CN101780036A - Butyrate clevidipine lipid microsphere injection and preparation method thereof - Google Patents
Butyrate clevidipine lipid microsphere injection and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a lipid microsphere injection of butyrate clevidipine which is a rapid-effect hypotensive medicine and can be intravenously injected and a preparation method thereof. The lipid microsphere injection comprises butyrate clevidipine, oil for injection, an emulsifying agent, polyethylene glycol ester, medical additive and water for injection. The lipid microsphere injection can effectively control the medicine release at the same time of ensuring the curative effect and reduce the occurrence rate of adverse reactions.
Description
Technical field
The invention belongs to technical field of medicine, be specifically related to lipid microsphere injection of a kind of fugitive antihypertensive drug butyrate clevidipine and preparation method thereof.
Background technology
Controlling of blood pressure is vital under the clinical condition of numerous disease stably, for example when carrying out operation on vessels of heart, cerebral operations, operated eye and Minimally Invasive Surgery, need in special time, safely patient's blood pressure be reduced to a level that is beneficial to operation rapidly, make it recover normal after the operation more again rapidly.Under above-mentioned medical conditions, key will give to reach the dual needs that guarantee patient safety and blood pressure lowering under the condition of minimum injection volume simultaneously.In addition, fast and effeciently control hypertensive emergency, very important to stoping nonvolatil whole latter stage organ failure.Should be noted that blood pressure lowering the time fast and prevent because hypoperfusion and the ischemia that hypopiesia causes.For not having impaired sign of target organ and patient that can oral drugs, the oral blood pressure lowering medicine is comparatively suitable.Yet, must give antihypertensive drugs by vein for occurring organ failure's sign or critical patient that can't oral drugs.
Most injection depressor of the present clinical practice of China can non-selectively act on resistance vessel, induces the patient of heart and injury and Hypovolemia acute hypotension to occur.Can be used at present controlling in the medicine of critically ill patient blood pressure, do not have a kind ofly to take into account in blood vessel selectivity, the infusion process onset rapidly, finish rapidly and do not have a toxic requirement of intravenous injection.Therefore develop that a kind of drug level is suitable, adverse reaction rate is low, and can reduce rapidly and accurately the antihypertensive formulation of controlling blood pressure is significant in the treatment of perioperative hypertension and acute hypertension.
Butyrate clevidipine (clevidipine butyrate) is the fugitive dihydropyridine calcium channel blocker of a kind of a new generation, and this medicine is the novel used for intravenous injection antihypertensive drug of the first approval listing of U.S. FDA over 10 years.The chemical constitution of butyrate clevidipine is similar to felodipine, belongs to esters together, and easily by the esterase institute metabolism in blood and the tissue, being hydrolyzed to does not have active metabolite, so activity in vivo is extremely short.Butyrate clevidipine is almost insoluble in water, but have to a certain degree fat-soluble, patent CN1072934 discloses the method for dihydropyridines medicine butyrate clevidipine being made intravenous injection emulsion, this injectable emulsion reaches post-operative treatment before the operation on heart patient's that grows up operation all have good blood pressure lowering curative effect, and it is rapid-action, duration of efficacy is short, can reach the pressure value of expectation.The patented product goes on the market in the U.S..
But clinical practice is found, is existed important dependency between the urgent rising of blood pressure or the generation of reduction and untoward reaction.Listing butyrate clevidipine injectable emulsion mainly comes controlling blood pressure to change according to patient's blood pressure response and target blood pressure by regulating drip velocity.The inhomogeneity of artificial adjusting factor in the administration process, the systemic effect of release and medicine may be the major reason that produces untoward reaction such as general hypotension, reflex tachycardia and bounce-back hypertension during causing it to use fast.
In addition, listing butyrate clevidipine injectable emulsion prescription mainly is made up of oil for injection, phospholipid, glycerol and water, need under 5 ℃ of conditions, cold preservation place, variations in temperature in the storage process (as cold preservation-room temperature-cold preservation) causes that easily the gathering of emulsion droplet merges, particle diameter increases, even situation such as local breakdown of emulsion oil slick.
