CN101129366A - Nimodipine pharmaceutical composition and method of producing the same - Google Patents
Nimodipine pharmaceutical composition and method of producing the same Download PDFInfo
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- CN101129366A CN101129366A CNA2007101433876A CN200710143387A CN101129366A CN 101129366 A CN101129366 A CN 101129366A CN A2007101433876 A CNA2007101433876 A CN A2007101433876A CN 200710143387 A CN200710143387 A CN 200710143387A CN 101129366 A CN101129366 A CN 101129366A
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- nimodipine
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- poloxamer
- injection
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Abstract
The invention discloses a new nimodiping drug composition and making method, which is made of nimodiping, sorbitol or dehydration sorbitol fatty acid simple lipid surface activator, benign solvent of nimodiping, auxiliary solubilizer and injecting water to form the concentrated solution of injection or oral agent. The invention has big density, good stability, low findings and simple making technique, which can't induce damage for brain tissue due to cerebrovascular spasm.
Description
Technical field
The present invention relates to nimodipine injection or medicine preparation for oral use and preparation method thereof.
Technical background
Nimodipine is second filial generation l, the 4-dihydropyridine calcium channel blocker, and molecular formula is C
21H
26N
2O
7, molecular weight is 418.45.It has vasoconstriction and ischemia resisting effect to brain, nimodipine is external to prevent or eliminate various vaso-active substances (as 5-hydroxy tryptamine, prostaglandin and histamine) or the vasoconstriction that causes of blood and catabolite thereof, nimodipine also has neural and psychopharmacology character.To studies show that of acute brain blood supply disorder patient, nimodipine can expansion of cerebral vascular and is improved cerebral blood supply, usually greater than normal position, nimodipine can obviously reduce subarachnoid hemorrhage patient's ischemic potassium through damage and mortality rate to the perfusion increase at cerebral lesion and hypoperfusion position.
Nimodipine is the bihydropyridine type calcium-channel antagonists, is fat-soluble, easily by blood brain barrier, can reach higher concentration in brain.The expansion of cerebral vascular of nimodipine improves effect such as brain blood supply and has obtained certainly and be applied to clinical over nearly 20 years, is mainly used to prevent and treat the acute ischemic cerebrovascular disease disease, and migraine, angina pectoris, myocardial infarction and disease of inner ear are also had good drug effect.It mainly blocks the calcium channel of central nervous system's inner cell film to nimodipine through the zoopery confirmation, regulate the level of intracellular Ca2+ effectively, make it to keep normal physiological function, particularly outstanding to cerebrovascular effect, can effectively prevent and treat the cerebral tissue ischemic lesions that causes because of the caused cerebral vasospasm of subarachnoid hemorrhage.It can reduce erythrocyte fragility and blood viscosity, anticoagulant, and antithrombotic forms, and selectivity expansion of cerebral vascular under optimal dose influences peripheral blood vessel hardly.
The nimodipine raw material is a light yellow crystalline powder, and odorless is tasteless, and is easily molten in acetone, chloroform, in ethanol, dissolve, and slightly soluble in ether, then insoluble in water.This medicine is used for many years as clinical cerebrovascular medicine, but because of there are shortcomings such as poorly water-soluble, first pass effect be obvious in himself physicochemical property reason, it directly influences the performance of clinical drug effect.So can overcome first pass effect when nimodipine is prepared into the liquid preparation that vein uses, improve bioavailability, but, increase its dissolubility so be necessary to seek suitable method owing to itself be insoluble in water.The existing nimotop vial trade name of China market has Nimotop, Ni Lisu etc., contain a large amount of ethanol in the injection, the human liver there is certain infringement, and a large amount of ethanol like this, in use to patient's zest and side effect big (as pain, phlebitis etc.), the injection on the market
Contain surfactant, the stabilizing agent of higher concentration in the lyophilized powder, liver is had certain injury equally.So be necessary that though the patent of injection nimodipine preparation method is also arranged at present, the more loaded down with trivial details additives that maybe need add of preparation method are domestic also the pharmaceutical grade standard as yet owing to exist with its exploitation novel form, so also exist not enough.
