CN101269035A - Nicergoline sustained-release dropping pill and preparation method thereof - Google Patents
Nicergoline sustained-release dropping pill and preparation method thereof Download PDFInfo
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- CN101269035A CN101269035A CNA2008101118289A CN200810111828A CN101269035A CN 101269035 A CN101269035 A CN 101269035A CN A2008101118289 A CNA2008101118289 A CN A2008101118289A CN 200810111828 A CN200810111828 A CN 200810111828A CN 101269035 A CN101269035 A CN 101269035A
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Abstract
The invention relates to a drug compound playing the role of retarding Alpha-receptors and expanding blood vessels, and is used for improving low desires and affective disorders due to cerebral arteriosclerosis and stroke sequelae and treating vascular dementia. The drug compound aims to supplement the deficiency of the prior oral pharmaceutical formulation used for hemangiectasis and provide a drug compound oral formulation, sustained-release nicergoline dropping pill which has high bioavailability, steady plasma concentration, low frequency of drug taking, low cost and absence of contamination during the production. The sustained-release nicergoline dropping pill adopts nicergoline as the ingredient and is prepared jointly with the medicinal carrier used as the stroma.
Description
Technical field
The present invention relates to a kind of have alpha-receptor retardation and vasodilative effect, be used to improve low and the affective disorder of being intended to that cerebral arteriosclerosis and apoplexy sequela cause, and be used for the treatment of the pharmaceutical composition of vascular dementia, being particularly related to the nicergoline is a kind of pharmaceutical composition that feedstock production forms, the oral sustained release dropping pill formulation.
Background technology
Existing nicergoline is semisynthetic ergot derivative, has a one receptor blocking effect and vasorelaxation action, is used to improve low and the affective disorder of being intended to that cerebral arteriosclerosis and apoplexy sequela cause clinically.Or be used for the treatment of acute and chronic peripheral circulatory disturbance (as: extremity vascular occlusive disease, Raynaud's syndrome, other tip poor circulation symptom), and can be used for the treatment of vascular dementia, when treating especially in early days cognition, memory etc. there are improvement, and the order of severity that can palliate a disease.
Have report to show, nicergoline can improve the level of body ATP by suppressing the decomposition that adenylate cyclase activity suppresses ATP, thereby improves the brain cell energy metabolism, increases picked-up and the utilization of brain cell to oxygen and glucose.Zoopery shows that nicergoline can promote the synthetic and release of the acetylcholine of senile rat hippocampus, improves the level of striatum and cerebral cortex acetylcholine, thereby improves its cognition and learning functionality.Nicergoline can increase the dopamine transduction of dopaminergic compact district in the brain, and second message,second messenger's phosphoinositide transduction in striatum and the cortex cell.Also there is report to show that nicergoline can improve the proteinic biosynthesis in the motor-driven brain of brain behavior district.These show that all nicergoline can improve the cognitive function of body comprehensively.
Nicergoline can be oral, every day 2-3 time, and the successive administration time enough, at least six months, and whether continue administration by doctor decision.The main adverse reaction of this medicine is a hypotension, dizziness, and stomachache etc., long term administration has increased incidence rate of adverse reaction.It is steady to take back medicine blood drug level for medicine patient of the present invention, and it is little to fluctuate, and has reduced incidence rate of adverse reaction.
With the nicergoline is the pharmaceutical preparation that feedstock production forms, and tablet, capsule, injection etc. are arranged, and through clinical verification, determined curative effect is the common drug that clinical and family is used for the treatment of this type of disease.Owing to reasons such as technologies of preparing, the oral formulations of most drug, exist all after taking that dissolve scattered time limit is long, dissolution is low, absorption is relatively poor, blood drug level is unstable, medicining times is many, have problems such as liver sausage first pass effect and bioavailability are lower, thereby influence the performance of drug effect, also directly affect therapeutic effect.In addition, conventional peroral dosage form as tablet, capsule etc., because the technology of granulation is arranged, therefore can produce bigger dust pollution in preparation process, can staff's health be worked the mischief to a certain extent, also can cause certain pollution to environment simultaneously.Moreover, the complex manufacturing of conventional oral formulations, production cost is higher, thereby patient's drug cost is also improved thereupon, is unfavorable for improving the ability of seeking medical advice of extensive patients, also is unfavorable for improving the general health level of society.
The advantage that though injection has is rapid-action, bioavailability is high, but its complex manufacturing, cost is higher, also inconvenient simultaneously with using, the toxicity, side effect reaction appears easily, shortcomings such as the patient suffering is big so still be necessary to seek a kind of more suitable nicergoline oral formulations, satisfy the health demand of extensive patients.
