CN1823789A - Oryzanol composition and its preparation method - Google Patents
Oryzanol composition and its preparation method Download PDFInfo
- Publication number
- CN1823789A CN1823789A CN 200510132221 CN200510132221A CN1823789A CN 1823789 A CN1823789 A CN 1823789A CN 200510132221 CN200510132221 CN 200510132221 CN 200510132221 A CN200510132221 A CN 200510132221A CN 1823789 A CN1823789 A CN 1823789A
- Authority
- CN
- China
- Prior art keywords
- compositions
- injection
- phospholipid
- oryzanol
- cholate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
A thiaminogen composition in the form of injection or freeze-dried powder injection is prepared from the thiaminogen, surfactant, the water for injection and selective excipient.
Description
Technical field
The present invention relates to oryzanol composition, specifically, but relate to oryzanol composition of used for intravenous injection and preparation method thereof.
Background technology
Oryzanol (oryzanol) is several triterpene alcohol that propose from Testa oryzae oil and the Gamma OZ of sterol, it can adjust the diencephalon function, and can activate hypothalamus relevant and cerebral limbic system with autonomic nervous system, can improve autonomic imbalance, symptoms such as incretion balance obstacle and spiritual nervous disorder, so can treat the multiple disease relevant with autonomic imbalance, as to periodic psychosis, the injury of head syndrome, menopausal syndrome, pre-menstrual period nercousness, vascular headache and based on the diseases such as neurosis of autonomic imbalance all has certain curative effect.
Because of oryzanol is insoluble in water, and easily oxidation, can't be made into stable injection of aqueous solution so far.Clinical main application be oral formulations, should not be absorbed by the body, so curative effect is not remarkable.It is the oryzanol injection of solvent with vegetable oil that Chinese patent CN00123428 has disclosed a kind of, has improved bioavailability, and clinical efficacy obviously is better than conventional tablet.Yet with the injection of oil as solvent, owing to be oil solution, can only intramuscular injection, exist onset slow, and drawback such as special pain during injection, the continuous intramuscular injection of needs of patients one month, enclosed mass appears in injection site easily, and patient's compliance is poor.Therefore, this area is starved of oryzanol is made the preparation with good aqueous solubility and stability.
Summary of the invention
But it is the compositions of solvent, stable intravenously administrable that the technical problem to be solved in the present invention makes oryzanol with water for injection, the toleration when improving patient's medication.The inventor is through further investigation, final finds to utilize surfactant, but oryzanol and adjuvant can be made the oryzanol composition of used for intravenous injection, addresses the above problem effectively.
But an object of the present invention is to provide the oryzanol composition of used for intravenous injection.
But the oryzanol composition of used for intravenous injection provided by the invention is the oryzanol that comprises effective dose, and the liquid infusion preparation of surfactant and water for injection.
But the oryzanol composition of used for intravenous injection provided by the invention can also be by the oryzanol that comprises effective dose, and the liquid of surfactant, excipient and water for injection, through lyophilization, and the lyophilized formulations of making.
The suitable dosage range of described oryzanol is 5mg-100mg every day, and the preferred dosage scope is 10mg-60mg every day.
Described surfactant can be cholate, phospholipid, poloxamer (poloxamer), and tween in one or more mixture.For liquid infusion preparation of the present invention, the content of described surfactant can be 0.01%～30% of composition total weight.When described compositions was lyophilized formulations, the content of surfactant described in the solution before carrying out step of freeze drying was the weight ratio 0.01%～30% that accounts for described liquor capacity.
Described surfactant can be phospholipid or phospholipid and poloxamer.
When surfactant is phospholipid or phospholipid and poloxamer, but the oryzanol composition of used for intravenous injection of the present invention also comprise the triglyceride compounds, etc. open regulator.
But the oryzanol composition of the present invention's used for intravenous injection can preferably include (by the weight ratio of compositions volume) 0.001%-10%, the more preferably oryzanol of 0.01%-5%, 0.3-15%, the more preferably phospholipid of 1-8% or phospholipid and poloxamer, 2-30%, the more preferably triglyceride compounds of 8-20%, the grade of 1.0-10% is opened the water for injection of regulator and surplus.When described compositions is lyophilized formulations, preferably include (by the weight ratio of liquor capacity) 0.001%-10% in the solution before carrying out step of freeze drying, the more preferably oryzanol of 0.01%-5%, 0.3-15%, the more preferably phospholipid of 1-8% or phospholipid and poloxamer, 2-30%, the more preferably triglyceride compounds of 8-20%, the grade of 1.0-10% is opened the water for injection of regulator and surplus.
Described phospholipid comprises soybean phospholipid, egg yolk lecithin, the egg yolk sphingomyelins, the Semen sojae atricolor sphingomyelins, hydrogenated soya phosphatide, the hydrogenation egg yolk lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidyl glycerol, phosphatidylinositols, dipalmitoyl phosphatidyl choline (DPPC), two palmityl PHOSPHATIDYL ETHANOLAMINE (DPPE), distearoyl phosphatidylcholine (DSPC), two Petiolus Trachycarpi phosphatidyl glycerol fat (DPPG), two Petiolus Trachycarpi Phosphatidylserine (DPPS), dimyristoyl phosphatidyl choline (DMPC), GLYCEROL,DIMYRISTOYL PHOSPHATIDYL (DMPG), two myristoyl PHOSPHATIDYL ETHANOLAMINE (DMPE), dilinoleoylphosphatidylcholine (DLPC), dilinoleic acid glyceride phosphatidylcholine (Dilinoleoylphosphatidylcholine, DLPC), dilinoleic acid glyceride PHOSPHATIDYL ETHANOLAMINE (DilinoleoylPhosphatidylethanolamine, DLPE), dilinoleic acid glyceride phosphatidyl glycerol (DilinoleoylPhosphatidylglycerol, DLPG) and their mixture.In the described compositions of preferred described injection formulation or in the solution of described lyophilized formulations before carrying out step of freeze drying (by the weight percent meter that accounts for described compositions or described liquor capacity), phospholipid consumption 1-5%, poloxamer consumption 0-10%; More preferably the phospholipid consumption is 1-3%, and the poloxamer consumption is 0-5%.
Described triglyceride compounds is selected from any one or more than one the mixture in long chain triglyceride, medium chain triglyceride, the structured triglyceride.Comprise vegetable oil, fish oil, Animal fat, hydrogenated vegetable oil, partially hydrogenated vegetable oil, semi-synthetic triglyceride, synthetic glycerine three esters or their mixture composition.Preferred soybean oil, Oleum Cocois, safflower oil, Semen Maydis oil, olive oil, Petiolus Trachycarpi oil, Oleum Brassicae campestris, Oleum Arachidis hypogaeae semen, sunflower oil, Oleum sesami, Oleum Camelliae, Oleum Ricini, Oleum Gossypii semen, castor oil hydrogenated, hydrogenated coconut oil, partially hydrogenated soybean oil, triolein, linolein, trilinolenin, medium chain length fatty acid triglyceride, be rich in a kind of in the oil of omega-3 unsaturated fatty acid or the mixture of several compositions wherein.
Described grade is opened regulator and is selected from glycerol for injection, sorbitol, mannitol, the glucose one or more mixture.In the described compositions of described injection formulation or in the described solution of described lyophilized formulations before carrying out step of freeze drying (by the weight percent meter that accounts for described compositions or described liquor capacity), the preferably glycerine consumption is 2.0-3.0%, the sorbitol consumption is 4.0-6.0%, the consumption of mannitol is 4.0-6.0%, and the glucose consumption is 4.0-10.0%; More preferably glycerol 2.0-2.5%, sorbitol 4.0-5.0%, mannitol 4.0-5.0%, glucose 5.0-10.0%.When waiting regulator to contain more than one above-mentioned substance, the total amount of each material should be the percentage by weight 1.0-10% of described compositions or described liquor capacity.
