CN100408043C - Medicinal composition containing polydatin and its use - Google Patents
Medicinal composition containing polydatin and its use Download PDFInfo
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- CN100408043C CN100408043C CNB2005100826972A CN200510082697A CN100408043C CN 100408043 C CN100408043 C CN 100408043C CN B2005100826972 A CNB2005100826972 A CN B2005100826972A CN 200510082697 A CN200510082697 A CN 200510082697A CN 100408043 C CN100408043 C CN 100408043C
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Abstract
The present invention relates to a medicinal composition containing polydatin and an application thereof. The composition comprises polydatin and solvent for dissolving the polydatin, wherein the solvent comprises 40 to 95% of ethanol and 0 to 60% of propylene glycol and water on a volume basis. The concentration of the polydatin in the composition can be higher than or equal to 6 mg/ml. The composition has good stability during low-temperature storage. The composition can be admitted by intravenous drip, intramuscular injection and other stomach intestine external ways. The composition can also be used for oral administration or be used for preparing spraying agents or aerosol.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition and application thereof that contains polygonin.
Background technology
1963, advanced him and separate acquisition polygonin (polydatin) from plant polygonum cuspidatum (Polygonum cuspidatum Sieb.et Zucc.) in wild village, finds that thereafter polygonin also is present in plants such as storehouse leaf PiceameyeriRehd. Et Wils., Fructus Vitis viniferae, Semen arachidis hypogaeae.The chemical constitution of polygonin is 3,4 ', 5-trihydroxy stilbene-3-β-D-glucoside (3,4 ', 5-trihydroxy-trans stilbene-3-β-D-glucoside), for trans diphenylethylene [is stilbene, the Stilbene class] chemical compound, its structural formula is as follows.
Studies show that in recent decades, polygonin have physiologically actives such as microcirculation improvement, blood fat reducing, antitumor.But the clinical preparation that does not still have this chemical compound at present appears on the market.
In the basic pharmacology research of polygonin, in the body experimental study, polygonin adopts the intravenous route administration more, and it is the polydatin medicinal composition of 2～5mg/ml that test specimen adopts water or normal saline compound concentration more.But existing document does not all have the feasible compound method of solution and further specifies.Following table has been enumerated described polygonin dosage of part pharmaceutical research document and trial drug concentration.
On the other hand, according to existing pharmaceutical research data, can predict corresponding clinical effective dose.For example, in the every test that with the rat is experimental animal, polygonin single-dose dosage many 10mg/kg body weight or more than; Body surface area computing method according to standard in this area adopts should be more than 112mg/ time with the corresponding human dosage of these dosage (calculating with the 70kg body weight).Obviously, adopt the routine clinical injection specification of 1～20ml, then required polygonin concentration should be not less than 5.6mg/ml in its solution.
In fact, the dissolubility of polygonin in conventional water or normal saline solution is limited, and its conventional aqueous solution is difficult to reach the described concentration of above-mentioned document.For example, the saturated concentration of polygonin in water and normal saline all is lower than 0.5mg/ml under the room temperature, far below above-mentioned 2～5mg/ml administration concentration.
Regulate methods such as pH value, heating, interpolation surfactant, be the common method that improves the compound dissolution degree, still, studies show that, for preparation polydatin medicinal composition stable, drug effect concentration, the value of these methods is limited.
For example, the regulator solution pH value can increase the dissolubility of polygonin, still, under the room temperature, obtains the polygonin aqueous solution of concentration greater than 3mg/ml, and the solvent pH value is about more than 12, and whole pH value of solution is about more than 10.Those skilled in that art all know, and clinically generally require in pH 4.0～9.0 scopes with solution, obviously, only are difficult to prepare the polygonin aqueous solution of drug effect concentration by pH regulator.In addition, because polygonin less stable in the solution of high pH value, therefore, the clinical practice of high pH value polydatin medicinal composition preparation will further be restricted.
Above-mentioned document 19 adopts the method for heating for dissolving to obtain polydatin medicinal composition.According to test, the heating for dissolving obtained aqueous solution, solute can be separated out when temperature descends, and behind equilibrium at room temperature, polygonin concentration is lower than 0.5mg/ml in the solution.Obviously, this method and be not suitable for being prepared into the medicine preparation.
Chinese patent application 02134928.2 has been described employing pH regulator method and/or has been added the method that surfactant (Tween 80) prepares the polygonin injection solution.Studies show that when preparation contained the polydatin medicinal composition of 0.5% Tween 80, pH 8.5, when this solution concentration reached 4mg/ml, then solution can not stored refrigerated (can separate out the polygonin crystallization during 4 ℃ of cold preservations).Because polygonin (solution) is to temperature and illumination sensitivity, therefore low temperature and lucifuge storage should be the preferred storage condition of polygonin preparation (solution), and cold preservation to place be to help the storage condition commonly used that keeps the injection active component stable, therefore, be not suitable for the defective that obviously there is medicine storage aspect in injection that this condition places.In addition, available data shows because the Tweens surfactant has potential haemolysis and antihypertensive activity, preparation for intravenous administration should avoid using as far as possible (Zhuan Yue etc., practical drug preparation technique, the People's Health Publisher, 1999:p417).
Can improve the dissolubility of polygonin as cosolvent with propylene glycol.Chinese patent application 02134928.2 has promptly been described the method for preparing injection solution with 5%～20% propylene glycol, but studies show that, under the room temperature condition, the dissolubility of polygonin in 20% aqueous solution of propylene glycol is lower than 5mg/ml, about 3.5mg/ml, and the solution instability, placing promptly had the solute polygonin to separate out after 12 hours.In addition, containing 20% propylene glycol, 0.5% tween, pH 8.5, concentration according to the preparation of the described method of patent 02134928.2 embodiment 1-2 is the polygonin solution of 8mg/ml, and cold director's phase also stores and can separate out the polygonin crystallization; This implements described unit formulation with 100ml 0.9% sodium chloride injection (normal saline) dilution, and gained compatibility solution instability has crystallization to separate out.