Summary of the invention
Purpose of the present invention is to replenish the existing deficiency that is used for angiectatic oral drug preparation, and a kind of bioavailability height is provided, and it is steady to have blood drug level, medicining times is few, and is cheap, and free of contamination aborning drug composition oral preparation nicergoline sustained-release dropping pill.Nicergoline sustained-release dropping pill involved in the present invention is a raw material with the nicergoline, is prepared from the pharmaceutically suitable carrier as substrate.Be prepared by the following technical solutions, can obtain nicergoline sustained-release dropping pill involved in the present invention:
[primary raw material]
Nicergoline: English name nicergolin
Chemical name: 10 α-methoxyl group-1,6-dimethyl Ergota woods-8 β-methanol-based-5-bromo-nicotinic acid ester
[preparation method]
1. component constitutes: calculate according to percentage by weight, nicergoline sustained-release dropping pill involved in the present invention is made up of the substrate of 10-40% nicergoline and 60-90%, and substrate comprises 40-80% hydrophilic framework material and 10-30% hydrophobicity framework material.
2. in the said components, the hydrophilic framework material in the described substrate is made up of Polyethylene Glycol (PEG) 4000 or Polyethylene Glycol (PEG) 6000 or Polyethylene Glycol (PEG) 10000 or their mixture of polyoxyethylene stearate (40) ester.
3. in the said components, the hydrophobicity framework material in the described substrate is made up of glyceryl monostearate or stearic acid or cohune eleostearic acid or their mixture of octadecanol.
4. constitute given ratio according to component, accurately take by weighing nicergoline and substrate, be placed on heating while stirring in the heating container, standby until the fused solution that obtains containing nicergoline and substrate and/or emulsion and/or suspension;
5. adopt homemade or general drop pill machine (as the TZDW-1 type drop pill machine of Changzheng Tianmin High Science ﹠ Technology Co., Ltd., Beijing's production), and the temperature control system of adjustment drop pill machine, make the water dropper temperature heating of drop pill machine and remain on (50～90) ℃, the temperature cooling of condensing agent also remains on (10～-5) ℃;
6. when treating that the temperature of condensing agent in dropping-pill machine head and the condensation column is stable respectively and reaching desired state of temperature, will contain fused solution and/or the emulsion and/or the suspension of nicergoline and substrate, place in the water dropper jar of drop pill machine, splash in the condensing agent,
7. will shrink the drop pill taking-up of molding by the outlet of drop pill machine, remove the surface condensation agent, be drying to obtain.
Annotate: above-mentioned condensing agent can be any one in liquid paraffin, methyl-silicone oil, the vegetable oil.
[beneficial effect]
Nicergoline (nicergoline) is a kind of vasodilator with alpha-receptor retardation, be usually used in improving low and the affective disorder (as: bradykinesia of being intended to that cerebral arteriosclerosis and apoplexy sequela cause, absent minded, hypomnesis, lack idea, melancholy, uneasy), or be used for the treatment of acute and chronic peripheral circulatory disturbance (as: extremity vascular occlusive disease, Raynaud's syndrome, other tip poor circulation symptom), and can be used for the treatment of vascular dementia, when treating especially in early days to cognition, memory etc. has improvement, and the order of severity that can palliate a disease.
With the nicergoline is the pharmaceutical preparation that feedstock production forms, and tablet, capsule, injection etc. are arranged, and through clinical verification, determined curative effect is the common drug that clinical and family is used for the treatment of this type of disease.Owing to reasons such as technologies of preparing, the oral formulations of most drug, exist all after taking that dissolve scattered time limit is long, dissolution is low, absorption is relatively poor, blood drug level is unstable, medicining times is many, have problems such as liver sausage first pass effect and bioavailability are lower, thereby influence the performance of drug effect, also directly affect therapeutic effect.In addition, conventional peroral dosage form as tablet, capsule etc., because the technology of granulation is arranged, therefore can produce bigger dust pollution in preparation process, can staff's health be worked the mischief to a certain extent, also can cause certain pollution to environment simultaneously.Moreover, the complex manufacturing of conventional oral formulations, production cost is higher, thereby patient's drug cost is also improved thereupon, is unfavorable for improving the ability of seeking medical advice of extensive patients, also is unfavorable for improving the general health level of society.
The advantage that though injection has is rapid-action, bioavailability is high, but its complex manufacturing, cost is higher, also inconvenient simultaneously with using, the toxicity, side effect reaction appears easily, shortcomings such as the patient suffering is big so still be necessary to seek a kind of more suitable nicergoline oral slow-releasing preparation, satisfy the health demand of extensive patients.
