CN104689328B

CN104689328B - Oryzanol composition

Info

Publication number: CN104689328B
Application number: CN201510128432.5A
Authority: CN
Inventors: 徐愈富; 夏云; 李敏; 郭明娟; 林丽娟
Original assignee: Shandong Pku High-Tech Huatai Pharmaceutical Co Ltd
Current assignee: Shandong Pku High-Tech Huatai Pharmaceutical Co Ltd
Priority date: 2015-03-23
Filing date: 2015-03-23
Publication date: 2017-07-04
Anticipated expiration: 2035-03-23
Also published as: CN104689328A

Abstract

The present invention relates to a kind of oryzanol composition.Specifically, on the one hand, the present invention relates to a kind of pharmaceutical composition, it includes the weight portion of oryzanol 20 and oily 200~4000 weight portions.On the other hand, the present invention relates to a kind of pharmaceutical composition, its oryzanol for including 20 weight portions, and 200~4000 weight portions (such as 300~3000 weight portions, such as 500~2000 weight portions, such as 750~1500 weight portions, such as 1000 weight portions) oil；The oil is saturated fat acid glycerol three ester, and the pharmaceutic adjuvants such as water, lower alcohol are not contained in described pharmaceutical composition.Pharmaceutical composition with oil as matrix of the present invention, it is a kind of finish pharmaceutical composition in liquid condition with oil as matrix of the oryzanol for being available for oral or injection to use.Said composition is presented advantageous feature as used in the description.

Description

Oryzanol composition

Technical field

The invention belongs to pharmaceutical technology field, it is related to a kind of pharmaceutical composition with oil as matrix, more particularly to one kind can The finish pharmaceutical composition in liquid condition with oil as matrix of the oryzanol used for oral or injection.It is of the invention further It is related to prepare the preparation method of finish pharmaceutical composition of the present invention.

Background technology

Oryzanol (Oryzanol, or Oryzanolum), is based on the ferulic acid ester and sterol of ring jackfruit alcohols A kind of natural mixture that the ferulic acid ester of class is constituted, the molecular formula of its typical component cycloartenyl ferulate is： C40H58O4, molecular weight is：602.88, chemical structural formula is：

Another typical case in oryzanol is 24- methylene γ-oryzanols.

Oryzanol raw material and tablet were recorded in version Chinese Pharmacopoeia two in 1977 early in 1977, were become a full member in new drug Oryzanol injection has also been recorded in standard the 46th.The outward appearance of oryzanol for white to light yellow crystal powder, it is tasteless, have spy An unusually sweet smell taste.Oryzanol is primarily present in rice bran oil and its oil foot.In rice bran oil oryzanol, ring jackfruit alcohols ferulic acid ester Content is about 70~80%.The discovery oryzanol that studies for a long period of time has different physiological roles, mainly includes：Reduction blood fat, resistance courage The absorption of sterol, reduce serum cholesterol, prevent lipid oxidation and prevention of cardiovascular disease.In addition, oryzanol can be with The various physical disturbances states and vegetative dystonie after women enters into the climacteric period are relaxed, is improved diencephalon and is regarded bed bottom function Imbalance.

The tablet and parenteral solution for clinically having oryzanol at present are used, and there is no other formulations to use.Although people attempt Clinic provides more dosage form selections, but has never broken through since the seventies in last century, this preparations shaping with oryzanol Property difficulty is relevant greatly.Oryzanol is insoluble in water, oxidizable, causes to be difficult to make a kind of preparation of stabilization.Relatively low solubility and Oxidizable the characteristics of do not only result in oryzanol practical application in absorptivity it is low, quality is also difficult to control to aborning.In order to solve These problems, researcher has carried out certain groping.For example, prior art discloses many preparation skills about oryzanol Art.

CN1340341A (00122929.X, Gu Yanfeng) discloses a kind of oryzanol injection and production technology, is related to life Thing technical field of pharmaceutical chemistry.Be with the neutralized free-fat acid treatment of vegetable oil and decolouring and deodorizing, then after hot air sterilization will Oil is placed in 100~1000 milli Tesla magnetic fields and acts on 2~10 hours, carries out molecule cutting, magnetization oil molecule.Finally with use stone The refined oryzanol of oily ether backflow is heated to 80~120 DEG C and dissolves by the ratio of 900~930g: 20~40g, cooled and filtered, goes out It is bacterium, filling.It is believed that said preparation is widely used in incidence damages the headache syndrome of institute lemma, vegetative dystonia, more The diseases such as term syndrome, the vomiting of pregnancy, peripheral neuritis, premenstrual tension and primary dysmenorrhea.

CN1338255A (00123428.5, Xu Zhiwen) discloses a kind of oily gammariza injection, and the parenteral solution is by height Purity oryzanol powder and refining vegetable oil dissolving are formed, and every 40 milligrams of oryzanol powder match somebody with somebody 2 milliliters of refining vegetable oils, and described is high-purity Oryzanol content is 100% in degree oryzanol powder, and the acid number of the refining vegetable oil is 0.56, and saponification number is 185-200, iodine value It is 79-128.It is believed that the invention is proved through 256 clinical observations:No matter in terms of SCL-90 scorings or in terms of clinical efficacy Pole is significantly better than oryzanol tablet, and treatment vegetative nerve functional disturbance is evident in efficacy better than oryzanol tablet.

CN101057826A (200710015604.3, model gram) is related to a kind of oryzanol for using ethyl oleate as solvent Parenteral solution and preparation method thereof.Problem to be solved is exactly what background technology was present：The paddy for using vegetable oil to be prepared for solvent Tie up the problems such as plain parenteral solution is easy in placement process to produce precipitation, and quality is difficult to control.Solve what the technical problem was used Technical scheme is：A kind of oryzanol injection for using ethyl oleate as solvent, it is characterised in that use ethyl oleate conduct The solvent of parenteral solution.Its preparation method is:Oryzanol 10G~100G is taken, oiling acetoacetic ester dissolves and is settled to 1000ML, then Above-mentioned solution is degerming with filtering with microporous membrane, and after the assay was approved, filling in medicine bottle, sealing is made parenteral solution.It is believed that the hair The bright manufacture and use that can be applied to oryzanol injection, with without precipitation, the significant advantage such as easily absorb.

CN1823789A (200510132221.5, hundred promises) discloses a kind of oryzanol composition that can be used for intravenous injection, The liquid injection preparation of the oryzanol including effective dose, surfactant and water for injection, the content of surfactant is group The 0.01%~30% of compound gross weight；Also include the oryzanol of effective dose, surfactant, excipients and water for injection The freeze-dried lyophilized formulations being made of liquid, surface-active contents account for the weight of the liquor capacity than 0.01%~ 30%.And the method for preparing said composition.It is believed that the suitable dosage range of the oryzanol is daily 5mg-100mg, conveniently make With, tolerance is improved, simple production process is feasible, it is possible to achieve industrialized production.

CN103536548A (201310481576.X, Weicon) disclose a kind of lyophilized compound powder of injection oryzanol and Its preparation method, the main ingredient for being related to medicine and medicine manufacture technology field, said composition is：Mass percent be 0.1%~ 99.9% oryzanol and 99.9%~0.1% chitosan nano.It is believed that the beneficial effect of the invention is：1) paddy dimension is improved Solubility of the element in water and its dissolution time can be shortened, be conducive to clinical practice；2) antibacterial effect of oryzanol is strengthened, Oryzanol consumption can be clinically reduced, oryzanol adverse reaction is reduced；3) liquid is easy to process, simplifies aseptic industry and operated Journey；4) shitosan can effectively encapsulate DNA, protect DNA from degraded, increase the mobility of film fat, reduce the microviscosity of film, change Membrane protein configuration, these effects are all conducive to the transcellular transport of medicine；5) improve the stability of preparation.

CN1771967A (200410094556.8, Hu Caizhong) discloses oryzanol liposome and preparation method thereof, it gram Take that oryzanol oral absorption is poor, the low shortcoming of bioavilability improves the stability of preparation.By oryzanol and phosphatide, courage Liposome or proliposome that the auxiliary materials such as sterol are prepared from, wherein can also add the auxiliary materials such as supporting agent.Membrane material phosphatide can be with Using natural phospholipid or synthetic phospholipid, phosphatide is 0.1: 1~40: 1 with the weight ratio of medicine.Preparation method can be noted using ethanol Enter method, film dispersion method, reverse phase evaporation, extrusion molding, Mechanical Method, supporting agent can be sorbierite, mannitol, sucrose, chlorination Sodium, water soluble starch, dextran, glucose, lactose etc..The ratio of supporting agent and phosphatide is 0.01: 1~400: 1.Selectivity Act on the automatic nervous system of diencephalon and the maincenter of internal system, can improve vegetative dystonia, improve in point Secrete disequilibrium and spiritual nervous disorder.It is believed that the liposome can be used for various neurosiss, menopausal syndrome, premenstruum (premenstrua) Cataonia, periodic psychosis etc..Can also be used for the auxiliary treatment of vascular headache and postconcussion syndrome.

CN1557294A (200410012115.9, Ma Zhimei) is related to a kind of preparation side of the soft gelatin pharmaceutical containing oryzanol Method, it is characterised in that its preparation process is as follows:(1) oryzanol of 5-40 parts or 100-300 parts is weighed first, is made into ultra-fine Oryzanol micro mist is standby；Then the edible oil for weighing 200-1200 parts is placed in measurer, adds proper amount of surfactant, is stirred Mix；(2) above-mentioned oryzanol micro mist is added under agitation in the measurer of above-mentioned Sheng edible oil, crosses colloid mill, standing disappears Bubble；(3) encapsulating machine is encapsulated on the liquid that will be prepared, and dries, and obtains finished product oryzanol soft capsule, it is believed that the invention can be by human body Rapid dispersion absorbs, bioavilability is high, and Clinical practice is convenient, can reduce medication pain, improves patient dependence.

CN101480405A (200810240135.X, century Bo Kang) discloses a kind of oryzanol medicinal composition, described Pharmaceutical composition includes oryzanol, phosphatide, bile acid and/or its salt.It is believed that the pharmaceutical composition of the disclosure of the invention is effectively improved The water solubility and stability of oryzanol, the pharmaceutical composition particle diameter for being provided, stability is superior to existing product.Further , parenteral solution, freeze-dried powder the invention provides pharmaceutical composition and preparation method thereof.

CN101797228A (200910214065.5, Zhanjiang) discloses a kind of preparation method of oryzanol microemulsion, To be dissolved in vegetable oil by oryzanol, with nonionic surfactant as emulsifying agent, with fatty alcohol as auxiliary agent, add water or Sodium-chloride water solution, by transparent or big translucent, limpid and stable micro emulsion is obtained after stirring；Paddy dimension in micro emulsion Cellulose content can be adjusted with the need within the specific limits, and its maximum level weight percent is 3%, and water content is in 50%-91% Scope.The particle diameter of micro emulsion drop does not rise turbid, not stratified in 8-100nm scopes in 20-90 DEG C of temperature range this microemulsion.Pass through Oryzanol microemulsion prepared by the present invention has transparent or big translucent, limpid and stable property, paddy dimension in micro emulsion Cellulose content can be adjusted with the need within the specific limits, and its maximum level is 3%.Water content is in 50%-91% scopes.Micro emulsion drop Particle diameter in 8-100nm scopes.Do not risen in 20-90 DEG C of temperature range this microemulsion turbid, not stratified.