Adopt tween 80, poloxamer 188 to be stabilizing agent in this patent, the second alcohol and water is formed mixed solvent, principle by the mixed micelle solubilising, it has been prepared into the injection nimodipine dosage form of high concentration, the two all can improve the stability of the water solublity and the pharmaceutical aqueous solution of medicine, compare with market nimodipine preparation, have concentration big (more than 20 times), good stability, the low characteristics of adjuvant.
Summary of the invention
This product is the mixed micelle system that poloxamer and tween are formed, hydrophobic chain in the micelle is made disordered motion like oil at the nuclear core, and micellar aqueous solution is transparent fully, because of outwardly hydrophilic group is in the water, and hydrophobic nuclear core does not contact with water, whole micelle is nuclear-shell spherical structure, and system stability is very high, is a kind of thermodynamically metastable fixed system, temperature is very little to the influence of system, this product in-20 ℃～110 ℃ temperature ranges, physicochemical property temperature, stable content.Safe and reliable clinically, needn't worry in use, transportation, storing process, to have medicine crystal the variation of physicochemical property such as to separate out.
Owing to contain certain density tween 80, poloxamer 188 mixed surfactants in this product, the critical micelle concentration of its concentration the two formed mixed micelle far above it, cause the balance between surfactant monomer and the micelle further to move to forming the micelle direction, forming the how micellar while, the micelle nuclear core water content that forms reduces, compact gradually, radius also dwindles, and micelle is more stable.Because there is the very high association dynamic stability of separating micelle inside, even the concentration of mixed surfactant is lower than mixed C MC and separates association after this product and normal saline, the dilution of glucose for injection compatible, its speed is also low, general solution associates the time more than 10 hours, is enough to finish before separating association the task of pharmaceutical carrier.
Even (less than 30nm) has the good permeability of organizing because the mixed micelle particle diameter is little, especially can assemble at the tissue with seepage blood vessel, and promptly so-called the enhancing sees through and retention effect (EPR), and this makes this product have natural passive target effect.Its particle diameter is again greater than can be by the degree of renal excretion, and wherein particle diameter less less than can being prolonged the time in vivo by the limit of the non-special picked-up of mononuclear cell.Mixed micelle can reduce blood viscosity and vascular resistance, thereby improves microvascular transport efficacy.Because the hydrophilic-structure of its shell (being difficult for by albumen or phagocyte identification), micelle is long at blood and in-house holdup time, can improve EPR and arrives position such as tumor, and improve the probability of arrival target area.
The purpose of invention is to overcome the deficiencies in the prior art, a kind of new injection nimodipine compositions with good solubility and stability is provided, and because the solubilization of above-mentioned mixed micelle, make that the concentration of nimodipine is minimum in the medicinal liquid can reach 4mg/ml, be 20 times of marketed drug concentration (0.2mg/ml).Nimodipine medicament in the concentrated solution is in the micelle nuclear, has nanometer administration characteristics.Said composition comprises nimodipine, Tweens and poloxamer class surfactant, the ethanol cosolvent of effective therapeutic dose.
The proportionate relationship of the amount between each component is as follows:
Nimodipine 4mg
Tween 50～600mg
Poloxamer 50～600mg
Ethanol 0.01～0.99ml
Water for injection 0.01～0.99ml
In the described compositions, the Tweens surfactant is selected from a kind of or its mixture in Tween-60 and the tween 80.
Described blend compositions surfactant poloxamer is selected from a kind of or its mixture in poloxamer 188 and the poloxamer 407.
The present invention also comprises the preparation method of the injection nimodipine of above prescription, and this method may further comprise the steps:
1. nimodipine is dissolved in the ethanol, fully dissolving.
2. poloxamer 188 and tween 80 are dissolved in the water.
