CN102526042A - Stable liquid medicinal composition - Google Patents
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- CN102526042A CN102526042A CN2010105811673A CN201010581167A CN102526042A CN 102526042 A CN102526042 A CN 102526042A CN 2010105811673 A CN2010105811673 A CN 2010105811673A CN 201010581167 A CN201010581167 A CN 201010581167A CN 102526042 A CN102526042 A CN 102526042A
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Abstract
The invention relates to a medicinal composition. The composition has high stability, is resistant to strict high-temperature sterilization, and has high light stability. An additive is reduced greatly in comparison to the conventional product of the same type, production is convenient to realize, and cost is reduced.
Description
Technical field
The present invention relates to technical field of medicine, be specifically related to liquid preparation that contains vinpocetine and preparation method thereof.
Background technology
Vinpocetine (Vinpocetine), and chemistry ethyl by name (13as, 13bs)-13a-ethyl-2,3,5,6-13a, 13b six hydrogen-1H-indole [3,2,1-de] pyridines [3,2,1-ij] [1,5] one benzodiazine-12-carboxylic acid, molecular formula is: C
22H
26N
2O
2, molecular weight is 350.5, structural formula is:
Vinpocetine has multiple effect, can improve cerebral metabolism, blood flow and hemorheology properties.
Neuroprotective: vinpocetine can be alleviated the cytotoxicity that excitatory amino acid brings out, and suppresses sodium-ion channel and calcium channel, NMDA and ampa receptor that voltage relies on, strengthens the neuroprotective of adenosine.
Promote cerebrum metabolism: vinpocetine can increase absorption and the consumption of cerebral tissue to glucose and oxygen; Improve the anoxia endurance of brain; Strengthen the unique energy source-glucose of brain-the see through transportation of blood brain barrier, the metabolism of glucose is transformed into more favourable aerobic metabolism path.The alternative cGMP-phosphodiesterase that calcium ion-calmodulin, CaM relies on, cGMP and the cAMP level in the increase brain of suppressing of vinpocetine.Vinpocetine can improve concentration and the ATP/AMP ratio of ATP; Promote norepinephrine and 5-hydroxy tryptamine renewal in the brain.Vinpocetine is Wheat Protein also.
Improve big brain microcirculation: but the vinpocetine anticoagulant, reduce the pathologic blood viscosity and raise, increase RCD, suppress erythrocyte and take in adenosine, and vinpocetine also can promote the oxygen transportation organized through reducing erythrocytic oxygen affinity.
Selectivity increases big cerebral blood flow: vinpocetine can increase cardiac output brain supply percentage ratio, reduce cerebral vascular resistance and do not influence body circulation parameter (like blood pressure, cardiac output, pulse, peripheral blood vessel drag overall), vinpocetine can not cause " stealing the blood phenomenon ".And in the administration process, it can also promote the blood supply (promptly stealing the upset of blood effect) in the low perfusion property ischemia zone of impaired (also not having necrosis).
Because determined curative effect, safety are good; Vinpocetine all has launch at home and abroad; And recorded by European Pharmacopoeia and British Pharmacopoeia; The listing dosage form has oral formulations (calan tablets) and injection (injection vinpocetine and injection vinpocetine), clinically is used to improve the various symptoms that cerebral infarction sequela, apoplexy sequela, cerebral arteriosclerosis etc. are brought out.
Because its physicochemical properties are special, the vinpocetine liquid preparation particularly preparation of injection need overcome difficulties:
(1) poorly water-soluble, vinpocetine are almost insoluble in water, and poorly water-soluble brings challenges to preparation research, as processing liquid preparation or injection, must overcome difficulties, and are that medicine can dissolve fully, reach the requirement that can supply inject;
(2) vinpocetine aqueous solution high temperature is unstable, and degraded produces impurity easily, but accelerated degradation under the situation of solution state heating especially; Main performance is the hydrolysis of two keys in the molecule; Generate the ethyl vincamine, therefore, in the quality standard of European Pharmacopoeia and British Pharmacopoeia vinpocetine; The clear and definite known impurities relevant with vinpocetine has four kinds, also stipulated the limit of other unknown impurities.
