 0.2 g |
| Tween -80 | 0.2 g |
| Glycerol for injection | 2.75 g |
| Water for injection | To 100 mL |
Method for preparing:
With embodiment 1.
Embodiment 9:
Prescription
| Bisulfate clopidogrel (in clopidogrel) | 0.075 g |
| The injection soybean oil | 30.0 g |
| Ovum Gallus domesticus Flavus lecithin | 2.4 g |
| Poloxamer F-68 | 0.2 g |
| Tween 80 | 0.2 g |
| Glycerol for injection | 2.5 g |
| Water for injection | To 100 mL |
Method for preparing:
With embodiment 1.
Embodiment 10:
Prescription
| Bisulfate clopidogrel (in clopidogrel) | 0.050 g |
| The injection MCT Oil | 3.5 g |
| The injection soybean oil | 2.5 g |
| Ovum Gallus domesticus Flavus lecithin | 1.2 g |
| Poloxamer F-68 | 0.2 g |
| Glycerol for injection | 3.0 g |
| Water for injection | To 100 mL |
Method for preparing:
With embodiment 1.
Embodiment 11:
Prescription
| Bisulfate clopidogrel (in clopidogrel) | 0.075 g |
| Safflower oil | 5.0 g |
| Fish oil | 2.5 |
| The injection MCT Oil | 5.0 g |
| Ovum Gallus domesticus Flavus lecithin | 0.5 g |
| Poloxamer F-68 | 0.6 g |
| Tween -80 | 0.4 g |
| Glycerol for injection | 2.5 g |
| Water for injection | To 100 mL |
Method for preparing:
With embodiment 1.
Embodiment 12:
Prescription
| Bisulfate clopidogrel (in clopidogrel) | 0.075 g |
| Olive oil | 8.0 g |
| The injection soybean oil | 2.0 g |
| Hydrogenated yolk lecithin | 0.8 g |
| Poloxamer F-68 | 0.4 g |
| Tween -80 | 0.3 g |
| Glycerol for injection | 2.25 g |
| Water for injection | To 100 mL |
Method for preparing:
With embodiment 1.
Embodiment 13:
Prescription
| Bisulfate clopidogrel (in clopidogrel) | 0.075 g |
| Oleum Camelliae | 10.0 g |
| Oleum Ricini | 7.5 g |
| Hydrogenated yolk lecithin | 3.4 g |
| Poloxamer F-68 | 0.5 g |
| Tween -80 | 0.2 g |
| Glycerol for injection | 2.5 g |
| Water for injection | To 100 mL |
Method for preparing:
With embodiment 1.
Embodiment 15:
Prescription
| Bisulfate clopidogrel (in clopidogrel) | 0.075 g |
| Oleum Gossypii semen | 4.5 g |
| Semen Coicis oil | 11.5 |
| Hydrogenated soya phosphatide | 2.2 g |
| Poloxamer F-68 | 0.6 g |
| Tween -80 | 0.2 g |
| Glycerol for injection | 2.5 g |
| Water for injection | To 100 mL |
Method for preparing:
With embodiment 1.
Embodiment 16:
Prescription
| Bisulfate clopidogrel (in clopidogrel) | 0.075 g |
| Oleum Fructus Bruceae | 5.5 g |
| The injection soybean oil | 12.5 g |
| Ovum Gallus domesticus Flavus lecithin | 2.0 g |
| Poloxamer F-68 | 0.5 g |
| Tween -80 | 0.2 g |
| Glycerol for injection | 2.5 g |
| Water for injection | To 100 mL |
Method for preparing:
With embodiment 1.
Test case:
According to embodiment 1 preparation sample, its test result is following:
1. physicochemical property inspection
1) outward appearance
Perusal, the even emulsion liquid of white or off-white color.
2) granularity and particle size distribution
Adopt the Coulter LS230 laser particle size analyzer of U.S. Beckman company to measure granularity and particle size distribution.The mean diameter of three lot sample article is respectively (152 ± 21) nm, (156 ± 21) nm and (159 ± 22) nm.