Therefore, invent a kind of novel butyrate clevidipine used for intravenous injection fat micro sphere preparation, make it can take into account quick acting simultaneously, accurately controlling blood pressure reduces untoward reaction, and the raising bin stability is pressing for of clinical practice.
Lipoid microsphere be a kind of be soft substrate with fatty oil, the microsome disperse system of being sealed by immobilized artificial membrane and macromolecular material outward, mean diameter is 200nm, adventitia is a lecithin, internal layer is soft matrix oil, wherein wraps up fat-soluble medicine.Lipoid microsphere can contain the adjuvant of Polyethylene Glycol (PEG) chain by adding, makes the new drug carrier system, the influence that the medicine that is wrapped up is produced following several aspects:
1. control the release of medicine.Polyethyleneglycol modified lipoid microsphere can be avoided after the administration rapidly by reticuloendothelial system phagocytic, thereby realizes drug release characteristic comparatively stably, helps regulating suitable duration of efficacy.
2. targeting.Lipoid microsphere is distribution of specific in vivo, improves the local valid density of medicine, reduces the whole body toxic and side effects.
3. promote drug absorption.Endothelial cellular membrane and level and smooth muscle cell membrane main component are phospholipid, and the lipoid microsphere adventitia mainly also is a phospholipid, and according to the mechanism of similar compatibility biology, lipoid microsphere is easy to cross over cell membrane, promotes the fast Absorption of medicine, makes the medicine quick acting of release.
4. improve bin stability.Contain the adding of macrogol ester adjuvant, can increase the space steric effect between emulsion droplet, avoid long term store or increase phenomenon by the particle accumulation that variations in temperature causes.
5. improve drug loading.Fat-soluble medicine may be dissolved in the soft matrix oil and phospholipid layer in the lipoid microsphere, improves the dissolubility of medicine in preparation, effectively reduces dosage.
6. increase drug safety: some have toxicity or irritating medicine, make fat micro sphere preparation and can improve curative effect of medication greatly, reduce its toxic and side effects.
Therefore, the technical advantage of lipoid microsphere high-efficiency low-toxicity has the space of developing on a large scale very much with the preparation method that is easy to suitability for industrialized production aspect the fat-soluble medicine transmission.
Summary of the invention
The objective of the invention is defective at existing butyrate clevidipine injectable emulsion, provide a kind of butyrate clevidipine lipid microsphere injection and preparation method thereof, with the purpose that reaches safe and effective, control drug release, selective local blood pressure lowering, reduces adverse effect and increase preparation stored stability.
Another object of the present invention is to provide the preparation method of above-mentioned butyrate clevidipine lipid microsphere injection.
For achieving the above object, the present invention has taked following technical scheme: it is mixed by following raw materials by weight:
Butyrate clevidipine 0.01～1%
Oil for injection 1～35%
Emulsifying agent 0.01～10%
Polyethylene Glycol compounds 0.1～10%
Medical additive 0.01～20%
The water for injection surplus
The present invention's technical scheme preferably is that it is mixed by following raw materials by weight:
Butyrate clevidipine 0.01～0.2%
Oil for injection 5～30%
Emulsifying agent 0.5～8%
Polyethylene Glycol compounds 0.1～5%
Medical additive 1～10%
The water for injection surplus
Wherein, described oil for injection is selected from more than one mixture of soybean oil, Oleum Camelliae, Oleum sesami, fish oil, Oleum Arachidis hypogaeae semen, safflower oil, olive oil, triglyceride, medium chain triglyceride or its.