Obviously, in the scope that clinical preparation allows, by regulating pH value, add the Tweens surfactant or only adopting propylene glycol all can not obtain ideal clinical preparation scheme with the polygonin injection as cosolvent.Therefore, researching and developing the stable solution-type pharmaceutical composition that contains drug effect concentration polygonin is of great practical significance for the clinical practice that realizes polygonin.
Summary of the invention
The object of the present invention is to provide a kind of pharmaceutical composition and application thereof that contains polygonin, this pharmaceutical composition can comprise the polygonin of drug effect concentration, can keep stable when low tempertaure storage.Said composition can keep compatibility solution-stabilized, clear and bright according to routine clinical usage and dosage compatibility.
In the disclosed documents and materials, extract polygonin with ethanol as solvent from the Rhizoma Polygoni Cuspidati medical material and see report, the application of ethanol in the polygonin separation and purification also is found in open source literature; But the application of ethanol in containing the polygonin pharmaceutical formulation then do not appear in the newspapers.The more important thing is that polygonin does not appear in the newspapers at ethanol and the solubility behavior characteristic that contains in the ethanol mixed solvent.Document and research show that all polygonin has good dissolubility in ethanol; On the other hand, document and research also show, under room temperature (25 ℃) condition, the dissolubility of polygonin in pure water very low (＜0.5mg/ml).Usually, after a kind of solute dissolves, add the low solubility solvent in good solvent, the dissolubility that makes solute in good solvent is significantly descended.This area is adopted " water extract-alcohol precipitation " or " alcohol extracting-water precipitating " method separation and Extraction thing or is utilized mixed solvent to carry out recrystallization and all is based on this principle.But the inventor discovers that polygonin has unique solubility behavior in ethanol-water mixed solvent, and its rule is different fully with above-mentioned universal law.As the ethanol of polygonin good solvent, when mixing with polygonin low solubility aqueous solvent, in the certain proportion scope, poor solvent increases, and mixed solvent does not descend to the dissolubility of polygonin, raises to some extent unexpectedly on the contrary.For example, under the room temperature condition, the dissolubility＜0.5mg/ml of polygonin in pure water; The about 20mg/ml of dissolubility in dehydrated alcohol; Unexpectedly, in the ethanol water of about 50%～95% (v/v), the dissolubility of polygonin is all greater than 20mg/ml.For example, in 50% ethanol water, the about 25mg/ml of the dissolubility of polygonin, the about 75mg/ml of the dissolubility in 90% ethanol water.This result shows, the ethanol water of 50%～95% (v/v) has " latent solvent " effect to polygonin, that is: in the certain proportion scope, ethanol-water mixed solvent is better than wherein any single solvent of pure water and straight alcohol to the dissolubility of polygonin.Research finds that also in 15% ethanol-water solution, the dissolubility of polygonin is about 1mg/ml; In 30% ethanol-water solution, its dissolubility is about 6mg/ml; That is to say that surpass certain proportion, " latent solvent " character of mixed solvent will no longer exist.
The inventor also further is surprised to find that, in above-mentioned ethanol-water solution, form new mixed solvent if add a certain amount of propylene glycol, then polygonin is in the certain proportion scope of this mixed solvent, dissolubility can further improve, and promptly is higher than its dissolubility in corresponding single solvent (alcohol-water, propylene glycol) respectively.For example, form new mixed solvent with 60% alcohol-water and propylene glycol according to the ratio of 10: 2.5 (v/v), then the dissolubility of polygonin is about 75mg/ml, far above its dissolubility (being about 42mg/ml and 60mg/ml respectively) in 60% alcohol-water and solvent propylene glycol.This solution is investigated through low tempertaure storage, has good stability.Research is also found, surpasses certain proportion, and " latent solvent " character of mixed solvent also will no longer exist.
For intravenous administration, the contained concentration of alcohol of injection can not be too high.Given this, but the present invention adopts concentrated solution for injection to realize the injection of intravenous continuous drip administration.So-called concentrated solution for injection is meant facing with preceding employing injection normal saline and is diluted to specified multiple, and then passes through the injection of intravenous injection or intravenous drip administration.Test shows, and is good with the compatibility stability of polygonin injection in the injection normal saline of alcohol-water or water-ethanol-mixed with propylene glycol solvent preparation, and with the sample solution of propylene glycol-water preparation, compatibility instability.In addition, studies show that, the clinical compatibility stability of mixed solvent is better than alcohol-water, and mixed solvent configuration proportion difference under certain condition, the compatibility stability of sample solution is difference to some extent also.
This shows that alcohol-water and/or mixed with propylene glycol solvent that the present invention illustrates proper ratio first can produce specific " latent solvent " effect to polygonin; Have only the alcohol-water and/or the mixed with propylene glycol solvent of proper ratio just can prepare concentrated solution for injection with compatibility stability, and this solution is low tempertaure storage for a long time, and these character can be applied to clinical pharmaceutical formulation for preparation and have very important significance.
Because water, ethanol, propylene glycol are pharmaceutically acceptable solvent, therefore, based on purpose of the present invention and above-mentioned discovery, the invention provides a kind of solution-type pharmaceutical composition that can comprise high-concentration polydatin.In this article, the pharmaceutical composition that will contain polygonin sometimes abbreviates polydatin medicinal composition as.
Polydatin medicinal composition provided by the invention comprises polygonin, and the solvent that is used to dissolve polygonin, by volume, and described solvent comprises 40%～95% ethanol, 0%～60% propylene glycol, and the water of surplus.
In this article, if no special instructions, described percentage composition is volumn concentration.According to Chinese Pharmacopoeia, etoh solvent promptly refers to 95% ethanol if no special instructions.
In polydatin medicinal composition provided by the invention, the concentration of polygonin in described solvent should be usually and is not less than 6mg/ml.
Further, the concentration of polygonin in described solvent is 6mg～150mg/ml.
Preferably, the concentration of polygonin in described solvent is 20mg～100mg/ml.
In polydatin medicinal composition provided by the invention, the concentration of polygonin should be not less than 6mg/ml, and this is because according to existing pharmaceutical research data, can predict corresponding clinical effective dose.For example, in the every test that with the rat is experimental animal, polygonin single-dose dosage many 10mg/kg body weight or more than; According to body surface area computing method conventional in this area, should be more than 112mg/ time with the corresponding human dosage of these dosage (calculating) with the 70kg body weight.Obviously, if adopt the routine clinical injection specification of 1～20ml, then required polygonin concentration should be not less than 5.6mg/ml in its solution.