3) Zeta-potential
Adopt the DELSA 440 SX potentiometric analyzers of U.S. Beckman company to measure Zeta-potential.The Zeta-potential of three lot sample article is respectively :-37.10 mV ,-37.40 mV and-38.60 mV.The result shows that the average Zeta-potential of three lot sample article is-37.70 mV, satisfies stable particle liquid system Zeta-potential is controlled at the requirement in-20 ~-45 mV scopes, and it is well stable to show that also preparation of the present invention has.
4）?pH
Use pH meter to measure the pH value of Emulsion.The pH value of three lot sample article is respectively 7.54,7.50 and 7.49.5) osmotic pressure
Use Vapro
5520 osmometers to measure the osmotic pressure value of Emulsion.The osmotic pressure value of three lot sample article is respectively 279 mmol/kg, 280 mmol/kg and 279 mmol/kg.
6) (Entrapment Efficiency EE%) measures for content and envelop rate
Adopt the methanol breakdown of emulsion, measure content with the HPLC method.
The entrapment efficiency determination method: get Emulsion sample 2mL, add in the ultra-filtration centrifuge tube, centrifugal 10 min of 4000 rpm, HPLC measures the aqueous phase drug concentrations.Press following formula computational envelope rate:
Wherein: C
TotalBe the medicine total concentration in the Emulsion;
C
WaterDrug level for aqueous phase;
R ＇ is the response rate (counting 96.02%);
A is the percentage ratio (being about 90%) that water accounts for the Emulsion cumulative volume.
The content of three lot sample article is respectively 99.38%, 101.12% and 98.07%; Envelop rate is respectively 99.75%, 99.78% and 99.76%.
2. study on the stability
1) centrifugal stability
Get bisulfate clopidogrel sub-micro injection breast sample, behind centrifugal 15 min of 4,000 rpm, three lot sample article still are the even emulsion liquid of milky, phenomenons such as flocculation, layering, breakdown of emulsion do not occur; Behind centrifugal 10 min of 15,000 rpm, three lot sample article still are the even emulsion liquid of milky, phenomenons such as flocculation, layering, breakdown of emulsion all do not occur.Can think that the bisulfate clopidogrel sub-microemulsion injection is centrifugal has good stability.
2) freeze-thaw stability
Freezing-thawing test (freezing heat cycles experiment) is used to investigate the toleration of dispersion to variations in temperature; Its ultimate principle is through changing the temperature of dispersion environment of living in; Cause the variation of mentioning self-energy; Observe metamorphosis such as consequent particle diameter, with the condition of storage of strictness control medicine.
Bisulfate clopidogrel sub-micro injection breast sample is put into-20 ℃ of refrigerator and cooled and is frozen 12 h, takes out to be positioned in the room temperature and melts, and places 12 h, and this is a freeze-thaw cycle.Carry out freeze-thaw cycle so repeatedly three times, observe its outward appearance and measure its granularity and particle size distribution.The result of bisulfate clopidogrel sub-microemulsion injection freezing-thawing test sees table 1.
Through refrigerated Emulsion its colour changed into yellow, still, melt the back color restoration, the phenomenon of breakdown of emulsion, fuel-displaced or flocculation does not appear.Can be found out that by table 1 result the particle diameter of Emulsion becomes big after the freeze thawing, but still in the safety range of intravenous injection emulsion, and along with the increase of number of freezing and thawing, particle diameter becomes basically no longer greatly, particle size distribution also no longer broadens.This explanation number of freezing and thawing is to the particle diameter of bisulfate clopidogrel sub-microemulsion injection and do not make significant difference; Show that this preparation can stand violent variation of ambient temperature, reflected that to a certain extent the prepared bisulfate clopidogrel sub-microemulsion injection of prescription of the present invention and method for preparing has good stable property.But for the physical stability that guarantees preparation and the controllability of each item index thereof, suggestion bisulfate clopidogrel sub-microemulsion injection avoids freezing as far as possible in transportation and storage process.
3) shelf-stability
According to three batches of embodiment 1 preparation bisulfate clopidogrel sub-microemulsion injections, respectively at (6 ± 2) ℃ and (25 ± 2) ℃ condition held 6 months, respectively at 0,1,2,3, June, its outward appearance was observed in sampling, measured its granularity and particle size distribution and content.The result sees table 2 and table 3.