Described emulsifying agent is selected from one or more in lecithin, soybean lecithin, hydrogenated soy phosphatidyl choline, Ovum Gallus domesticus Flavus lecithin, hydrolecithin, two Semen Myristicae phospholipid acid choline, two Semen Myristicae phosphatidyl glycerol, dioleoyl phospholipid phatidylcholine, two palmityl phosphatidic acid, two Palmic acid phosphatidylcholines, PHOSPHATIDYL ETHANOLAMINE, PEG derivatization phospholipid acyl ethanolamine and the PEG derivatization phospholipid acyl serine;
It is 1000～10000 Polyethylene Glycol vitamin e succinate, stearate that described Polyethylene Glycol compounds is selected from molecular weight; Polyglycol distearate and molecular weight are the mixture of 200～10000 Polyethylene Glycol; Myrj 45, polyoxyethylene aliphatic alcohol ether or its mixture.
Described medical additive is selected from one or more in antioxidant, osmotic pressure regulator, pH regulator agent, complexing of metal ion agent and the antiseptic.
Wherein, because phospholipid, oil for injection are all easily oxidized, therefore also contain antioxidant in the lipid microsphere injection of the present invention, it is selected from sodium sulfite, sodium sulfite, sodium pyrosulfite, vitamin C and the vitamin E one or more.
As required, lipid microsphere injection of the present invention can add osmotic pressure regulator, and it is selected from sodium chloride, sorbitol, xylitol, glucose, mannitol, propylene glycol and the glycerol one or more.
As required, lipid microsphere injection of the present invention can add the pH regulator agent, comprises all kinds of buffer salt system such as citric acid-sodium citrate, acetic acid-sodium acetate, phosphate agent etc., and NaOH solution, HCl solution.
As required, lipid microsphere injection of the present invention can add the complexing of metal ion agent, as in EDTA or the b diammonium disodium edta salt etc. one or more.
Butyrate clevidipine lipid microsphere injection related among the present invention can prepare by following steps:
1. medicine and emulsifying agent are added in the oil for injection, 35～80 ℃ of following stirring and dissolving, mix homogeneously obtains oil phase.
2. macrogol ester, acceptable accessories adds in the water for injection, and 20～80 ℃ of following stirring and dissolving get water.
3. under 30～75 ℃, water and oil phase are mixed shearing formation colostrum.
4. this colostrum is passed through high pressure homogenizer, pressure is adjusted into 500～1000bar, and under high pressure homogenizing obtains lipid microsphere injection 5～15 times.
5. with the aperture filtering with microporous membrane of 0.45～2.0 μ m.
6. fill the nitrogen fill, sterilization promptly gets butyrate clevidipine lipid microsphere injection.
It all is injection ranks that preparation among the present invention is formed, and can be used for intravenous injection, and the mean diameter of prepared butyrate clevidipine lipid microsphere is 200～400nm, has excellent particle size distribution.
The advantage of butyrate clevidipine lipid microsphere of the present invention is: the adding of (1) macrogol ester, can avoid lipoid microsphere after administration rapidly by reticuloendothelial system phagocytic, the release of may command butyrate clevidipine from lipoid microsphere, make it present drug release characteristic comparatively stably, help regulating suitable duration of efficacy, reduce untoward reaction such as bounce-back property hypertension.(2) distribution of specific in vivo can accumulate in the blood vessel wound site, realizes the selective local blood pressure lowering, avoids perioperative more effectively because the operation wound position that hypertension causes is opened and split and hemorrhage, reduces the whole body toxic and side effects simultaneously.(3) macrogol ester helps improving stability of formulation, can prevent to assemble unstable situations such as merging because of storage requirement changes the emulsion droplet that causes in the put procedure.(4) butyrate clevidipine may be dissolved in the soft matrix oil and phospholipid layer in the lipoid microsphere, improves the dissolubility of medicine in preparation greatly, effectively reduces dosage.
Description of drawings
Fig. 1 is extracorporeal releasing test testing result figure of the present invention
The specific embodiment
Below by specific embodiment in detail the present invention is described in detail, but the present invention is not limited in following embodiment.
