CN1903173A - Nimodipine nanometer granule and its prepn. method - Google Patents
Nimodipine nanometer granule and its prepn. method Download PDFInfo
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- CN1903173A CN1903173A CNA2006100910360A CN200610091036A CN1903173A CN 1903173 A CN1903173 A CN 1903173A CN A2006100910360 A CNA2006100910360 A CN A2006100910360A CN 200610091036 A CN200610091036 A CN 200610091036A CN 1903173 A CN1903173 A CN 1903173A
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- nimodipine
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Abstract
A nanoparticle of nimodipine contains nimodipine, the carrier chosen from poloxamer cholesterol ester of fatty acid and cholesterol ester of fatty acid, stabilizer and water. Its preparing process is also disclosed.
Description
Technical field
The present invention relates to a kind of Nimodipine nanometer granule and preparation method thereof, it is characterized in that comprising nimodipine, carrier, stabilizing agent and water, wherein carrier has been selected novel adjuvant fatty acid poloxamer cholesteryl ester (PPGC) and fatty acid PEG cholesteryl ester (PEGP) for use, nanoparticle particle diameter≤the 1um of preparation has the advantage of drug loading height and good stability.
Background technology
The nimodipine chemical name is: 1-Methylethyl-2-methoxyethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrobenzophenone)-3,5-pyridine dicarboxylate.Molecular weight is 418.45.
Nimodipine is a kind of Ca channel blocker.Under the normal condition, the contraction of smooth muscle depends on Ca and enters in the cell, causes the depolarization of transmembrane current.Nimodipine enters in the cell, suppresses smooth muscle contraction by effective prevention Ca, reaches the purpose of removing vasospasm.Zoopery proves that nimodipine is many by force far beyond the effect of other position tremulous pulsies of whole body to arteriocerebral effect, and because it has the very high fat characteristics of having a liking for, easily sees through blood brain barrier.When being used for the hemorrhage treatment of subarachnoid space, the concentration in the cerebrospinal fluid can reach 12.5ng/ml.Inference can be used for preventing the posthemorrhagic vasospasm of subarachnoid space clinically thus, yet it is still unclear to use the mechanism of action of this medicine at human body.Still have protection in addition and promote memory, promotion intelligence restitution.So optionally act on the cerebrovascular smooth muscle, expansion of cerebral vascular, the cerebral blood flow increasing amount significantly reduces the ischemic brain injury that vasospasm causes.The posthemorrhagic cerebral vasospasm of subarachnoid space and the convalescent blood flow circulation of acute cerebrovascular disease that are applicable to a variety of causes improve.
Nimodipine is a poorly water soluble drugs, dissolubility is little in the water, has stronger liver first pass metabolism effect, cause oral administration biaavailability low, the bioavailability of health volunteer and Patients with Subarachnoid Hemorrhage is respectively 5%～13% and 3%～28%, and oral onset is slower, this has just determined nimodipine when being used for the treatment of disease such as the convalescent blood flow of posthemorrhagic cerebral vasospasm of subarachnoid space and acute cerebrovascular disease circulation improvement, preferably adopt intravenous administration, so that quick acting.And all contain organic solvents such as promoting the dissolved ethanol of principal agent in the present commercially available nimotop vial, cause producing injection pain; Nimotop vial is when clinical use in addition, because medicine can adsorb with common tube for transfusion, the principal agent loss is serious, for overcoming this problem, needs to use the PE of costliness to manage, and several and medicine equivalence of its price does not possess advantage.
Polyethylene Glycol (PEG) is the mixture that oxirane and water polycondensation form, and its molecular weight ranges is 1500-40000.
Poloxamer (Poluoshamu) trade name is pluronic (pluronic) F-68.Be white or the translucent waxy solid of little yellow, little have a foreign odor.In water and ethanol in easily molten, in dehydrated alcohol and ethyl acetate, dissolve.Purposes: as surfactant, emulsifying agent, suppository base, excipient etc.Poloxamer prevents to can be used for intravenous formulations by haemolysis because of having significantly, can play the hydrotropy effect to some medicine.
Poloxamer molecular formula: H (C2H4O) a (C3H6O) b (C2H4O) cOH, wherein a and c are 2～130, and b is 15～67, and containing polyoxyethylene is 81.8% ± 1.9%.Mean molecule quantity be 1000～7000 should be 90.0%～110.0% of labelled amount.Mean molecule quantity is 7000.
Cholesterol claims cholesterol again, is a kind of derivant of cyclopentanoperhy drophenanthrene, by staying body portion and a long side chain to form.The Chang Zuowei stabilizing agent uses in nanometer formulation.