The result shows, (6 ± 2) ℃ and (25 ± 2) ℃ condition held 6 months, there are no significant changes for its outward appearance, granularity and indexs such as particle size distribution and content, still meets the intravenous administration requirement.
3. pharmacodynamic study
1) grouping and administration
Get 18 of rats, be divided into three groups at random, 6 every group, fasting is 12 hours before the test.The first group is a model group, in the sodium chloride injection of tail vein injection 9 mL/kg; The second group is a test group, in the bisulfate clopidogrel sub-microemulsion injection of tail vein injection 6.75 mg/kg (in clopidogrel); Third group of positive matched group is irritated the bisulfate clopidogrel sheet that stomach gives 6.75 mg/kg (in clopidogrel).
2) ferric chloride is induced the foundation of rat carotid artery thrombus model
1.5 h after the administration, lumbar injection 20% urethane (7 mLkg
-1), with rat anesthesia, separating bilateral carotid, right carotid is subsequent use.The separation length of left carotid is about 2 cm; Distal end carries out arterial cannulation; Connect eight and lead physiograph, the monitoring blood pressure wraps up with the filter paper (0.25 cm * 1 cm) that 20% liquor ferri trichloridi soaks at proximal part; Its underlying small pieces aluminium foil (0.5 cm * 1.5 cm) is used to protect circumvascular nerve, tissue.Record is reduced to 0 o'clock time from being wrapping to blood pressure, and this is the artery thrombosis time.
2 h after the administration, with filter paper (0. 5 cm * 1 cm) the parcel right carotid that 20% liquor ferri trichloridi soaks, its underlying small pieces aluminium foil (1 cm * 1.5 cm) is used to protect circumvascular nerve, tissue.Remove filter paper after wrapping up 10 min, the blood vessel in the accurate intercepting 0.5 cm length in right carotid filter paper parcel place blots residual blood with filter paper; With its weight of analytical balance weighing; Weigh once more behind the removal of thromboses, both subtract each other, and are the endovascular thrombus weight of this section.
Calculating thrombosis suppression ratio (Thrombosis inhibition rate, TIR), computing formula is following:
Wherein, W
0: the thrombus weight of model group;
W: the thrombus weight of administration group.
3) data statistic analysis and processing
4) result of the test
(1) TFT
[0064]According to the result of the test that table 4 shows, compare with model group, test group ability significant prolongation common carotid artery TFT (
p＜0.05), prolongs ratio and be about 70.76%; Positive controls also can prolong the artery thrombosis time, and prolong ratio and be about 22.74%, but do not have statistical significance (
p＞0.05); Compare with positive controls, the TFT of test group obviously prolongs, prolong ratio and be about 39.12%, difference have the significance meaning (
p＜0.05).Statistical result shows that the bisulfate clopidogrel sub-microemulsion injection obviously has the effect of prolong rats common carotid artery TFT, and effect is superior to the bisulfate clopidogrel sheet.
(2) thrombosis suppression ratio
[0066]The result of table 5 shows that compare with model group, test group and positive controls all can significantly reduce the arterial thrombus weight of formation, have statistical significance (
p＜0.01); Compare with positive controls, the thrombus weight that test group forms obviously reduces, have statistical significance (
p＜0.01).Test group and positive controls are respectively 44.67% and 29.62% to rat carotid artery thrombosis suppression ratio.Statistical result shows that the bisulfate clopidogrel sub-microemulsion injection obviously has the effect that suppresses thrombosis, and effect is superior to the bisulfate clopidogrel sheet.
Claims (10)
1. clopidogrel and salt sub-microemulsion injection thereof, it is characterized in that: in 100 mL injection, it comprises:
。
2. clopidogrel according to claim 1 and salt sub-microemulsion injection thereof is characterized in that: in 100 mL injection, it comprises:
3. clopidogrel according to claim 1 and 2 and salt sub-microemulsion injection thereof is characterized in that described clopidogrel salt is selected from sulfate, hydrochlorate, benzene sulfonate, amino acid salts, citrate, maleate, fumarate.