3. the solution of step in is 1. joined 2. in the solution, add 60 ℃ of insulations of active carbon, 5～60min then, filter the back packing and carry out steam or pressure sterilizing again.
Through evidence: tween and poloxamer all have solubilising, Stabilization to nimodipine, but use the amount that needs to be higher than their mixing consumption far away separately.Add the dissolubility that certain ethanol can increase nimodipine in the system simultaneously, and can make to be embodied in the bigger range of temperature does not have crystal to separate out, draw technology preparation through experiment sieving, simple, with low cost, the used adjuvant of this technology is low, and embodies good stability.
Can add some excipient commonly used in this prescription equally, carry out spray-dired steps necessary and become powder.The powder that obtains after the spray drying adds the spontaneous formation micellar solution in an amount of lyase dissolving back, has the micelle administration characteristics, can be used for injection, oral.
The present invention has been explained in the following examples and test in more detail.Yet, only limit to these embodiment and use going up in all senses all to should not be construed as.
Specific embodiment
Example 1
Nimodipine 4mg
Tween 80 0.40g
Poloxamer 188 0.55g
Ethanol 0.4ml
Water for injection is to 1ml
Preparation method: nimodipine joins in the ethanol, and Tween 80 and poloxamer 188 are dissolved in water in certain, and two kinds of solution are mixed, add water for injection to prescribed volume, add active carbon and adsorb 20min down at 60 ℃, flowing steam sterilization is packed promptly again.
Example 2
Nimodipine 4mg
Tween 80 0.40g
Poloxamer 407 0.60g
Ethanol 0.4ml
Water for injection is to 1ml
Preparation method: nimodipine joins in the ethanol, and Tween 80 and poloxamer 407 are dissolved in water in certain, and two kinds of solution are mixed, and adds water for injection to prescribed volume, adds active carbon at 60 ℃ of absorption 30min down, the hot repressing sterilization, and packing is promptly.
Example 3
Nimodipine 2mg
Propylene glycol 0.084
Tween 80 0.166
50% alcohol is to 2ml
Preparation method: nimodipine joins in the ethanol, and Tween 80 and propylene glycol are dissolved in water in certain, and two kinds of solution are mixed, add water for injection to prescribed volume, add active carbon and adsorb 60min down at 60 ℃, flowing steam sterilization 20min packs promptly again.
Example 4
Nimodipine 2mg
Tween 80 0.028g
Glycerol 0.009g
50% ethanol is to 2ml
Preparation method: nimodipine joins in the ethanol, and Tween 80 and glycerol are dissolved in water in certain, and two kinds of solution are mixed, and adds water for injection to prescribed volume, adds active carbon at 60 ℃ of absorption 20min down, the 20min that sterilizes again, and packing is promptly.
Example 5
Nimodipine 4mg
Tween 80 0.15g
Poloxamer 188 0.54g
Ethanol 0.4ml
Mannitol 0.15g
Water for injection is to 1ml
Preparation method: nimodipine joins in the ethanol, and Tween 80 and poloxamer 188 are dissolved in water in certain, and two kinds of solution are mixed, in mixed liquor, add quantitative mannitol, add water for injection to prescribed volume, filtration sterilization, carry out spray drying afterwards, packing, packing are promptly.
Example 6
Nimodipine 4mg
Tween 80 0.2g
Poloxamer 407 0.3g
Ethanol 0.4ml
Mannitol 0.15g
Water for injection is to 1ml
Preparation method: nimodipine joins in the ethanol, and Tween 80 and poloxamer 188 are dissolved in water in certain, and two kinds of solution are mixed, in mixed liquor, add quantitative mannitol, add water for injection to prescribed volume, filtration sterilization, carry out spray drying afterwards, packing, packing are promptly.
In the foregoing description, according to " chemicals zest, anaphylaxis and hemolytic investigative technique guideline ", carry out following experimentation, compositions in the presentation of results this patent claims, can be satisfied with clinical Secure Application well, reach the demand of " safety, stable, effective " of clinical application product.