When surfactant is phospholipid or phospholipid and poloxamer, but the oryzanol composition of used for intravenous injection of the present invention also can comprise the second surface activating agent.The content of (by the weight percent meter that accounts for described compositions or described liquor capacity) described second surface activating agent is 0-10%, more preferably 0-5% in the described compositions of described injection formulation or in the described solution of described lyophilized formulations before carrying out step of freeze drying.Described second surface activating agent is selected from one or more mixture in tween, polyoxyethylene castor oil, 12 hydroxy stearic acid esters of Polyethylene Glycol (trade name Solutol HS 15), Polyethylene Glycol, cholate, hydroxypropyl beta cyclodextrin, the polyvidone.
Described cholate comprises: cholic acid and salt thereof, deoxycholic acid and salt thereof, glycocholic acid and salt thereof.
Described tween can be one or more the mixture in the Tweens surfactant, for example tween 20, Tween-40, Tween-60, tween 80 or its mixture.
But the oryzanol composition of used for intravenous injection of the present invention also can further add the stabilizing agent such as oleic acid, cholesterol and/or enuatrol etc., such as vitamin C and derivant, sulfites, thio-compounds, amino acids, vitamin E and derivant thereof, butylated hydroxyarisol, di-tert-butyl hydroxy-methylbenzene, propyl gallate.
Described surfactant can be phospholipid and cholate.
When surfactant is phospholipid and cholate, in the described compositions of described injection formulation or in the described solution of described lyophilized formulations before carrying out step of freeze drying (by the weight percent meter that accounts for described compositions or described liquor capacity), the content of described phospholipid and cholate is 0.01%-30%, is preferably 0.1%-15%.The molar ratio of phospholipid and cholate is 0.1: 1-2: 1.Preferred 0.8: 1-1.5: 1.Described phospholipid is identical with the foregoing phospholipid range of definition.Described cholate is identical with the foregoing cholate range of definition.
Described surfactant can be a cholate.Described cholate is identical with the foregoing cholate range of definition.Preferred glycocholic acid of described cholate and salt thereof or deoxycholic acid and salt thereof.In the described compositions of described injection formulation or in the described solution of described lyophilized formulations before carrying out step of freeze drying (by the weight percent meter that accounts for described compositions or described liquor capacity), the content of described cholate is 0.01%-30%, more preferably 0.01%-20%, more preferably 0.1%-10%.
When surfactant is cholate, but the oryzanol composition of used for intravenous injection of the present invention also can comprise the second surface activating agent.In the described compositions of described injection formulation or in the described solution of described lyophilized formulations before carrying out step of freeze drying (by the weight percent meter that accounts for described compositions or described liquor capacity), the content of described second surface activating agent is 0-20%, more preferably 0-10%.Described second surface activating agent is selected from one or more the mixture in tween, polyoxyethylene castor oil, 12 hydroxy stearic acid esters of Polyethylene Glycol, Polyethylene Glycol, hydroxypropyl beta cyclodextrin, the polyvidone.
When surfactant is tween.Described tween is selected from tween 20, Tween-40, Tween-60, tween 80, preferred tween 80.In the described compositions of described injection formulation or in the described solution of described lyophilized formulations before carrying out step of freeze drying (by the weight percent meter that accounts for described compositions or described liquor capacity), the content of described tween is 0.01%-20%, more preferably 0.1%-5%.
When surfactant is tween, but the oryzanol composition of used for intravenous injection of the present invention also can comprise the second surface activating agent.In the described compositions of described injection formulation or in the described solution of described lyophilized formulations before carrying out step of freeze drying (by the weight percent meter that accounts for described compositions or described liquor capacity), the content of described second surface activating agent is 0-20%, more preferably 0-10%, more preferably 0-5%.Described second surface activating agent is selected from one or more the mixture in cholate, polyoxyethylene castor oil, 12 hydroxy stearic acid esters of Polyethylene Glycol, Polyethylene Glycol, hydroxypropyl beta cyclodextrin, the polyvidone.
But the oryzanol composition of used for intravenous injection provided by the invention can also be by the above-mentioned various mixed liquors of forming with excipient and water for injection, through lyophilization, and the lyophilized formulations of making.
Described excipient is conventional or becomes known for preparing lyophilized formulations, acceptable excipient pharmaceutically.Described excipient comprises one or more the mixture in the conventional or known pharmaceutically acceptable excipient of mannitol, sorbitol, lactose, glucose, sodium chloride, dextran and other.
But the oryzanol composition of used for intravenous injection provided by the invention can further include other adjuvants of pharmaceutically accepting, for example antioxidant, pH regulator agent, isoosmotic adjusting agent, stabilizing agent, antiseptic etc.Preferred antioxidant is selected from sulfites, thio-compounds, amino acids, vitamin C and derivant thereof, vitamin E and derivant thereof, butylated hydroxyarisol, di-tert-butyl hydroxy-methylbenzene, propyl gallate.
But the present invention also provides a kind of method of oryzanol composition of preparation used for intravenous injection, and it comprises:
(1) preparation contains the oil phase of triglyceride compounds, oryzanol and phospholipid or phospholipid and poloxamer;
(2) preparation be dissolved with wait to open regulator or etc. the water of a regulator and second surface activating agent;
(3) oil phase is mixed with water evenly, sterilization obtains product.
Oil phase at described (1) step gained can also further contain antioxidant and/or stabilizing agent.
In described (1) step, make the oil phase that contains triglyceride compounds, oryzanol and phospholipid or phospholipid and poloxamer according to conventional or known method and program.Triglyceride compounds, oryzanol and phospholipid or phospholipid and poloxamer can be successively with any order or adding simultaneously, mix homogeneously.Contain antioxidant and/or stabilizing agent as oil phase, can add antioxidant and/or stabilizing agent in step by step any of this step.For example, can earlier the triglyceride compounds be added in the container, oryzanol joins in the container, after heating (for example 50-150 ℃) is stirred to medicine dissolution, is cooled to 50-80 ℃ and adds phospholipid or phospholipid and poloxamer.Or earlier phospholipid or phospholipid and poloxamer are dissolved in an amount of ethanol and add (after waiting to be uniformly dispersed, ethanol is removed in decompression again).Contain antioxidant and/or stabilizing agent as oil phase, can add antioxidant, stabilizing agent after, continue to stir and to treat phospholipid or phospholipid and poloxamer dissolving, mix homogeneously forms oil phase.
In described (2) step, contain the solution of the water for injection that waits a regulator and second surface activating agent according to conventional or known method preparation.Deng open regulator and second surface activating agent can be successively with any order or add simultaneously, be dissolved in the water for injection.Contain antioxidant and/or stabilizing agent as water, can add antioxidant and/or stabilizing agent in step by step any of this step.For example, can be that an amount of water for injection is placed another container, be heated to 50-80 ℃, will wait a regulator to add wherein; Add the second surface activating agent, antioxidant and/or stabilizing agent, stirring and dissolving.
In described (3) step, according to routine or known method that oil phase is mixed with water evenly, according to conventional or known method sterilization, obtain product.Can be that it was the product of solvent that stirring, homogenize obtain with water after oil phase and water mixed.For example, under agitation pour oil phase into aqueous phase, or water is under agitation poured in the oil phase, under 50-80 ℃ of condition, formed colostrum in high-speed stirred 0.5-1 hour, regulate pH4-9 with the pH regulator agent.The colostrum that makes is carried out homogenize with high pressure homogenizer or ultrasonic probe, filter through filter, logical nitrogen, fill is sealed.The fat milk that fill is good places the rotation high-pressure sterilizing pot to carry out 100-121 ℃, the 12-30min sterilization.