The used solvent of the present invention can significantly improve the dissolubility of polygonin in solution, improve the stability of polydatin medicinal composition when cryopreservation simultaneously, thereby the concentration that can control polygonin is not less than 6mg/ml, with preparation and the clinical application that is more conducive to pharmaceutical preparation.Yet, it will be appreciated by those skilled in the art that, when using solvent of the present invention,, also should belong to scope of the present invention even the concentration of polygonin is lower than 6mg/ml.
In polydatin medicinal composition provided by the invention, described solvent also can further comprise water.
Preferably, by volume, described solvent comprises 50～80% ethanol, 0～50% propylene glycol, and the water of surplus.
Preferably, described solvent is the mixed solvent that contains a certain amount of propylene glycol, by volume, and described solvent comprises 40～80% ethanol, 5～60% propylene glycol, and the water of surplus.
Preferred, by volume, described solvent comprises 40%～60% ethanol, 10～30% propylene glycol, and the water of surplus.
Most preferred, by volume, described solvent comprises 45% ethanol, 20% propylene glycol, and the water of surplus.
In the polydatin medicinal composition provided by the invention, water in the described mixed solvent can be purified water, water for injection, the last acceptable sodium chloride solution of physiology or glucose solution (for example, 0.9% sodium-chloride water solution, 5% glucose solution or glucose saline) or physiology last acceptable buffer solution, for example Na
2CO
3-NaHCO
3Buffer, Na
2HPO
4-NaH
2PO
4Buffer, Tris buffer and Hepes buffer etc.When described polydatin medicinal composition is used for the different approaches administration, can from the water of mentioned kind, be selected as required, for example, when being used for drug administration by injection, the water in the usual solvents should be water for injection, normal saline or buffer etc.; When being used for oral administration etc., common available purified water.
Preferably, the water in the described mixed solvent is that the physiology of pH6.0～9.0 goes up acceptable buffer solution, and for example pH is about 6.0～9.0 Na
2HPO
4-NaH
2PO
4Buffer etc.
Preferred, it is that 7.5～9.0 physiology goes up acceptable buffer solution that the water in the described mixed solvent is preferably pH.
Most preferred, the water in the described mixed solvent is that the physiology of pH about 8.5 goes up acceptable buffer solution, for example Na of pH 8.5
2CO
3-NaHCO
3Buffer etc.
Polydatin medicinal composition provided by the invention can be used for the parenteral drug administration by injection.Wherein, when being used for intravenously administrable, direct dropleting medicine-feeding or above-mentioned polygonin injection is diluted in 0.9% sodium chloride injection or 5% glucose injection dropleting medicine-feeding; When being used for intramuscular administration, but direct injection or be diluted to administration behind the debita spissitudo with normal saline.Polydatin medicinal composition of the present invention can also be used as oral administration solution, or further makes spray or aerosol.
Therefore, the dosage form of polydatin medicinal composition provided by the invention can be injection, oral administration solution, spray or aerosol etc.
Further, polydatin medicinal composition provided by the invention contains the active component of unit dose, and unit dose can contain polygonin 3～1500mg, preferably contain polygonin 6～500mg, more preferably contain polygonin 50～250mg, in a preferred embodiment of the present invention, contain polygonin 100mg.The liquor capacity that comprises the unit dose polygonin can be 0.5～250ml, preferred 2～20ml, and more preferably 2～10ml, in a preferred embodiment of the present invention, liquor capacity is 5ml.
Polydatin medicinal composition provided by the invention can also be chosen wantonly and contain other pharmaceutically conventional pharmaceutic adjuvant that uses, for example, polydatin medicinal composition of the present invention can be chosen the material that increases suspension viscosity wantonly, as sodium carboxymethyl cellulose, Sorbitol, methylcellulose etc.; Can choose wantonly and contain suitable stabilizers or antioxidant, as sodium sulfite, vitamin C etc.; When being used for oral administration, also can add suitable correctives etc., to improve mouthfeel.
The present invention also provides the application of the pharmaceutical composition that contains polygonin in the medicine of preparation treatment or prevention and microcirculation disturbance relevant disease, polydatin medicinal composition of the present invention has significant expansion blood capillary, reduce blood capillary inner blood viscosity, suppress hemocyte sticks effect, thereby have significant microcirculation improvement effect, can be used for the treatment of or prevent the shock and with the microcirculation disturbance diseases associated.
Results of pharmacodynamic test shows, compare with the dopamine positive drug control group with the blank group, the polygonin injection has the obvious treatment effect to hemorrhagic dogs, significantly improve 24hr, 48hr and the long-term surviving rate of shock back animal, its curative effect to shock is better than positive control medicine dopamine.
The present invention explores a kind of method that adopts mixed solvent to improve drug solubility through a large amount of experimental studies.This method is used for medication preparation, the solution of the polygonin of the effective therapeutic dose that contains with good grounds known achievement in research measuring and calculating can be provided, thus, it is clinical to the invention enables the pharmacy activity component polygonin to be applied to the treatment effective dose, and this compares improvement and the raising that matter is arranged with existing technical merit.Animal experiment and solution stability testing show, polydatin medicinal composition provided by the invention is safe and effective, have good stability, and therefore, this solution has preferable potential applicability in clinical practice.
In order to understand essence of the present invention better,,, describe in detail but do not limit the present invention by description to better embodiment of the present invention below in conjunction with accompanying drawing.
Brief description of drawings
Fig. 1 is the variation of hemorrhagic dogs mean arterial pressure;
Fig. 2 is the comparison of hemorrhagic dogs pulse pressure difference rate of change.
The specific embodiment
Employed polygonin provides by king technique center, sea, Shenzhen in following test, purity 99.63%, and lot number 20030829, its concrete preparation method is referring to Chinese patent application 200310112538.3.
Used other test material of the present invention if no special instructions, is commercially available purchase product.