CN102058537A (200910238090.7, century Bo Kang) discloses a kind of solid dispersion compositions of oryzanol Thing, comprising oryzanol and the PVP as carrier material.The further medicinal system the invention discloses the solid dispersions Agent and preparation method.It is believed that the invention solid dispersions are in dissolution rate, stability, water solubility, the technical indicator such as bioavilability It is upper to be better than existing product.

CN102058606A (201110004491.3, century Bo Kang) discloses a kind of pharmaceutical composition of oryzanol, solution Oryzanol of having determined is insoluble in the problem of water.It is believed that the pharmaceutical composition of the disclosure of the invention includes oryzanol and polyoxyethylene stearate Ester, stabilization, water-soluble oryzanol medicinal composition are obtained by the way that oryzanol is added in the s6 of melting Solution.The preparation method and product formulation use of further disclosure of the invention described pharmaceutical composition solution.

CN102755334A (201210270880.5, century Bo Kang) discloses a kind of cycloartenyl ferulate Pharmaceutical composition, solves the problems, such as that cycloartenyl ferulate is insoluble in water.It is believed that the drug regimen of the disclosure of the invention Thing includes cycloartenyl ferulate and s6, molten by the way that cycloartenyl ferulate is added to Stabilization, water-soluble oryzanol medicinal composition solution are obtained in the s6 for melting.The further disclosure of the invention The preparation method and product formulation use of described pharmaceutical composition solution.

CN101482543A (200810119549.7, century Bo Kang) discloses a kind of high-efficient liquid phase analysis side of oryzanol Method, belongs to analytical chemistry field.Using liquid phase process of the invention, can rapidly, accurately analyze oryzanol, oryzanol and carry Take and isolate and purify active ingredient cycloartenyl ferulate and 24- methylene basic ring jackfruit alcohol in product, oryzanol medicine The content of ferulic acid ester, while obtaining the content of other plurality of impurities compositions.It is believed that the liquid phase process of the disclosure of the invention can also It is applied to the oryzanol drug quality research such as oryzanol stability of drug products, destruction.

However, above-mentioned various preparation techniques fail to realize industrialized production, such as various solid pharmaceutical preparations are not applied to Existing tablet manufacturing, various other preparation techniques in addition to parenteral solution and tablet also not can apply to clinic, or even respectively Parenteral solution technology is planted also equally to fail for actual production.Their technical difficulty is real, and such as century Bo Kang is at them Invention in mention, Chinese Patent Application No. 00123428.5 discloses a kind of vegetable oil solubility preparation of oryzanol, improves life Thing availability, clinical effectiveness is better than general tablet.But must intramuscular injection, patient's pain during due to oil soluble preparation clinical practice Sense is stronger, and is easily caused muscle caking.Simultaneously oil soluble preparation work it is slow, it is necessary to time of about one month carry out it is lasting Intramuscular injection.Chinese patent application 2007100156403 in order to solve to bring using plant oil formulation easy precipitation, unstable ask Topic, the oil soluble preparation of oryzanol is made using ethyl oleate instead of vegetable oil, so as to the effect for reaching stabilization, being not likely to produce precipitation Really.But the invention to remain unchanged and be easily caused patient's pain, muscle knot without the intramuscular injection that inherently solution oil soluble preparation brings The drawbacks of block, compliance difference.Chinese patent application 2004100945568 discloses oryzanol raw material and is combined with cholesterol, phosphatide The technical scheme of liposome is prepared as, overcomes that oryzanol oral result is poor, biological utilisation using the preparation of the inventive technique scheme The low problem of rate.But it is the technological process very high of a cost to prepare liposome, and production process quality is difficult to control, it is impossible to obtain Obtain the reliable oryzanol liposome of steady quality.Patent CN100386082C discloses a kind of ejection preparation of oryzanol, the hair It is bright, in combination with the method for second surface activating agent, to obtain a kind of injection by by oryzanol and surfactant, cosolvent Preparation.But the injection that the program is obtained is emulsion for injection, it is necessary to including oil phase, and the more difficult control of emulsion particle diameter for preparing System, stability is not relatively good, and newborn machine etc. equipment is needed in the preparation, operates complex, high cost.Particularly mention, existing In some technical schemes, oil soluble preparation can not possibly be removed due to vegetable oil, actually a kind of semisolid preparation, be stablized at room temperature Property is poor.In fact, the solution of all appliable plant oil hydrotropies all has less stable.

Therefore, this area still expects there is the new method for preparing oryzanol preparation, e.g. prepares oryzanol liquid system The method of agent (liquid preparation for being for example available for oral or injection to use).

The content of the invention

The purpose of the present invention is that it can with oral or injection administration and again for clinic provides a kind of new oryzanol preparation With good pharmaceutical properties.The inventors discovered that, use oil as finish combination prepared by the matrix of the present composition Thing unexpectedly has advantage as described in the present invention.The present invention is accomplished based on this discovery.

In view of the present composition can be provided with the form of parenteral solution, oral liquid, soft capsule etc., therefore it can be as Presently commercially available tablet and the replacement formulation of parenteral solution.

Therefore, first aspect present invention provides a kind of pharmaceutical composition, it includes the weight portion of oryzanol 20, and oil 200 ~4000 weight portions.For example it includes the weight portion of oryzanol 20, and oily 300~3000 weight portions；For example it includes oryzanol 20 Weight portion, and oily 500~2000 weight portions；For example it includes the weight portion of oryzanol 20, and oily 750~1500 weight portions；For example It includes the weight portion of oryzanol 20, and oily 1000 weight portion.

Pharmaceutical composition according to a first aspect of the present invention, wherein the oil is saturated fat acid glycerol three ester, and structure Into in whole saturated fatty acids of the saturated fat acid glycerol three ester, including more than 95% C6~C12 chain lengths aliphatic acid, example Such as include the aliphatic acid of more than 96% C6~C12 chain lengths, such as including the aliphatic acid of more than 98% C6~C12 chain lengths.

Pharmaceutical composition according to a first aspect of the present invention, wherein the oil is saturated fat acid glycerol three ester, and structure Into in whole saturated fatty acids of the saturated fat acid glycerol three ester, including more than 95% C8~C10 chain lengths aliphatic acid, example Such as include the aliphatic acid of more than 96% C8~C10 chain lengths, such as including the aliphatic acid of more than 98% C8~C10 chain lengths.

Pharmaceutical composition according to a first aspect of the present invention, wherein the oil is saturated fat acid glycerol three ester, and structure Into in whole saturated fatty acids of the saturated fat acid glycerol three ester, including more than 95% octanoic acid and capric acid, for example include More than 96% octanoic acid and capric acid, such as including more than 98% octanoic acid and capric acid.

Pharmaceutical composition according to a first aspect of the present invention, wherein the whole for constituting the saturated fat acid glycerol three ester is pungent In acid and capric acid, octanoic acid is (0.5~5) with the ratio of capric acid：1.

Pharmaceutical composition according to a first aspect of the present invention, wherein the whole for constituting the saturated fat acid glycerol three ester is pungent In acid and capric acid, octanoic acid is (1~4) with the ratio of capric acid：1.

Pharmaceutical composition according to a first aspect of the present invention, wherein the whole for constituting the saturated fat acid glycerol three ester is pungent In acid and capric acid, octanoic acid is (1.1~3.5) with the ratio of capric acid：1.

Pharmaceutical composition according to a first aspect of the present invention, wherein the whole for constituting the saturated fat acid glycerol three ester is pungent In acid and capric acid, octanoic acid is (1.1~3.0) with the ratio of capric acid：1.

Pharmaceutical composition according to a first aspect of the present invention, wherein the whole for constituting the saturated fat acid glycerol three ester is pungent In acid and both capric acid, the amount of octanoic acid is 45~85%, preferably 50~80%.

Pharmaceutical composition according to a first aspect of the present invention, wherein the whole for constituting the saturated fat acid glycerol three ester is pungent In acid and both capric acid, the amount of capric acid is 15~55%, preferably 20~50%.

Pharmaceutical composition according to a first aspect of the present invention, wherein constituting whole saturations of the saturated fat acid glycerol three ester Aliphatic acid includes more than 95% octanoic acid and capric acid；In whole octanoic acids and both capric acid, the amount of octanoic acid is 45~85% (preferably 50~80%), the amount of capric acid is 15~55% (preferably 20~50%).

Pharmaceutical composition according to a first aspect of the present invention, wherein constituting whole saturations of the saturated fat acid glycerol three ester Aliphatic acid includes more than 95% octanoic acid and capric acid；In whole octanoic acids and both capric acid, the amount of octanoic acid is 45~85% (preferably 50~80%), the amount of capric acid is 15~55% (preferably 20~50%)；And in whole octanoic acids and both capric acid, Octanoic acid is (0.5~5) with the ratio of capric acid：1 [such as (1~4)：1, such as (1.1~3.5)：1, such as (1.1~3.0)：1].

Pharmaceutical composition according to a first aspect of the present invention, it is in the composition of liquid condition.In an embodiment In, the composition in liquid condition is the form of transparent solution.

Pharmaceutical composition according to a first aspect of the present invention, it is the seal-packed parenteral solution form of vial.Now people Can generally be referred to as oryzanol injection.

Pharmaceutical composition according to a first aspect of the present invention, it is the oral liquid of drug bottle packaging.Now people Oryzanol oral liquid can be generally referred to as.

Pharmaceutical composition according to a first aspect of the present invention, it is the soft capsule form being sealed in soft capsule shell. Now people can generally be referred to as oryzanol soft capsule.Here, during for medicament in soft gelatin capsules, medicine group of the present invention Compound simply means to the content of the soft capsule, and its soft capsule shell may be considered the inner packing with medicine directly contact.

Pharmaceutical composition according to a first aspect of the present invention, wherein also including oleic acid.In one embodiment, wherein with Comprising the weight portion meter of oryzanol 20, the amount of oleic acid is 0.5~10 weight portion.In one embodiment, wherein being tieed up with comprising paddy Plain 20 weight portion meters, the amount of oleic acid is 1~5 weight portion.

Pharmaceutical composition according to a first aspect of the present invention, when being particularly made into oral formulations, wherein can also contain There is one or more medicinal additive, selected from flavouring class, antioxidant class, surfactant-based, tackifier class, plant Oil (refers to other vegetable oil in addition to the oil of saturated fat acid glycerol three ester described herein, such as peanut oil, rapeseed oil).It is right In the amount of these medicinal additives, the amount of vegetable oil is no more than the 50% of fluid composition gross weight, or preferably, vegetable oil Amount no more than 100 times of oryzanol weight；10%, Huo Zheyou of the amount of other medicinal additives no more than composition total weight Selection of land, 50 times of amount no more than oryzanol weight of medicinal additive.