The aqueous phase that preparation method of the present invention also can further be included in (2) step adds the step of conventional or known pharmaceutically acceptable excipient, and the lyophilization after the sterilization in (3) step, makes the step of lyophilized formulations.Described excipient comprises mannitol, sorbitol, lactose, glucose, sodium chloride, dextran and other conventional or known pharmaceutically acceptable excipient.
But the present invention also provides the method for the oryzanol composition of another preparation used for intravenous injection, and it comprises:
(1) preparation contains the oil phase of triglyceride compounds, oryzanol;
(2) preparation be dissolved with wait to open regulator or etc. open regulator and stabilizing agent etc. open regulator and second surface activating agent or etc. the water of a regulator and stabilizing agent and second surface activating agent and phospholipid or phospholipid and poloxamer;
(3) oil phase is mixed with water evenly, sterilization obtains product.
Oil phase at described (1) step gained can also further contain antioxidant.
In described (1) step, make the oil phase that contains triglyceride compounds, oryzanol according to conventional or known method and program.Triglyceride compounds, oryzanol can be successively with any order or adding simultaneously, mix homogeneously.Contain antioxidant as oil phase, can add antioxidant in step by step any of this step.For example, the triglyceride compounds is added in the container, oryzanol joins in the container, is heated to 50-150 ℃, and stirs, and can add or not add antioxidant, continue to stir, and mix homogeneously forms oil phase.
In described (2) step, according to conventional or known method preparation contain stabilizing agent, etc. open the solution of the water for injection of regulator, second surface activating agent and phospholipid or phospholipid and poloxamer.Stabilizing agent, etc. open regulator and second surface activating agent and phospholipid or phospholipid and poloxamer can be successively with any order or add simultaneously, be dissolved in the water for injection.For example, can be that an amount of water for injection is placed another container, be heated to 50-80 ℃, with stabilizing agent, etc. open regulator and phospholipid or phospholipid and poloxamer and add wherein; Add the second surface activating agent, stirring and dissolving.
In described (3) step, according to routine or known method that oil phase is mixed with water evenly, according to conventional or known method sterilization, obtain product.Can be that it was the product of solvent that stirring, homogenize obtain with water after oil phase and water mixed.For example, under agitation pour oil phase into aqueous phase, or water is under agitation poured in the oil phase, under 50-80 ℃ of condition, formed colostrum in high-speed stirred 0.5-1 hour, regulate pH4-9 with the pH regulator agent.The colostrum that makes is carried out homogenize with high pressure homogenizer or ultrasonic probe, under agitation add water to full dose, the check semi-finished product.Filter through filter, logical nitrogen, fill is sealed.The fat milk that fill is good places the rotation high-pressure sterilizing pot to carry out 100-121 ℃, the 12-30min sterilization.
The aqueous phase that another preparation method of the present invention also is included in (2) step adds the step of conventional or known pharmaceutically acceptable excipient, and the lyophilization after the sterilization in (3) step, makes the step of lyophilized formulations.Described excipient comprises mannitol, sorbitol, lactose, glucose, sodium chloride, dextran and other conventional or known pharmaceutically acceptable excipient.
But the present invention also provides the method for the oryzanol composition of another preparation used for intravenous injection, and it comprises:
(1) preparation contains the alcoholic solution of oryzanol, phospholipid;
(2) preparation contains the aqueous solution of cholate;
(3) with (1) step and (2) step gains mix homogeneously;
(4) add water for injection to full dose, sterilization gets product, or adds excipient, makes lyophilized formulations through Freeze Drying Technique again.
Described alcohol is conventional or known pharmaceutically acceptable alcoholic solvent, for example ethanol, propylene glycol, glycerol, benzyl alcohol, Polyethylene Glycol.Described (1) step can be that oryzanol, phospholipid are dissolved in ethanol and the benzyl alcohol with any order.Described (3) step can be that (1) step gains are under agitation added in (2) the step gains.Also can add other acceptable accessories in described (3) step.
But the present invention also provides the method for the oryzanol composition of another preparation used for intravenous injection, and it comprises:
(1) oryzanol, cholate are dissolved in the sodium hydroxide solution, regulate pH value to 5-10;
(2) in (1) step gains, add phospholipid, stirring and dissolving;
(3) add water for injection to full dose in (1) step gains, sterilization gets product, or adds excipient, makes lyophilized formulations through Freeze Drying Technique again.
Described (2) step can be phospholipid directly to be added or dissolves or be distributed in the alcoholic solution add.Described alcohol is conventional or known pharmaceutically acceptable alcoholic solvent, can be selected from ethanol, propylene glycol, glycerol, benzyl alcohol, Polyethylene Glycol.Also can add other acceptable accessories in described (3) step.
But the present invention also provides the method for the oryzanol composition of another preparation used for intravenous injection, it comprises: with oryzanol, cholate heating for dissolving in sodium hydroxide solution, regulate pH value to 5-10, add to the full amount of water for injection, sterilization, get product, or add excipient, make lyophilized formulations through Freeze Drying Technique again.Also can comprise the step that adds other acceptable accessories in the described method.
But the present invention also provides the method for the oryzanol composition of another preparation used for intravenous injection, and it comprises: the oryzanol heating for dissolving in the benzyl alcohol solution of tween, is added to the full amount of water for injection, sterilization, get product, or add excipient, make lyophilized formulations through Freeze Drying Technique again.Also can comprise the step that adds other acceptable accessories in the described method.
The present invention has solved the problem that prior art exists effectively by using surfactant.The present invention is owing to made oryzanol can solve oryzanol poor stability in aqueous solution, the problem of easily separating out for the lipomul of intravenously administrable.Directly intravenously administrable is rapid-action, has solved intramuscular injection and has been prone to local enclosed mass, the problem of pain.Preparation method is simple simultaneously, helps realizing suitability for industrialized production.The present invention has also used the cholate (BS) of the title that " physiology detergent " arranged to be ionic surfactant, and oryzanol is had stronger solubilising power.When the present invention used the kinds of surface activating agent, in the combination that has, the mixed micelle system of the mutual composite formation of surfactant had the characteristic that characteristic of solubilizing is better than single surfactant solution.Thereby oryzanol composition of the present invention, be solvent with water for injection, can intravenously administrable, the convenient use improved toleration.And the production technology simple possible, can realize suitability for industrialized production.
The specific embodiment
Below will the invention will be further described by embodiment, these descriptions are not that content of the present invention is done further to limit.One skilled in the art will understand that to be equal to replacement to what content of the present invention was done, or corresponding the improvement, still belong within protection scope of the present invention.
Embodiment 1
With injection soybean oil 30g, oryzanol 4.5g adds in the container, and this container is placed oil bath, is heated to 100 ℃, is stirred to medicine dissolution, is cooled to 80 ℃, and fabaceous lecithin 11g has high input.Vitamin E 0.1g is stirred to the phospholipid dissolving and forms even oil phase.Water for injection 80ml is placed another container, add glycerol 2.5g, form water in 80 ℃ of stirring and dissolving; Oil phase is under agitation added aqueous phase, continue to stir and made colostrum in 40 minutes, regulate pH to 8 with sodium hydroxide solution; Add the injection water to 100ml, with high pressure homogenizer or ultrasonic probe, homogenize is till the emulsion droplet particle diameter passed examination with colostrum.Filter through filter, logical nitrogen divides to be filled to the 1ml ampoule, seals.Carry out 100 ℃ with the rotation autoclave, sterilize under the condition of 30min.