(3) the vinpocetine aqueous solution is to photo-labile, under illumination condition, and vinpocetine aqueous solution yellowing, vinpocetine is degraded, and produces impurity, influence security of products, and the brown ampoule of the article employing of vinpocetine injection listing is at present packed.
For this poorly water-soluble and hydrolabil crude drug, it is very difficult processing the safe and effective vinpocetine injection that meets the injection prescription.
Publication number is that 101066244 Chinese patent discloses vinpocetine injection and preparation technology thereof.Said preparation principal agent and adjuvant weight portion ratio are vinpocetine 3～20, cosolvent 0.1～1, antioxidant 0.5～10, physically stable agent 50～100, vascular stimulation regulator 0.5～10.The preparation process mainly comprises: dissolving, standardize solution, adjusting pH, activated carbon adsorption, filtration, fill.Product is not carried out high temperature sterilize in this technology, belong to sterile production technology.
Publication number is that 1572296 Chinese patent discloses vinpocetine freeze-dried powder and preparation technology thereof.This patent is processed freeze-dried powder to vinpocetine injection problem of unstable with vinpocetine, and this lyophilized injectable powder is made up of vinpocetine, frozen-dried supporting agent and cosolvent.Its preparation adopts conventional lyophilized formulations preparation technology to carry out, and is sterile production technology, does not have the final sterilization step.
Publication number is that 101264064 Chinese patent discloses a kind of vinpocetine freeze-dried powder and preparation technology thereof.The described lyophilized injectable powder of this patent is made up of vinpocetine, mannitol and hydrochloric acid.Its preparation is same adopts conventional lyophilized formulations preparation technology to carry out, and is sterile production technology, does not have the final sterilization step.
According to existing knowledge, do not comprise the high temperature sterilize step in the production technology of vinpocetine injection, more do not see the research report of the sterilization process production vinpocetine injection that employing is excessively killed.And the serious bad accident of the injection that takes place frequently in recent years is mostly because medicine unstable, causes the aseptic assurance water article of production technology lower, the Product Safety problem that causes.
Summary of the invention
For injection; The aseptic level that guarantees of its production technology is one of vital index; The production technology of injection is divided into two kinds; A kind of is sterile production technology, relies on the aseptic control of production process and final aseptic filtration to guarantee the aseptic of product, like sterile injection powder and the injection handled without final sterilization; Another kind is to combine production process control and aseptic filtration; Finally also product is carried out high temperature sterilize (being chosen in 115 ℃ or the 121 ℃ of following sterilization of temperature conditions certain hours usually); Guarantee the aseptic of final products, most of injection adopt the terminal sterilization explained hereafter.
Obviously; For sterile production technology; The aseptic level of production environment, equipment, supplementary material requires very high, and the antibacterial water article before aseptic filtration are very big to the aseptic level affects of finished product, because the microporous filter membrane pressure filtration of 0.22 μ m is adopted in aseptic filtration usually; And filter membrane may become and causes passing through of antibacterial greatly in the aperture under the situation of pressurization, and the morphotropism of antibacterial also possibly increase the probability of antibacterial through filter membrane in addition.Therefore, the aseptic assurance level of this production technology is lower, requires very high to environment, equipment, supplementary material etc.; Production cost also is much higher than terminal sterilization technology; Especially for lyophilized formulations, freeze-drying time is more than 20 hours usually, and the production time is long; Consume mass energy, production cost increases greatly.And for the terminal sterilization production technology; Aseptic level in the control production process is also passed through aseptic filtration simultaneously, and final products adopt high temperature sterilize, even the contaminating microorganisms of occasionality aborning; Also can microorganism thoroughly be killed through high-temperature sterilizing process; Therefore, the aseptic assurance level of the injection of this explained hereafter is the highest, and safety significantly is superior to adopting the injection of aseptic explained hereafter; Relatively low, with short production cycle to the aseptic level requirement of production environment, equipment, supplementary material simultaneously, cost also significantly reduces.
Therefore, consider from the angle of safety, the production technology production that injection should first-selected terminal sterilization, and the F0 in the sterilization process parameter should be not less than 8, preferably selects excessively to kill condition, for example 121 ℃ of sterilization 12min above (F0=12).This requirement for vinpocetine be have challenging very greatly because the vinpocetine aqueous solution under high-temperature condition easily degraded produce impurity, thereby increased the risk that untoward reaction takes place, influence security of products.