Pharmaceutical composition according to a first aspect of the present invention, wherein described flavouring class, can improve product taste, such as Menthol, peppermint oil, milk chocolate essence (such as BFL1227 types, International Flavors＆Fragrances companies Product), sorbierite etc..

Pharmaceutical composition according to a first aspect of the present invention, wherein described antioxidant class, can improve product chemistry steady It is qualitative, such as BHA (BHA), toluene di-tert-butyl phenol (BHT).

Pharmaceutical composition according to a first aspect of the present invention, wherein the described surfactant-based dissolving for increasing medicine Degree (such as in alimentary canal with digestive juice mixed dissolution), such as Tween-80, Arlacel-80.

Pharmaceutical composition according to a first aspect of the present invention, it shines gas chromatography and determines aliphatic acid composition, what is measured In whole saturated fatty acids, the amount of caproic acid, laurate and tetradecylic acid each respectively lower than 3% (such as each respectively lower than 2%, For example each respectively lower than 1%).

Pharmaceutical composition according to a first aspect of the present invention, it shines gas chromatography and determines aliphatic acid composition, what is measured In whole saturated fatty acids, (such as octanoic acid and capric acid amount sum are higher than 96%, such as pungent higher than 95% for octanoic acid and capric acid amount sum Acid and capric acid amount sum are higher than 98%).

Pharmaceutical composition according to a first aspect of the present invention, it shines gas chromatography and determines aliphatic acid composition, what is measured In whole saturated fatty acids, the amount of caproic acid, laurate and tetradecylic acid each respectively lower than 3% (such as each respectively lower than 2%, It is for example respective to be respectively lower than 1%), and octanoic acid and capric acid amount sum are (such as sad to be higher than with capric acid amount sum higher than 95% 96%, such as octanoic acid and capric acid amount sum are higher than 98%).

Pharmaceutical composition according to a first aspect of the present invention, it shines gas chromatography and determines aliphatic acid composition, what is measured All in octanoic acid and both capric acid, the amount of octanoic acid is 45~85%, preferably 50~80%.

Pharmaceutical composition according to a first aspect of the present invention, it shines gas chromatography and determines aliphatic acid composition, what is measured All in octanoic acid and both capric acid, the amount of capric acid is 15~55%, preferably 20~50%.

Pharmaceutical composition according to a first aspect of the present invention, it shines gas chromatography and determines aliphatic acid composition, what is measured All in octanoic acid and both capric acid, the amount of octanoic acid is 45~85% (preferably 50~80%), the amount of capric acid for 15~55% (preferably 20~50%).

Pharmaceutical composition according to a first aspect of the present invention, it shines gas chromatography and determines aliphatic acid composition, what is measured All in octanoic acid and both capric acid, the amount of octanoic acid is 45~85% (preferably 50~80%), the amount of capric acid for 15~55% (preferably 20~50%)；And octanoic acid is (0.5~5) with the ratio of capric acid：1 [such as (1~4)：1, such as (1.1~3.5)：1, for example (1.1~3.0)：1].

Pharmaceutical composition according to a first aspect of the present invention, wherein being this for determining the gas chromatography of aliphatic acid composition Any gas chromatography that can be used for determining aliphatic acid composition known to field.The gas phase for example in the related drug standards enumerated The gas chromatography enumerated in chromatography, such as various countries or international organization's drug standards such as pharmacopeia.Such as Chinese Pharmacopoeia, the U.S. Pharmacopeia, European Pharmacopoeia, Pharmacopeia of Japan etc. and the various versions in their any age.For example in may be referred to version in 2010 Method under " aliphatic acid composition " item of two " soybean oil " kinds of state's pharmacopeia.And with the development of analytical technology, in oil Aliphatic acid composition remains able to expect have more excellent analysis method to occur.

Pharmaceutical composition according to a first aspect of the present invention, (or, in the present invention, if not otherwise indicated), wherein using It is as follows in the gas chromatography for determining pharmaceutical composition or prepare the oily aliphatic acid composition that the pharmaceutical composition is used：

Chromatographic column：Material be fused silica (fused silica), 30m long,Fixing phase is poly- second two Alcohol 20000, film is thick 0.5 μm；

Carrier gas：Chromatographic grade helium；

Flow velocity：1.3ml/min；

Temperature：

Detection：Flame ion；

Split ratio：1:100；

Sample size：1μl；

Sensitivity：Main peak peak height is the 50% to 70% of recorder full scale in the chromatogram of reference solution (a)；

System suitability：Separating degree in the chromatogram of reference solution (a) between methyl caprylate and methyl caprate peak 4.0 are not less than, the signal to noise ratio at methyl caproate peak is not less than 5, the chromatogram of reference solution (a) in the chromatogram of reference solution (b) The number of theoretical plate at middle methyl caprate peak is not less than 15000；

Test solution：In 25ml conical flasks, 0.10g test substances are made to be dissolved in the 20g/l NaOH methyl alcohol of 2ml In solution, seethed with excitement 30min under reflux condenser, and 2.0ml boron trifluoride-methanol solution, reboiling are added by condenser 30min；4ml heptane, reboiling 5min are added by condenser；Cooling, adds 10.0ml saturated nacl aqueous solutions, and shaking is about 15 seconds, a certain amount of saturated nacl aqueous solution was added so that upper strata mutually reaches the neck of flask；2ml upper stratas phase is taken, 3 are washed with water Secondary, each 2ml uses anhydrous sodium sulfate drying；

Reference solution (a)：The 0.50g calibration substance mixtures constituted described in Table X are taken, is dissolved in heptane, then with identical Solvent is diluted to 50.0ml；

Reference solution (b)：1.0ml reference solutions (a) is diluted to 10.0ml with heptane；

Reference solution (c)：Take mixture (its fatty acid mixt phase with test substance of 0.50g fatty acid methyl esters When), it is dissolved in heptane, then 50.0ml is diluted to same solvent；

Table X：The mixture of calibration substance

Analysis：Differentiate the peak of reference solution (c) chromatogram, the composition of each aliphatic acid of test sample is calculated with normalization method.

Test solution：Materials (pharmaceutical composition prepares their oil) 0.1g, in putting 50ml conical flasks, plus 0.5mol/L potassium hydroxide methanol solution 2ml, are heated to reflux 30 minutes in 65 DEG C of water-baths, let cool, plus 15% boron trifluoride first Alcoholic solution 2ml, then be heated to reflux in 65 DEG C of water-baths 30 minutes, let cool, plus heptane 4ml, continue to be heated back in 65 DEG C of water-baths Stream lets cool after 5 minutes, plus saturated nacl aqueous solution 10ml washings, shakes up, and standing makes layering, takes upper liquid, washes with water 3 times, Each 2ml, upper liquid through anhydrous sodium sulfate drying, as need testing solution.Separately methyl caproate, methyl caprylate, capric acid are taken respectively Methyl esters, methyl laurate, methyl myristate reference substance, plus n-hexane dissolution and diluting be made in every lml it is each containing above-mentioned reference substance The solution of 0.1mg, as reference substance solution.Reference solution (a) is methyl caproate, methyl caprylate, methyl caprate, laurate first Ester, methyl myristate compare 2 with weight:60:30:4:2 solution prepared with normal hexane.Reference solution (b)：1.0ml references is molten Liquid (a) is diluted to 10.0ml with heptane；

Carrier gas：Chromatographic grade helium；

Flow velocity：1.3ml/min；

Temperature：

Detection：Flame ion；

Split ratio：1:100；

Sample size：1μl；

The μ l of each test fluid 1 injection gas chromatographs are taken, chromatogram is recorded.By area normalization method with calculated by peak area.

Further, second aspect present invention provide a kind of pharmaceutical composition, its oryzanol for including 20 weight portions, and 200~4000 weight portions (such as 300~3000 weight portions, such as 500~2000 weight portions, such as 750~1500 weight portions, Such as 1000 weight portions) oil；The oil is saturated fat acid glycerol three ester；The pharmaceutical composition determines fat according to gas chromatography Fat acid composition, the wherein amount of caproic acid, laurate and tetradecylic acid are each less than 3%, and octanoic acid and capric acid amount sum are higher than 95%.

Pharmaceutical composition according to a second aspect of the present invention, it shines gas chromatography and determines aliphatic acid composition, what is measured In whole saturated fatty acids, caproic acid is less than 2.0%, and laurate is less than 3.0%, and tetradecylic acid is less than 1.0%, and octanoic acid and capric acid Amount sum is higher than 95%.

Pharmaceutical composition according to a second aspect of the present invention, it shines gas chromatography and determines aliphatic acid composition, wherein surveying In all octanoic acid and capric acid that obtain, the ratio of octanoic acid and capric acid is (0.5~5)：1.

Pharmaceutical composition according to a second aspect of the present invention, it shines gas chromatography and determines aliphatic acid composition, wherein surveying In all octanoic acid and capric acid that obtain, the ratio of octanoic acid and capric acid is (1~4)：1.

Pharmaceutical composition according to a second aspect of the present invention, it shines gas chromatography and determines aliphatic acid composition, wherein surveying In all octanoic acid and capric acid that obtain, the ratio of octanoic acid and capric acid is (1.1~3.5)：1.

Pharmaceutical composition according to a second aspect of the present invention, it shines gas chromatography and determines aliphatic acid composition, wherein surveying In all octanoic acid and capric acid that obtain, the ratio of octanoic acid and capric acid is (1.1~3.0)：1.

Pharmaceutical composition according to a second aspect of the present invention, it shines gas chromatography and determines aliphatic acid composition, what is measured All in octanoic acid and both capric acid, the amount of octanoic acid is 45~85%, preferably 50~80%.

Pharmaceutical composition according to a second aspect of the present invention, it shines gas chromatography and determines aliphatic acid composition, what is measured All in octanoic acid and both capric acid, the amount of capric acid is 15~55%, preferably 20~50%.

Pharmaceutical composition according to a second aspect of the present invention, it shines gas chromatography and determines aliphatic acid composition, what is measured Whole saturated fatty acids include the octanoic acid of more than 95% (such as more than 96%, such as more than 98%) and capric acid；What is measured All in octanoic acid and both capric acid, the amount of octanoic acid is 45~85% (preferably 50~80%), the amount of capric acid for 15~55% (preferably 20~50%).

Pharmaceutical composition according to a second aspect of the present invention, it shines gas chromatography and determines aliphatic acid composition, what is measured Whole saturated fatty acids include the octanoic acid of more than 95% (such as more than 96%, such as more than 98%) and capric acid；What is measured All in octanoic acid and both capric acid, the amount of octanoic acid is 45~85% (preferably 50~80%), the amount of capric acid for 15~55% (preferably 20~50%)；And in whole octanoic acids and capric acid, octanoic acid is (0.5~5) with the ratio of capric acid：1 [such as (1~4)：1, example Such as (1.1~3.5)：1, such as (1.1~3.0)：1].