The shady and cool place of the fat milk room temperature of preparation stores half a year, and significant change does not all take place for physicochemical property such as Emulsion outward appearance, particle diameter, Zeta potential, pH value and content, shows that this Emulsion is stable.The results are shown in Table 1
Table 1 Emulsion room temperature reserved sample observing result
| Time (moon) | 0 | 1 | 2 | 3 | 6 |
| Outward appearance content mean diameter (nm) surface potential (mv) pH value | Little yellow 100.5 325.1-33.7 7.31 | Little yellow 99.61 323.7-34.8 7.25 | Little yellow 99.82 326.9-33.9 7.33 | Little yellow 99.94 326.2-33.0 7.29 | Little yellow 98.86 328.6-34.0 7.24 |
Embodiment 2
Injection soybean oil 7.5g, olive oil 7.5g, oryzanol 40mg are added in the container, this container is placed oil bath, be heated to 70 ℃, be stirred to medicine dissolution, form even oil phase.Water for injection 80ml is placed another container, add egg yolk lecithin 1.5g, poloxamer 0.5g, 12 hydroxy stearic acid ester 0.5g of Polyethylene Glycol, glucose 5.0g, sodium sulfite 0.2g forms water in 70 ℃ of stirring and dissolving; Water is under agitation added in the oil phase, continue to stir and make colostrum half an hour, regulate pH to 8.5 with sodium hydroxide solution; Add the injection water to 100ml, with high pressure homogenizer or ultrasonic probe, homogenize is till the emulsion droplet particle diameter passed examination with colostrum.Filter through filter through microporous filter membrane, logical nitrogen, fill is sealed.Carry out 115 ℃ with the rotation autoclave, sterilize under the condition of 30min.
The shady and cool place of the fat milk room temperature of preparation stores half a year, and significant change does not all take place for physicochemical property such as Emulsion outward appearance, particle diameter, Zeta potential and content, shows that this Emulsion is stable.The results are shown in Table 2.
Table 2 Emulsion room temperature reserved sample observing result
| Time (moon) | 0 | 1 | 2 | 3 | 6 |
| Outward appearance content mean diameter (nm) surface potential (mv) pH value | White 99.72 278.3-41.0 7.82 | White 99.10 275.4-40.8 7.79 | White 99.35 276.9-41.5 7.80 | White 98.93 278.7-41.2 7.78 | White 98.74 280.2-40.4 7.75 |
Embodiment 3
With injection soybean oil 10g, medium chain fatty acid ester 10g, oryzanol 2g add in the container, this container is placed oil bath, be heated to 70 ℃, be stirred to medicine dissolution, 3-phosphatidylcholine 4.0g is added with ethanol 2.0ml dissolving back, volatilize ethanol, form even oil phase.Water for injection 80ml is placed another container, add sorbitol 5.0g, poloxamer 4.0g forms water in 70 ℃ of stirring and dissolving; Water is under agitation added in the oil phase, continue to stir and made colostrum in 1 hour, add the injection water, regulate pH to 7.0 with sodium hydroxide solution to 100ml; With high pressure homogenizer or ultrasonic probe, homogenize is till the emulsion droplet particle diameter passed examination with colostrum.Filter through filter, logical nitrogen divides to be filled to the 2ml ampoule, seals.Carry out 100 ℃ with the rotation autoclave, sterilize under the condition of 30min.
The shady and cool place of the fat milk room temperature of preparation stores half a year, and significant change does not all take place for physicochemical property such as Emulsion outward appearance, particle diameter, Zeta potential and content, shows that this Emulsion is stable.The results are shown in Table 3.
Table 3 Emulsion room temperature reserved sample observing result
| Time (moon) | 0 | 1 | 2 | 3 | 6 |
| Outward appearance content mean diameter (nm) surface potential (mv) pH value | Little yellow 99.65 340.2-36.1 6.70 | Little yellow 99.02 343.7-36.7 6.68 | Little yellow 99.17 342.9-35.5 6.65 | Little yellow 98.93 339.4-36.2 6.69 | Little yellow 98.70 340.9-35.8 6.63 |
Embodiment 4
With injection Oleum Camelliae 15g, oryzanol 0.4g adds in the container, and this container is placed oil bath, is heated to 120 ℃, is stirred to medicine dissolution, is cooled to 80 ℃, and the fabaceous lecithin 1.8g that has high input, is stirred to the phospholipid dissolving and forms even oil phase oleic acid 0.2g.Water for injection 80ml is placed another container, add glycerol 2.25g, sodium cholate 8.0g forms water in 80 ℃ of stirring and dissolving; Oil phase is under agitation added aqueous phase, continue to stir and made colostrum in 50 minutes, regulate pH to 8; Add the injection water to 100ml, with high pressure homogenizer or ultrasonic probe, homogenize is till the emulsion droplet particle diameter passed examination with colostrum.Filter through filter, logical nitrogen divides to be filled to the 10ml ampoule, seals.Carry out 115 ℃ with the rotation autoclave, sterilize under the condition of 20min.
The shady and cool place of the fat milk room temperature of preparation stores half a year, and significant change does not all take place for physicochemical property such as Emulsion outward appearance, particle diameter, Zeta potential and content, shows that this Emulsion is stable.The results are shown in Table 4.
Table 4 Emulsion room temperature reserved sample observing result
| Time (moon) | 0 | 1 | 2 | 3 | 6 |
| Outward appearance content mean diameter (nm) surface potential (mv) pH value | Little yellow 100.1 290.7-39.6 7.56 | Little yellow 99.70 288.5-39.3 7.60 | Little yellow 99.25 289.3-39.8 7.59 | Little yellow 99.78 292.1-39.0 7.54 | Little yellow 98.97 291.8-39.2 7.50 |
Embodiment 5
With injection soybean oil 5g, safflower oil 5g, oryzanol 0.1g adds in the container, and this container is placed oil bath, is heated to 140 ℃, is stirred to medicine dissolution, is cooled to 80 ℃, drops into egg yolk lecithin 1.5g, is stirred to the phospholipid dissolving and forms even oil phase.Water for injection 80ml is placed another container, add mannitol 5.0g, form water in 80 ℃ of stirring and dissolving; Oil phase is under agitation added aqueous phase, continue to stir and made colostrum in 1 hour, regulate pH to 7; Add the injection water to 100ml, with high pressure homogenizer or ultrasonic probe, homogenize is till the emulsion droplet particle diameter passed examination with colostrum.After filter filters, divide to be filled to cillin bottle.Lyophilized preparation is made in lyophilization.Add 5% glucose or 0.9% sodium chloride during use, used for intravenous injection.
Embodiment 6
With injection soybean oil 30g, oryzanol 8.5g, soybean phospholipid 11g, oleic acid 0.2g, vitamin E 0.1g add in the container, and this container is placed oil bath, are heated to medicine dissolution, continue to be stirred to the phospholipid dissolving and form even oil phase.Water for injection 80ml is placed another container, add glycerol 2.25g, form water in 80 ℃ of stirring and dissolving; Oil phase is under agitation added aqueous phase, continue to stir and made colostrum in 30 minutes, regulate pH to 8 with sodium hydroxide solution; Add the injection water to 100ml, with high pressure homogenizer or ultrasonic probe, homogenize is till the emulsion droplet particle diameter passed examination with colostrum.Filter through filter, logical nitrogen, fill is sealed in the 1ml ampoule.With 100 ℃, the 30min flowing steam sterilization.