Embodiment 1
Prescription:
w/w(％)
Butyrate clevidipine 0.01
Soybean oil 10
Soybean lecithin 1.5
Polyethylene glycol 1000 vitamin E succinic acid ester 0.4
Glycerol 2.3
Sodium hydroxide is regulated pH to 5.0～8.0
The water for injection surplus
Preparation method:
1. butyrate clevidipine and soybean lecithin are added in the soybean oil, 35～80 ℃ of following stirring and dissolving, mix homogeneously obtains oil phase.
2. with polyethylene glycol 1000 vitamin E succinic acid ester, glycerol adds in the water for injection, and 20～80 ℃ of following stirring and dissolving get water.
3. under 30～75 ℃, water and oil phase are mixed shearing formation colostrum.
4. this colostrum is passed through high pressure homogenizer, pressure is adjusted into 500～1000bar, and under high pressure homogenizing obtains lipid microsphere injection 5～15 times.
5. adjust pH to 5.0～8.0 of lipid microsphere injection with sodium hydroxide.
6. with the aperture filtering with microporous membrane of 0.45～2.0 μ m.
7. fill the nitrogen fill, sterilization promptly gets butyrate clevidipine lipid microsphere injection.
The mean diameter of obtained butyrate clevidipine lipid microsphere is 224.3 ± 21.4nm, and (Polydispersity Index is 0.102 PI) to polydispersity coefficient.
Embodiment 2
Prescription:
w/w(％)
Butyrate clevidipine 0.03
Ovum Gallus domesticus Flavus lecithin 2.5
Glycerol 2.0
Macrogol 2000 stearate 0.6
Vitamin E 0.5
Sodium hydrogen phosphate is regulated pH to 5.0～8.0
The water for injection surplus
Preparation method:
1. butyrate clevidipine, Ovum Gallus domesticus Flavus lecithin and vitamin E are added in the fish oil, 35～80 ℃ of following stirring and dissolving, mix homogeneously obtains oil phase.
2. with the Macrogol 2000 stearate, glycerol adds in the water for injection, and 20～80 ℃ of following stirring and dissolving get water.
3. under 30～75 ℃, water and oil phase are mixed shearing formation colostrum.
4. this colostrum is passed through high pressure homogenizer, pressure is adjusted into 500～1000bar, and under high pressure homogenizing obtains lipid microsphere injection 5～15 times.
5. adjust pH to 5.0～8.0 of lipid microsphere injection with sodium hydrogen phosphate.
6. with the aperture filtering with microporous membrane of 0.45～2.0 μ m.
7. fill the nitrogen fill, sterilization promptly gets butyrate clevidipine lipid microsphere injection.
The mean diameter of obtained butyrate clevidipine lipid microsphere is 283.3 ± 11.6nm, and (Polydispersity Index is 0.085 PI) to polydispersity coefficient.
Embodiment 3
Prescription:
w/w(％)
Butyrate clevidipine 0.05
Olive oil 10
Hydrolecithin 3.0
Solutol?HS?15 2.0
Glycerol 2.5
The water for injection surplus
Preparation method:
1. butyrate clevidipine and hydrolecithin are added in the olive oil, 35～80 ℃ of following stirring and dissolving, mix homogeneously obtains oil phase.
2. with Solutol HS 15, glycerol adds in the water for injection, and 20～80 ℃ of following stirring and dissolving get water.
3. under 30～75 ℃, water and oil phase are mixed shearing formation colostrum.
4. this colostrum is passed through high pressure homogenizer, pressure is adjusted into 500～1000bar, and under high pressure homogenizing obtains lipid microsphere injection 5～15 times.
5. with the aperture filtering with microporous membrane of 0.45～2.0 μ m.
6. fill the nitrogen fill, sterilization promptly gets butyrate clevidipine lipid microsphere injection.
The mean diameter of obtained butyrate clevidipine lipid microsphere is 204.6 ± 21.7nm, and (Polydispersity Index is 0.113 PI) to polydispersity coefficient.