If nimodipine can be prepared into nanoparticle, pharmaceutical pack is wrapped in the macromolecular material capsule, avoided the adding of organic solvent on the one hand, reduced sticking of medicine and tube for transfusion, more promote the breast grain of packaging medicine to enter target tissue release medicine rapidly, reduce adverse reaction rate, improve safety and clinical compliance, and can delay drug release to a certain extent, thereby prolong action time.
Of the present invention group of requirement according to preparation, adopted by poloxamer (POL) or Polyethylene Glycol (PEG) and cholesterol with fat diacid or the bonded novel adjuvant (Poloxamer-G-Cholesterol of fatty acid anhydride, POGC) or (PEG-G-Cholesterol, PEGC), and with prepared Nimodipine nanometer granule as main adjuvant, because new dressing water-wet side poloxamer and the good emulsification property of PEG and hydrophobic section cholesterol and nimodipine are with the good combination of molecular separating force, improve the medicine carrying ability of nanoparticle greatly, guaranteed the stable existence of medicine in nanoparticle.
This variety development success, the economic benefit of generation and social benefit are self-evident, can substitute existing nimotop vial, bring safe, effective and cheap therapeutic process to extensive patients.
The present invention adopts high-pressure emulsification low-temperature setting method, is carrier material with POGC or PEGC, the preparation Nimodipine nanometer granule, and investigate its physical stability and internal metabolism behavior, this work does not appear in the newspapers both at home and abroad at present.
Summary of the invention
Nimodipine nanometer granule of the present invention and preparation method thereof, it comprises nimodipine, carrier, stabilizing agent and water, and its parts by weight are:
Nimodipine 0.01-1
Carrier 0.5-10
Stabilizing agent 1.0-20
Water 70-99
Wherein carrier is selected the cholesteryl ester that Biodegradable Polymers is modified, Biodegradable Polymers wherein, specifically refer to a kind of in poloxamer, the Polyethylene Glycol, the material of formation is called after fatty acid poloxamer cholesteryl ester (POGC) and fatty acid PEG cholesteryl ester (PEGC) respectively; Wherein the fatty acid carbons atomic number is 2-10.
Stabilizing agent select lecithin, triglyceride, mono fatty acid glyceride, in one or more; Specifically comprise bean bandit acid, Palmic acid, wych-elm acid, sad, capric acid, glyceryl monostearate, single trimyristin, monopalmitin, single Rikemal B 200, single caprylin, single caprin, glyceryl monostearate, two trimyristins, glycerol-1,3-dipalmitate, two Rikemal B 200s, two caprylins, two caprins, glycerol stearate, bean bandit acid triglyceride, Trihexanoylglycerol, wych-elm acid triglyceride, sad triglyceride, the capric acid triglyceride; Lecithin comprises soybean phospholipid, egg yolk lecithin, hydrogenated soya phosphatide, hydrogenation egg yolk lecithin, two nutmeg phosphatidylcholine, two nutmeg phosphatidyl glycerol, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine and distearyl phosphatidyl glycerol.
Nimodipine nanometer granule of the present invention can also contain freeze drying protectant, is selected from glucose, sorbitol, lactose, maltose, mannitol, trehalose and the low molecular dextran one or more.
Nimodipine nanometer granule of the present invention, the wherein particle diameter≤1um of nanoparticle.
The present invention with novel adjuvant poloxamer (POL) or Polyethylene Glycol (PEG) and cholesterol with fat diacid or the bonded novel adjuvant (Poloxamer-G-Cholesterol of fatty acid anhydride, POGC) or (PEG-G-Cholesterol, PEGC) its synthetic method is as follows:
3～10g cholesterol and 0.1～1g 4-dimethylamino pyridine (DMAP) are placed 0.01～1ml dichloromethane (perhaps DMF), stir, slowly add 0.5～2.0g fatty acid anhydride, nitrogen protection is reaction 2h down, order adds 20-50g Polyethylene Glycol or 100～150g poloxamer and 1.0～3.0g dicyclohexylcarbodiimide (DCC) behind the natural cooling, slowly stirs 24hr to 1 week, rotary evaporation after reaction is finished, product dissolves with chloroform, gets crude product through ether sedimentation; Again through refining fatty acid poloxamer cholesteryl ester or the fatty acid polyglycol ethylene glycol cholesteryl ester of promptly getting of repeated precipitation.
Wherein the carbon number of fatty acid is 2-10.
The preparation technology of Nimodipine nanometer granule:
Nimodipine, POGC or PEGP and the stabilizing agent heating of recipe quantity are dissolved, add in an amount of sterilized water for injection, stir and make dissolving; Mix above-mentioned two kinds of systems, add water to 100ml, high-speed stirred gets colostrum; Under the logical condition of nitrogen gas, the colostrum for preparing is met granularity requirements with the high pressure homogenizer homogenizing to detecting through laser particle analyzer, regulate pH value 5.0～7.0; the freeze drying protectant that adds recipe quantity in the aforesaid liquid, stirring and dissolving, aseptic filtration; fill, lyophilization are promptly.