The shady and cool place of the fat milk room temperature of preparation stores half a year, and significant change does not all take place for physicochemical property such as Emulsion outward appearance, particle diameter, Zeta potential, pH value and content, shows that this Emulsion is stable.The results are shown in Table 5
Table 5 Emulsion room temperature reserved sample observing result
| Time (moon) | 0 | 1 | 2 | 3 | 6 |
| Outward appearance content mean diameter (nm) surface potential (mv) pH value | Little yellow 99.20 543.8-30.9 7.58 | Little yellow 98.35 551.0-31.5 7.45 | Little yellow 99.08 548.3-30.3 7.49 | Little yellow 99.36 556.1-29.5 7.42 | Little yellow 98.29 561.8-30.2 7.53 |
Embodiment 7
Oryzanol 200mg
Deoxycholic acid 2.5g
Thioglycerol 10mg
Water for injection is to 10ml
Oryzanol and deoxycholic acid heating for dissolving in the sodium hydroxide solution of 5mol/L, with the anti-pH to 7.0 that transfers of 1mol/L hydrochloric acid, are added the thioglycerol stirring and dissolving, add to the full amount of water for injection.Adding 0.1% injection active carbon stirred 30 minutes.Behind the decarbonization filtering, 0.45 μ m microporous filter membrane fine straining divides to be filled in the 1ml ampoule, 100 ℃ of 30min flowing steam sterilizations, promptly.
Embodiment 8
Oryzanol 40mg
Deoxycholic acid 0.5g
Tween 80 0.5g
Water for injection is to 10ml
Oryzanol and deoxycholic acid heating for dissolving in the sodium hydroxide solution of 5mol/L, with the anti-pH to 7.0 that transfers of 1mol/L hydrochloric acid, are added the Tween 80 stirring and dissolving, add to the full amount of water for injection.Adding 0.1% injection active carbon stirred 30 minutes.Behind the decarbonization filtering, 0.45 μ m microporous filter membrane fine straining, fill to ampoule, 100 ℃ of 30min flowing steam sterilizations, promptly.
Embodiment 9
Oryzanol 50mg
Deoxycholic acid 0.5g
Hydroxypropyl beta cyclodextrin 0.9g
Water for injection is to 10ml
Oryzanol and deoxycholic acid heating for dissolving in the sodium hydroxide solution of 5mol/L, with the anti-pH to 7.0 that transfers of 1mol/L hydrochloric acid, are added the hydroxypropyl beta cyclodextrin stirring and dissolving, add to the full amount of water for injection.Adding 0.1% injection active carbon stirred 30 minutes.Behind the decarbonization filtering, 0.45 μ m microporous filter membrane fine straining, fill to ampoule, 100 ℃ of 30min flowing steam sterilizations, promptly.
Embodiment 10
Oryzanol 10mg
Glycocholic acid 0.3g
Hydroxypropyl beta cyclodextrin 0.05g
Sodium pyrosulfite 5mg
Water for injection is to 500ml
Oryzanol and glycocholic acid heating for dissolving in the sodium hydroxide solution of 5mol/L, with the anti-pH to 7.0 that transfers of 1mol/L hydrochloric acid, are added the sodium pyrosulfite stirring and dissolving, add to the full amount of water for injection.Adding 0.05% injection active carbon stirred 30 minutes.Behind the decarbonization filtering, 0.45 μ m microporous filter membrane fine straining, fill to infusion bottle, 121 ℃, the 20min pressure sterilizing, promptly
Embodiment 11
Oryzanol 100mg
NaTDC 1.5g
Phosphatidase 10 .5g
Benzyl alcohol 0.2g
Ethanol 0.2g
Water for injection is to 10ml
Oryzanol and lecithin heating for dissolving in benzyl alcohol and ethanol, are dissolved in NaTDC in the water for injection.Under agitation oryzanol solution is added in 80 ℃ of deoxycholic acid sodium water solutions, add 80 ℃ of waters for injection to full dose.Adding 0.1% injection active carbon stirred 30 minutes.Behind the decarbonization filtering, 0.45 μ m microporous filter membrane fine straining, fill to ampoule, 100 ℃ of 30min flowing steam sterilizations, promptly
Embodiment 12
Oryzanol 5mg
Cholic acid 0.15g
Phosphatidase 12 0mg
Vitamin E 5mg
Water for injection is to 10ml
Oryzanol and cholic acid heating for dissolving in the sodium hydroxide solution of 5mol/L, with the anti-pH to 7.0 that transfers of 1mol/L hydrochloric acid, are added phospholipid, vitamin E stirring and dissolving, add to the full amount of water for injection.Adding 0.05% injection active carbon stirred 30 minutes.Behind the decarbonization filtering, 0.22 μ m microporous filter membrane fine straining degerming, fill to cillin bottle, technology lyophilization routinely, promptly.
Embodiment 13
Oryzanol 250mg
Deoxycholic acid 2.5g
Phosphatidase 10 .3g
Ethanol 0.25ml
Vitamin C 15mg
Water for injection is to 10ml
Oryzanol and deoxycholic acid heating for dissolving in the sodium hydroxide solution of 5mol/L, are added the vitamin C stirring and dissolving, phospholipid is added after with dissolve with ethanol, add to the full amount of water for injection.Adding 0.1% injection active carbon stirred 30 minutes.Behind the decarbonization filtering, 0.45 μ m microporous filter membrane fine straining divides to be filled in the 2ml ampoule, 100 ℃ of 30min flowing steam sterilizations, promptly.
Embodiment 14
Oryzanol 20mg
Tween 80 0.4g
Benzyl alcohol 0.15g
Polyethylene Glycol 2g
Water for injection is to 10ml
The oryzanol heating for dissolving in the mixture of Tween 80 and benzyl alcohol, is added Polyethylene Glycol, and heating water for injection adds 0.1% injection active carbon and stirred 30 minutes to full dose.Behind the decarbonization filtering, 0.45 μ m microporous filter membrane fine straining divides to be filled in the ampoule, 100 ℃ of 30min flowing steam sterilizations, promptly.
Embodiment 15
Oryzanol 150mg
Tween 80 2.0g
NaGC 4mg
Sodium sulfite 10mg
Benzyl alcohol 1.2g
Triethanolamine 0.5ml
Water for injection is to 10ml
The oryzanol heating for dissolving in the mixture of Tween 80 and benzyl alcohol, is added triethanolamine, sodium sulfite, NaGC are added after with water dissolution, heating water for injection adds 0.1% injection active carbon and stirred 30 minutes to full dose.Behind the decarbonization filtering, 0.45 μ m microporous filter membrane fine straining divides to be filled in the 2ml ampoule, 100 ℃ of 30min flowing steam sterilizations, promptly.
Embodiment 16
Oryzanol 10mg
Tween 80 0.2g
Benzyl alcohol 0.1g
Hydroxypropyl beta cyclodextrin 0.4g
Water for injection is to 10ml
The oryzanol heating for dissolving in the mixture of Tween 80 and benzyl alcohol, is added hydroxypropyl beta cyclodextrin with water for injection dissolving back, heating water for injection adds 0.1% injection active carbon and stirred 30 minutes to full dose.Behind the decarbonization filtering, 0.45 μ m microporous filter membrane fine straining, fill to ampoule, 100 ℃ of 30min flowing steam sterilizations, promptly.
Embodiment 17
The pharmacodynamic study result who adopts injection of the present invention to carry out is as follows:
1. injection 0.5-10mg/kg/ day of the present invention quiet notes can reduce obviously that oxytocin causes uterine contraction rat pain reaction turn round the body number of times;
2. injection 0.5-10mg/kg/ day of the present invention, quiet notes can obviously reduce the autonomic activities number of times of hot flushes in rats;
3. injection 1-10mg/kg/ day of the present invention, quiet notes can obviously increase the weight in climacteric rat model uterus, obviously promote climacteric rat model vagina, endometrium adenomatosis, promote vagina, uterine epithelial cell keratinization, promote that the cellular morphology trend is normal.