Vinpocetine aqueous solution photostability is poor, and solution colour shows that by the colourless yellow that becomes vinpocetine degrades under the illumination condition under illumination, and vinpocetine injection listing article need fill in brown ampoule, and the condition of storage regulation is answered the shading preservation simultaneously.
To the problems referred to above,, the liquid preparation of vinpocetine can withstand high temperatures be sterilized in order to improve the stability of vinpocetine; Adopt the terminal sterilization explained hereafter, obtain the product that aseptic assurance level is high, safety is good, the inventor has carried out a large amount of research; Surprised discovery is also played function of stabilizer when adding hydrochloric acid and/or phosphoric acid as solubilizing agent, the adding of hydrochloric acid and/or phosphoric acid makes the stability of vinpocetine in solution improve greatly; Can tolerate long-time high temperature sterilize; Obtain high-quality vinpocetine injection, and this product has good stability through still invariant color behind the strong illumination.
Technical scheme of the present invention is following:
Pharmaceutical composition of the present invention is the aqueous solution that comprises vinpocetine, HCl and pH regulator agent, and the mol ratio of vinpocetine and HCl is 1: 10～1: 0.3.
In the pharmaceutical composition of the present invention, the mol ratio of vinpocetine and HCl is 1: 10～1: 0.5.
In the pharmaceutical composition of the present invention, the mol ratio of vinpocetine and HCl is 1: 10～1: 6.74.
In the pharmaceutical composition of the present invention, said pH regulator agent is organic base or inorganic base.
PH regulator agent of the present invention is NaOH and/or KOH, and preferred NaOH can be mixed with certain density aqueous solution with it during use.
In the present invention, the pH of compositions is adjusted to 2.5～4.2, and preferred, the pH of compositions is adjusted to 3.0～4.0.
The present invention also provides a kind of method that improves the vinpocetine aqueous stability, comprises following steps:
(1) preparation contains the aqueous solution of HCl;
(2) add vinpocetine, stirring and dissolving;
(3) pH value of the above-mentioned solution of adjustment.
The present invention also provides a kind of method for preparing of vinpocetine injection, specifically may further comprise the steps: hydrochloric acid is added in the suitable quantity of water and stirs, add vinpocetine; Stirring makes it to dissolve fully, adds the pH regulator agent and regulates pH to required scope, mends and adds water to capacity; Add the injection stage active carbon in 60 ℃ of insulated and stirred absorption 20～30 minutes, filter embedding; In 121 ℃ of sterilizations 15 minutes, promptly get the vinpocetine injection.
According to the vinpocetine injection of technical scheme preparation of the present invention, the stability of active component vinpocetine improves greatly, after through the high temperature sterilize under the stringent condition; Aseptic level is fully guaranteed, and the degradation material of vinpocetine does not increase, and in long-term put procedure, has good stability; Especially stable in properties under the strong illumination condition, color and related substance all do not change, therefore; This product quality is better, and safety is higher.Compare with existing vinpocetine injection, having simplified prescription and having formed, can adopt common ampoule and needn't adopt brown ampoule; Reduce production costs; Improve the quality of products, and can avoid adopting of the interference of coloured ampoule, have obvious improvement test items such as character, visible foreign matters.
The specific embodiment
Below in conjunction with embodiment the present invention is done detailed elaboration, but be not limited to the embodiment of these concrete records.
For clearer explanation advantage of the present invention, also enumerated the method for preparing of comparative study, and carried out comparative study with the prepared sample of the present invention with sample.
The preparation of comparative study sample: get 1400ml water for injection, it is 2.0 that tartarize is regulated pH, adds vinpocetine 10g, stirring and dissolving; The NaOH aqueous solution that adds 1mol/l is regulated pH to 3.0～4.0, mends and adds water to capacity, adds injection stage active carbon (0.1%; W/v) in 60 ℃ of insulated and stirred absorption 30 minutes, filter, embedding is in the colourless transparent glass ampoule; Every of 2ml in 121 ℃ of sterilizations 15 minutes, promptly gets.