Embodiment 4
Prescription:
w/w(％)
Butyrate clevidipine 0.06
Medium chain triglyceride 5.0
Soybean oil 5.0
Ovum Gallus domesticus Flavus lecithin 4.0
Macrogol 2000 vitamin E amber
0.5
The amber acid esters
Propylene glycol 3.5
The water for injection surplus
Preparation method:
1. butyrate clevidipine and Ovum Gallus domesticus Flavus lecithin are added in the mixture of medium chain triglyceride and soybean oil, 35～80 ℃ of following stirring and dissolving, mix homogeneously obtains oil phase.
2. with the Macrogol 2000 vitamin e succinate, propylene glycol adds in the water for injection, and 20～80 ℃ of following stirring and dissolving get water.
3. under 30～75 ℃, water and oil phase are mixed shearing formation colostrum.
4. this colostrum is passed through high pressure homogenizer, pressure is adjusted into 500～1000bar, and under high pressure homogenizing obtains lipid microsphere injection 5～15 times.
5. with the aperture filtering with microporous membrane of 0.45～2.0 μ m.
6. fill the nitrogen fill, sterilization promptly gets butyrate clevidipine lipid microsphere injection.
The mean diameter of obtained butyrate clevidipine lipid microsphere is 184.1 ± 26.3nm, and (Polydispersity Index is 0.105 PI) to polydispersity coefficient.
Embodiment 5
Prescription:
w/w(％)
Butyrate clevidipine 0.07
Fish oil 15
Soybean lecithin 1.8
PEG derivatization phospholipid acyl ethanolamine 0.3
Poloxamer?188 1.2
Glycerol 2.4
The water for injection surplus
Preparation method:
1. butyrate clevidipine, soybean lecithin and PEG derivatization phospholipid acyl ethanolamine are added in the fish oil, 35～80 ℃ of following stirring and dissolving, mix homogeneously obtains oil phase.
2. with Poloxamer 188, glycerol adds in the water for injection, and 20～80 ℃ of following stirring and dissolving get water.
3. under 30～75 ℃, water and oil phase are mixed shearing formation colostrum.
4. this colostrum is passed through high pressure homogenizer, pressure is adjusted into 500～1000bar, and under high pressure homogenizing obtains lipid microsphere injection 5～15 times.
5. with the aperture filtering with microporous membrane of 0.45～2.0 μ m.
6. fill the nitrogen fill, sterilization promptly gets butyrate clevidipine lipid microsphere injection.
The mean diameter of obtained butyrate clevidipine lipid microsphere is 202.7 ± 16.1nm, and (Polydispersity Index is 0.094 PI) to polydispersity coefficient.
Embodiment 6
Prescription:
w/w(％)
Butyrate clevidipine 0.08
Fish oil 10
Medium chain triglyceride 15
Ovum Gallus domesticus Flavus lecithin 4.5
Polyethylene Glycol 5000 stearates 0.6
Glycerol 2.5
Sodium hydrogen phosphate is regulated pH to 5.0～8.0
The water for injection surplus
Preparation method:
1. butyrate clevidipine and Ovum Gallus domesticus Flavus lecithin are added in the mixture of medium chain triglyceride and fish oil, 35～80 ℃ of following stirring and dissolving, mix homogeneously obtains oil phase.
2. with Polyethylene Glycol 5000 stearates, glycerol adds in the water for injection, and 20～80 ℃ of following stirring and dissolving get water.
3. under 30～75 ℃, water and oil phase are mixed shearing formation colostrum.
4. this colostrum is passed through high pressure homogenizer, pressure is adjusted into 500～1000bar, and under high pressure homogenizing obtains lipid microsphere injection 5～15 times.
5. adjust pH to 5.0～8.0 of lipid microsphere injection with sodium hydrogen phosphate.
7. with the aperture filtering with microporous membrane of 0.45～2.0 μ m.