The preparation of polygonin injection
Material: dehydrated alcohol (or ethanol), analytical pure, Guangzhou chemical reagent two factories; Water for injection, extra large king's industry city; 0.9% sodium chloride solution is prepared with water for injection; The sodium chloride glucose solution is prepared with water for injection; Propylene glycol, analytical pure, Guangzhou chemical reagent two factories; Carbonate buffer solution takes by weighing an amount of natrium carbonicum calcinatum and sodium bicarbonate, with water for injection preparation, pH value of solution 8.5～9.0.
[embodiment 1]
One, prescription
The raw material consumption
Polygonin 400.00g
Dehydrated alcohol 3.50L
Water for injection is to 5.00L
Make 1000
Two, method for making
Measure dehydrated alcohol 3.50L, add an amount of water for injection, mixing adds polygonin 400.00g, and 40 ℃ ultrasonic makes moltenly, and water for injection is settled to scale, 0.2 μ m filtering with microporous membrane, and embedding is in 1000 ampoule bottles.Facing the time spent is diluted to debita spissitudo with 0.9% sodium chloride injection or 5% glucose injection.
[embodiment 2]
One, prescription
The raw material consumption
Polygonin 125.00g
Dehydrated alcohol 2.50L
0.9% sodium chloride solution is to 5.00L
Make 1000
Two, method for making
Measure dehydrated alcohol 2.50L, add an amount of 0.9% sodium chloride solution, mixing adds polygonin 125.00g, and 40 ℃ ultrasonic makes moltenly, and sodium chloride solution is settled to scale, 0.2 μ m filtering with microporous membrane, and embedding is in 1000 ampoule bottles.
[embodiment 3]
One, prescription
The raw material consumption
Polygonin 125.00g
Ethanol is to 5.00L
Make 1000
Two, method for making
Measure ethanol by recipe quantity, add polygonin 125.00g, 40 ℃ ultrasonic makes moltenly, and ethanol is settled to scale, 0.2 μ m filtering with microporous membrane, and embedding is in 1000 ampoule bottles.Facing the time spent is diluted to debita spissitudo with 0.9% sodium chloride injection or 5% glucose injection.
[embodiment 4]
One, prescription
The raw material consumption
Polygonin 100.00g
Propylene glycol 1.00L
Dehydrated alcohol 2.25L
Na
2CO
3-NaHCO
3Buffer is to 5.00L
Make 1000
Two, method for making
Measure the 2.25L dehydrated alcohol, add 1.00L propylene glycol and carbonate buffer solution, mixing adds polygonin 100.00g, ultrasonicly makes moltenly, and buffer is settled to scale.Cross the microporous filter membrane of 0.45 μ m, coarse filtration.Subsequent filtrate is crossed the microporous filter membrane of 0.22 μ m, and the plate and frame ultrafilter is equipped with the poly (ether sulfone) film (PES) of 10,000 molecular cut offs, depyrogenation.The embedding of brown bottle inflated with nitrogen.
[embodiment 5]
One, prescription
The raw material consumption
Polygonin 325.00g
Propylene glycol 3.00L
Dehydrated alcohol 2.00L
0.9% sodium chloride solution is to 5.00L
Make 1000
Two, method for making
Measure recipe quantity dehydrated alcohol, propylene glycol, mixing adds polygonin 325.00g, and 40 ℃ ultrasonic makes moltenly, and 0.9% sodium chloride solution is settled to scale.Cross the microporous filter membrane of 0.45 μ m, coarse filtration.Subsequent filtrate is crossed the microporous filter membrane of 0.22 μ m, and the plate and frame ultrafilter is equipped with the PES film of 10,000 molecular cut offs, depyrogenation.The embedding of brown bottle inflated with nitrogen.Facing the time spent is diluted to debita spissitudo with 0.9% sodium chloride injection or 5% glucose injection.
[embodiment 6]
One, prescription
The raw material consumption
Polygonin 500.00g
Propylene glycol 0.50L
Ethanol 3.68L
Water for injection is to 5.00L
Make 1000
Two, method for making
Measure recipe quantity ethanol, propylene glycol and water for injection, mixing adds polygonin 500.00g, and 40 ℃ ultrasonic makes moltenly, and water for injection is settled to scale.Cross the microporous filter membrane of 0.45 μ m, coarse filtration.Subsequent filtrate is crossed the microporous filter membrane of 0.22 μ m, and the plate and frame ultrafilter is equipped with the PES film of 10,000 molecular cut offs, depyrogenation.The embedding of brown bottle inflated with nitrogen.Facing the time spent is diluted to debita spissitudo with 0.9% sodium chloride injection or 5% glucose injection.
[embodiment 7]
One, prescription
The raw material consumption
Polygonin 150.00g
Propylene glycol 1.25L
Ethanol 10.50L
Glucose saline is to 25.00L
Make 100 bottles
Two, method for making
Measure recipe quantity ethanol, propylene glycol and sodium chloride glucose solution, mixing adds polygonin 150.00g, and 40 ℃ ultrasonic makes moltenly, and the sodium chloride glucose solution is settled to scale.Cross the microporous filter membrane of 0.45 μ m, coarse filtration.Subsequent filtrate is crossed the microporous filter membrane of 0.22 μ m, and the plate and frame ultrafilter is equipped with the PES film of 10,000 molecular cut offs, depyrogenation.The fill of brown bottle inflated with nitrogen.
The preparation of polygonin oral administration solution
Material: ethanol, analytical pure, Guangzhou chemical reagent two factories; Propylene glycol, analytical pure, Guangzhou chemical reagent two factories; Pure water, extra large king's industry city.
[embodiment 8]
One, prescription
The raw material consumption
Polygonin 110.00g
Propylene glycol 0.18L
Ethanol 1.16L
Pure water is to 2.00L
Be distributed into 1000
Two, method for making
Measure recipe quantity ethanol, propylene glycol and pure water, mixing adds the 110.00g polygonin, and 40 ℃ ultrasonic makes moltenly, and pure water is settled to scale.0.45 behind the μ m filtering with microporous membrane, divide to install in 1000 vials.