Nicergoline sustained-release dropping pill involved in the present invention is compared with the nicergoline sheet has following beneficial effect:
1. nicergoline sustained-release dropping pill involved in the present invention; utilize hydrophilic framework material and hydrophobicity framework material to mix mutually as substrate; make solid dispersion with nicergoline; making medicine be molecule, colloid or microcrystalline state is scattered in the substrate; the total surface area of medicine increases; because of substrate has the hydrophilic framework material; medicine had wetting action; can make medicine molten microgranule or the solution of loosing into rapidly; thereby make the dissolving of medicine and absorb quickening; thereby improved bioavailability, brought into play effects such as efficient, quick-acting.Again because of substrate has the hydrophobicity framework material, function such as it is controlled to make medicine have a release, and patient's medicining times is few, and the time of proving effective is long.
2. nicergoline sustained-release dropping pill involved in the present invention, contact promptly with saliva and to dissolve rapidly, and absorb by oral mucosa, not only rapid-action, and the influence of not taken food, promptly all can containing take after meal ante cibum, can not produce any residual harmful substance at gastric yet, thereby make that patient's medication is safer, also have medication convenience, characteristic of accurate simultaneously.
3. nicergoline sustained-release dropping pill involved in the present invention mixes nicergoline mutually with molten matrix, splashes in the not miscible condensed fluid and makes.Therefore, the stability of drug height, not facile hydrolysis, oxidation, and the operation be under liquid state, to carry out, no dust pollution is not subject to the influence of crystal formation, thereby has guaranteed the quality of medicine, has increased stability.
4. production technology, the equipment of preparation drop pill are simple, easy to operate, the automaticity height, and labor intensity is low, the production efficiency height.Workshop does not have dust simultaneously, helps labor protection and environmental protection yet.
5. the production cost of preparation drop pill is usually with about 50% of other oral formulations of kind, and compares with oral liquid, and the dosage of drop pill is accurate, thereby makes the patient take metering control easily.
The specific embodiment
Now with several groups of specific embodiments, be described further with regard to the preparation method of nicergoline sustained-release dropping pill of the present invention.
First group:
In gross weight 100g, take by weighing substrate PEG4000 40%, PEG600010%, PEG10000 5%, polyoxyethylene stearate (40) ester 10%, stearic acid 15%, glyceryl monostearate 10%, raw material nicergoline 10%; By above-mentioned preparation method preparation.
Products obtained therefrom, 2 hours cumulative release percentage rate are that 33～51%, 6 hours cumulative release percentage rate are that 64～77%, 10 hours cumulative release percentage rate are 80～91%, and roundness is better, and hardness is better.
Second group:
In gross weight 100g, take by weighing substrate PEG4000 35%, PEG6000 25%, and PEG10000 10%, stearic acid 10%, glyceryl monostearate 7%, raw material nicergoline 13%; By above-mentioned preparation method preparation.
Products obtained therefrom, 2 hours cumulative release percentage rate are that 56%～71%, 6 hours cumulative release percentage rate are that 68～85%, 10 hours cumulative release percentage rate are 84～95%, and roundness is better, and hardness is better.
The 3rd group:
In gross weight 100g, take by weighing substrate PEG4000 30%, PEG10000 20%, polyoxyethylene stearate (40) ester 5%, stearic acid 15%, cohune eleostearic acid 3%, octadecanol 7%, raw material nicergoline 20%; By above-mentioned preparation method preparation.
Products obtained therefrom, 2 hours cumulative release percentage rate are that 41%～56%, 6 hours cumulative release percentage rate are that 55～76%, 10 hours cumulative release percentage rate are 79～94%, and roundness is better, and hardness is better.
The 4th group:
In gross weight 100g, take by weighing substrate PEG6000 40%, PEG10000 10%, glyceryl monostearate 15%, cohune eleostearic acid 10%, raw material nicergoline 25%; By above-mentioned preparation method preparation.
Products obtained therefrom, 2h cumulative release percentage rate is 45%～61%, and 6h cumulative release percentage rate is 62～78%, and 10h cumulative release percentage rate is 80～93%, and roundness is better, and hardness is better.
The 5th group:
In gross weight 100g, take by weighing substrate PEG4000 35%, PEG6000 20%, glyceryl monostearate 10%, stearic acid 5%, raw material nicergoline 30%; By above-mentioned preparation method preparation.
Products obtained therefrom, 2h cumulative release percentage rate is 55%～73%, and 6h cumulative release percentage rate is 70～86%, and 10h cumulative release percentage rate is 87～98%, and roundness is better, and hardness is better.