Pharmaceutical composition according to a second aspect of the present invention, wherein being this for determining the gas chromatography of aliphatic acid composition Any gas chromatography that can be used for determining aliphatic acid composition known to field.The gas phase for example in the related drug standards enumerated The gas chromatography enumerated in chromatography, such as various countries or international organization's drug standards such as pharmacopeia.Such as Chinese Pharmacopoeia, the U.S. Pharmacopeia, European Pharmacopoeia, Pharmacopeia of Japan etc. and the various versions in their any age.For example in may be referred to version in 2010 Method under " aliphatic acid composition " item of two " soybean oil " kinds of state's pharmacopeia.And with the development of analytical technology, in oil Aliphatic acid composition remains able to expect have more excellent analysis method to occur.

Pharmaceutical composition according to a second aspect of the present invention, (or, in the present invention, if not otherwise indicated), wherein using It is as follows in the gas chromatography for determining pharmaceutical composition or prepare the oily aliphatic acid composition that the pharmaceutical composition is used：

Carrier gas：Chromatographic grade helium；

Flow velocity：1.3ml/min；

Temperature：

Detection：Flame ion；

Split ratio：1:100；

Sample size：1μl；

Table X：The mixture of calibration substance

Test solution：Materials (composition prepares their oil) 0.1g, in putting 50ml conical flasks, plus 0.5mol/L Potassium hydroxide methanol solution 2ml, is heated to reflux 30 minutes in 65 DEG C of water-baths, lets cool, plus 15% boron trifluoride methanol solution 2ml, then be heated to reflux in 65 DEG C of water-baths 30 minutes, let cool, plus heptane 4ml, continue to be heated to reflux in 65 DEG C of water-baths 5 minutes Afterwards, let cool, plus saturated nacl aqueous solution 10ml washings, shaking up, standing makes layering, takes upper liquid, washes 3 times with water, every time 2ml, upper liquid through anhydrous sodium sulfate drying, as need testing solution.It is another take respectively methyl caproate, methyl caprylate, methyl caprate, Methyl laurate, methyl myristate reference substance, plus n-hexane dissolution and dilution be made each 0.1mg containing above-mentioned reference substance in every lml Solution, as reference substance solution.Reference solution (a) is methyl caproate, methyl caprylate, methyl caprate, methyl laurate, 14 Sour methyl esters compares 2 with weight:60:30:4:2 solution prepared with normal hexane.Reference solution (b)：1.0ml reference solutions (a) is used Heptane is diluted to 10.0ml；

Carrier gas：Chromatographic grade helium；

Flow velocity：1.3ml/min；

Temperature：

Detection：Flame ion；

Split ratio：1:100；

Sample size：1μl；

Pharmaceutical composition according to a second aspect of the present invention, it is in the composition of liquid condition.In an embodiment In, the composition in liquid condition is the form of transparent solution.

Pharmaceutical composition according to a second aspect of the present invention, it is the seal-packed parenteral solution form of vial.Now people Can generally be referred to as oryzanol injection.

Pharmaceutical composition according to a second aspect of the present invention, it is the oral liquid of drug bottle packaging.Now people Oryzanol oral liquid can be generally referred to as.

Pharmaceutical composition according to a second aspect of the present invention, it is the soft capsule form being sealed in soft capsule shell. Now people can generally be referred to as oryzanol soft capsule.Here, during for medicament in soft gelatin capsules, medicine group of the present invention Compound simply means to the content of the soft capsule, and its soft capsule shell may be considered the inner packing with medicine directly contact.

Pharmaceutical composition according to a second aspect of the present invention, wherein also including oleic acid.In one embodiment, wherein with Comprising the weight portion meter of oryzanol 20, the amount of oleic acid is 0.5~10 weight portion.In one embodiment, wherein being tieed up with comprising paddy Plain 20 weight portion meters, the amount of oleic acid is 1~5 weight portion.

Pharmaceutical composition according to a second aspect of the present invention, when being particularly made into oral formulations, wherein can also contain There is one or more medicinal additive, selected from flavouring class, antioxidant class, surfactant-based, tackifier class.

Pharmaceutical composition according to a second aspect of the present invention, wherein described flavouring class, can improve product taste, such as Menthol, peppermint oil, milk chocolate essence (such as BFL1227 types, International Flavors＆Fragrances companies Product), sorbierite etc..

Pharmaceutical composition according to a second aspect of the present invention, wherein described antioxidant class, can improve product chemistry steady It is qualitative, such as BHA (BHA), toluene di-tert-butyl phenol (BHT).

Pharmaceutical composition according to a second aspect of the present invention, wherein the described surfactant-based dissolving for increasing medicine Degree (such as in alimentary canal with digestive juice mixed dissolution), such as Tween-80, Arlacel-80.

According to a first aspect of the present invention or second aspect pharmaceutical composition, wherein the oryzanol is in the drug regimen Concentration in thing is 20mg:0.2~4ml, such as 20mg:0.3~3.0ml, such as 20mg:0.5~2ml, such as 20mg:0.75 ~1.5ml, such as 20mg:1ml.

According to a first aspect of the present invention or second aspect pharmaceutical composition, its relative density be 0.92-1.2, for example 0.92-1.1；Whole liquid obtained in embodiments described below of the present invention 1 to embodiment 14 and embodiment 31 to embodiment 36 The relative density of pharmaceutical composition is in the range of 0.92-1.2.

Third aspect present invention further relates to a kind of pharmaceutical preparation, and it is included described in first aspect present invention or second aspect Pharmaceutical composition, and wrap up the pharmaceutically acceptable lapping of said composition.

Pharmaceutical preparation according to a third aspect of the present invention, wherein the lapping is included but is not limited to：Plastics, glass, Capsule skin.

Pharmaceutical preparation according to a third aspect of the present invention, it is the soft capsule or drops that capsule suitcase is wrapped up in, or The oral solutions or drops of plastic bottle or vial parcel, or the parenteral solution that vial is wrapped up.

Pharmaceutical preparation according to a third aspect of the present invention, it is the sterile solution for injection of vial parcel.

Any technical characteristic that any embodiment of either side of the present invention or the either side has is equally applicable Any embodiment of other any embodiments or other either sides, as long as they will not be conflicting, certainly mutual Between where applicable, if necessary can individual features be made with appropriate modification.Make into one with feature to various aspects of the present invention below The description of step.Particularly, in either side of the invention, any one or more technical characteristics of its any embodiment can be with It is combined in any other embodiments of this aspect, it is also possible to be combined in any embodiment of another aspect；And appoint Any embodiment of one side can be combined with any embodiment of this aspect or other side；As long as this combination will not There is contradiction.

All documents recited in the present invention, their full content is incorporated herein by reference, and if these are literary Offer expressed implication with it is of the invention inconsistent when, be defined by statement of the invention.Additionally, the various terms that use of the present invention and Phrase has well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this to these terms and Phrase is described in more detail and explains, the term and phrase for referring to if any inconsistent with common art-recognized meanings, with institute's table of the present invention The implication stated is defined.

It is further described to various aspects of the present invention below.

The various terms that the present invention is used have the general sense that those skilled in the art routinely understand, typically contain with this When justice is inconsistent, it is defined by the present invention.

In the present invention, as the oil of saturated fat acid glycerol three ester, it can be the product or day of natural origin So source and through such as but not limited to extracting, purification, purifying, the product of the treatment such as refined, such as described natural origin can be Vegetable oil.In the present invention, as the oil of saturated fat acid glycerol three ester, it can also be artificial manufactured goods, and for example it can be with The glyceride particularly triglycerides that to be saturated fatty acid be esterified and formed with glycerine.

In the present invention, be related to percentage, percentage, %, than, ratio etc. when, refer to the ratio of weight unless otherwise noted Rate.

In the present invention, refer to " constitute whole saturated fatty acids of the saturated fat acid glycerol three ester include 95% with On octanoic acid and capric acid " or it is similar state, refer to according to gas chromatography (abbreviation GC or GC method) GC methods for example of the present invention Determine, in the oil used by the present composition, or in the end-product of the present invention comprising active component, whole saturated fatty acids In, octanoic acid and capric acid summation account for more than 95%.Other similar statements also have similar meaning.

In the present invention, refer to " in all octanoic acid and capric acid of the composition saturated fat acid glycerol three ester, the sad and last of the ten Heavenly stems The ratio of acid is (0.5~5)：1 " or similar statement, refer to for example of the present invention according to gas chromatography (abbreviation GC or GC method) GC methods are determined, and in the oil used by the present composition, in whole octanoic acids and both capric acid, octanoic acid is (0.5 with the ratio of capric acid ~5)：1.Other similar statements also have similar meaning.

In the present invention, refer to " wherein constitute the saturated fat acid glycerol three ester all octanoic acid and both capric acid in, The amount of octanoic acid is 45~85% " or (including on capric acid) similar statement, refer to according to gas chromatography (abbreviation GC or GC Method) GC methods measure for example of the present invention, it is pungent in whole octanoic acids and both capric acid in the oil used by the present composition The amount of acid is 45~85%.Other similar statements also have similar meaning.

In the present invention, described oil is the main part of the present composition；And oryzanol is the present composition Active component.Therefore, the oil in pharmaceutical composition of the present invention substantially can be as the drug matrices of pharmaceutical composition of the present invention Or liquid carrier, in art of pharmacy, its definition is clear and definite, that is, form the main material of medicament, or major auxiliary burden, right The physicochemical property of medicament can play an important role.

In the pharmaceutical composition of either side of the present invention, wherein be essentially free of lower alcohol, the Lower alcohols as but It is not limited to ethanol, glycerine, propane diols.In the pharmaceutical composition of either side of the present invention, wherein being essentially free of water. It was found that, even when the above-mentioned lower alcohol or water less than 5% is added in the compositions of the present invention, resulting composition is through 45 DEG C Forulic acid increment rate is all higher than 150% after disposal April.Further it has been found that work as making cycloartenyl ferulate or 24- When methylene γ-oryzanol is dissolved in the water with its semi-saturation concentration, this two kinds of solution are after 45 DEG C of disposal April Forulic acid increment rate is all higher than 120%.

In the present invention, described oil, as a kind of oil liquid carrier, is a kind of aliphatic acid with medium chain Triglycerides, and it is often referred to the fatty acid triglycercide with C6~C14 chain lengths.It is highly preferred that above-mentioned fatty acid glycerine Three esters, refer to the fatty glyceride of C8~C12；Fatty acid triglycercide such as to be prepared with C8~C12 saturated fatty acids, it is special It is not the fatty acid triglycercide prepared with C8 and C10 saturated fatty acids.These fatty acid triglycercides can make acquisition by oneself, Or can be bought from market, or the fatty acid triglycercide demand of the invention that market is bought voluntarily carried out it is pre- Treatment.Some commercially available typical fatty acid triglycercides constituted with C8 and C10 saturated fatty acids have812 or810、LABRAFAC CC、MCT or be the production of Chinese Tieling product.In the present invention,810 can be abbreviated as M-810, and LABRAFAC CC can be abbreviated as L-CC, and other materials herein can also make field Similar the writing a Chinese character in simplified form of technical staff's understanding.In addition, the commercially available MCT of these different brands, can obtain caprylic/capric ratio 0.5~5 Broad range in commercially available sample.