Concrete experimental technique:
1, muscle irritation experiment
Get the qualified back of quarantine animal health rabbit, the male and female dual-purpose, adopt rabbit consubstantiality left and right sides Self-control method, left side quadriceps femoris injection this product, the injection of right lateral thigh musculus quadriceps is administered once with 5% glucose injection of volume, puts to death animal after 48 hours, the perusal intramuscular injection site has or not hyperemia, edema, degeneration and necrosis etc. to stimulate phenomenon, and marks according to the degree of irritant reaction.Draw the medicine position after observing end, with 10% formaldehyde fixed, section, HE dyeing, microscopically (10 * 10) is observed between flesh and is had or not pathological changes such as hyperemia, inflammatory cell infiltration.According to macroscopic scoring and the result of histopathologic examination medicine muscle irritation degree is carried out overall merit.
The nimodipine concentrated solution for injection of embodiment of the invention 1-6 preparation is the medicine of treatment cerebrovascular disease, can clinical practice have intramuscular injection for the intravenous drip administration, produce zest to muscular tissue on every side when in a single day this test the phenomenon of leakage takes place during for clinical practice theoretical foundation is provided.
Experimental result: the result shows that embodiment 1-6 has no stimulation to muscle at the maximum administration concentration 0.016mg/ml of clinical instillation.
2, blood vessel irritation experiment
Get the qualified back of quarantine animal health rabbit, the male and female dual-purpose adopts rabbit consubstantiality left and right sides Self-control method, left side auricular vein blood vessel instillation this product, and right side isopyknic 5% glucose injection that instils, once a day, continuous 5 days.Perusal and write down blood vessel and surrounding tissue has or not abnormal change before the administration, during the administration, after the last administration; Put to death animal behind the last administration 96h, get both sides auricular vein blood vessel and surrounding tissue, with 10% formaldehyde fixed, section, HE dyeing, under the light microscopic (10 * 10) observe blood vessel endothelium have or not impaired, break and surrounding tissue has or not pathological changes such as edema, hemorrhage and inflammatory cell infiltration, and judge the blood vessel irritation extent of reaction by standards of grading.
Experimental result: the result shows that embodiment of the invention 1-6 at the maximum administration concentration of clinical instillation 0.016mg/ml family rabbit ear vein dropleting medicine-feeding, does not see obvious irritation to tame rabbit ear vein blood vessel.
3, initiatively anaphylaxis experiment of whole body
The concentrated solution high dose that embodiment of the invention 1-6 makes, low dosage respectively the next day abdominal cavity sensitization once, continuous five times, and after last sensitization the 14th day, each group is the nimodipine concentrated solution of intravenous injection respective concentration respectively.The result shows that the high and low dose group of embodiment of the invention 1-6 there is no anaphylaxis.
4, haemolysis and agglutination test
Adopt conventional external test tube method (observation method of naked eye),, do not see haemolysis and coacervation in 3 hours concentrated solution and the 2% red blood cell suspension mixing of the embodiment of the invention 1-6 of the maximum administration concentration 0.016mg/ml of clinical instillation.
5, bacterial endotoxin checking experiment
Through the interference test conclusive evidence, the embodiment of the invention is checked noiseless to bacterial endotoxin.According to clinical consumption, embodiment sample bacterial endotoxin check result is up to specification.
Claims (13)
1. the pharmaceutical composition of a nimodipine is characterized in that comprising the mixed system that nimodipine, sorbitol or anhydrous sorbitol fatty acid monoester class surfactant, the optimum solvent of nimodipine, secondary solubilizer, the water for injection for the treatment of effective dose is formed.
2. pharmaceutical composition according to claim 1, it is characterized in that described sorbitol or anhydrous sorbitol fatty acid monoester class surfactant are selected from Tweens or this dish class surfactant, as tween 20, Tween-40, Tween-60, tween 80, this dish 20, this dish 60, one or more in the span 80, be preferably the Tweens surfactant, most preferably be Tween 80.