8. fill the nitrogen fill, sterilization promptly gets butyrate clevidipine lipid microsphere injection.
The mean diameter of obtained butyrate clevidipine lipid microsphere is 301.8 ± 24.0nm, and (Polydispersity Index is 0.073 PI) to polydispersity coefficient.
Embodiment 7
w/w(％)
Butyrate clevidipine 0.1
Ovum Gallus domesticus Flavus lecithin 1.2
Solutol?HS?15 0.5
Glycerol 2.2
Sodium hydrogen phosphate is regulated pH to 5.0～8.0
The water for injection surplus
Preparation method:
1. butyrate clevidipine and Ovum Gallus domesticus Flavus lecithin are added in the soybean oil, 35～80 ℃ of following stirring and dissolving, mix homogeneously obtains oil phase.
2. with Solutol HS 15, glycerol adds in the water for injection, and 20～80 ℃ of following stirring and dissolving get water.
3. under 30～75 ℃, water and oil phase are mixed shearing formation colostrum.
4. this colostrum is passed through high pressure homogenizer, pressure is adjusted into 500～1000bar, and under high pressure homogenizing obtains lipid microsphere injection 5～15 times.
5. adjust pH to 5.0～8.0 of lipid microsphere injection with sodium hydrogen phosphate.
6. with the aperture filtering with microporous membrane of 0.45～2.0 μ m.
7. fill the nitrogen fill, sterilization promptly gets butyrate clevidipine lipid microsphere injection.
The mean diameter of obtained butyrate clevidipine lipid microsphere is 293.2 ± 13.1nm, and (Polydispersity Index is 0.068 PI) to polydispersity coefficient.
Embodiment 8
Prescription:
w/w(％)
Butyrate clevidipine 0.08
Fish oil 10
Medium chain triglyceride 15
Ovum Gallus domesticus Flavus lecithin 4.5
Polyethylene Glycol 5000 stearates 0.6
Glycerol 2.5
Sodium hydrogen phosphate is regulated pH to 5.0～8.0
Myrj 45 0.5
Polyoxyethylene aliphatic alcohol ether 0.5
The water for injection surplus
Preparation method:
1. butyrate clevidipine and Ovum Gallus domesticus Flavus lecithin are added in the mixture of medium chain triglyceride and fish oil, 35～80 ℃ of following stirring and dissolving, mix homogeneously obtains oil phase.
2. with Polyethylene Glycol 5000 stearates, glycerol, Myrj 45, Myrj 45 add in the water for injection, and 20～80 ℃ of following stirring and dissolving get water.
3. under 30～75 ℃, water and oil phase are mixed shearing formation colostrum.
4. this colostrum is passed through high pressure homogenizer, pressure is adjusted into 500～1000bar, and under high pressure homogenizing obtains lipid microsphere injection 5～15 times.
5. adjust pH to 5.0～8.0 of lipid microsphere injection with sodium hydrogen phosphate.
9. with the aperture filtering with microporous membrane of 0.45～2.0 μ m.
10. fill the nitrogen fill, sterilization promptly gets butyrate clevidipine lipid microsphere injection.
The mean diameter of obtained butyrate clevidipine lipid microsphere is 301.8 ± 24.0nm, and (Polydispersity Index is 0.073 PI) to polydispersity coefficient.
Embodiment 9
Prescription:
w/w(％)
Butyrate clevidipine 0.08
Fish oil 10
Medium chain triglyceride 15
Ovum Gallus domesticus Flavus lecithin 3.5
Two palmityl phosphatidic acid 1
Polyethylene Glycol 5000 stearates 0.6
Glycerol 2.5
Citric acid-sodium citrate buffer is regulated pH to 5.0～8.0
Myrj 45 0.5
Polyoxyethylene aliphatic alcohol ether 0.5
The water for injection surplus
Preparation method:
1. butyrate clevidipine, two palmityl phosphatidic acid and Ovum Gallus domesticus Flavus lecithin are added in the mixture of medium chain triglyceride and fish oil, 35～80 ℃ of following stirring and dissolving, mix homogeneously obtains oil phase.