In the present invention, described oil can also be artificial preparation, and for example it can be with reference to CN1594274A Described side in (200410041184.2, Southern Yangtze University), CN104203896A (201380011748.5, Pu Luo meter Di Ke) Prepared by method, according to these art methods can be readily available caprylic/capric than in 0.5~5 broad range Sample.

In the present invention, it is middle chain saturated fatty acid of the main saturated fatty acid by composition described herein with octanoic acid and capric acid Triglycerides, they may be generally referred to as caprylic/capric triglyceride, medium chain triglyceride, MCT Oil, in Chain oil, median chain triglyceride oil and similar appellation, they generally also may be simply referred to as MCT in this area, the present invention for convenience of description, When needed can also be using this referred to as.

Oil used in the present invention can be a kind of oil of above-mentioned natural or artificial source, or it is various natural or The oily mixture of artificial source.

Additionally, for the present invention, can also be referred to using the present invention or present invention is NM any two kinds Or various fatty acid triglycercides mixes to be met the performance requirement of oil of the present invention, and and then realize of the invention Purpose.For example can using two or more, pungent/last of the ten Heavenly stems than the fatty acid triglycercide less than 1.1 or more than 3.5, by it Mix in certain proportion be met it is of the present invention oil performance requirement.In this sense, oil of the invention It can be the artificial preparation of two or more oil.

Oryzanol is applied to food by Japan, and oneself has more than 20 years history.The 33 food enterprise parties of in July, 1987 Japan are ground The development of healthy food is begged for, and is had a meeting again within 2 months in next year, the functional food raw material reached common understanding after the meeting has 35 kinds, oryzanol The 15th kind is classified as, its major function is anti-oxidant, anti-aging.1991, future of functional foods in Japan contact can announce on work( The report of energy property material exploitation actuality, oryzanol lists the 7th class in., the food additives base of Japanese Society of Public Health's issue in 1994 Quasi- specification, oryzanol lists antioxidant etc. in.

Oryzanol is primarily present in mao oil extracted from rice husks and its oil foot, and the content of oryzanol is 0.3~0.5% in rice bran layer.Rice Chaff oryzanol when squeezing is heated is dissolved in oil, and in general hair oil extracted from rice husks the content of oryzanol is about 1.5%~3%.Its content with Weather conditions, rice variety and the rice bran that paddy is planted take the process conditions difference of oil and slightly difference, the rice bran of frigid zone paddy Amount containing oryzanol is higher than tropical paddy；High temperature is squeezed and extraction takes oil, and the content of oryzanol is higher than cold pressing in crude oil. In many vegetable oil materials, such as maize germ oil, wheat-germ oil, highland barley oil extracted from rice husks, rapeseed oil, with hair oil extracted from rice husks oryzanol content Highest, so oryzanol is extracted from hair oil extracted from rice husks.

The combination fat of oryzanol system forulic acid and phytosterol, it can be extracted from rice bran oil in the cereal grease such as embryo oil. Its outward appearance for white to off-white color crystalline powder, it is tasteless, various greases are dissolved under heating, it is water insoluble.

The physiological function of oryzanol mainly includes following aspect：1st, reduction blood fat：The effect of oryzanol reduction blood fat embodies ：1. serum total cholesterol, content of triglyceride are reduced；2. liver lipids are reduced；3. Serum LPO Levels are reduced；4. hinder Cholesterol is deposited in arterial wall；5. gall-stone formation index is reduced；6. suppress cholesterol to be absorbed in alimentary canal.2nd, lipid peroxidation inhibition： Rat oral intake oryzanol dosage is divided into 0.1g/kg, 0.5g/kg and 1g/kg, as a result shows its lipid peroxidation value, Gu Wei Element group does not decline 19.2%, 21.6%, 21.4% than control component, and antioxidation is obvious.3rd, toxicological study aspect：Mouse, Oral Administration in Rats LD50 values are all higher than 25g/kg, subacute, chronic toxicity test (30d, 90d, 180d) no problem, wherein rat It is without exception that oral maximum dose level 2.89g/kg continues 182d；The oral maximum dose level 100g/kg of dog continue 12 months it is also without exception, Other such as antigenicity, allergenicity experiments are without exception.4th, oryzanol mainly improves vegetative dystonia, improves interior point Disequilibrium and spiritual nervous disorder are secreted, therefore there is certain adjustment effect to nervous breakdown patient；Simultaneously can stabilization feelings Thread, anxiety reduction and tense situation, and improve the health care of sleep；It is also commonly used for the auxiliary treatment of premenstrual syndrome, menopausal syndrome.

Application aspect on oryzanol in clinic, oryzanol mainly acts on automatic nervous system and the secretion of diencephalon Maincenter, thus improve and adjust vegetative dystonia, the symptom such as incretion balance obstacle and psychataxia.It is generally used for week Phase property mental disease, climacteric metancholia of women, premenstrual tension disease, postconcussion syndrome, vascular headache, vegetative nerve work( Can imbalance and various neurosiss etc..Common dose is 10~20 milligrams every time, and it is oral that 3 times a day.Discovered in recent years paddy is tieed up Element also has preferable curative effect to some other disease.Clinical practice is as follows：

(1) hyperlipidemia is treated：Oryzanol can suppress the synthesis of cholesterol.But oral dose will more greatly, and 100 in the least every time Gram, 3 times a day, and after taking 2 months, serum cholesterol and triglycerides are decreased obviously.

(2) angina pectoris is treated：10~20 milligrams every time, 3 times a day, can substantially mitigate symptom.

(3) chronic gastritis is treated：Daily 50~600 milligrams (generally 300 milligrams), 2~4 weeks is a course for the treatment of, is as a result had 60.6% people obtains positive effect.Also someone is also obtained full using large dose oral administration treatment abdominal distention after meal, loose stools and heating etc. The effect of meaning.

(4) peptic ulcer is treated：50~200 milligrams are each taken, 3 times a day.Through trying out one group of 46 patient, pass through After treatment in 4~12 weeks, 34 acquisition positive effects, 9 patient symptoms improve.

(5) can be used for beauty：Oryzanol is referred to as " beauty element ", because it can reduce the fragility of capillary, improves skin Skin microcirculation function, treatment climacteric skin disease, the desquamative eczema of women face, head pityriasis etc..Oryzanol and Wei Sheng Plain E is shared and can also treat alopecia seborrheica and improve skin colour, prevents chapped skin.

(6) multiple canker sore is treated：50 milligrams every time, it is oral that 3 times a day, fully recovers, and can reduce recurrence within 3~6 days Rate.

(7) there is growth-promoting effect：Body weight has " increasingly increasing " trend after teenager takes paddy vitamin.Therefore someone's handle Its one of medicine as child development disorders.The oryzanol also effect with estrogen, can treat the hair of ovarian function Educate incomplete.

(8) children's allotriophagy is treated：It is daily oral 3 times, 10 milligrams every time, taken effect by taking medicine continuously one week.It is thought that paddy is tieed up Element can be by adjusting diencephalon and vegetative nerve function, so as to eliminate different food bitterly.

(9) oryzanol is also commonly used for the auxiliary treatment of menopausal syndrome, and to climacteric insomnia, worrying too much has improvement well Effect.

(10) oryzanol plays the role of good trophic nerve, can improve vegetative dystonia, improves endocrine Disequilibrium, has certain adjustment effect to nervous breakdown patient；Meanwhile, oryzanol can set the mind at rest, anxiety reduction and Tense situation, it is also possible to play the effect for improving the health care of sleep.

(11) oryzanol has antiarrhythmic effect.It can drop myocardial excitability by adjusting vegetative nerve function It is low.The effect for reducing fat of oryzanol can also improve the blood supply of cardiac muscle, play a part of to improve the health care of sleep.Friend's old man night is easy Wake up, suitably take oryzanol effect more preferable.

(12) though oryzanol has certain adjustment effect to insomnia, nervous breakdown patient, for the trouble that severe is had a sleepless night Person's effect is little.Therefore severe is had a sleepless night in clinical medical treatment, with the method for the combination of Chinese tradiational and Western medicine, with oryzanol tabletses, vitamin B1 pieces and Vitamin B6 Tablets, the taste shenan capsule of pure Chinese medicinal preparation nine etc. carry out synthesis treatment, can obtain fast and effectively preferable treatment Effect.On consumption, it is proposed that insomniac can per os hora somni 2-3 pieces every night, the maintenance of 2 every night is gradually transitions by obtaining after effect Dosage.

Oryzanol indication clinically is：For vegetative dystonia, cycle nerve and climacteric synthesis Levy, primary dysmenorrhea, pre-menstrual period nercousness, vascular headache etc..The trade name network of its commercially available parenteral solution is quiet again.Usage and dosage For：Deep intramuscular injection, one time a day, each 40mg (1)；For primary dysmenorrhea, in the moon, premenstrual 10 days start, every time 40mg (1), 20 days as one therapeutic course.

Clinically made by the oryzanol injection network of Shandong PKU Hi-tech Huatai Pharmaceutical Co., Ltd.'s production is quiet again With for quite a long time and achieving huge social benefit.

Specific embodiment

Following examples further illustrate the present invention, rather than the limitation present invention.Hereafter preparation process is for the mesh of citing , and the comparability based on each citing and make some specific description, those skilled in the art completely may be used according to existing knowledge Therefrom to summarize the method that the present invention prepares pharmaceutical composition that obtains.In the present invention some examples hereafter, the present invention is prepared During composition, if not otherwise indicated, auxiliary material used is that pharmaceutical grade is other.

In embodiment below, when using homemade caprylic/capric triglyceride, it is with reference in CN104203896A The method of embodiment 1 and embodiment 3 is homemade in different batches, in the preparation method using a certain proportion of high-purity octanoic acid and Capric acid is esterified with the glycerine of high-purity, and (caprylic/capric ratio can be obtained in that the caprylic/capric triglyceride of quantitative ratio Quantitatively obtained by the octanoic acid of addition simultaneously and the ratio of both capric acid；In addition, can be obtained by adjusting the addition of calcium oxide Obtain have different saponification numbers caprylic/capric triglyceride), wherein the pungent last of the ten Heavenly stems it is total, pungent/last of the ten Heavenly stems than etc. parameter, the measure of each parameter is such as Hereinafter described or as described in the prior art.

