CN104800157B - A kind of ethacrynic acid lipide microsphere injection and preparation method thereof - Google Patents
A kind of ethacrynic acid lipide microsphere injection and preparation method thereof Download PDFInfo
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- CN104800157B CN104800157B CN201510165374.3A CN201510165374A CN104800157B CN 104800157 B CN104800157 B CN 104800157B CN 201510165374 A CN201510165374 A CN 201510165374A CN 104800157 B CN104800157 B CN 104800157B
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Abstract
The invention belongs to pharmaceutical technology field, and in particular to a kind of lipide microsphere injection containing ethacrynic acid and preparation method thereof.Parenteral solution of the present invention is made up of ethacrynic acid, oil for injection, emulsifying agent, stabilizer, isotonic regulator and water for injection.Said preparation is nonirritant, small toxicity, stability are good, cost is low, suitable for industrialized production.
Description
Invention field
The invention belongs to pharmaceutical technology field, exactly it is related to a kind of ethacrynic acid lipide microsphere injection and its system
Preparation Method.
Background technology
Encephaledema refers to the increase of intracerebral moisture, the pathological phenomenon for causing brain volume to increase, be brain tissue to it is various it is pathogenic because
The reaction of element.If can not diagnose and handle in time, encephaledema is aggravated, or develops into diffusivity by limitation, and brain will be produced
Seriously endanger, form the Secondary cases pathological change of irreversibility, brain death occurs.This final result, it is that brain tissue generality is damaged
Caused by evil and the secondary brain stem of hernia cerebri seriously damage.
The degree of encephaledema and duration, to disease lapse to and prognosis is very significant considering that, should have in time
The treatment processing of effect.The medicine for being conventionally used to treat encephaledema is usually the osmotic diuretics such as mannitol.But this kind of medicine
Not only dosage is big, it is necessary to rapid intravenous drop for thing, and increases cardiac load due to increase circulating blood volume, to heart function not
Good patient is totally unfavorable.In addition, the mannitol of Clinical practice is supersaturated solution, crystallization can be separated out under normal temperature, into people
Crystallite can be formed after body in kidney, renal tubule is blocked and causes kidney function damage.Dissolving knot is had to when therefore, using mannitol
Crystalline substance, so as to increase the labor intensity of medical personnel.Because drawbacks described above has caused the clinical practice of mannitol to receive greatly
Limitation, it is necessary to seek substitute mannitol intracranial pressure medicine.
Ethacrynic acid also known as ethacrynic acid, diuresis is powerful, rapid, is clinically used for congestive heart failure, acute edema with the lung involved
Swollen, renal edema, cirrhotic ascites, ascites of liver cancer, snail fever ascites, encephaledema and other oedema.But ethacrynic acid has very
Big adverse reaction, common person is relevant with water and rock-soil coupling, especially heavy dose of or prolonged application when, such as orthostatic low blood
Pressure, shock, hypopotassaemia, hypochloraemia, hypochloremic alkalosis, hyponatremia, hypocalcemia and relevant with this thirsty, weary
Power, DOMS, arrhythmia cordis etc..Rare person has allergic reaction (including fash, even interstitial nephritis, heart arrest), regarded
Feel fuzzy, xanthopsy, photaesthesia, dizziness, have a headache, receive poor, Nausea and vomiting, stomachache, diarrhoea, pancreatitis, muscle rigidity etc., bone
Marrow suppresses to cause granulocyte to reduce, and thrombocytopenic purpura and alpastic anemia, hepatic disorder, refers to, toe feels different
Often, hyperglycemia, glucose in urine is positive, and original diabetes aggravate, hyperuricemia.But gastrointestinal reaction, watery diarrhea and ototoxicity
It is common compared with FRUSEMIDE.Still cause blood urine and hemorrhage of digestive tract.There is stronger ear source property toxicity, at present clinically less use.
Because ethacrynic acid is not soluble in water, clinical injection is needed with its sodium salt, and is needed before use with 5% glucose injection
Slowly instiled after liquid or physiological saline 50ml dilutions or intravenous, match somebody with somebody solution must be used in 24 hours it is complete, to medical worker with
Carry out operational trouble and the possibility of mistake occurs, and be easier to cause secondary pollution in operation.
Therefore, how a kind of ethacrynic acid injection that can be widely applied to clinic is provided, turns into current this area skill
The problem of art personnel pay close attention to.