The 6th group:
In gross weight 100g, take by weighing substrate PEG4000 35%, PEG6000 15%, and PEG10000 10%, glyceryl monostearate 13%, octadecanol 7%, raw material nicergoline 20%; By above-mentioned preparation method preparation.
Products obtained therefrom, 2h cumulative release percentage rate is 51%～68%, and 6h cumulative release percentage rate is 70～85%, and 10h cumulative release percentage rate is 80～96%, and roundness is better, and hardness is better.
The 7th group:
In gross weight 100g, take by weighing substrate PEG6000 30%, PEG10000 14%, polyoxyethylene stearate (40) ester 6%, stearic acid 12%, cohune eleostearic acid 3%, raw material nicergoline 35%; By above-mentioned preparation method preparation.
Products obtained therefrom, 2h cumulative release percentage rate is 57%～69%, and 6h cumulative release percentage rate is 71～88%, and 10h cumulative release percentage rate is 85～98%, and roundness is better, and hardness is better.
The 8th group:
In gross weight 100g, take by weighing substrate polyoxyethylene stearate (40) ester 20%, PEG6000 30%, stearic acid 20%, glyceryl monostearate 10%, raw material nicergoline 20%; By above-mentioned preparation method preparation.
Products obtained therefrom, 2h cumulative release percentage rate is 37%～57%, and 6h cumulative release percentage rate is 65～73%, and 10h cumulative release percentage rate is 75～90%, and roundness is better, and hardness is better.
Claims (3)
1. one kind is used for angiectatic nicergoline sustained-release dropping pill, is raw material with the nicergoline, with being prepared from by certain component formation, wherein as the hydrophilic framework material of substrate and pharmaceutically suitable carrier of hydrophobicity framework material:
1.1 described component constitutes: calculate according to percentage by weight, nicergoline sustained-release dropping pill involved in the present invention is made up of the substrate of 10-40% nicergoline and 60-90%, and substrate comprises 40-80% hydrophilic framework material and 10-30% hydrophobicity framework material;
1.2 the hydrophilic framework material in the described substrate is made up of Polyethylene Glycol (PEG) 4000 or Polyethylene Glycol (PEG) 6000 or Polyethylene Glycol (PEG) 10000 or their mixture of polyoxyethylene stearate (40) ester;
1.3 the hydrophobicity framework material in the described substrate is made up of glyceryl monostearate or stearic acid or cohune eleostearic acid or their mixture of octadecanol.
2. according to the described nicergoline sustained-release dropping pill of claim 1, its preparation method is as follows:
2.1 constitute given ratio according to component, accurately take by weighing nicergoline and substrate, be placed on heating while stirring in the heating container, standby until the fused solution that obtains containing nicergoline and substrate and/or emulsion and/or suspension;
2.2 adopt homemade or general drop pill machine (as the TZDW-1 type drop pill machine of Changzheng Tianmin High Science ﹠ Technology Co., Ltd., Beijing's production), and the temperature control system of adjustment drop pill machine, make the water dropper temperature heating of drop pill machine and remain on (50～90) ℃, the temperature cooling of condensing agent also remains on (10～-5) ℃;
2.3 when treating that the temperature of condensing agent in dropping-pill machine head and the condensation column is stable respectively and reaching desired state of temperature, will contain fused solution and/or the emulsion and/or the suspension of nicergoline and substrate, place in the water dropper jar of drop pill machine, splash in the condensing agent;
Take out 2.4 will shrink the drop pill of molding by the outlet of drop pill machine, remove the surface condensation agent, be drying to obtain.
3. preparation method according to claim 2 is characterized in that described condensing agent can be any one in liquid paraffin, methyl-silicone oil, the vegetable oil.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101118289A CN101269035A (en) | 2008-05-16 | 2008-05-16 | Nicergoline sustained-release dropping pill and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101118289A CN101269035A (en) | 2008-05-16 | 2008-05-16 | Nicergoline sustained-release dropping pill and preparation method thereof |
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| Publication Number | Publication Date |
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| CN101269035A true CN101269035A (en) | 2008-09-24 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNA2008101118289A Pending CN101269035A (en) | 2008-05-16 | 2008-05-16 | Nicergoline sustained-release dropping pill and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017006290A1 (en) | 2015-07-08 | 2017-01-12 | Kunshan Rotam Reddy Pharmaceutical Co., Ltd | Modified release nicergoline compositions |
-
2008
- 2008-05-16 CN CNA2008101118289A patent/CN101269035A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017006290A1 (en) | 2015-07-08 | 2017-01-12 | Kunshan Rotam Reddy Pharmaceutical Co., Ltd | Modified release nicergoline compositions |
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Open date: 20080924 |