A specific method of caprylic/capric triglyceride is prepared with reference to embodiment in CN104203896A 1 and embodiment 3 It is：To addition octanoic acid and capric acid (the two mol ratio in the 250mL flasks containing glycerine (37.5mmol) and equipped with condenser Caprylic/capric ratio determines in the caprylic/capric triglyceride according to obtained in expecting, the caprylic/capric ratio for adding in this example= 2, octanoic acid amount is 100mmol, and capric acid amount is 50mmol, and the two total amount of adding is 150mmol, is 4 times of moles of glycerine) and oxygen Change calcium (0.55mmol).The mixture is heated 22 hours at 175 DEG C under partial vacuum (1 support, pump vacuum).Condenser In water temperature be for about 35 DEG C so as to maintain octanoic acid and capric acid gentle reflux and accelerate water removal under vacuo.Reaction is cooled down It is dissolved in hot ethanol (95%, 400mL) to room temperature and by residue.By the solution charcoal treatment, ethyl acetate/hexane is used (8%) filtered on silica gel and washed, solvent is evaporated off, obtain the pure products of colorless oil.Determined through GC, product octanoic acid/ Capric acid ratio=2.04；Constitute in all octanoic acid and both capric acid of gained saturated fat acid glycerol three ester, the amount of octanoic acid is 67.11%, the amount of capric acid is 32.89%；Show there can be quantitative ratio by adding the octanoic acid and capric acid of quantitative ratio and obtaining The medium chain triglyceride of caprylic/capric composition.In addition after measured, whole saturated fats of the saturated fat acid glycerol three ester are constituted Fat acid in, including 99.7% octanoic acid and capric acid.In addition, it has been found that four times moles that are glycerine with octanoic acid and both capric acid total amount Amount feeds intake, and changes octanoic acid and during both capric acid ratio, can obtain with octanoic acid and capric acid rate of charge identical caprylic/capric than Caprylic/capric triglyceride.The saponification number of obtained caprylic/capric triglyceride is 335 in above example, it has been found that, when When changing the consumption of calcium oxide (based on glycerine), thus it is possible to vary the saponification number of end-product, and calcium oxide addition is bigger Then saponification number is lower, can be readily available caprylic/capric triglyceride of the saponification number in the range of 150~400.In the present invention Hereinafter, if not otherwise specified, the saponification number of caprylic/capric triglyceride used is in the range of 320~350.

In embodiment below, if not otherwise specified, oily caprylic/capric triglyceride used and final using it The composition for arriving, aliphatic acid composition therein is through the test example 1A hereinbelow and GC methods (two methods described in test example 1B Test result is consistent) GC methods are determined, and the aliphatic acid composition result of raw material oil is constituted with the aliphatic acid of final product composition Result is identical.

As previously mentioned, in view of oryzanol is based on the mixture of the ferulic acid ester of ring jackfruit alcohols, and Its main, typical component is cycloartenyl ferulate.Therefore in the present invention can with cycloartenol Ah Wei's acid esters is the object of oryzanol content monitoring, and to describe the quality state of composition or raw material, composition or oryzanol are former Content (%, the mg/mg, i.e., the ring wood spinach included per 100mg raw materials or in composition of cycloartenyl ferulate in material The mg amounts of trailing plants enol ferulic acid ester) it is by CN101482543B (200810119549.7, century Bo Kang) specification [0037] It is measured to [0068] section methods described.

Further, since oryzanol is the ferulic acid ester institute group based on the ferulic acid ester of ring jackfruit alcohols and sterols Into a kind of natural mixture, in normal state, these composition in forulic acid in esterified state presence, but they May with the presence of part in free state (raw material per se with and dissociate from the carboxylate of raw material or preparation ).Free forulic acid in for bulk drug or composition, can refer to leaf money duckweed etc. literature method (Ye Ziping, etc., HPLC determines the content of forulic acid in blood-nourishing soft Chinese angelica capsule, contemporary Chinese Chinese medicine, 2007,9 (1):18；This article Section 1 and the 2nd Section institute support method；The method can be described as " leaf money duckweed method " in the present invention) it is measured ferulaic acid content (%, with relative to thing The amount of cycloartenyl ferulate is represented in material；That is, for certain batch materials, often comprising 100mg cycloartenol asafoetides The mg amounts of forulic acid in the material of acid esters), and can be by containing with the forulic acid after investigating before investigation during study on the stability is tested Amount changes to evaluate the stability of composition.

Composition prepared by following embodiment, unless otherwise noted, is sealed in the vial of inflated with nitrogen, so as to Carry out the experiment of correlation.Various oil or miscella used, constitute the oily saturated fatty acid in following each embodiment In acid, laurate and tetradecylic acid are below 1.0%.

During each prepares the embodiment of composition below, gained end-product its pungent last of the ten Heavenly stems total value, pungent/last of the ten Heavenly stems ratio, soap after measured The parameters such as change value, they are identical with the oil or the data of miscella for feeding intake used in the example, i.e., before and after composition is prepared These parameters are basically unchanged.

First, embodiment part (preparing fluid composition)

Embodiment 1：Prepare fluid composition

Prescription (with 1000 parts of preparations that feed intake, every part of recipe quantity is as follows)：

Oryzanol	20mg
		(the pungent last of the ten Heavenly stems is always=99.7% for caprylic/capric triglyceride；Pungent/last of the ten Heavenly stems ratio=2.04)	Add to 1000mg

Preparation method：Oryzanol is taken, the oil of about 90% formula ratio is added, stirring and dissolving adds oil to full dose, and stirring is equal It is even；Make the liquid for preparing degerming by 0.22 μm of polytetrafluoroethylene (PTFE) filtering with microporous membrane, be dispensed into ampoule bottle, seal, every bottle (specification is 1ml to 1ml:20mg；Can also every bottle other volumes are dispensed to obtain the parenteral solution of other specifications)；Then 121.0 DEG C Pressure sterilizing 30min, obtains the fluid composition as parenteral solution that injectable is used.MCT is own product.

Embodiment 2：Prepare fluid composition

Oryzanol	20mg
		(the pungent last of the ten Heavenly stems is always=98.8% for caprylic/capric triglyceride；Pungent/last of the ten Heavenly stems ratio=1.13)	Add to 1000mg

Preparation method：Injecta composition is obtained with reference to the method for embodiment 1.MCT is own product.

Embodiment 3：Prepare fluid composition

Oryzanol	20mg
		(the pungent last of the ten Heavenly stems is always=98.5% for caprylic/capric triglyceride；Pungent/last of the ten Heavenly stems ratio=1.32)	Add to 1000mg

Embodiment 4：Prepare fluid composition

Oryzanol	20mg
		(the pungent last of the ten Heavenly stems is always=99.1% for caprylic/capric triglyceride；Pungent/last of the ten Heavenly stems ratio=1.56)	Add to 1000mg

Embodiment 5：Prepare fluid composition

Oryzanol	20mg
		(the pungent last of the ten Heavenly stems is always=98.8% for caprylic/capric triglyceride；Pungent/last of the ten Heavenly stems ratio=2.48)	Add to 1000mg

Embodiment 6：Prepare fluid composition

Oryzanol	20mg
		(the pungent last of the ten Heavenly stems is always=98.9% for caprylic/capric triglyceride；Pungent/last of the ten Heavenly stems ratio=3.06)	Add to 1000mg

Embodiment 7：Prepare fluid composition

Oryzanol	20mg
		(the pungent last of the ten Heavenly stems is always=99.2% for caprylic/capric triglyceride；Pungent/last of the ten Heavenly stems ratio=3.48)	Add to 1000mg

Embodiment 8：Prepare fluid composition

Oryzanol	20mg
		(the pungent last of the ten Heavenly stems is always=98.2% for caprylic/capric triglyceride；Pungent/last of the ten Heavenly stems ratio=1.35)	Add to 1000mg

Preparation method：Injecta composition is obtained with reference to the method for embodiment 1.MCT is M-810.

Embodiment 9：Prepare fluid composition

Oryzanol	20mg
		(the pungent last of the ten Heavenly stems is always=97.1% for caprylic/capric triglyceride；Pungent/last of the ten Heavenly stems ratio=1.52)	Add to 1000mg

Embodiment 10：Prepare fluid composition

Oryzanol	20mg
		(the pungent last of the ten Heavenly stems is always=96.4% for caprylic/capric triglyceride；Pungent/last of the ten Heavenly stems ratio=1.97)	Add to 1000mg

Preparation method：Injecta composition is obtained with reference to the method for embodiment 1.MCT is M-810 and M-812 with 2:1 mixing Thing.

Embodiment 11：Prepare fluid composition

Oryzanol	20mg
		(the pungent last of the ten Heavenly stems is always=98.2% for caprylic/capric triglyceride；Pungent/last of the ten Heavenly stems ratio=2.56)	Add to 1000mg

Preparation method：Injecta composition is obtained with reference to the method for embodiment 1.MCT is L-CC.

Embodiment 12：Prepare fluid composition

Oryzanol

20mg

(the pungent last of the ten Heavenly stems is always=97.8% for caprylic/capric triglyceride；Pungent/last of the ten Heavenly stems ratio=3.03)

Add to 1000mg

Preparation method：Injecta composition is obtained with reference to the method for embodiment 1.MCT be L-CC andMCT is with 1:3 Mixture.

Embodiment 13：Prepare fluid composition

Embodiment 1, embodiment 2, embodiment 6, embodiment 8, the formula of embodiment 11, material, preparation method are respectively referred to, it is different Be only that caprylic/capric triglyceride consumption is changed to 750mg, obtain five injection fluid samples.

Embodiment 14：Prepare fluid composition

Embodiment 1, embodiment 2, embodiment 6, embodiment 8, the formula of embodiment 11, material, preparation method are respectively referred to, it is different Be only that caprylic/capric triglyceride consumption is changed to 1500mg, obtain five injection fluid samples.

Embodiment 21：Prepare fluid composition

With reference to the formula and preparation method of embodiment 1, different is only the caprylic/capric glycerine three for using self-control different size instead Ester, it includes more than 97% octanoic acid and capric acid, but the octanoic acid of different size MCT and the ratio of capric acid be respectively 0.72,0.79, 0.91st, 1.03, four injection fluid samples are obtained, marker number can be distinguished for E211, E212, E213, E214.

Embodiment 22：Prepare fluid composition

With reference to the formula and preparation method of embodiment 1, different is only the caprylic/capric glycerine three for using self-control different size instead Ester, it includes more than 97% octanoic acid and capric acid, but the octanoic acid of different size MCT and the ratio of capric acid be respectively 3.76,4.03, 4.59th, 5.12, four injection fluid samples are obtained, marker number can be distinguished for E221, E222, E223, E224.

Embodiment 23：Prepare fluid composition

The dispensing and preparation method of E211, E212, E213, E214 of embodiment 21 are respectively referred to, different will only use Caprylic/capric triglyceride consumption is changed to 750mg (relative to every 20mg oryzanol), obtains four injection fluid samples, can be respectively Marker number is E231, E232, E233, E234；In addition, respectively referring to matching somebody with somebody for E211, E212, E213, E214 of embodiment 21 Material and preparation method, different is only that the caprylic/capric triglyceride consumption that will be used is changed to 1500mg (relative to every 20mg paddy dimension Element), four injection fluid samples are obtained, marker number can be distinguished for E235, E236, E237, E238.