3. pharmaceutical composition according to claim 1 is characterized in that the optimum solution of described nimodipine can be one or more in ethanol, acetone, chloroform, the ethyl acetate, and preferred alcohol is the optimum solvent of nimodipine.
4. pharmaceutical composition according to claim 1 is characterized in that described high molecular surfactant can be in Polyethylene Glycol, polyethylene base ketopyrrolidine, the poloxamer one or more, preferred poloxamer; Wherein poloxamer class surfactant can be poloxamer 188, and one or both in the poloxamer 407 are preferably poloxamer 188;
5. pharmaceutical composition according to claim 1 is characterized in that described secondary solubilizer is the short chain polyalcohols.
6. pharmaceutical composition according to claim 5 is characterized in that described secondary solubilizer is one or more in ethylene glycol, propylene glycol, isopropyl alcohol, the glycerol, preferably glycerine.
7. according to any one pharmaceutical composition among the claim 1-6, the dosage form of wherein said pharmaceutical composition can be injection, oral agents.
8. pharmaceutical composition according to claim 7 is characterized in that in described injection sorbitol or anhydrous sorbitol fatty acid monoester class surfactant concentrations are 5mg～1000mg/ml, and the concentration of preferred Tween 80 is 10mg～600mg/ml.
9. pharmaceutical composition according to claim 7 is characterized in that the concentration of high molecular surfactant in the described injection is 5mg～1000mg/ml, is preferably 10mg～600mg/ml; Short chain polyalcohols secondary solubilizer concentration is 0.1mg/ml～1000mg/ml, is preferably 0.1mg/ml～500mg/ml.
10. pharmaceutical composition according to claim 7 is characterized in that the volumn concentration of the good solution of nimodipine in the described injection is 0.01～99.99, is preferably 0.3～0.7.
11. pharmaceutical composition according to claim 7 is characterized in that described injection pH value scope is 3.0～9.0, preferred pH value scope is 4.5～7.5.
12. according to the preparation of drug combination method of claim 1-12, comprise nimodipine is dissolved in ethanol, tween, poloxamer and the water, form the step of injection, oral agents.
13. according to the preparation method of claim 12, it is characterized in that optimizing prescriptions is: the nimodipine of therapeutic dose, the concentration of surfactant Tween 80 are 10mg～600mg/ml; The optimum solvent of nimodipine is an ethanol, is preferably 0.1mg/ml～500mg/ml; Secondary solubilizer is a poloxamer 188, is preferably 10mg～600mg/ml and an amount of water composition.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CNA2007101433876A CN101129366A (en) | 2007-08-23 | 2007-08-23 | Nimodipine pharmaceutical composition and method of producing the same |
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2007101433876A CN101129366A (en) | 2007-08-23 | 2007-08-23 | Nimodipine pharmaceutical composition and method of producing the same |
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| CN101129366A true CN101129366A (en) | 2008-02-27 |
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| US20170296522A1 (en) * | 2016-04-13 | 2017-10-19 | Grace Therapeutics Llc | Stable nimodipine parenteral formulation |
| WO2017180718A1 (en) | 2016-04-13 | 2017-10-19 | Grace Therapeutics Llc | Stable nimopidine parenteral formulation |