2. with Polyethylene Glycol 5000 stearates, glycerol, Myrj 45, Myrj 45 add in the water for injection, and 20～80 ℃ of following stirring and dissolving get water.
3. under 30～75 ℃, water and oil phase are mixed shearing formation colostrum.
4. this colostrum is passed through high pressure homogenizer, pressure is adjusted into 500～1000bar, and under high pressure homogenizing obtains lipid microsphere injection 5～15 times.
5. adjust pH to 5.0～8.0 of lipid microsphere injection with sodium hydrogen phosphate.
is the filtering with microporous membrane of 0.45～2.0 μ m with the aperture.
fills the nitrogen fill, and sterilization promptly gets butyrate clevidipine lipid microsphere injection.
The mean diameter of obtained butyrate clevidipine lipid microsphere is 301.8 ± 24.0nm, and (Polydispersity Index is 0.073 PI) to polydispersity coefficient.
Extracorporeal releasing test
Get embodiment 5 prepared butyrate clevidipine lipid microsphere injections and butyrate clevidipine respectively and be dissolved in injection and the commercially available Emulsion 5ml of butyrate clevidipine that usual vehicle (adding the Solutol hydrotropy) is made, putting molecular cut off is 12,000～14, in 000 the bag filter, in 37 ℃ of pH 7.4PBS (containing Tween 80 0.1%) solution, carry out the research of release in vitro degree, the result as shown in Figure 1, the result shows butyrate clevidipine lipid microsphere injection may command drug release, make it present drug release process comparatively stably, help regulating suitable duration of efficacy, reduce untoward reaction.
Safety and pharmacodynamics test
Involved in the present invention is a kind of butyrate clevidipine lipid microsphere injection with Gong injection of fugitive, powerful antihypertensive effect.Embodiment 7 prepared butyrate clevidipine lipid microsphere injections are carried out blood vessel irritation test, sensitivity test and external hemolytic test, and the result shows that the butyrate clevidipine lipid microsphere injection that the present invention prepares is safe.In addition the butyrate clevidipine lipid microsphere injection of embodiment 7 gained and butyrate clevidipine are dissolved in injection and the commercially available Emulsion of butyrate clevidipine that usual vehicle (adding the Solutol hydrotropy) makes and respectively spontaneous hypertensive rat are carried out intravenously administrable, investigate the equivalence of lipoid microsphere injection, administering mode is progressively to increase venoclysis speed in 15 minutes, when mean arterial blood pressure has reduced by 30% than control level, stop administration, that blood pressure recovers is normal (by the control level 70% to 90%) the required time is blood pressure turnaround time.Blood pressure lowering is renderd a service and is blood pressure drops 20% needed dosage.
Blood pressure recovery time and blood pressure lowering are renderd a service as shown in the table:
From The above results as can be seen, butyrate clevidipine is made lipid microsphere injection does not influence drug effect, so butyrate clevidipine lipid microsphere injection is a kind of safe and effective novel antihypertensive drugs preparation.
Stability study---accelerated tests
Get embodiment 7 prepared butyrate clevidipine lipid microsphere injections and commercially available butyrate clevidipine intravenous injection emulsion respectively, putting temperature is 30 ± 2 ℃, relative humidity is to place 6 months in 65% ± 5% the climatic chamber, respectively at the 0th, 1,2,3 and sampling in 6 months, detects.Product appearance, content and particle size distribution are as shown in the table:
The result shows that the self-control butyrate clevidipine lipid microsphere injection is in the accelerated test process, and indexs such as outward appearance and particle size distribution are all stable than commercially available product.