Embodiment 24：Prepare fluid composition

The dispensing and preparation method of E221, E222, E223, E224 of embodiment 22 are respectively referred to, different will only use Caprylic/capric triglyceride consumption is changed to 750mg (relative to every 20mg oryzanol), obtains four injection fluid samples, can be respectively Marker number is E241, E242, E243, E244；In addition, respectively referring to matching somebody with somebody for E221, E222, E223, E224 of embodiment 22 Material and preparation method, different is only that the caprylic/capric triglyceride consumption that will be used is changed to 1500mg (relative to every 20mg paddy dimension Element), four injection fluid samples are obtained, marker number can be distinguished for E245, E246, E247, E248.

Various embodiments above, using the preparation method (filtration sterilization, ampoule bottle heat sealing, pressure sterilizing) of classical parenteral solution It is made parenteral solution.Certainly they can also direct packaging in vial (can also be plastic bottle such as high-density polyethylene bottle) Oral liquid formulations are made, or soft capsule preparation can be prepared into by the method for Examples below of the present invention.So that these liquid Composition is in different dosage forms and can be used for different methods of administration.

Embodiment 31：Prepare the present composition

Prescription (with 10000 parts of preparations, the prescription per deal is as follows)：

Oryzanol	20mg
		Peppermint oil	0.001mg
(the pungent last of the ten Heavenly stems is always=97.9% for LABRAFAC CC；Pungent/last of the ten Heavenly stems ratio=2.13)	Add to 1000mg

Preparation method：Oryzanol is taken, the oil of about 90% formula ratio, and other auxiliary materials, stirring and dissolving is added, oil is added extremely Full dose, stirs, and obtains final product the present composition, is transparent liquid, deposit-free.

It (can also be that plastic bottle is for example high that the half liquid of the present embodiment composition prepared by more than is packaged in vial Density polyethylene bottle) in, it is oral liquid；Second half is prepared as follows into soft capsule preparation：

Capsule skin is formulated：Gelatin 40%, glycerine 18%, sorbierite 7%, water 35%.

Following step method is used, the invention described above is wrapped in the capsule skin of preparation in the composition of liquid, in every 20mg containing active component.

Gelatin is taken, adds suitable quantity of water to make gelatin water absorption and swelling.The another other compositions removed outside gelatin, are placed in glue pot, And it is heated to 70 DEG C.After dissolving is mixed, add swelling gelatin to glue pot, stir evenly, melt and keep temperature 70 C in tank left The right side, then it is evacuated to glue bubble-free.Then put glue, the filtering of 100 mesh, and by filtrate insulation stand more than 2 hours it is standby.Will be molten The gelatin frozen glue liquid for melting is cast in cold drum-like cylinder by automatic rotation pressure capsule machine (RGY6-20 types encapsulating machine), and system is each Frozen glue bar twice about 5~6in wide.Frozen glue bar passes across roller, there is provided suitable bar arrangement, then by capsule heart oryzanol medicine Liquid is fitted into automatic rotation pressure capsule machine.Capsule heart fluid temperature is controlled at 25 DEG C or so, carries out pelleting.Extrude capsule and pill and by sizing Afterwards, washed with 95% ethanol.Dry, after after ethanol volatilization, the drier into automatic rotation pressure capsule machine is dried 3-5 hours.It is right Dried capsule and pill carries out selecting ball.After selecting qualified ball, carry out packaging and obtain final product.

Oral liquid or soft capsule preparation in vial are more than packaged in, they can make as typical oral formulations With.

Embodiment 32：Prepare the present composition

Preparation method：Prepared according to the method for embodiment 31, obtain the fluid composition in oral liquid and soft capsule.

Embodiment 33：Prepare the present composition

Oryzanol	20mg
		Tween 80	0.4mg
(the pungent last of the ten Heavenly stems is always=99.5% for caprylic/capric triglyceride；Pungent/last of the ten Heavenly stems ratio=3.13)	Add to 2000mg

Preparation method：Prepared according to the method for embodiment 31, obtain the fluid composition in oral liquid and soft capsule.MCT is certainly System.

Embodiment 34：Prepare the present composition

Oryzanol

20mg

Peanut oil	40mg
		(the pungent last of the ten Heavenly stems is always=98.4% for caprylic/capric triglyceride；Pungent/last of the ten Heavenly stems ratio=2.53)	Add to 1000mg

Preparation method：Prepared according to the method for embodiment 31, obtain the fluid composition in oral liquid and soft capsule.MCT is certainly System.Although adding a small amount of peanut oil in this example, but said composition, the final combination comprising peanut oil are tested by GC methods In thing the pungent last of the ten Heavenly stems it is total=96.1%；It is pungent/last of the ten Heavenly stems ratio=2.54.

Embodiment 35：Prepare the present composition

Oryzanol	20mg
		Rapeseed oil	40mg
(the pungent last of the ten Heavenly stems is always=97.8% for caprylic/capric triglyceride；Pungent/last of the ten Heavenly stems ratio=1.68)	Add to 1000mg

Preparation method：Prepared according to the method for embodiment 31, obtain the fluid composition in oral liquid and soft capsule.MCT is certainly System.Although adding rapeseed oil in this example, but said composition is tested by GC methods, in the final composition comprising rapeseed oil The pungent last of the ten Heavenly stems is always=95.7%；It is pungent/last of the ten Heavenly stems ratio=1.67.

Embodiment 36：Prepare the present composition

Oryzanol	20mg
		BFL1227	5mg
BHA	0.1mg
		M-810/M-812 mixed (1:3 mix, and the pungent last of the ten Heavenly stems is always=96.8%；Pungent/last of the ten Heavenly stems ratio=1.13)	To 1000mg

Obtained in above example 1 to embodiment 14, embodiment 21 to embodiment 24, embodiment 31 to embodiment 36 all Fluid composition, they are transparent liquid, are showed no sediment.

2nd, test example part

Test example 1A：The method of the aliphatic acid composition that gas-chromatography is tested in composition or oil

This test example is provided will using the gas-chromatography test various compositions for referring to of the invention and right of the present invention The method of various compositions in the range of asking or the aliphatic acid composition in the oil for being used in the present invention.

Chromatographic column：Material：Fused silica (fused silica)；Size：30m long,Fixing phase：It is poly- Ethylene glycol 20000, film is thick 0.5 μm.

Carrier gas：Chromatographic grade helium.

Flow velocity：1.3ml/min.

Temperature：

Detection：Flame ion

Split ratio：1:100

Sample size：1μl

Sensitivity：Main peak peak height is the 50% to 70% of recorder full scale in the chromatogram of reference solution (a).

System suitability：Separating degree in the chromatogram of reference solution (a) between methyl caprylate and methyl caprate peak It is not less than 4.0；The signal to noise ratio at methyl caproate peak is not less than 5 in the chromatogram of reference solution (b)；The chromatogram of reference solution (a) The number of theoretical plate at middle methyl caprate peak is not less than 15000.

Test solution：In 25ml conical flasks, 0.10g test substances are made to be dissolved in the 20g/l NaOH methyl alcohol of 2ml In solution, seethed with excitement 30min under reflux condenser, and 2.0ml boron trifluoride-methanol solution, reboiling are added by condenser 30min.4ml heptane, reboiling 5min are added by condenser.Cooling, adds 10.0ml saturated nacl aqueous solutions, and shaking is about 15 seconds, a certain amount of saturated nacl aqueous solution was added so that upper strata mutually reaches the neck of flask.2ml upper stratas phase is taken, 3 are washed with water Secondary, each 2ml uses anhydrous sodium sulfate drying.

Reference solution (a)：The 0.50g calibration substance mixtures constituted described in Table X are taken, is dissolved in heptane, then with identical Solvent is diluted to 50.0ml.

Reference solution (b)：1.0ml reference solutions (a) is diluted to 10.0ml with heptane.

Reference solution (c)：Take mixture (its fatty acid mixt phase with test substance of 0.50g fatty acid methyl esters When), it is dissolved in heptane, then 50.0ml is diluted to same solvent.Also commercially available fatty acid methyl ester admixture can be used.

Table X：The mixture [note 1] of calibration substance

Note [1] for the GC of capillary column and breach import (split inlet) system, when using calibration curve When carrying out quantitative analysis, recommend to adding the component with maximum mixture of chain lengths to be measured in calibration mixture.

The numerical value that note [2] is calculated using calibration curve is given by taking PEG 20000 post as an example.

Qualitative analysis：Differentiate the peak of reference solution (c) chromatogram；These peaks can also be by using the color of reference solution (a) The information of spectrogram and Table X differentiates to draw calibration curve：

A) use isothermal operation condition, it is assumed that retention time reduce logarithm as fatty acid carbon atoms number function；It is logical The mode for crossing " the equivalent chain length " of thus obtained straight line and different chromatographic peak differentiates chromatographic peak.The calibration curve of saturated acid It is main track.The point that the logarithm value that the retention time of unsaturated acids is reduced is located in the line corresponds to the carbon of referred to as " equivalent chain length " The non integer value of atom.

B) linear temperature program is used, it is assumed that retention time is corresponding with the carbon number of aliphatic acid；By referring to calibration Curve differentiates.

Quantitative analysis：In general, using normalized, the peak area sum wherein in chromatogram in addition to the solvents sets It is 100%.The percentage that the area sum at whole peaks is accounted for by the area for determining respective peaks calculates the amount of certain component.Less than total The peak of less than the 0.05% of area does not consider.

Test example 1B：The method of the aliphatic acid composition that gas-chromatography is tested in composition or oil

Test solution：Materials (present composition prepares their oil) 0.1g, in putting 50ml conical flasks, plus 0.5mol/L potassium hydroxide methanol solution 2ml, are heated to reflux 30 minutes in 65 DEG C of water-baths, let cool, plus 15% boron trifluoride first Alcoholic solution 2ml, then be heated to reflux in 65 DEG C of water-baths 30 minutes, let cool, plus heptane 4ml, continue to be heated back in 65 DEG C of water-baths Stream lets cool after 5 minutes, plus saturated nacl aqueous solution 10ml washings, shakes up, and standing makes layering, takes upper liquid, washes with water 3 times, Each 2ml, upper liquid through anhydrous sodium sulfate drying, as need testing solution.Separately methyl caproate, methyl caprylate, capric acid are taken respectively Methyl esters, methyl laurate, methyl myristate reference substance, plus n-hexane dissolution and diluting be made in every lml it is each containing above-mentioned reference substance The solution of 0.1mg, as reference substance solution.Reference solution (a) is methyl caproate, methyl caprylate, methyl caprate, laurate first Ester, methyl myristate compare 2 with weight:60:30:4:2 solution prepared with normal hexane.Reference solution (b)：1.0ml references is molten Liquid (a) is diluted to 10.0ml with heptane；

Carrier gas：Chromatographic grade helium；

Flow velocity：1.3ml/min；

Temperature：

Detection：Flame ion；

Split ratio：1:100；

Sample size：1μl；

Test example 2：High-temperature treatment is tested

Whole parenteral solutions obtained in whole parenteral solutions, embodiment 21 to embodiment 24 obtained in embodiment 1 to embodiment 14, Whole glass bottle oral liquids, make them be placed in 45 DEG C of insulating boxs and place April obtained in embodiment 31 to embodiment 36, test Oryzanol content in each composition (is characterized, similarly hereinafter) with the content of cycloartenyl ferulate, and with 0 month (i.e. without 45 The reagent of DEG C disposal) oryzanol comparision contents in sample, calculate residual after oryzanol in each composition was disposed through 4 months temperature Remaining rate (%).