4. injection 1.5-15mg/kg/ day of the present invention the quiet notes keratinization that can promote to pluck ovary mouse vagina cell.
Annotate: rat 0.5-10mg/kg is equivalent to people's consumption 5-100mg/ people approximately.Mice 1.5-15mg/kg is equivalent to people's consumption 10-100mg/ people approximately
Above-mentioned pharmacodynamics test shows: injection of the present invention has the antagonism uterine contraction, and relieving dysmenorrhea improves the pharmacological action of climacteric syndrome, and its effective dose is that scope is 5mg-100mg every day.
Claims (42)
- But 1, a kind of oryzanol composition of used for intravenous injection, it is characterized in that comprising effective dose oryzanol and and pharmaceutically acceptable surfactant, described compositions is injection or lyophilized formulations.
- 2, compositions as claimed in claim 1 is characterized in that described surfactant is one or more the mixture in cholate, phospholipid, poloxamer, the tween.
- 3, compositions as claimed in claim 2, it is characterized in that described phospholipid comprises soybean phospholipid, egg yolk lecithin, the egg yolk sphingomyelins, the Semen sojae atricolor sphingomyelins, hydrogenated soya phosphatide, the hydrogenation egg yolk lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidyl glycerol, phosphatidylinositols, dipalmitoyl phosphatidyl choline (DPPC), two palmityl PHOSPHATIDYL ETHANOLAMINE (DPPE), distearoyl phosphatidylcholine (DSPC), two Petiolus Trachycarpi phosphatidyl glycerol fat (DPPG), two Petiolus Trachycarpi Phosphatidylserine (DPPS), dimyristoyl phosphatidyl choline (DMPC), GLYCEROL,DIMYRISTOYL PHOSPHATIDYL (DMPG), two myristoyl PHOSPHATIDYL ETHANOLAMINE (DMPE), dilinoleoylphosphatidylcholine (DLPC), dilinoleic acid glyceride phosphatidylcholine (Dilinoleoylphosphatidylcholine, DLPC), dilinoleic acid glyceride PHOSPHATIDYL ETHANOLAMINE (DilinoleoylPhosphatidylethanolamine, DLPE), dilinoleic acid glyceride phosphatidyl glycerol (DilinoleoylPhosphatidylglycerol, DLPG) in one or more mixture; Described cholate comprises one or more the mixture in cholic acid and salt, deoxycholic acid and salt thereof, glycocholic acid and the salt thereof.
- 4, compositions as claimed in claim 1 or 2, it is characterized in that in the described compositions of described injection formulation or in the solution of described lyophilized formulations before carrying out step of freeze drying, the content of described surfactant is the weight ratio 0.01%-30% that accounts for described compositions or described liquor capacity.
- 5, compositions as claimed in claim 1 is characterized in that described surfactant is phospholipid or phospholipid and poloxamer.
- 6, compositions as claimed in claim 5, it is characterized in that described compositions also comprise the triglyceride compounds, etc. open regulator.
- 7, compositions as claimed in claim 6, it is characterized in that in the described compositions of described injection formulation or in the solution of described lyophilized formulations before carrying out step of freeze drying, contain (by the weight ratio that accounts for described compositions or described liquor capacity) oryzanol of 0.001%-10%, the phospholipid of 0.3-15% or phospholipid and poloxamer, 2-30% triglyceride compounds, 1.0-10% etc. open the water for injection of regulator and surplus.
- 8, compositions as claimed in claim 7 is characterized in that in the described compositions of described injection formulation or the content of oryzanol described in the described solution of described lyophilized formulations before carrying out step of freeze drying is that the content of 1-5%, poloxamer is that 0-10%, triglyceride kind compound content are 8-20% for the content of (by the weight percent meter that accounts for described compositions or described liquor capacity) 0.01%-5%, phospholipid.
- 9, as one of any described compositions in the claim 6 to 8, it is characterized in that described triglyceride compounds is selected from any one or more than one the mixture in long chain triglyceride, medium chain triglyceride and the structured triglyceride.
- 10, compositions as claimed in claim 6 is characterized in that described triglyceride compounds comprises that one or more the mixture in vegetable oil, fish oil, Animal fat, hydrogenated vegetable oil, partially hydrogenated vegetable oil, semi-synthetic triglyceride and synthetic glycerine three esters forms.
- 11, compositions as claimed in claim 10 is characterized in that described triglyceride compounds is soybean oil, Oleum Cocois, safflower oil, Semen Maydis oil, olive oil, Petiolus Trachycarpi oil, Oleum Brassicae campestris, Oleum Arachidis hypogaeae semen, sunflower oil, Oleum sesami, Oleum Camelliae, Oleum Ricini, Oleum Gossypii semen, castor oil hydrogenated, hydrogenated coconut oil, partially hydrogenated soybean oil, triolein, linolein, trilinolenin, medium chain length fatty acid triglyceride, is rich in a kind of in the oil of omega-3 unsaturated fatty acid or more than one mixture.
- 12, as one of any described compositions of claim 6 to 8, it is characterized in that described grade open regulator be selected from glycerol for injection, sorbitol, mannitol, and glucose in one or more mixture.
- 13, compositions as claimed in claim 11, it is characterized in that in the described compositions of described injection formulation or in the described solution of described lyophilized formulations before carrying out step of freeze drying (by the weight percent meter that accounts for described compositions or described liquor capacity) described glycerol consumption be 2.0-3.0%, the sorbitol consumption is 4.0-6.0%, the mannitol consumption is 4.0-6.0%, and the glucose consumption is 4.0-10.0%; When waiting regulator to contain more than one above-mentioned substance, the total amount of each material should be the percentage by weight 1.0-10% that accounts for described compositions or described liquor capacity.
- 14, compositions as claimed in claim 13, it is characterized in that (by the weight percent meter that accounts for described compositions or described liquor capacity) described glycerol consumption is 2.0-2.5%, the sorbitol consumption is 4.0-5.0%, and the mannitol consumption is 4.0-5.0%, and the glucose consumption is 5.0-10.0%; When waiting regulator to contain more than one above-mentioned substance, the total amount of each material should be the percentage by weight 1.0-10% that accounts for described compositions or described liquor capacity.
- 15, as one of any described compositions among the claim 5-8, it is characterized in that described compositions also comprises is selected from tween, polyoxyethylene castor oil, 12 hydroxy stearic acid esters of Polyethylene Glycol, Polyethylene Glycol, cholate, hydroxypropyl beta cyclodextrin, with one or more the second surface activating agent in the polyvidone, and/or comprise oleic acid, the mixture of one or more in the stabilizing agent of cholesterol and enuatrol, and/or comprise vitamin C and derivant thereof, sulfites, thio-compounds, amino acids, vitamin E and derivant thereof, butylated hydroxyarisol, the di-tert-butyl hydroxy-methylbenzene, with one or more the mixture in the propyl gallate; The content of (by the weight percent meter that accounts for described compositions or described liquor capacity) described second surface activating agent is 0-10% in the described compositions of described injection formulation or in the described solution of described lyophilized formulations before carrying out step of freeze drying.
- 16, as one of any described compositions among the claim 1-3, it is characterized in that described surfactant is phospholipid and cholate, or phospholipid, cholate and comprise the second surface activating agent that is selected from one or more mixture in tween, polyoxyethylene castor oil, 12 hydroxy stearic acid esters of Polyethylene Glycol, Polyethylene Glycol, hydroxypropyl beta cyclodextrin, the polyvidone.