Nimodipine nanometer granule is the white loose block, and the back mean diameter of redissolving is controlled at below the 0.3 μ m, and the envelop rate of nimodipine reaches more than 90%.
Specific embodiment
Embodiment one
Prescription: nimodipine 0.01-1.0g, POGC0.5～10.0g, glyceryl monostearate 1.0～6.0g, fatty acid 1.0～6.0g, lecithin 2.0～6.0g, mannitol 2.0～10.0g, water for injection adds to 30ml.
Preparation method one:
A) with glyceryl monostearate 2.0g, fatty acid 1.0g, lecithin 1.0g, POGC2.0g and nimodipine 1mg heating and melting, colostrum is made in the water for injection (PH10-11) and the mannitol 5.0g stirring that add recipe quantity, regulate pH value 4.5～7.0, the reuse high pressure homogenizer is up to specification to granularity to the high pressure homogenize emulsifying that circulates of colostrum system.
B) after above-mentioned Emulsion filters, lyophilization, the inflated with nitrogen gland both got.
Preparation method two:
A) with glyceryl monostearate 3.0g, fatty acid 1.0g, lecithin 1.0g, POGC 10.0g and nimodipine 50mg heating and melting, colostrum is made in the water for injection (PH10-11) and the mannitol 10.0g stirring that add recipe quantity, regulate pH value 4.5～7.0, the reuse high pressure homogenizer is up to specification to granularity to the high pressure homogenize emulsifying that circulates of colostrum system.
B) after above-mentioned Emulsion filters, lyophilization, the inflated with nitrogen gland both got.
Embodiment two
Prescription: nimodipine 0.01-1.0g, PEGC1.0～10.0g, glyceryl monostearate 1.0～6.0g, lecithin 2.0～6.0g, mannitol 2.0～6.0g, water for injection adds to 30ml.
A) with glyceryl monostearate 1.0g, lecithin 1.0g, PEGC3.0g and nimodipine 0.0005g heating and melting, colostrum is made in the water for injection (PH10-11) and the mannitol 5.0g stirring that add recipe quantity, regulate pH value 4.5～7.0, the reuse high pressure homogenizer is up to specification to granularity to the high pressure homogenize emulsifying that circulates of colostrum system.
B) after above-mentioned Emulsion filters, lyophilization, the inflated with nitrogen gland both got.
Embodiment three
Prescription: nimodipine 0.01-1.0g, POGC 1.0～8.0g, mono laurate acid glyceride 1.0～6.0g, lecithin 1.0～3.0g, mannitol 2.0～6.0g, low molecular dextran 2.0～6.0g, water for injection adds to 100ml.
Nimodipine 0.005g, POGC0.5g, mono laurate acid glyceride 2.0g and lecithin 1.0g heating dissolve; add in the suitable quantity of water solution of mannitol 3.0g; stir; high-speed stirred is to emulsion droplet mean diameter≤0.5 micron; add freeze drying protectant low molecular dextran 2.0g; behind the dissolution filter, lyophilization, the inflated with nitrogen gland both got.
Embodiment four
Prescription: nimodipine 0.01-1.0g, PEGC 1.0～8.0g, single caprin 1.0～6.0g, mannitol 2.0～6.0g, sodium alginate 2.0～10.0g, water for injection adds to 30ml.
A) with nimodipine 0.005g, the PEGC5.0g of recipe quantity, single caprin 2.0g heating and melting, colostrum is made in the water for injection and the mannitol 5.0g stirring that add recipe quantity, regulate pH value 4.5～7.0, the reuse high pressure homogenizer circulates high pressure homogenize emulsifying to granularity≤0.5 micron to the colostrum system; Add an amount of freeze drying protectant sodium alginate 5.0g, after the filtration, lyophilization, the inflated with nitrogen gland both got.
Embodiment five (medicine for experiment relatively)
Trial drug:, be mixed with the solution that contains nimodipine 0.4mg/ml with 0.9% sodium chloride injection during test according to the preparation of embodiment () provider method; Nimotop vial is buied from market, specification: 0.4mg/ml.
Experimental animal: healthy rat, body weight 0.16～0.2kg, totally 20,10 every group.
Administration: 5ml/Kg
The blood sampling time point: 6,15,30,60min, 2,4,6,9h
Conclusion: nanoparticle of the present invention is compared with commercially available nimotop vial, onset time basically identical, removing speed is slower in vivo, can reduce dosage, has played the effect of efficacy enhancing and toxicity reducing, the results are shown in Figure of description 1.