Oryzanol remnants rates (%)=[the valley dimension cellulose contents of 4 valleys dimension cellulose content ÷ 0] × 100%

Result shows：Oryzanol remnants rates (%) is 80.5% in whole samples obtained in embodiment 21 and embodiment 23 Between~89.1%, and the pungent/last of the ten Heavenly stems of caprylic/capric triglyceride used is lower than smaller display oryzanol remnants rates；Implement Oryzanol remnants rates (%) is between 83.5%~90.7% and used in whole samples obtained in example 22 and embodiment 24 Pungent/the last of the ten Heavenly stems of caprylic/capric triglyceride is lower than bigger display oryzanol remnants rates；It is each obtained in embodiment 1 to embodiment 14 Oryzanol remnants rates (%) is 96.8%~99.4% in whole samples obtained in sample and embodiment 31 to embodiment 36 Between.

In addition, determining the content of forulic acid in the sample before and after the above-mentioned disposal through 45 DEG C-April, calculate high through this with following formula Forulic acid increment rate before and after temperature disposal：

Forulic acid increment rate=[0 month ferulaic acid content of (April ferulaic acid content -0 month ferulaic acid content) ÷] × 100%

Result shows：In whole samples obtained in embodiment 21 and embodiment 23 forulic acid increment rate 141%~ Between 237%, and the pungent/last of the ten Heavenly stems of caprylic/capric triglyceride used is bigger than smaller display forulic acid increment rate；Embodiment 22 And in whole samples obtained in embodiment 24 forulic acid increment rate between 153%~215%, and caprylic/capric used Pungent/the last of the ten Heavenly stems of triglycerides is bigger than bigger display forulic acid increment rate；Each sample and reality obtained in embodiment 1 to embodiment 14 Forulic acid increment rate is between 21%~36% in applying whole samples obtained in example 31 to embodiment 36.It can be seen that, with this hair The composition of bright feature has particularly excellent active component stability and impurity increases slow.

Complementary testing 21：Oryzanol injection is obtained according to the dispensing of CN1340341A specifications embodiment 1, proportioning and method, The sample is designated as 341#.Oryzanol injection (plant is obtained according to the dispensing of CN1338255A specifications embodiment 1, proportioning and method Oil is soybean oil, saponification number 193, iodine value 106), the sample is designated as 255#.According to the dispensing of CN101057826A specifications embodiment 1, Proportioning and method are obtained oryzanol injection, and the sample is designated as 826#.According to the dispensing of CN101480405B specifications embodiment 1, match somebody with somebody Than oryzanol injection is obtained with method, the sample is designated as 405#.Will be pungent used by injection soybean oil 10g, the embodiment of the present invention 1 Acid/Triglyceride DDD 10g, oryzanol 2g are added in container, and this container is placed in oil bath, are heated to 70 DEG C, stirring to medicine Thing dissolves, and is added after 3- phosphatid ylcholines 4g is dissolved with ethanol 2ml, volatilizes ethanol, forms homogeneous oil phase；By water for injection 80ml is placed in another container, adds sorbierite 5g, poloxamer 4g to form water phase in 70 DEG C of stirring and dissolvings；By water in stirring In lower addition oil phase, continue stir be made colostrum within 1 hour, inject water to 100ml, with sodium hydroxide solution adjust pH to 7.0；Colostrum high pressure homogenizer is homogenized to emulsion droplet size passed examination, is filtered through filter, lead to nitrogen, packing to 2ml peaces Small jar, sealing；Sterilized under the conditions of carrying out 100 DEG C, 30min with rotary high pressure sterilizer, obtain fluid composition sample and be designated as 789#. This five samples are carried out into 45 DEG C of constant temperature disposal April according to the method for test example 2, and determines relevant parameter, as a result oryzanol is remaining In the range of 84.4% to 92.6%, forulic acid increment rate is in the range of 198%~304% for rate (%).

Test example 3：Low temperature disposal experiment

People generally expect to place them in cool dark place during medicine long-term storage, and this drug storage environment is usual 20 DEG C can be less than, or even can be less than 10 DEG C, meeting more very is less than 5 DEG C.Although oryzanol has excellent in oil of the invention Solubility, but whether it is still beneficial to investigate the physical change that they place at low temperature, particularly may determine that them There is the generation of solubility reduction.

Low temperature disposes test method：Placed 4 months at a temperature of the liquid sealed in vial is placed in into 5 ± 1 DEG C, surveyed Oryzanol content (being characterized with the content of cycloartenyl ferulate, similarly hereinafter) in fixed now liquid, is designated as content A1；So The sample through being postponed at this 4 months is stood 24 hours at 25 DEG C afterwards, then determines the oryzanol content in now parenteral solution, be designated as Content A2；Oryzanol relative amount is calculated with following formula：

Oryzanol relative amount=(A1 ÷ A2) × 100%

The situation that active component has solubility reduction in showing liquid if the oryzanol relative amount is less than 100% is sent out Raw (serious is likely to result in precipitation), although the situation of this solubility reduction can be obtained after placing certain hour at room temperature To disappear, but then it is that those skilled in the art extremely expect if this situation can be overcome.

As a result：Whole glass obtained in whole parenteral solutions, embodiment 31 to embodiment 36 obtained in embodiment 1 to embodiment 14 The bottled oral liquid of glass, their oryzanol relative amount is in the range of 88%~94%, and each of which is quiet through 25 DEG C Put the oryzanol content after 24 hours equal with content at 0 month, this shows that these samples have after being placed for a long time through low temperature Micro content reduction (being probably that solubility reduction triggers), but this phenomenon can be recovery.In addition, the present inventor In complementary testing, when to complete obtained in whole parenteral solutions, embodiment 31 to embodiment 36 obtained in embodiment 1 to embodiment 14 Portion's glass bottle oral liquid supplement addition oleic acid (injection) 1mg, 2.5mg or 5mg (both with respect to the oryzanol meter of every 20mg) When, gained with the addition of the fluid composition of oleic acid when the disposal of above-mentioned 5 DEG C of placements 4 months is carried out, and oryzanol relative amount is equal In the range of 99.6%~100.2%.

Test example 4：Safety testing

The embodiment of the present invention 1, embodiment 3, parenteral solution obtained in embodiment 6, shine the implementation in the complementary testing of test example 3 Example 1, embodiment 3, embodiment 6 are formulated and preparation method and add 2.5mg oleic acid (both with respect to the oryzanol meter of every 20mg) again and obtain Three parenteral solutions, and commercially available oryzanol injection (Chinese medicines quasi-word H20031238, Beijing University high-tech China is safe to produce), totally 7 injections Fluid samples, according to existing drug registration laws and regulations requirement (《Chemical induced irritation, anaphylaxis and hemolytic investigative technique instruct former Then problem》Seminar；Chemical induced irritation, anaphylaxis and hemolytic investigative technique guideline, drug research technological guidance Principle, Beijing：China Medical Science Press, 2006：124) local irritation test and anaphylaxis experiment, are carried out, is as a result shown Show that these samples meet the requirement of these specifications, for example, be showed no " bulge " phenomenon in injection site.Show that these are combined Thing has good security.

Test example 5：The property of injection is investigated

The embodiment of the present invention 1, embodiment 3, parenteral solution obtained in embodiment 6, shine the implementation in the complementary testing of test example 3 Example 1, embodiment 3, embodiment 6 are formulated and preparation method and add 2.5mg oleic acid (both with respect to the oryzanol meter of every 20mg) again and obtain Three parenteral solutions, and commercially available oryzanol injection (Chinese medicines quasi-word H20031238, Beijing University high-tech China is safe to produce), totally 7 injections Fluid samples, the method for issuing standard WS1- (X-419) -2003Z according to office of State Food and Drug Administration determines each gainer Index.As a result, for this 7 injection fluid samples, every Testing index is in the range of quality standard regulation.

Above disclosed is only presently preferred embodiments of the present invention, can not limit the right of the present invention with this certainly Scope.The equivalent variations made according to scope of the present invention patent, belong to the scope that the present invention is covered.

Claims

1. a kind of pharmaceutical composition, it includes the weight portion of oryzanol 20 and oily 750 ~ 1500 weight portions；The oil is saturated fat Acid glycerol three ester, and constitute whole saturated fatty acids of the saturated fat acid glycerol three ester, including more than 95% octanoic acid and Capric acid；And in constituting all octanoic acid and capric acid of the saturated fat acid glycerol three ester, octanoic acid and the ratio of capric acid for (1.13 ~ 3.48)：1.

2. pharmaceutical composition according to claim 1, it includes the weight portion of oryzanol 20 and oily 1000 weight portion.

3. pharmaceutical composition according to claim 1, the oil is saturated fat acid glycerol three ester, and constitutes the saturated fat In whole saturated fatty acids of acid glycerol three ester, including more than 96% octanoic acid and capric acid.

4. pharmaceutical composition according to claim 1, the oil is saturated fat acid glycerol three ester, and constitutes the saturated fat In whole saturated fatty acids of acid glycerol three ester, including more than 98% octanoic acid and capric acid.

5. pharmaceutical composition according to claim 1, it is in the composition of liquid condition.

6. pharmaceutical composition according to claim 5, the composition in liquid condition is the form of transparent solution.

7. pharmaceutical composition according to claim 1, it is the seal-packed parenteral solution form of vial.

8. pharmaceutical composition according to claim 1, it is the oral liquid of drug bottle packaging.

9. pharmaceutical composition according to claim 1, it is the soft capsule form being sealed in soft capsule shell.

10. pharmaceutical composition according to claim 1, wherein also including oleic acid；Wherein in terms of comprising the weight portion of oryzanol 20, oil The amount of acid is 1 ~ 5 weight portion.

11. pharmaceutical compositions according to claim 1, it is oral formulations, and wherein also containing one or more Medicinal additive, selected from flavouring class, antioxidant class, surfactant-based, tackifier class, vegetable oil.

12. pharmaceutical compositions according to claim 1, it shines gas chromatography and determines aliphatic acid composition, full in the whole for measuring In aliphatic acid, the amount of caproic acid, laurate and tetradecylic acid is each respectively lower than 3%, and octanoic acid and capric acid amount sum are higher than 95%.

A kind of 13. pharmaceutical preparations, it includes claim 1-12 any one described pharmaceutical compositions, and wraps up said composition Pharmaceutically acceptable lapping.

14. pharmaceutical preparations according to claim 13, the lapping is selected from：Plastics, glass, capsule skin.

15. pharmaceutical preparations according to claim 13, it is the soft capsule or drops that capsule suitcase is wrapped up in, or plastic bottle Or the oral solutions or drops of vial parcel, or the parenteral solution that vial is wrapped up.

16. pharmaceutical preparations according to claim 13, it is the sterile solution for injection of vial parcel.