- 17, compositions as claimed in claim 16, it is characterized in that in the described compositions of described injection formulation or in the described solution of described lyophilized formulations before carrying out step of freeze drying (by the weight percent meter that accounts for described compositions or described liquor capacity), the content of described phospholipid and cholate is 0.01%～30%, and the molar ratio of phospholipid and cholate is 0.1: 1～2: 1.
- 18, compositions as claimed in claim 17, the content that it is characterized in that described phospholipid and cholate is 0.1%～15%.The molar ratio of phospholipid and cholate is 0.8: 1～1.5: 1.
- 19, as one of any described compositions in the claim 1,2, it is characterized in that described surfactant is a cholate, or cholate and comprise the second surface activating agent that is selected from one or more mixture in tween, polyoxyethylene castor oil, 12 hydroxy stearic acid esters of Polyethylene Glycol, Polyethylene Glycol, hydroxypropyl beta cyclodextrin, the polyvidone.
- 20, compositions as claimed in claim 19, it is characterized in that in the described compositions of described injection formulation or in the described solution of described lyophilized formulations before carrying out step of freeze drying (by the weight percent meter that accounts for described compositions or described liquor capacity), the content of described cholate is 0.01%-30%.
- 21, compositions as claimed in claim 20, the content that it is characterized in that described cholate is 0.01%-20%.
- 22, compositions as claimed in claim 21, the content that it is characterized in that described cholate is 0.1%-10%.
- 23, as one of any described compositions in the claim 1,2, it is characterized in that described surfactant is a tween.
- 24, compositions as claimed in claim 23 is characterized in that described tween, is selected from tween 20, Tween-40, Tween-60 and tween 80.
- 25, compositions as claimed in claim 24, it is characterized in that described tween is a tween 80, in the described compositions of described injection formulation or in the described solution of described lyophilized formulations before carrying out step of freeze drying (by the weight percent meter that accounts for described compositions or described liquor capacity), described tween 80 content is 0.01%-20%.
- 26, compositions as claimed in claim 25 is characterized in that described tween 80 content is 0.1%-5%.
- 27, compositions as claimed in claim 23 is characterized in that described compositions also comprises one or more the second surface activating agent of mixture that is selected from cholate, polyoxyethylene castor oil, 12 hydroxy stearic acid esters of Polyethylene Glycol, Polyethylene Glycol, hydroxypropyl beta cyclodextrin, the polyvidone; In the described compositions of described injection formulation or in the described solution of described lyophilized formulations before carrying out step of freeze drying (by the weight percent meter that accounts for described compositions or described liquor capacity), the content of described second surface activating agent is 0-20%.
- 28, as one of any described compositions among claim 1-3,6-8,10-11, the 13-14, it is characterized in that when described compositions is lyophilized formulations, described compositions also further contain routine or become known for preparing lyophilized formulations, acceptable excipient pharmaceutically, described excipient comprises one or more the mixture in the conventional or known pharmaceutically acceptable excipient of mannitol, sorbitol, lactose, glucose, sodium chloride, dextran and other.
- 29, as one of any described compositions among the claim 1-2, it is characterized in that described compositions also further contains pharmaceutically acceptable antioxidant, pH regulator agent, isoosmotic adjusting agent, stabilizing agent, antiseptic, excipient and/or other adjuvants of pharmaceutically accepting.
- 30, compositions as claimed in claim 29 is characterized in that described antioxidant is selected from one or more the mixture in vitamin C and derivant, sulfites, thio-compounds, amino acids, vitamin E and derivant thereof, butylated hydroxyarisol, di-tert-butyl hydroxy-methylbenzene and the propyl gallate.
- But 31, a kind of method of oryzanol composition of preparation used for intravenous injection, it comprises:(1) preparation contains the oil phase of triglyceride compounds, oryzanol and phospholipid or phospholipid and poloxamer;(2) preparation be dissolved with wait to open regulator or etc. the water of a regulator and second surface activating agent;(3) oil phase is mixed with water evenly, sterilization obtains injection products; Or the adding excipient, make lyophilized formulations through Freeze Drying Technique again.
- 32, method as claimed in claim 31 is characterized in that the oil phase of described (1) step gained or the water of (2) step gained, also further contains antioxidant and/or stabilizing agent.
- But 33, a kind of method of oryzanol composition of preparation used for intravenous injection, it comprises:(1) preparation contains the oil phase of triglyceride compounds, oryzanol;(2) preparation be dissolved with (a) wait to open regulator or etc. open regulator and stabilizing agent or etc. open regulator and second surface activating agent or etc. regulator and stabilizing agent and second surface activating agent, and (b) water of phospholipid or phospholipid and poloxamer;(3) oil phase is mixed with water evenly, sterilization obtains injection products; Or the adding excipient, make lyophilized formulations through Freeze Drying Technique again.
- 34, method as claimed in claim 33 is characterized in that the oil phase of described (1) step gained or the water of (2) step gained, also further contains antioxidant.
- But 35, a kind of method of oryzanol composition of preparation used for intravenous injection, it comprises:(1) preparation contains the alcoholic solution of oryzanol, phospholipid;(2) preparation contains the aqueous solution of cholate;(3) with (1) step and (2) step gains mix homogeneously;(4) add water for injection to full dose, sterilization promptly gets the injection finished product, or adds excipient, makes lyophilized formulations through Freeze Drying Technique again.
- 36, method as claimed in claim 35 is characterized in that described alcohol is conventional or known pharmaceutically acceptable alcoholic solvent, comprises ethanol, propylene glycol, glycerol, benzyl alcohol, Polyethylene Glycol.
- But 37, a kind of method of oryzanol composition of preparation used for intravenous injection, it comprises: oryzanol, cholate heating for dissolving in sodium hydroxide solution, are regulated pH value 5-10, add to the full amount of water for injection, sterilization promptly gets the injection finished product; Or the adding excipient, make lyophilized formulations through Freeze Drying Technique again.
- But 38, a kind of method of oryzanol composition of preparation used for intravenous injection, it comprises:(1) oryzanol, cholate are dissolved in the sodium hydroxide solution, regulate pH value to 5-10;(2) in (1), add phospholipid, stirring and dissolving;(3) add water for injection to full dose, sterilization gets product, or adds excipient, makes lyophilized formulations through Freeze Drying Technique again.
- 39, method as claimed in claim 38 is characterized in that described (2) step is with the phospholipid dissolving or is distributed to adding again in the pharmaceutically acceptable alcoholic solution.
- But 40, a kind of method of oryzanol composition of preparation used for intravenous injection, it comprises: the oryzanol heating for dissolving in the benzyl alcohol solution of tween, is added to the full amount of water for injection, sterilization, get product, or add excipient, make lyophilized formulations through Freeze Drying Technique again.
- 41, compositions as claimed in claim 1, its suitable dosage range are 5mg-100mg every day.