[embodiment 9]
One, prescription
The raw material consumption
Polygonin 120.00g
Ethanol 1.68L
Propylene glycol 0.10L
Pure water is to 2.00L
Be distributed into 1000
Two, method for making
Measure recipe quantity ethanol, propylene glycol and pure water, add the 120.00g polygonin, 40 ℃ ultrasonic makes moltenly, and pure water is settled to scale.Cross 0.45 μ m microporous filter membrane, fill.
The preparation of polygonin spray
Material: ethanol, analytical pure, Guangzhou chemical reagent two factories; Propylene glycol, analytical pure, Guangzhou chemical reagent two factories; Pure water, extra large king's industry city.
[embodiment 10]
One, prescription
The raw material consumption
Polygonin 120.00g
Ethanol 8.42L
Propylene glycol 1.00L
Pure water is to 20.00L
Be distributed into 1000
Two, method for making
Measure recipe quantity ethanol, propylene glycol, add an amount of pure water, mixing adds the 120.00g polygonin, and 40 ℃ ultrasonic makes moltenly, and pure water is settled to scale.Cross 0.45 μ m microporous filter membrane, coarse filtration.0.22 the filtering with microporous membrane of μ m, filtrate is irritated in soniclizer.The mist particle diameter major part can suck in alveolar bronchiole and the alveolar below 5 μ m.Be diluted to debita spissitudo with 0.9% sodium chloride injection or 5% glucose injection during use.
The preparation of polygonin aerosol
[embodiment 11]
One, material
Ethanol, analytical pure, Guangzhou chemical reagent two factories; Propylene glycol, analytical pure, Guangzhou chemical reagent two factories; Fluorine Lyons F12, Zhejiang fluorescence chemical industry company limited.
Two, prescription
The raw material consumption
Polygonin 100.00g
Propylene glycol 1.00L
Ethanol 2.25L
Freon F12 to 5000.00g
Make 1000 bottles
Three, method for making
The polygonin that takes by weighing 100.00g adds in the mixed solvent of ethanol and propylene glycol, is stirred to molten.Cross the microporous filter membrane of 0.45 μ m, coarse filtration.0.22 the filtering with microporous membrane of μ m, the fill of filtrate divided dose, sealing-in dosage valve system, and then pressurization injection F12 shake up, and promptly get the polygonin aerosol.
The dissolubility of polygonin in different solvents and mixed solvent relatively
[embodiment 12] pH is to the influence of polygonin dissolubility
One, material
Deionized water, extra large king's industry city; Sodium hydroxide, Dong Jiang, Dongguan chemical reagent company limited; Hydrochloric acid, Dong Jiang, Dongguan chemical reagent company limited.
Two, method
Regulate deionized water with 0.2N sodium hydroxide and 0.2N hydrochloric acid solution, making pH is 5.0～12.0.Precision is measured each 20ml of above-mentioned solution, adds an amount of polygonin respectively, 40 ℃ of ultrasonic 20min, the solution supersaturation, leave standstill 8 hours under the room temperature after, 0.45 μ m filtering with microporous membrane, this filtrate is the saturated solution of polygonin in different pH value aqueous solutions.Reference literature 20 (Wu Ye etc., the HPLC method is measured the content of polidatin, hesperidin in the clearing gallbladder capsule, Chinese patent medicine, 1999,21 (5): 226) employing HPLC method is measured the polygonin content in the filtrate, calculates the dissolubility of polygonin.
Three, result
The result is as shown in table 1.The result shows that under the room temperature, when solvent pH value≤11.0, the dissolubility of polygonin aqueous solution all is lower than 1mg/ml; Solvent pH value 12, polygonin concentration is about 5mg/ml, but whole pH value of solution is about 10.
Table 1pH is to the influence of polygonin dissolubility
| Solvent pH | 5.0 | 6.0 | 7.0 | 8.0 | 9.0 | 10.0 | 11.0 | 12.0 |
| Dissolubility (mg/ml) | ＜0.5 | ＜0.5 | ＜0.5 | ＜0.5 | ＜0.5 | ＜0.5 | 0.7 | 4.5 |
The dissolubility of [embodiment 13] polygonin in ethanol-water solution and normal saline
One, material
Dehydrated alcohol: analytical pure, Guangzhou chemical reagent two factories; Pure water, extra large king's industry city; 0.9% sodium chloride injection, lot number C040514-092, Kelun Pharm Ind Co., Ltd., Sichuan.
Two, method
With dehydrated alcohol and pure water preparation series concentration is the ethanol water of 15%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% (v/v).Precision is measured each 20ml of ethanol water of water, dehydrated alcohol, 0.9% sodium chloride injection (normal saline) and above-mentioned series concentration, add an amount of polygonin respectively, 40 ℃ of ultrasonic 20min, the solution supersaturation, after leaving standstill 8 hours under the room temperature, 0.45 μ m filtering with microporous membrane, this filtrate are the saturated concentration of polygonin in the different concentration ethanol aqueous solution.Reference literature 20 adopts the polygonin content in the HPLC method mensuration filtrate, calculates the dissolubility of polygonin.
Three, result
The result is as shown in table 2.The result shows, under the room temperature, the dissolubility of polygonin in pure water and normal saline all is lower than 0.5mg/ml, the about 20mg/ml of dissolubility in dehydrated alcohol, highest solubility is in the ethanol water of finite concentration scope, for example, in 70% (v/v) ethanol water, the polygonin dissolubility is up to 80mg/ml.In 50%～95% ethanol water, the polygonin dissolubility all is higher than its dissolubility in dehydrated alcohol greater than 20mg/ml.The result shows that 50%～95% ethanol water has " latent solvent " effect to polygonin.
The dissolubility of table 2 polygonin in ethanol-water solution and normal saline
| Ethanol content (%) | 0 | 15 | 30 | 40 | 50 | 60 | 70 | 80 | 90 | 95 | 100 | Normal saline |
| Dissolubility (mg/ml) | ＜0.5 | 1.1 | 6.2 | 9.2 | 26.1 | 42.4 | 80.9 | 76.8 | 75.4 | 30.7 | 21.4 | ＜0.5 |
The dissolubility of [embodiment 14] polygonin in propylene glycol-aqueous solution
One, material
1,2-propylene glycol, analytical pure, Guangzhou chemical reagent two factories; Pure water, extra large king's industry city.