Extracting lactic acid, phosphoric acid prepare sample equally according to preceding method in addition, and is subsequent use.
Embodiment 1
Prescription:
Vinpocetine 10g
1mol/l hydrochloric acid 200ml
Water adds to 2000ml.
Method for preparing: hydrochloric acid added in the entry stir all evenly, make the hydrochloric acid solution that volume is about configuration amount 70%, add vinpocetine, stir and make it to dissolve fully; The NaOH aqueous solution that adds 1mol/l is regulated pH to 3.0～4.0, mends and adds water to capacity, adds injection stage active carbon (0.1%; W/v) in 60 ℃ of insulated and stirred absorption 30 minutes, filter, embedding is in the colourless transparent glass ampoule; Every of 2ml in 121 ℃ of sterilizations 15 minutes, promptly gets the vinpocetine injection.
Embodiment 2
Prescription:
Vinpocetine 10g
1mol/l hydrochloric acid 160ml
Water adds to 2000ml.
Method for preparing: hydrochloric acid added in the entry stir all evenly, make the hydrochloric acid solution that volume is about configuration amount 70%, add vinpocetine, stir and make it to dissolve fully; The NaOH aqueous solution that adds 1mol/l is regulated pH to 3.0～4.0, mends and adds water to capacity, adds injection stage active carbon (0.1%; W/v) in 60 ℃ of insulated and stirred absorption 30 minutes, filter, embedding is in the colourless transparent glass ampoule; Every of 2ml in 121 ℃ of sterilizations 15 minutes, promptly gets the vinpocetine injection.
Embodiment 3
Prescription:
Vinpocetine 10g
1mol/l hydrochloric acid 120ml
Water adds to 2000ml.
Method for preparing: hydrochloric acid added in the entry stir all evenly, make the hydrochloric acid solution that volume is about configuration amount 70%, add vinpocetine, stir and make it to dissolve fully; The NaOH aqueous solution that adds 1mol/l is regulated pH to 3.0～4.0, mends and adds water to capacity, adds injection stage active carbon (0.1%; W/v) in 60 ℃ of insulated and stirred absorption 30 minutes, filter, embedding is in the colourless transparent glass ampoule; Every of 2ml in 121 ℃ of sterilizations 15 minutes, promptly gets the vinpocetine injection.
Embodiment 4
Prescription:
Vinpocetine 10g
1mol/l hydrochloric acid 80ml
Water adds to 2000ml.
Method for preparing: hydrochloric acid added in the entry stir all evenly, make the hydrochloric acid solution that volume is about configuration amount 70%, add vinpocetine, stir and make it to dissolve fully; The NaOH aqueous solution that adds 1mol/l is regulated pH to 3.0～4.0, mends and adds water to capacity, adds injection stage active carbon (0.1%; W/v) in 60 ℃ of insulated and stirred absorption 30 minutes, filter, embedding is in the colourless transparent glass ampoule; Every of 2ml in 121 ℃ of sterilizations 15 minutes, promptly gets the vinpocetine injection.
Embodiment 5
Prescription:
Vinpocetine 10g
1mol/l hydrochloric acid 60ml
Water adds to 2000ml.
Method for preparing: hydrochloric acid added in the entry stir all evenly, make the hydrochloric acid solution that volume is about configuration amount 70%, add vinpocetine, stir and make it to dissolve fully; The NaOH aqueous solution that adds 1mol/l is regulated pH to 3.0～4.0, mends and adds water to capacity, adds injection stage active carbon (0.1%; W/v) in 60 ℃ of insulated and stirred absorption 30 minutes, filter, embedding is in the colourless transparent glass ampoule; Every of 2ml in 121 ℃ of sterilizations 15 minutes, promptly gets the vinpocetine injection.
Embodiment 6
Prescription:
Vinpocetine 10g
1mol/l hydrochloric acid 40ml
Water adds to 2000ml.