At present, the lipid microsphere research on ethacrynic acid has no report.
The content of the invention
The invention provides a kind of lipide microsphere injection containing ethacrynic acid, and the parenteral solution is by ethacrynic acid, injection
Formed with oil, emulsifying agent, stabilizer, isotonic regulator and water for injection.
The percentage by weight of above-mentioned lipide microsphere injection composition is：Ethacrynic acid 1~10%, oil for injection 5~40%,
Emulsifying agent 0.5~5%, stabilizer 0.01~0.5%, isotonic regulator 2~15%, remaining is water for injection.
Preferably, the percentage by weight of above-mentioned lipide microsphere injection composition is：Ethacrynic acid 2~5%, oil for injection 15
~25%, emulsifying agent 1~3%, stabilizer 0.05~0.1%, isotonic regulator 5~10%, remaining is water for injection.
Oil for injection in above-mentioned lipide microsphere injection be one kind in long chain triglycerides and medium chain triglyceride or
Several mixtures；The one or more being chosen in particular from soybean oil, safflower oil, sesame oil, cottonseed oil and fish oil.
The emulsifying agent in above-mentioned lipide microsphere injection includes oil soluble emulsifying agent and water soluble emulsifier, oil-soluble
Emulsifying agent is the one or more in egg yolk lecithin, soybean lecithin, hydrogenation yolk phospholipid, hydrogenated soya phosphatide；It is water-soluble
Emulsifying agent is the one or more in polyoxyethylene sorbitan monoleate, poloxamer F68；Stabilizer is in oleic acid, vitamin E, amino acid
It is one or more of；Isotonic regulator is the one or more in glycerol for injection, xylitol, glucose, sodium hydroxide.
Present invention also offers a kind of preparation method of ethacrynic acid lipide microsphere injection, this method specific steps are such as
Under：
1. water soluble emulsifier, isotonic regulator are added in appropriate water for injection, 60~80 DEG C are heated to, stirring point
Dissipate uniform aqueous phase；
2. the ethacrynic acid of recipe quantity, oil for injection, oil soluble emulsifying agent, stabilizer are heated at a temperature of 60~80 DEG C
It is dispersed with stirring the uniform drug containing oil phase that must be clarified；
3. in the case where tissue mashing machine stirs, medicine oil will be carried and be mutually slowly added to be added in oil phase in aqueous phase or by aqueous phase, treated
After being added completely into, stirred 3~5 minutes with 8000~20000 revs/min, produce colostrum；
4. colostrum is cooled into room temperature, full dose is settled to water for injection, pH to 4 is adjusted with sodium hydroxide or hydrochloric acid solution
~6, it is transferred in high pressure homogenizer, the homogeneous 5~10 times under the conditions of 600~1200bar, 30 DEG C~60 DEG C；
5. 0.22 micron membrane filter filters, inflated with nitrogen, lid sealing is rolled.
The preparation method of above-mentioned ethacrynic acid lipide microsphere injection, preferable preparation technology are as follows：
1. water soluble emulsifier, isotonic regulator are added in appropriate water for injection, 75 DEG C are heated to, is dispersed with stirring
It is even to obtain aqueous phase；
2. by the ethacrynic acid of recipe quantity, oil for injection, oil soluble emulsifying agent, stabilizer at a temperature of 75 DEG C heating stirring
Be uniformly dispersed the drug containing oil phase that must be clarified；
3. in the case where tissue mashing machine stirs, medicine oil will be carried and be mutually slowly added to be added in oil phase in aqueous phase or by aqueous phase, treated
After being added completely into, stirred 3~5 minutes with 15000 revs/min, produce colostrum；
4. colostrum is cooled into room temperature, pH to 5.5~6.5 or so is adjusted with sodium hydroxide or hydrochloric acid solution, with injection
Full dose is settled to water, is transferred in high pressure homogenizer, the homogeneous 5~10 times under the conditions of 700~800bar, 30 DEG C~45 DEG C；
5. 0.22 micron membrane filter filters, inflated with nitrogen, lid sealing is rolled.
The present invention has the advantages that：
1st, lipide microsphere injection is made through high-speed stirred and high-pressure homogeneous emulsification, medicine is wrapped in oil phase or interfacial film
In, it can avoid directly contacting with blood vessel, so as to reduce medicine in excitant caused by injection site；
2nd, lipide microsphere injection is made in ethacrynic acid, release is slow, reduces the side effect of ethacrynic acid, reduces
The generation of adverse reaction.