Two, method
Prepare the aqueous solution of propylene glycol of series concentration with propylene glycol and pure water from 20% (v/v).Precision is measured propylene glycol and above-mentioned each 20ml of series concentration solution, adds an amount of polygonin respectively, 40 ℃ of ultrasonic 20min, the solution supersaturation, after leaving standstill 8 hours under the room temperature, 0.45 μ m filtering with microporous membrane, this filtrate is the saturated concentration of polygonin in the variable concentrations aqueous solution of propylene glycol.Reference literature 20 adopts the polygonin content in the HPLC method mensuration filtrate, calculates the dissolubility of polygonin.
Three, result
The result is as shown in table 3.The result shows, under the room temperature, the dissolubility of polygonin in aqueous solution of propylene glycol be along with the increase of propylene glycol concentration in the solution, the also corresponding increase of dissolubility, the about 60mg/ml of highest solubility.In 20% aqueous solution of propylene glycol, the dissolubility of polygonin is about 3.5mg/ml, this solution instability, and room temperature was placed after 12 hours promptly has the solute polygonin to separate out.
The dissolubility of table 3 polygonin in propylene glycol-aqueous solution
| Content of propylene glycol (%) | 20 | 35 | 50 | 65 | 80 | 100 |
| Dissolubility (mg/ml) | 3.5 | 4.9 | 24.4 | 28.3 | 33.6 | 60.2 |
The dissolubility of [embodiment 15] polygonin in ethanol-propylene glycol-water mixed solvent
One, material
Dehydrated alcohol, analytical pure, Guangzhou chemical reagent two factories; 1,2-propylene glycol, analytical pure, Guangzhou chemical reagent two factories; Pure water, extra large king's industry city.
Two, method
Precision is measured the ethanol water of 45%, 60%, 75% (v/v), the accurate propylene glycol that adds of 10: 1 by volume, 10: 2,10: 2.5,10: 3,10: 4 ratio, preparation mixed solvent.In the gained mixed solvent, the actual propylene glycol that contains is about 10%～30% (v/v), contains about 32%～68% (v/v) of ethanol.Precision is measured each 20ml of above-mentioned mixed solvent, adds an amount of polygonin respectively, 40 ℃ of ultrasonic 20min, the solution supersaturation, leave standstill 8 hours under the room temperature after, 0.45 μ m filtering with microporous membrane, this filtrate is the saturated concentration of polygonin in different mixed solutions.Reference literature 20 adopts the polygonin content in the HPLC method mensuration filtrate, calculates the dissolubility of polygonin.
Three, result
The result is as shown in table 4.The result shows, (1) mixed solvent of preparing according to a certain percentage with 60%, 75% alcohol-water and propylene glycol, dissolubility to polygonin both had been higher than the preceding ethanol-water solution of mixing, also be higher than the single solvent propylene glycol, that is to say, for alcohol-water and propylene glycol, the mixed solvent of certain proportion scope has " latent solvent " effect to polygonin.(2) (adopt ethanol in view of the general specification in this area as solvent for injection, about 50% (the Zhao Xinxian chief editor of its maximum concentration, " Chinese medicine ", Guangdong science and technology publishing house, 2000:p128), preferably prepare mixed solvent with 60% alcohol-water and propylene glycol according to 10: 2.0～10: 4.0 ratio, alcoholic acid actual content all is not more than 50% in the solution at this moment, and the concentration of polygonin all is higher than 60mg/ml.
The dissolubility of table 4 polygonin in ethanol-propylene glycol-water mixed solvent
Annotate: (1) * does not contain propylene glycol; (2) dissolubility of polygonin in propylene glycol is about 60mg/ml
The stability study of polydatin medicinal composition
The present invention further investigates the stability of polydatin medicinal composition, the stability when observing solution and placing in the cold director phase, the stability of observing solution when being diluted to drug effect concentration with 0.9% sodium chloride injection or 5% glucose injection simultaneously.Result of the test shows that 60% alcoholic solution and propylene glycol are with about 10: 2.5 ratio preparation mixed solvent, the optimal stability of polydatin medicinal composition.
The stability of the polydatin medicinal composition of [embodiment 16] distinct methods preparation relatively
One, material
Sample 1: the polygonin injection, according to the method preparation of embodiment 3;
Sample 2: the polygonin injection, according to the method preparation of embodiment 4;
Sample 3: the contrast injection, according to the embodiment 1-1 preparation of Chinese patent application 02134928.2;
Sample 4: the contrast injection, according to the embodiment 1-2 preparation of Chinese patent application 02134928.2.
(the embodiment 1-1 of Chinese patent application 02134928.2 and the injection formula of 1-2 are as follows respectively:
Embodiment 1-1: polygonin 40g, the NaOH aqueous solution 8L of pH8.5,3.6% NaCl aqueous solution is diluted to 10L, is distributed into 1000 then.
Embodiment 1-2: polygonin 80g, the NaOH aqueous solution 6L of pH8.5, propylene glycol 2L, tween 50ml, 3.6% NaCl aqueous solution is diluted to 10L, is distributed into 1000 then.)
Two, method
Above-mentioned four kinds of samples were placed for 1 week in 4 ℃ of refrigerators, taken out sample then, observation has or not solute to separate out; Get above-mentioned sample an amount of (being equivalent to polygonin 100mg) respectively, add in the 100ml 0.9%NaCl injection, room temperature was placed 3 hours, observed to have or not solute to separate out.
Three, result
The result is as shown in table 5.The result shows 1) sample 1 and 2 is positioned over 4 ℃ of environment for a long time and can keeps solution-stabilized, and sample 3 and 4 is positioned over the crystalline solid that 4 ℃ of environment are separated out the active component polygonin for a long time; 2) sample 1 and 2 is diluted in the 0.9%NaCl injection with 5: 100 (v/v), and room temperature can keep solution-stabilized more than placing 3hr; And sample 3 and 4 dilutes with the same terms, the solution instability, and active component is separated out.