Method for preparing: hydrochloric acid added in the entry stir all evenly, make the hydrochloric acid solution that volume is about configuration amount 70%, add vinpocetine, stir and make it to dissolve fully; The NaOH aqueous solution that adds 1mol/l is regulated pH to 3.0～4.0, mends and adds water to capacity, adds injection stage active carbon (0.1%; W/v) in 60 ℃ of insulated and stirred absorption 30 minutes, filter, embedding is in the colourless transparent glass ampoule; Every of 2ml in 121 ℃ of sterilizations 15 minutes, promptly gets the vinpocetine injection.
Embodiment 7
Prescription:
Vinpocetine 10g
1mol/l hydrochloric acid 20ml
Water adds to 2000ml.
Method for preparing: hydrochloric acid added in the entry stir all evenly, make the hydrochloric acid solution that volume is about configuration amount 70%, add vinpocetine, stir and make it to dissolve fully; The NaOH aqueous solution that adds 1mol/l is regulated pH to 3.0～4.0, mends and adds water to capacity, adds injection stage active carbon (0.1%; W/v) in 60 ℃ of insulated and stirred absorption 30 minutes, filter, embedding is in the colourless transparent glass ampoule; Every of 2ml in 121 ℃ of sterilizations 15 minutes, promptly gets the vinpocetine injection.
Embodiment 8
Prescription:
Vinpocetine 20g
1mol/l hydrochloric acid 200ml
Water adds to 2000ml.
Method for preparing: hydrochloric acid added in the entry stir all evenly, make the hydrochloric acid solution that volume is about configuration amount 70%, add vinpocetine, stir and make it to dissolve fully; The NaOH aqueous solution that adds 1mol/l is regulated pH to 3.0～4.0, mends and adds water to capacity, adds injection stage active carbon (0.1%; W/v) in 60 ℃ of insulated and stirred absorption 30 minutes, filter, embedding is in the colourless transparent glass ampoule; Every of 2ml in 121 ℃ of sterilizations 15 minutes, promptly gets the vinpocetine injection.
Embodiment 9 quality examinations
Respectively state the vinpocetine injection that embodiment makes and test last according to the national drug standards (WS1-X-177-2004Z); And with listing product (vinpocetine injection; Commodity are called Kai Wentong; Lot number is A81244A, and Huangary girui Gyogyszergyar produces) and comparative study compare with the assay of sample.
Assay
Measure according to HPLC (two appendix V of Chinese Pharmacopoeia version in 2010 D).
The test of chromatographic condition and system suitability is used octadecylsilane to be good for to close silica gel and is filler; Be mobile phase with methanol-sal volatile (get ammonium carbonate 1.75g, be dissolved in water and be diluted to 1000ml)-ether (85: 25: 3); The detection wavelength is 273nm.Number of theoretical plate calculates by the vinpocetine peak should be not less than 2500, and vinpocetine peak and the peak-to-peak separating degree of adjacent impurity should meet the requirements.
The algoscopy precision is measured these article 5ml, puts in the 100ml measuring bottle, is diluted to scale with mobile phase, shakes up, and precision is measured 5ml, puts in the 50ml measuring bottle, is diluted to scale with mobile phase, shakes up, and precision is measured 20 μ l, injects chromatograph of liquid, the record chromatogram; It is an amount of that other gets the vinpocetine reference substance, and tame mobile phase dissolving also quantitatively is diluted to the solution that contains 25 μ g among every 1ml approximately, measures with method,, promptly gets with calculated by peak area by external standard method.
Determination of related substances
It is an amount of that precision is measured these article, adds mobile phase and be diluted to the solution that contains vinpocetine 50 μ g among every 1ml approximately, as need testing solution; Precision is measured in right amount, adds mobile phase and is diluted to the solution that contains vinpocetine 10 μ g among every 1ml approximately, as prerun solution.According to the test of the chromatographic condition under the assay item, get prerun solution 20 μ l, inject chromatograph of liquid, regulate detector sensitivity, making meeting of main constituent chromatographic peak high is 60%～80% of full scale; Get need testing solution 20 μ l again, injection chromatograph of liquid, 2 times of writing down chromatogram to main constituent retention time.In the chromatogram of need testing solution as show impurity peaks, deduction adjuvant peak, single impurity peak area must not be greater than 0.8% of total peak area, each impurity peak area with must not be greater than 1.5% of total peak area.