Claims (11)
1. butyrate clevidipine lipid microsphere injection, it is mixed by following raw materials by weight:
Butyrate clevidipine 0.01～1%
Oil for injection 1～35%
Emulsifying agent 0.01～10%
Polyethylene Glycol compounds 0.1～10%
Medical additive 0.01～20%
The water for injection surplus
2. butyrate clevidipine lipid microsphere injection according to claim 1, it is mixed by following raw materials by weight:
Butyrate clevidipine 0.01～0.2%
Oil for injection 5～30%
Emulsifying agent 0.5～8%
Polyethylene Glycol compounds 0.1～5%
Medical additive 1～10%
The water for injection surplus
3. butyrate clevidipine lipid microsphere injection according to claim 1 and 2, wherein: described oil for injection is selected from more than one hybrid combining of soybean oil, Oleum Camelliae, Oleum sesami, Oleum Ricini, Oleum Helianthi, fish oil, Oleum Arachidis hypogaeae semen, safflower oil, olive oil, triglyceride, medium chain triglyceride or its.
4. butyrate clevidipine lipid microsphere injection according to claim 1 and 2, wherein: described emulsifying agent is selected from one or more in lecithin, soybean lecithin, hydrogenated soy phosphatidyl choline, Ovum Gallus domesticus Flavus lecithin, hydrolecithin, two Semen Myristicae phospholipid acid choline, two Semen Myristicae phosphatidyl glycerol, dioleoyl phospholipid phatidylcholine, two palmityl phosphatidic acid, two Palmic acid phosphatidylcholines, PHOSPHATIDYL ETHANOLAMINE, polyglycol derivatization phospholipid acyl ethanolamine, the polyglycol derivatization phospholipid acyl serine;
5. butyrate clevidipine lipid microsphere injection according to claim 1 and 2, wherein: it is 1000～10000 Polyethylene Glycol vitamin e succinate or stearate that described Polyethylene Glycol compounds is selected from molecular weight; Polyglycol distearate and molecular weight are the mixture of 200～10000 Polyethylene Glycol; Myrj 45, polyoxyethylene aliphatic alcohol ether or its mixture.
6. butyrate clevidipine lipid microsphere injection according to claim 1 and 2, wherein: described medical additive is selected from one or more in antioxidant, osmotic pressure regulator, pH regulator agent, complexing of metal ion agent and the antiseptic.
7. butyrate clevidipine lipid microsphere injection according to claim 6, wherein: described antioxidant is selected from one or more in sodium sulfite, sodium sulfite, sodium pyrosulfite, vitamin C and the vitamin E.
8. butyrate clevidipine lipid microsphere injection according to claim 6, wherein: described osmotic pressure regulator is selected from one or more in sodium chloride, glucose, mannitol, sorbitol, propylene glycol and the glycerol.
9. butyrate clevidipine lipid microsphere injection according to claim 6, wherein: described pH regulator agent is selected from NaOH solution, the buffer solution of HCl solution or citric acid-sodium citrate, acetic acid-sodium acetate, phosphate, boric acid-Borax.
10. butyrate clevidipine lipid microsphere injection according to claim 6, wherein: described complexing of metal ion agent is selected from one or more in EDTA, b diammonium disodium edta, the calcium disodium edetate.
11. the preparation method of butyrate clevidipine lipid microsphere injection according to claim 1 and 2, it may further comprise the steps:
1. in medicine and emulsifying agent and other oil-soluble adjuvant adding oil for injection, mix homogeneously obtains oil phase.
2. macrogol ester, acceptable accessories adds in the water for injection, and stirring and dissolving gets water.
3. water and oil phase are mixed shearing formation colostrum.
4. this colostrum is passed through high pressure homogenizer, under high pressure homogenizing obtains lipid microsphere injection.
5. use filtering with microporous membrane.
6. fill the nitrogen fill, sterilization.
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| CN102000027A (en) * | 2010-11-23 | 2011-04-06 | 北京中海康医药科技发展有限公司 | Clevidipine butyrate medium-length chain fat emulsion and preparation method thereof |
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