The stability of the polydatin medicinal composition of table 5 distinct methods preparation relatively
| The placement condition | Sample 1 | Sample 2 | |
Sample 4 |
| Stock solution placed for 1 week for 4 ℃ | - | - | + | + |
| Be diluted in 0.9%NaCl injection room temperature and place 3hr | - | - | + | + |
Annotate :-: no crystal is separated out; +: there is crystal to separate out
The polydatin medicinal composition low tempertaure storage study on the stability of [embodiment 17] distinct methods preparation
One, material
Sample 1～6: the polygonin injection, according to the method preparation of embodiment 13, the concentration of etoh solvent-water is respectively 50%, 60%, 70%, 80%, 90%, 95%;
Sample 7～10: the polygonin injection, according to the method preparation of embodiment 14, the concentration of solvent propylene glycol-water is respectively 50%, 65%, 80%, 100%;
Sample 11～26: the polygonin injection, according to the preparation of the method for embodiment 15, mixed solvent respectively with 45%, 60%, 75% alcohol-water/10: 1.0～10: 4.0 ratio of propylene glycol preparation.
Two, method
Above-mentioned sample solution is positioned over 1 week in 4 ℃ of refrigerators, and observation has or not solute to separate out.
Three, result
The result is as shown in table 6.The result shows that with the sample solution of alcohol-water and mixed solvent preparation, low tempertaure storage is stable; And with the sample solution of propylene glycol-water preparation only under propylene glycol high concentration condition (〉=80%) can keep solution-stabilized.
The stability of the polydatin medicinal composition of table 6 distinct methods preparation relatively
| The placement condition | Sample 1～6 | Sample 7,8 | Sample 9,10 | Sample 11～26 |
| Placed for 1 week for 4 ℃ | - | + | - | - |
[annotate :-: no crystal is separated out; +: have crystal to separate out]
Compatibility (dilution) stability study of the polydatin medicinal composition of [embodiment 18] distinct methods preparation
One, material
According to embodiment 15, respectively with 45%, 60%, the ratio preparation mixed solvent of 75% alcohol-water/propylene glycol 10/1,10/2,10/2.5,10/3,10/4, the preparation sample solution.In addition, according to embodiment 13,14, be that solvent prepares sample solution with 40%～95% alcohol-water and 50%～100% propylene glycol-water respectively.
Two, method
Get above-mentioned sample solution an amount of (being equivalent to polygonin 100mg approximately) respectively, add respectively in 100ml and the 250ml 0.9%NaCl injection, leave standstill 3hr, observation has or not solute to separate out.The compatibility solution that no solute is separated out is placed 3hr in 4 ℃ of refrigerators, continues to observe.
Three, result
The result is as shown in table 7.Result of the test shows 1) sample solution of alcohol-water or water-ethanol-mixed with propylene glycol solvent preparation, with 100ml and 250ml 0.9% sodium chloride solution (normal saline) dilution, compatibility is solution-stabilized, clear and bright; And the sample solution of variable concentrations propylene glycol-aqueous solution preparation is separated out a large amount of precipitations, compatibility solution instability immediately behind the compatibility; 2) compatibility solution low tempertaure storage (4 ℃) is investigated, and the compatibility stability of mixed solvent is better than the single solvent alcohol-water; 3) the configuration proportion difference of mixed solvent, the compatibility stability of sample solution is distinguished to some extent, and is wherein better with the mixed solvent of 60%, 75% alcohol-water preparation.Illustrate that the polygonin injection of ethanol-water solution or a certain proportion of water-ethanol-mixed with propylene glycol solvent preparation can reach routine clinical compatibility requirement, and concentration of alcohol 〉=60% of preferred mixed solvent.
The compatibility stability of table 7-1 polydatin medicinal composition is (being diluted in 100ml 0.9%NaCl injection) relatively
The compatibility stability of table 7-2 polydatin medicinal composition is (being diluted in 250ml 0.9%NaCl injection) relatively
[annotate :-: no crystal is separated out; +: there is crystal to separate out; *: leave standstill between 3～6hr, have micro-crystal to separate out; #: low tempertaure storage (4 ℃) has micro-crystal to separate out]
The polydatin medicinal composition of [embodiment 19] mixed solvent preparation join the comparative study of thing stability
One, material
The polygonin injection: according to 60% alcohol-water and 10: 2.0,10: 2.5,10: 3.0,10: 4.0 ratio of propylene glycol preparation mixed solvent, the metering of preparation unit contains the sample solution 5ml of polygonin 100mg respectively.
Two, method
With above-mentioned sample solution, be diluted in 100ml 0.9%NaCl injection, observe the stability of compatibility solution.
Three, result
The result is as shown in table 8.The result shows that mixed solvent is the polygonin injection of 60% alcohol-water/propylene glycol (V/V) preparation in 10: 2.5, compatibility stability the best.In view of the general specification in this area (adopts ethanol as solvent for injection, about 50% (Zhao Xinxian chief editor, " Chinese medicine ", the Guangdong science and technology publishing house of its maximum concentration, 2000:p128), with the tool clinical value of the polygonin injection of this ratio preparation.
The compatibility stability of the polydatin medicinal composition of table 8 different proportion mixed solvent preparation relatively
| The mixed solvent ratio | 10∶2.0 | 10∶2.5 | 10∶3.0 | 10∶4.0 |
| The compatibility stability of solution | 〉=2 weeks | 〉=4 weeks | 〉=2 weeks | ～1 week |
The pharmacodynamic study of polydatin medicinal composition
[embodiment 20] polydatin medicinal composition to the dog hemorrhagic shock therapeutical effect
One, test material
1, test sample
Polygonin injection: according to embodiment 4 preparations.
The injection normal saline: Anhui Huayuan Biological Pharmaceutical Industry Co., Ltd. produces, lot number 2003021203.
2, reference substance
Injection sample: Mingxing Pharmaceuticals Co., Ltd., Guangzhou City produces, lot number MC3105.
3, experimental animal
The Beagle dog: No.1 Military Medical Univ. animal provides, the quality certification number 001321, and credit number SYXK (Guangdong) 2003-0007, male and female are regardless of, body weight 8～12kg.