Assay is seen table 1.
Table 1 vinpocetine injection quality inspection result
Quality examination is the result show; Vinpocetine injection according to scheme preparation of the present invention complies with the national standard requirements; The impurity number is less than listing article and comparative study and uses sample, and single impurity and total impurities content is far smaller than the article of listing and the comparative study impurity content with sample, and the stability of vinpocetine significantly improves; Reduce the incidence rate of adverse reaction that causes owing to impurity greatly, safety is better guaranteed.
The test of embodiment 10 light stability
Get sample, the listing article that embodiment 1～8 makes and be positioned over illumination 4500Lx condition held 10 days with the comparative study sample, take a sample detection character, pH, related substance, content, the result sees table 2.
Table 2 light stability result of the test
The light stability result of the test shows; According to the sample of research approach of the present invention preparation in illumination 4500Lx condition held 10 days; Significant change does not all take place in outward appearance, pH, related substance, content; And listing article and comparative study with the color of sample by the colourless yellow that becomes, impurity number and impurity content all have obvious increase, and be good according to the vinpocetine injection light stability that the present invention program prepares; Significantly be superior to listing article and comparative study and use sample, show that the adding of hydrochloric acid improves the light stability of vinpocetine aqueous solution greatly.
Claims (8)
1. stable composition of liquid medicine, characteristic is the aqueous solution that comprises vinpocetine, HCl and pH regulator agent, the mol ratio of vinpocetine and HCl is 1: 10～1: 0.3.
2. pharmaceutical composition as claimed in claim 1, characteristic are that the mol ratio of vinpocetine and HCl is 1: 10～1: 0.5.
3. pharmaceutical composition as claimed in claim 2, characteristic are that the mol ratio of vinpocetine and HCl is 1: 10～1: 6.74.
4. pharmaceutical composition as claimed in claim 1, characteristic are that said pH regulator agent is organic base or inorganic base.
5. pharmaceutical composition as claimed in claim 2, characteristic are that said pH regulator agent is NaOH and/or KOH, preferred NaOH.
6. pharmaceutical composition as claimed in claim 1, characteristic are that the pH of said composition is adjusted to 2.5～4.2.
7. pharmaceutical composition as claimed in claim 1, characteristic are that the pH of said composition is adjusted to 3.0～4.0.
8. method that improves the vinpocetine aqueous stability comprises following steps:
(1) preparation contains the aqueous solution of HCl;
(2) add vinpocetine, stirring and dissolving;
(3) pH value of the above-mentioned solution of adjustment.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010105811673A CN102526042B (en) | 2010-12-09 | 2010-12-09 | Stable liquid medicinal composition |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010105811673A CN102526042B (en) | 2010-12-09 | 2010-12-09 | Stable liquid medicinal composition |
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| CN102526042B CN102526042B (en) | 2013-12-11 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103202805A (en) * | 2013-03-22 | 2013-07-17 | 东北制药集团股份有限公司 | Vinpocetine-containing pharmaceutical composition for injection and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1572296A (en) * | 2003-06-11 | 2005-02-02 | 山东绿叶制药股份有限公司 | Freeze dried vinpocetine powder injection and its preparation process |
| CN101264064A (en) * | 2008-04-17 | 2008-09-17 | 孙向阳 | Vinpocetine freeze-dried powder for injection and preparation thereof |
-
2010
- 2010-12-09 CN CN2010105811673A patent/CN102526042B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1572296A (en) * | 2003-06-11 | 2005-02-02 | 山东绿叶制药股份有限公司 | Freeze dried vinpocetine powder injection and its preparation process |
| CN101264064A (en) * | 2008-04-17 | 2008-09-17 | 孙向阳 | Vinpocetine freeze-dried powder for injection and preparation thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103202805A (en) * | 2013-03-22 | 2013-07-17 | 东北制药集团股份有限公司 | Vinpocetine-containing pharmaceutical composition for injection and preparation method thereof |
| CN103202805B (en) * | 2013-03-22 | 2015-02-25 | 东北制药集团股份有限公司 | Vinpocetine-containing pharmaceutical composition for injection and preparation method thereof |
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| CN102526042B (en) | 2013-12-11 |
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