- 42, compositions as claimed in claim 41, its suitable dosage range are 10mg-60mg every day.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005101322215A CN100386082C (en) | 2005-12-22 | 2005-12-22 | Oryzanol composition and its preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005101322215A CN100386082C (en) | 2005-12-22 | 2005-12-22 | Oryzanol composition and its preparation method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1823789A true CN1823789A (en) | 2006-08-30 |
| CN100386082C CN100386082C (en) | 2008-05-07 |
Family
ID=36934731
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005101322215A Active CN100386082C (en) | 2005-12-22 | 2005-12-22 | Oryzanol composition and its preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100386082C (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010069139A1 (en) * | 2008-12-17 | 2010-06-24 | 北京世纪博康医药科技有限公司 | Pharmaceutical composition and preparation method thereof |
| WO2010069140A1 (en) * | 2008-12-17 | 2010-06-24 | 北京世纪博康医药科技有限公司 | Medicinal product of oryzanol and preparation method thereof |
| WO2010069138A1 (en) * | 2008-12-17 | 2010-06-24 | 北京世纪博康医药科技有限公司 | Oryzanol composition and preparation method thereof |
| CN101596200B (en) * | 2008-06-02 | 2011-03-23 | 北京世纪博康医药科技有限公司 | Preparation of compound of cycloartenyl ferulate and purification process thereof |
| CN102058606A (en) * | 2011-01-11 | 2011-05-18 | 北京世纪博康医药科技有限公司 | Oryzanol medicinal composition |
| CN101590008B (en) * | 2008-05-29 | 2012-02-01 | 北京世纪博康医药科技有限公司 | Composition preparation of 24-methylene cycloartenol feruloyl esterase and purification process thereof |
| CN101480402B (en) * | 2008-12-17 | 2012-05-23 | 北京世纪博康医药科技有限公司 | Cycloartenyl ferulate composition and method for preparing the same |
| CN101480406B (en) * | 2008-12-17 | 2014-08-27 | 北京世纪博康医药科技有限公司 | 24-methylene cycloartenyl ferulate composition and method for preparing the same |
| CN104689328A (en) * | 2015-03-23 | 2015-06-10 | 山东北大高科华泰制药有限公司 | Oryzanol combination |
| CN112843006A (en) * | 2021-01-28 | 2021-05-28 | 上海嘉申医药研发有限公司 | Oryzanol phospholipid complex and preparation method and application thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5332110A (en) * | 1976-09-03 | 1978-03-27 | Yamanouchi Pharmaceut Co Ltd | Pharmaceutical composition containing gamma-oryzanol |
| CN1141100C (en) * | 2000-08-16 | 2004-03-10 | 许志文 | Oily gammariza injection |
| CN1340341A (en) * | 2000-08-25 | 2002-03-20 | 李艳丰 | Thiaminogen injection and its preparing process |
| CN1274304C (en) * | 2002-03-25 | 2006-09-13 | 徐州颐华医药科技有限公司 | Etomidate fatty emulsion injection preparation method |
| CN1242742C (en) * | 2004-01-14 | 2006-02-22 | 马志梅 | Oryzanol containing soft capsule preparation method |
-
2005
- 2005-12-22 CN CNB2005101322215A patent/CN100386082C/en active Active
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101590008B (en) * | 2008-05-29 | 2012-02-01 | 北京世纪博康医药科技有限公司 | Composition preparation of 24-methylene cycloartenol feruloyl esterase and purification process thereof |
| CN101596200B (en) * | 2008-06-02 | 2011-03-23 | 北京世纪博康医药科技有限公司 | Preparation of compound of cycloartenyl ferulate and purification process thereof |
| CN101480405B (en) * | 2008-12-17 | 2012-08-22 | 北京世纪博康医药科技有限公司 | Oryzanol composition and preparation method thereof |
| WO2010069139A1 (en) * | 2008-12-17 | 2010-06-24 | 北京世纪博康医药科技有限公司 | Pharmaceutical composition and preparation method thereof |
| CN101480404B (en) * | 2008-12-17 | 2011-07-20 | 北京世纪博康医药科技有限公司 | Medicinal product of oryzanol and preparation method thereof |
| WO2010069140A1 (en) * | 2008-12-17 | 2010-06-24 | 北京世纪博康医药科技有限公司 | Medicinal product of oryzanol and preparation method thereof |
| CN101480402B (en) * | 2008-12-17 | 2012-05-23 | 北京世纪博康医药科技有限公司 | Cycloartenyl ferulate composition and method for preparing the same |
| WO2010069138A1 (en) * | 2008-12-17 | 2010-06-24 | 北京世纪博康医药科技有限公司 | Oryzanol composition and preparation method thereof |
| CN101480403B (en) * | 2008-12-17 | 2013-04-17 | 北京世纪博康医药科技有限公司 | Medicament composition and preparation method thereof |
| CN101480406B (en) * | 2008-12-17 | 2014-08-27 | 北京世纪博康医药科技有限公司 | 24-methylene cycloartenyl ferulate composition and method for preparing the same |
| CN102058606A (en) * | 2011-01-11 | 2011-05-18 | 北京世纪博康医药科技有限公司 | Oryzanol medicinal composition |
| CN102058606B (en) * | 2011-01-11 | 2014-11-05 | 北京世纪博康医药科技有限公司 | Oryzanol medicinal composition |
| CN104689328A (en) * | 2015-03-23 | 2015-06-10 | 山东北大高科华泰制药有限公司 | Oryzanol combination |
| CN104689328B (en) * | 2015-03-23 | 2017-07-04 | 山东北大高科华泰制药有限公司 | Oryzanol composition |
| CN112843006A (en) * | 2021-01-28 | 2021-05-28 | 上海嘉申医药研发有限公司 | Oryzanol phospholipid complex and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100386082C (en) | 2008-05-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1823789A (en) | Oryzanol composition and its preparation method | |
| CN1091591C (en) | Lipophilic carrier preparations | |
| CN1309414C (en) | Hydrophilic binary systems for the administration of cyclosporine | |
| CN1088599C (en) | Therapeutic composition comprising an antigen or an in vivo generator for generating a compound comprising an amino acid sequence | |
| CN1042080A (en) | Pharmaceutical carrier | |
| CN1859898A (en) | Compositions for delivering highly water soluble drugs | |
| CN101065115A (en) | Liquid and semi-solid pharmaceutical formulations for oral administration of a substituted amide | |
| CN1090509A (en) | Pharmaceutical composition | |
| CN1255114C (en) | Amphotericin B aqueous composition | |
| CN101066260A (en) | Coenzyme Q10 emulsion and its freeze dried prepn and their prepn process | |
| KR20140012215A (en) | Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same | |
| CN1895239A (en) | Curcumin preparation and its making method | |
| CN1735401A (en) | Microemulsion concentrate for oral administration of water-insoluble anti-cold drug and method for preparing same | |
| CN1310648C (en) | A topical nanoparticulate spironolactone formulation | |
| CN1907291A (en) | Injectio for nanometer notoginsenoside and its preparing method | |
| CN1706371A (en) | Efficient sword-like iris seed prepn and its prepn process | |
| CN101480403B (en) | Medicament composition and preparation method thereof | |
| CN1915219A (en) | Stabilized liposome | |
| FI99080C (en) | Method for preparing emulsions for parenteral administration | |
| CN1226999C (en) | Solubilized pharmaceutical composition for parenteral administration | |
| CN1939315A (en) | Ganglioside solid lipid nano-particle of monosialic acid tetrahexose and its preparation | |
| CN1822830A (en) | Emulsifying systems containing azetidine derivatives | |
| CN1700906A (en) | Stable sterile filterable liposomal encapsulated taxane and other antineoplastic drugs | |
| CN1893932A (en) | Microemulsion preconcentrate comprising a renin inhibitor | |
| CN1973826A (en) | Injection containing lipoid microsphere of etoposide and its prepn process |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee | ||
| CP03 | Change of name, title or address |
Address after: 250000 Ji'nan, Shandong hi tech Zone, East China Road century wealth center C block, 201 Patentee after: SHANDONG BESTCOMM PHARMACEUTICAL CO., LTD. Address before: 250013 No. 11 mountain road, Shandong, Ji'nan Patentee before: Bainuo Medicines Development Co., Ltd., Jinan |