Two, test method
1, anesthesia and operation
After animal is weighed, anaesthetize with 3% pentobarbital sodium 1.0ml/kg intravenous injection.After the anesthesia, animal lies on the back fixing, the tracheal intubation of passing through.Separate bilateral femoral arterial and one-sided femoral vein, vascular catheterization.Arterial cannulation is respectively applied for recording blood pressure and blood-letting, and venous cannulation is used for administration and feeds back liquid.
2, hemorrhagic dogs Preparation of model
Observe and write down normal arterial pressure, the respiratory frequency of animal before the blood-letting, by recording ecg accurate recording heart rate.Open the switch that a side femoral arteriography communicates with blank infusion bottle, make in blood flows in the sterilization infusion bottle that heparin-saline is housed naturally, make mean arterial pressure drop to 40mmHg at 15min, by regulating the blood volume of emitting in the infusion bottle, make mean arterial pressure maintain this horizontal 120min (according to the average botal blood volume of dog is that 94.1ml/kg calculates, blood loss account for botal blood volume 60%).Then according to grouping administration processing respectively, 120min angular vein dropleting medicine-feeding finishes, continue to observe every index 120min, extract each pipeline, skin suture, the record animals survived time (the longest observation of time-to-live 7 days, the survival more than 7 days the person be considered as long-term surviving, its time-to-live calculates with 168hr).Operation and experimentation guarantee the sterile working, and experimentation notes keeping the body temperature of animal at 37 ℃.
3, dosage and method
Dosage: three dosage groups of polygonin injection dosage is respectively 1.8,3.0 and 5.0mg/kg, and the dosage of matched group dopamine is 3.0mg/kg.
Medication: will be subjected to the reagent thing to be diluted in the normal saline that capacity is 1/3 blood loss the administration of 120min continuous intravenous infusion.
4, observation index
Experimental observation arteriotony, heart rate and respiratory frequency, and observe animals survived time and different period survival rates.The observing time of every index for 30,60,90 and 120min in normal, shock back 0,60 and 120min, the administration process and administration finish after 0,30,60,90 and 120min.
Three, result of the test
1, the polygonin injection is to the influence of hemorrhagic dogs blood pressure
The results are shown in Figure 1, the result shows, compares with blank group and dopamine treatment group, high dose (5.0mg/kg) polygonin treatment can be kept the blood pressure of dog after the acute bleeding, blood pressure recovers very fast behind the begin treatment, and amplitude increases, and finishes to treat in back two hours and still keeps higher level.
2, the polygonin injection is to the influence of hemorrhagic dogs pulse pressure difference
The results are shown in Figure 2.The result shows, the polygonin injection is handled after the dog hemorrhagic shock, can partly recover the pulse pressure difference that reduces because of acute bleeding, makes pulse pressure return to normal level gradually, still maintains higher level after stopping to feed back liquid.Though the blank group is identical with the polygonin group with the trend that dopamine treatment group pulse pressure difference changes, the amplitude that raises is starkly lower than the polygonin group.
3, the variation of different group time-to-live of hemorrhagic dogs and survival rate
The results are shown in Table 9 and table 10.The result shows, compares with the blank group, and the time-to-live of the polygonin treatment group of each dosage all prolongs, and the day part survival rate also increases; In every group of 5 experimental animals, the blank group has only 1 survival, and the survival number of polygonin 1.8mg/kg treatment group is 3, and the survival number of other two dosage groups all is 4; The survival number of the dopamine treatment group then polygonin group with lowest dose level is identical.
The time-to-live of table 9 hemorrhagic dogs relatively
Annotate: the time-to-live of long-term surviving (survival is more than 7 days) animal calculated with 168 hours.
Table 10 hemorrhagic dogs time-to-live and different period survival rate be (only/5) relatively
Four, conclusion (of pressure testing)
Above-mentioned results of pharmacodynamic test shows, compare with the dopamine positive drug control group with the blank group, the polygonin injection has the obvious treatment effect to hemorrhagic dogs, significantly improve 24hr, 48hr and the long-term surviving rate of shock back animal, its curative effect to shock is better than positive control medicine dopamine.
More than the description of better embodiment of the present invention is not limited the present invention, those skilled in the art can make various changes or distortion according to the present invention, only otherwise break away from spirit of the present invention, all should belong to the scope of claims of the present invention.
Claims (9)
1. a pharmaceutical composition that contains polygonin comprises polygonin, and the solvent that is used to dissolve polygonin, it is characterized in that, and by volume, described solvent comprises 40%～95% ethanol, 0%～60% propylene glycol, and the water of surplus.
2. the described pharmaceutical composition of claim 1 is characterized in that, the concentration of described polygonin in described solvent is 6mg～150mg/ml.
3. the described pharmaceutical composition of claim 2 is characterized in that, the concentration of described polygonin in described solvent is 20mg～100mg/ml.
4. the described pharmaceutical composition of claim 1 is characterized in that, by volume, and described solvent comprises 50～80% ethanol, 0～50% propylene glycol, and the water of surplus.
5. the described pharmaceutical composition of claim 1 is characterized in that, by volume, and described solvent comprises 40～80% ethanol, 5～60% propylene glycol, and the water of surplus.
6. the described pharmaceutical composition of claim 5 is characterized in that, by volume, and described solvent comprises 40%～60% ethanol, 10～30% propylene glycol, and the water of surplus.
7. the described pharmaceutical composition of claim 6 is characterized in that, by volume, and described solvent comprises 45% ethanol, 20% propylene glycol, and the water of surplus.
8. the described pharmaceutical composition of one of claim 1～7 is characterized in that, described water is purified water, water for injection.
9. the described pharmaceutical composition of claim 1 is characterized in that, described pharmaceutical composition is injection, oral administration solution, spray or aerosol.
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| CN1403088A (en) * | 2002-10-08 | 2003-03-19 | 深圳海王药业有限公司 | Medicine composition containing polydatin or its salt and its use in preparing medicine |
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| CN1150026A (en) * | 1995-11-14 | 1997-05-21 | 随泽民 | External use arosol of giant knotweed rhizome for burn and scald |
| CN1403088A (en) * | 2002-10-08 | 2003-03-19 | 深圳海王药业有限公司 | Medicine composition containing polydatin or its salt and its use in preparing medicine |
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