Medicine illustrates for the experiment comparative drawings figs:
Mean-F1 prepares according to embodiment () provider method for the present invention
Mean-F2 is nimotop vial (commercially available)
Claims (7)
1, a kind of Nimodipine nanometer granule and preparation method thereof is characterized in that comprising nimodipine, carrier, stabilizing agent and water, and its parts by weight are:
Nimodipine 0.01-1
Carrier 0.5-10
Stabilizing agent 1.0-20
Water 70-99.
2,, it is characterized in that the cholesteryl ester of selecting Biodegradable Polymers to modify according to the carrier in the Nimodipine nanometer granule in the claim 1; Concrete select a kind of in poloxamer and the Polyethylene Glycol, the material of formation is respectively fatty acid poloxamer cholesteryl ester (POGC) and fatty acid polyglycol ethylene glycol cholesteryl ester (PEGC), and wherein the fatty acid carbons atomic number is 2-10.
3,, it is characterized in that selecting in lecithin, triglyceride, mono fatty acid glyceride and the difatty acid glyceride one or more according to the stabilizing agent in the Nimodipine nanometer granule in the claim 1.
4,, it is characterized in that to comprise freeze drying protectant: one or more in glucose, sorbitol, lactose, maltose, mannitol, trehalose and the low molecular dextran according to the Nimodipine nanometer granule in the claim 1.
5, according to the Nimodipine nanometer granule in the claim 1, its preparation method is: nimodipine, POGC or PEGC and the stabilizing agent heating of recipe quantity are dissolved, add an amount of sterilized water for injection, stir and make dissolving; Mix above-mentioned two kinds of systems, add water to 100ml, high-speed stirred gets colostrum; Under the logical condition of nitrogen gas, the colostrum for preparing is met granularity≤1um with high pressure homogenizer to detecting through laser particle analyzer, aseptic filtration, fill, lyophilization are promptly.
6, according to the fatty acid in the claim 3, it is characterized in that selecting satisfied fatty acid, specifically comprise bean bandit acid, Palmic acid, wych-elm acid, sad, capric acid, glyceryl monostearate,. single trimyristin, monopalmitin, single Rikemal B 200, single caprylin, single caprin, glyceryl monostearate, two trimyristins, glycerol-1,3-dipalmitate, two Rikemal B 200s, two caprylins, two caprins, glycerol stearate, bean bandit acid triglyceride, Trihexanoylglycerol, wych-elm acid triglyceride, sad triglyceride, the capric acid triglyceride.
7,, it is characterized in that described lecithin comprises soybean phospholipid, egg yolk lecithin, hydrogenated soya phosphatide, hydrogenation egg yolk lecithin, two nutmeg phosphatidylcholine, two nutmeg phosphatidyl glycerol, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine and distearyl phosphatidyl glycerol according to the lecithin in the claim 3.
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2006100910360A CN1903173A (en) | 2006-07-12 | 2006-07-12 | Nimodipine nanometer granule and its prepn. method |
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| CNA2006100910360A CN1903173A (en) | 2006-07-12 | 2006-07-12 | Nimodipine nanometer granule and its prepn. method |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552156A (en) * | 2012-03-27 | 2012-07-11 | 西安德天药业股份有限公司 | Nimodipine freeze-dried solid lipid nanoparticle and preparation method thereof |
| CN103263388A (en) * | 2012-12-18 | 2013-08-28 | 苏州大学 | Folic acid modified norcantharidin stealth niosome and preparation method thereof |
| CN107019682A (en) * | 2017-04-13 | 2017-08-08 | 中国药科大学 | A kind of Nimodipine lipid nanoparticle and its preparation technology |
| CN108403629A (en) * | 2018-04-26 | 2018-08-17 | 徐州医科大学 | A kind of long-acting suspension of oral Nimoldipine and preparation method thereof |
-
2006
- 2006-07-12 CN CNA2006100910360A patent/CN1903173A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552156A (en) * | 2012-03-27 | 2012-07-11 | 西安德天药业股份有限公司 | Nimodipine freeze-dried solid lipid nanoparticle and preparation method thereof |
| CN102552156B (en) * | 2012-03-27 | 2013-08-21 | 西安德天药业股份有限公司 | Nimodipine freeze-dried solid lipid nanoparticle and preparation method thereof |
| CN103263388A (en) * | 2012-12-18 | 2013-08-28 | 苏州大学 | Folic acid modified norcantharidin stealth niosome and preparation method thereof |
| CN107019682A (en) * | 2017-04-13 | 2017-08-08 | 中国药科大学 | A kind of Nimodipine lipid nanoparticle and its preparation technology |
| CN107019682B (en) * | 2017-04-13 | 2019-09-03 | 中国药科大学 | A kind of Nimodipine lipid nanoparticle and its preparation process |
| CN108403629A (en) * | 2018-04-26 | 2018-08-17 | 徐州医科大学 | A kind of long-acting suspension of oral Nimoldipine and preparation method thereof |
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