4. clopidogrel according to claim 1 and 2 and salt sub-microemulsion injection thereof is characterized in that, described oil for injection is selected from one or several in mineral oil, vegetable oil, neutral lipoid, sterol derivative, animal oil, the artificial oil; Described emulsifying agent is selected from one or several in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, hydrogenated soy phosphatidyl choline, hydrogenated yolk lecithin, the synthetic phospholipid, preferably soya lecithin, Ovum Gallus domesticus Flavus lecithin or the mixture of the two; Described co-emulsifier is selected from one or several in tween, span, the poloxamer; Preferred tween, poloxamer or the mixing of the two; Wherein tween is selected from one or several among Tween-20, Tween-40, Tween-60, Tween-80, the Tween-85, preferred Tween-80; Described isoosmotic adjusting agent is selected from glycerol for injection, sodium chloride or the mixture of the two, preferred glycerol for injection; Described pH regulator agent is selected from one or several in sodium hydroxide, sodium carbonate, the sodium bicarbonate, preferred sodium hydroxide.
5. clopidogrel according to claim 4 and salt sub-microemulsion injection thereof; It is characterized in that; Described oil for injection is selected from one or several in Semen Maydis oil, soybean oil, safflower oil, olive oil, Oleum Ricini, Oleum Gossypii semen, Oleum Camelliae, Semen Coicis oil, MCT Oil, fish oil, the Oleum Fructus Bruceae, preferred soybean oil, MCT Oil or the mixture of the two.
6. clopidogrel according to claim 1 and 2 and salt sub-microemulsion injection thereof; It is characterized in that; Comprise antioxidant in the described Emulsion composition; Described antioxidant is selected from one or several in sodium pyrosulfite, sodium thiosulfate, vitamin C, natural Vitamin E, the ascorbyl palmitate, preferred natural Vitamin E.
7. clopidogrel according to claim 1 and salt sub-microemulsion injection thereof is characterized in that: in 100 mL injection, it comprises:
8. the clopidogrel described in the claim 1 or 2 and the method for preparing of salt sub-microemulsion injection thereof is characterized in that this method in turn includes the following steps:
Step 1: clopidogrel and salt thereof are joined in the oil for injection that contains emulsifying agent, be heated to 60 ~ 80 ℃, stirring is dissolved it fully, makes oil phase;
Step 2: co-emulsifier and isoosmotic adjusting agent are joined in the water for injection, be heated to 60 ~ 80 ℃, stirring is dissolved it fully, makes water;
Step 3: under high-speed stirred, oil phase and water are mixed, make colostrum;
Step 4: colostrum is transferred in the high pressure homogenizer, and high pressure homogenize prepares Emulsion;
Step 5: the Emulsion behind step 4 homogenizing is regulated pH value with the pH regulator agent, filter, fill, inflated with nitrogen, sterilization promptly makes clopidogrel and salt sub-microemulsion injection thereof;
Inflated with nitrogen protection in the whole process of preparation.
9. the method for preparing of clopidogrel according to claim 8 and salt sub-microemulsion injection thereof is characterized in that:
In the step 3, under rotating speed 10,000 rpm ~ 17,000 rpm, oil phase and water are mixed, stir 3 times, each 3 min make colostrum;
In the step 4, colostrum is transferred in the high pressure homogenizer, 20 ~ 60 ℃ of homogenizing temperatures, with 400 ~ 800 bar homogenization pressure homogenizing;
In the step 5, the Emulsion behind step 4 homogenizing is regulated pH value to 7 ~ 9 with the pH regulator agent, cross 0.45 μ m microporous filter membrane, fill, inflated with nitrogen, 121 ℃ of sterilization 15 min promptly make clopidogrel and salt sub-microemulsion injection thereof.
10. according to Claim 8 or the method for preparing of 9 described clopidogrels and salt sub-microemulsion injection thereof, it is characterized in that described sterilization method is selected from sterilization of high steam formula or the sterilization of rotary water bath formula, preferred rotary water bath formula sterilization.
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