3rd, the present invention has the characteristics that preparation technology simple possible, product stability are good, beneficial to application clinically and work
Industry metaplasia is produced.
Embodiment
Embodiment 1：The preparation of ethacrynic acid lipide microsphere injection
(1) prescription：
(2) ethacrynic acid lipide microsphere injection step of preparation process is as follows：
1) glycerol for injection, polyoxyethylene sorbitan monoleate are scattered in appropriate water for injection, 75 is heated into magnetic stirring apparatus
DEG C stirring to all dissolve to obtain aqueous phase；
2) ethacrynic acid, amino acid, egg yolk lecithin of recipe quantity are added to the mixing that soybean oil and cottonseed oil are formed
In thing, the load medicine oil phase to being completely dissolved, clarified is stirred at 75 DEG C；
3) oil phase is added into aqueous phase, be placed in high-speed tissue mashing machine, with 10000 revs/min of stirring 3-5 minutes；
4) with 0.1molL-1 hydrochloric acid or sodium hydroxide solution regulation pH to 5.5~6.5, water for injection is settled to full dose,
It is transferred in high pressure homogenizer, at 40 DEG C, with 800bar pressure homogeneous 6~10 times；
5) 0.22 micron membrane filter filters, inflated with nitrogen, rolls lid sealing.
Embodiment 2：The preparation of ethacrynic acid lipide microsphere injection
(1) prescription：
(2) ethacrynic acid lipide microsphere injection step of preparation process is as follows：
1) glycerol for injection, poloxamer F68 are scattered in appropriate water for injection, 75 is heated into magnetic stirring apparatus
DEG C stirring to all dissolve to obtain aqueous phase；
2) ethacrynic acid of recipe quantity, egg yolk lecithin, soybean lecithin, vitamin E are added in soybean oil, 75
The load medicine oil phase to being completely dissolved, clarified is stirred at DEG C；
3) oil phase is added into aqueous phase, be placed in high-speed tissue mashing machine, with 15000 revs/min of stirring 3-5 minutes；
4) with 0.1molL-1 hydrochloric acid or sodium hydroxide solution regulation pH to 5.5~6.5, water for injection is settled to full dose,
It is transferred in high pressure homogenizer, at 40 DEG C, with 800bar pressure homogeneous 6~10 times；
5) 0.22 micron membrane filter filters, inflated with nitrogen, rolls lid sealing.
Embodiment 3：Ethacrynic acid lipide microsphere injection
(1) prescription：
(2) ethacrynic acid lipide microsphere injection step of preparation process is as follows：
1) glycerol for injection, polyoxyethylene sorbitan monoleate are scattered in appropriate water for injection, 75 is heated into magnetic stirring apparatus
DEG C stirring to all dissolve to obtain aqueous phase；
2) ethacrynic acid, amino acid, egg yolk lecithin of recipe quantity are added to the mixing that soybean oil and sesame oil are formed
In thing, the load medicine oil phase to being completely dissolved, clarified is stirred at 75 DEG C；
3) oil phase is added into aqueous phase, be placed in high-speed tissue mashing machine, with 15000 revs/min of stirring 3-5 minutes；
4) with 0.1molL-1 hydrochloric acid or sodium hydroxide solution regulation pH to 5.5~6.5, water for injection is settled to full dose,
It is transferred in high pressure homogenizer, at 40 DEG C, with 800bar pressure homogeneous 6~10 times；
5) 0.22 micron membrane filter filters, inflated with nitrogen, rolls lid sealing.
Embodiment 4：The preparation of ethacrynic acid lipide microsphere injection
(1) prescription：
(2) ethacrynic acid lipide microsphere injection step of preparation process is as follows：
1) glycerol for injection, poloxamer F68 are scattered in appropriate water for injection, 75 is heated into magnetic stirring apparatus
DEG C stirring to all dissolve to obtain aqueous phase；
2) ethacrynic acid, soybean lecithin, vitamin E of recipe quantity are added in soybean oil, stirred at 75 DEG C to
It is completely dissolved, the load medicine oil phase clarified；
3) oil phase is added into aqueous phase, be placed in high-speed tissue mashing machine, with 15000 revs/min of stirring 3-5 minutes；
4) with 0.1molL-1 hydrochloric acid or sodium hydroxide solution regulation pH to 5.5~6.5, water for injection is settled to full dose,
It is transferred in high pressure homogenizer, at 40 DEG C, with 800bar pressure homogeneous 6~10 times；
5) 0.22 micron membrane filter filters, inflated with nitrogen, rolls lid sealing.
