CN101313908A - Composition for treating autonomic nerve disorder, preparation and uses thereof - Google Patents
Composition for treating autonomic nerve disorder, preparation and uses thereof Download PDFInfo
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- CN101313908A CN101313908A CNA200810097493XA CN200810097493A CN101313908A CN 101313908 A CN101313908 A CN 101313908A CN A200810097493X A CNA200810097493X A CN A200810097493XA CN 200810097493 A CN200810097493 A CN 200810097493A CN 101313908 A CN101313908 A CN 101313908A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Abstract
The invention discloses a composition taking cycloartenyl ferulate and 24-methylene cycloartenyl ferulate as active ingredients, a preparation of the composition used as a medicine, and an application of the preparation. The total content of the cycloartenyl ferulate and the 24-methylene cycloartenyl ferulate is over 90 percent of the total active ingredients by weight percentage. As the medicine, the composition can be injection and frozen-dried powder injection and also can be an oral solid preparation, a medicine composition used for treating autonomic imbalance, climacteric syndrome, primary dysmenorrheal and premenstrual tension, periodic psychosis, vascular headache, head trauma syndrome, gastrointestinal imbalance and hyperlipemia, etc.
Description
Technical field
The present invention relates to a kind of autonomic nerve disorder, climacteric syndrome, primary dysmenorrhea, premenstrual tension syndrome, periodic psychosis, vascular headache, injury of head syndrome, gastrointestinal nervous disorder disease, the compositions of hyperlipemia, the preparation that contains this pharmaceutical composition, preparation technology and uses thereof for the treatment of.
Background technology
Along with the rhythm of modern society's live and work is accelerated gradually, modern metropolitan cities people's sub-health state allows of no optimist.Suffer from autonomic nerve disorder, climacteric syndrome, primary dysmenorrhea, premenstrual tension syndrome etc. according to statistics because the vegetative nerve malfunction causes sympathetic nerve and parasympathetic nervous disequilibrium, the sickness rate that is not organic disease is the trend that rises year by year.
Autonomic nerve disorder causes by psychic trauma and long-term nervous, fatigue usually, causes corticocerebral miopragia, causes that transition is excited and tired out and fall ill rapidly.These sick characteristics are: the slow symptom of onset is various.Common has: headache, dizzy, feel dizzy, tinnitus, insomnia, dreaminess, absent minded, memory weakens, abdominal distention uncomfortable in chest, inappetence, dyspepsia, constipation, diarrhoea etc.; Still have in addition that irritated irritability, anxiety, anxiety or lethargy are depressed, sore waist and aching in the waist and the back, fatigue and weak, symptoms such as cardiopalmus hyperhidrosis, coldness of the body cold extremities.This disease is all brought many inconvenience for patient's physical and mental health and family, and this palindromia rate height.
That climacteric syndrome is meant more is female in the body behind the postmenopausal women, progesterone level reduces cardiovascular, nerve, the hormonal system dysfunction that causes, causes symptom such as dysfunctional uterine hemorrhage, paroxysmal hectic fever and perspiration, pudendum and vaginal atrophy, osteoporosis and personality to change.Climacteric is that the people changes a bigger stage in life.It also is the time that life " the only way which must be passed " accounts for the 1/3-2/5 of the whole the natural duration of life of life this period.Women particularly, the ovary endocrine has had obvious decline in body, when organ function gradually descends, produces some symptoms such as emotional, irritable, melancholy, anxiety, indignation and liable to fits of temper etc.The women sees in early days that dizzy cardiopalmus is uncomfortable in chest more, emotional lability, being happy and angry uncertainly and menoxenia; And vegetative nerve symptom, as flushing, hectic fever, perspiration, dizzy, headache, tinnitus, numbness of the fingers, paraesthesia, insomnia, functional blood circulation symptom etc.The male sees irritated irritability, tinnitus, cardiopalmus, hyposexuality, tired easily in early days more.