| WO2019006134A1 (en) * | 2017-06-30 | 2019-01-03 | Nortic Holdings Inc. | Stable nimodipine parenteral formulation |
| US10342787B1 (en) * | 2018-01-25 | 2019-07-09 | Arbor Pharmaceuticals, Llc | Non-aqueous liquid nimodipine compositions |
| WO2019165066A2 (en) | 2018-02-22 | 2019-08-29 | Nortic Holdings Inc. | Stable nimodipine parenteral formulation |
| CN114557960A (en) * | 2022-03-16 | 2022-05-31 | 陕西省人民医院 | Medicine for treating subarachnoid hemorrhage and application thereof |
| US11517563B2 (en) | 2018-01-25 | 2022-12-06 | Azurity Pharmaceuticals, Inc. | Liquid nimodipine compositions |
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2007
- 2007-08-23 CN CNA2007101433876A patent/CN101129366A/en active Pending
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| US20180325882A1 (en) * | 2016-04-13 | 2018-11-15 | Nortic Holdings Inc. | Stable nimodipine parenteral formulation |
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| JP2019511522A (en) * | 2016-04-13 | 2019-04-25 | ノーティック ホールディングス インコーポレイテッド | Stable nimodipine parenteral formulation |
| US11433062B2 (en) * | 2016-04-13 | 2022-09-06 | Acasti Pharma U.S., Inc. | Stable nimodipine parenteral formulation |
| US20170296522A1 (en) * | 2016-04-13 | 2017-10-19 | Grace Therapeutics Llc | Stable nimodipine parenteral formulation |
| EP4032527A1 (en) * | 2016-04-13 | 2022-07-27 | Grace Therapeutics Inc. | Stable nimodipine parenteral formulation |
| EP3442586A4 (en) * | 2016-04-13 | 2019-11-20 | Nortic Holdings Inc. | Stable nimopidine parenteral formulation |
| US10765671B2 (en) | 2016-04-13 | 2020-09-08 | Nortic Holdings Inc. | Stable nimodipine parenteral formulation |
| US10092557B2 (en) * | 2016-04-13 | 2018-10-09 | Nortic Holdings Inc. | Stable nimodipine parenteral formulation |
| WO2017180718A1 (en) | 2016-04-13 | 2017-10-19 | Grace Therapeutics Llc | Stable nimopidine parenteral formulation |
| AU2020201863B2 (en) * | 2016-04-13 | 2022-04-28 | Acasti Pharma U.S., Inc. | Stable Nimopidine Parenteral Formulation |
| WO2019006134A1 (en) * | 2017-06-30 | 2019-01-03 | Nortic Holdings Inc. | Stable nimodipine parenteral formulation |
| US11207306B2 (en) | 2018-01-25 | 2021-12-28 | Arbor Pharmaceuticals, Llc | Non-aqueous liquid nimodipine compositions |
| US20190262326A1 (en) * | 2018-01-25 | 2019-08-29 | Arbor Pharmaceuticals, Llc | Non-Aqueous Liquid Nimodipine Compositions |
| US11413277B2 (en) | 2018-01-25 | 2022-08-16 | Arbor Pharmaceuticals, Llc | Non-aqueous liquid nimodipine compositions |
| US10342787B1 (en) * | 2018-01-25 | 2019-07-09 | Arbor Pharmaceuticals, Llc | Non-aqueous liquid nimodipine compositions |
| US11517563B2 (en) | 2018-01-25 | 2022-12-06 | Azurity Pharmaceuticals, Inc. | Liquid nimodipine compositions |
| US11759457B2 (en) | 2018-01-25 | 2023-09-19 | Azurity Pharmaceuticals, Inc. | Liquid nimodipine compositions |
| US11806338B2 (en) | 2018-01-25 | 2023-11-07 | Azurity Pharmaceuticals, Inc. | Non-aqueous liquid nimodipine compositions |
| US11819497B2 (en) | 2018-01-25 | 2023-11-21 | Azurity Pharmaceuticals, Inc. | Liquid nimodipine compositions |
| WO2019165066A2 (en) | 2018-02-22 | 2019-08-29 | Nortic Holdings Inc. | Stable nimodipine parenteral formulation |
| EP3755326A4 (en) * | 2018-02-22 | 2021-11-03 | Nortic Holdings Inc. | Stable nimodipine parenteral formulation |
| CN114557960A (en) * | 2022-03-16 | 2022-05-31 | 陕西省人民医院 | Medicine for treating subarachnoid hemorrhage and application thereof |
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Open date: 20080227 |