Embodiment 5：Ethacrynic acid lipide microsphere injection
(1) prescription：
(2) ethacrynic acid lipide microsphere injection step of preparation process is as follows：
1) glycerol for injection, polyoxyethylene sorbitan monoleate are scattered in appropriate water for injection, 75 is heated into magnetic stirring apparatus
DEG C stirring to all dissolve to obtain aqueous phase；
2) ethacrynic acid, amino acid, egg yolk lecithin of recipe quantity are added in soybean oil, stirred at 75 DEG C to complete
Fully dissolved, the load medicine oil phase clarified；
3) oil phase is added into aqueous phase, be placed in high-speed tissue mashing machine, with 15000 revs/min of stirring 3-5 minutes；
4) with 0.1molL-1 hydrochloric acid or sodium hydroxide solution regulation pH to 5.5~6.5, water for injection is settled to full dose,
It is transferred in high pressure homogenizer, at 40 DEG C, with 800bar pressure homogeneous 6~10 times；
5) 0.22 micron membrane filter filters, inflated with nitrogen, rolls lid sealing.
Experimental example 1：The accelerated stability development test of ethacrynic acid lipide microsphere injection
Ethacrynic acid lipide microsphere injection made from embodiment 1,3,5 is pressed into commercially available back, in 40 ± 2 DEG C of temperature, phase
To being placed 6 months under conditions of humidity 75 ± 5%, respectively at 0th month, 1 month, 2 months, 3 months, each sampling one in 6 months
It is secondary, check outward appearance, content, particle diameter, pH, envelop rate, the percolation ratio of test sample.It the results are shown in Table 1,2,3：
Table 1：Ethacrynic acid lipide microsphere injection Acceleration study result made from embodiment 1
Table 2：Ethacrynic acid lipide microsphere injection Acceleration study result made from embodiment 3
Table 3：Ethacrynic acid lipide microsphere injection Acceleration study result made from embodiment 5
Ethacrynic acid lipide microsphere injection is in 40 ± 2 DEG C of temperature, relative humidity 75 ± 5% it can be seen from table 1,2,3
Acceleration environment under carry out study on the stability, after 6 months, its outward appearance, content, particle diameter, pH, envelop rate, percolation ratio etc. do not occur
Significant changes, meet regulation.
Experimental example 2：The long-time stability development test of ethacrynic acid lipide microsphere injection
Ethacrynic acid lipide microsphere injection made from embodiment 1,2,3 is pressed into commercially available back, in 25 ± 2 DEG C of temperature, phase
To being placed 24 months under conditions of humidity 60 ± 10%, respectively at 0th month, 3 months, 6 months, 9 months, 12 months, 18
Each sampling of the moon, 24 months once, checks outward appearance, content, particle diameter, pH, envelop rate, the percolation ratio of test sample, it is physico to investigate its
Learn the change of stability.It the results are shown in Table 4,5,6：
Table 4：Ethacrynic acid lipide microsphere injection long-term experiment result made from embodiment 1
Table 5：Ethacrynic acid lipide microsphere injection long-term experiment result made from embodiment 2
Table 6：Ethacrynic acid lipide microsphere injection long-term experiment result made from embodiment 3
As a result show, the 24 months experimental results that keep sample for a long time show that indices are qualified and it is stable to keep, in temperature 25
± 2 DEG C, preserve under conditions of relative humidity 60 ± 10%, the term of validity should be not less than 2 years.
Claims (6)
- A kind of 1. lipide microsphere injection containing ethacrynic acid, it is characterised in that the parenteral solution by ethacrynic acid, oil for injection, Emulsifying agent, stabilizer, isotonic regulator and water for injection composition, the percentage by weight of each component are：Ethacrynic acid 2~5%, note Penetrate and use oil 15~25%, emulsifying agent 1~3%, stabilizer 0.05~0.1%, isotonic regulator 5~10%, remaining is injection Water；Wherein, one or more of the oil for injection in soybean oil, safflower oil, sesame oil, cottonseed oil and fish oil.
- 2. lipide microsphere injection as claimed in claim 1, it is characterised in that described emulsifying agent includes oil soluble emulsifying agent And water soluble emulsifier, wherein oil soluble emulsifying agent is egg yolk lecithin, soybean lecithin, hydrogenation yolk phospholipid, hydrogenated soybean One or more in phosphatide；Water soluble emulsifier is the one or more in polyoxyethylene sorbitan monoleate, poloxamer F68.
- 3. lipide microsphere injection as claimed in claim 1, it is characterised in that described stabilizer is oleic acid, vitamin E, ammonia One or more in base acid.
- 4. lipide microsphere injection as claimed in claim 1, it is characterised in that described isotonic regulator be glycerol for injection, One or more in xylitol, glucose, sodium hydroxide.
- 5. the preparation method of the lipide microsphere injection described in a kind of claim 1, it is characterised in that this method specific steps are such as Under：1. water soluble emulsifier, isotonic regulator are added in appropriate water for injection, 60~80 DEG C are heated to, is dispersed with stirring It is even to obtain aqueous phase；2. by the ethacrynic acid of recipe quantity, oil for injection, oil soluble emulsifying agent, stabilizer at a temperature of 60~80 DEG C heating stirring Be uniformly dispersed the drug containing oil phase that must be clarified；3. in the case where tissue mashing machine stirs, medicine oil will be carried and be mutually slowly added to be added in oil phase in aqueous phase or by aqueous phase, treated completely After addition, stirred 3~5 minutes with 8000~20000 revs/min, produce colostrum；4. colostrum is cooled into room temperature, pH to 5.0~7.0 is adjusted with sodium hydroxide or hydrochloric acid solution, is settled to water for injection Full dose, it is transferred in high pressure homogenizer, the homogeneous 5~10 times under the conditions of 600~1200bar, 30 DEG C~60 DEG C；5. 0.22 micron membrane filter filters, inflated with nitrogen, lid sealing is rolled.
- 6. preparation method as claimed in claim 5, it is characterised in that this method comprises the following steps that：1. water soluble emulsifier, isotonic regulator are added in appropriate water for injection, 75 DEG C are heated to, is dispersed with stirring uniform obtain Aqueous phase；2. heating stirring is disperseed at a temperature of 75 DEG C by the ethacrynic acid of recipe quantity, oil for injection, oil soluble emulsifying agent, stabilizer The uniform drug containing oil phase that must be clarified；3. in the case where tissue mashing machine stirs, medicine oil will be carried and be mutually slowly added to be added in oil phase in aqueous phase or by aqueous phase, treated completely After addition, stirred 3~5 minutes with 15000 revs/min, produce colostrum；4. colostrum is cooled into room temperature, pH to 5.5~6.5 is adjusted with sodium hydroxide or hydrochloric acid solution, with water for injection constant volume To full dose, it is transferred in high pressure homogenizer, the homogeneous 5~10 times under the conditions of 700~800bar, 30 DEG C~45 DEG C；5. 0.22 micron membrane filter filters, inflated with nitrogen, lid sealing is rolled.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3476858A (en) * | 1964-02-03 | 1969-11-04 | Merck & Co Inc | Diuretic combinations of hydrochlorothiazide and ethacrynic acid |
| CN101204373A (en) * | 2006-12-19 | 2008-06-25 | 李时海 | Paclitaxel lipid microspheres injection and preparation method thereof |
| CN101332176A (en) * | 2008-04-11 | 2008-12-31 | 广州贝氏药业有限公司 | Medicine composition for injecting cinnarizine lipid microsphere and preparation method thereof |
-
2015
- 2015-04-09 CN CN201510165374.3A patent/CN104800157B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3476858A (en) * | 1964-02-03 | 1969-11-04 | Merck & Co Inc | Diuretic combinations of hydrochlorothiazide and ethacrynic acid |
| CN101204373A (en) * | 2006-12-19 | 2008-06-25 | 李时海 | Paclitaxel lipid microspheres injection and preparation method thereof |
| CN101332176A (en) * | 2008-04-11 | 2008-12-31 | 广州贝氏药业有限公司 | Medicine composition for injecting cinnarizine lipid microsphere and preparation method thereof |
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| CN104800157A (en) | 2015-07-29 |
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