Primary dysmenorrhea is owing to its high incidence causes people's attention, in several investigation, find at young women, woman worker's absence rate that dysmenorrhea causes is between 34～50%, about 10% primary dysmenorrhea patient can seriously have to work in 1～3 day to every month, when the absent from duty and corresponding economic loss that causes in this situation of the U.S. has 600,000,000 work about every year and 2,000,000,000 dollars.In addition, be in a bad way but still adhere in the middle of the patient of work that cause production capacity to descend easily, possibility of accident occurrence rises, degradation under the work quality at those.Send out the property dysmenorrhea and refer to that the genitals does not have organic disease, before and after passing through or stomachache, the soreness of waist, lower abdomen between menstrual period, occur and weigh down and expand or other are uncomfortable, influence live and work.Its cause of disease it be unclear that in good 6 months～2 years of sending out after 15～25 years old and menophania, is one of adolescence common sympton.Its incidence rate report differs, and is about 42～90%, and wherein severe pain is through accounting for 18%.Its cause of disease is still unclear at present, and the research of the primary dysmenorrhea cause of disease has been expanded to physiology, psychology, social every field.
Premenstrual tension syndrome is meant that it is the clinical syndrome of main clinical manifestation with the anxiety for one group that the women produces premenstruum such as agitation, irritability, headache, insomnia, distending pain of the breast, abdominal distention etc.Premenstrual tension incidence rate height, performance is complicated, directly influences numerous women's physical and mental health.
Oryzanol is to treat the most frequently used medicine of above-mentioned disease at present, also is used for the functional food additive simultaneously and improves human body constitution, and prevention improves above-mentioned disease.Its raw material comes from the extract of Testa oryzae oil.Ring jackfruit alcohols ferulic acid ester is the micro-bioactive substance that exists in the Testa oryzae oil, and nineteen fifty-three is known too Lang Faxian by Japanese earth house, and names after extracting and be oryzanol, and it is mixed by the ferulic acid ester of tens kinds of sterols, triterpene alcohol and forms.The material composition complexity changes when present production technology confusion, the ratio of its constituent.And in the commercially available oryzanol, the percentage composition sum of main component cycloartenyl ferulate, 24-methylene basic ring jackfruit alcohol ferulic acid ester is about 70% only, contains other composition in a large number.Because composition is numerous, make the difficult quality of oryzanol control, and the water solublity extreme difference.Oryzanol mostly is oral formulations at present, and bioavailability is relatively poor.And oryzanol injection preparation in the market is the oil-soluble injection, only uses for intramuscular injection, is easy to generate side effect such as injection site pain even muscular death behind the patient infusion, and patient dependence is relatively poor.
Patent 02135610.6 discloses a kind of the purification with solvent extraction method and has obtained the method for 60-70% purity oryzanol, but the oryzanol purity of mentioning is lower.Patent 00122929.X discloses a kind of disease treatment purposes of oryzanol injection, but does not have further to further investigate the purification of oryzanol.
(grain and oils and fats 2002 1:37-40) have comprehensively been set forth the nutritive validity of oryzanol, and effects such as disease prevention are not discussed but use with regard to oryzanol purification and special component for oryzanol and the application in functional food thereof.
Therefore, prior art needs a kind of purity height in a hurry, can be used for intravenous oryzanol composition and a kind of convenience, economy, is suitable for the above method for compositions of preparation of industrialized great production.
Summary of the invention
The applicant is on the basis of big quantity research, oryzanol medicine material with working standard, by modern separation and purification means, remove the composition of the acyclic jackfruit alcohols ferulic acid ester in most of oryzanol raw material, the percentage composition sum that makes cycloartenyl ferulate among the present invention, 24-methylene basic ring jackfruit alcohol ferulic acid ester is brought up to more than 90% by original 70% and (is contained 90%).Ring jackfruit alcohols ferulic acid ester compositions behind the refining purification (the percentage composition sum of cycloartenyl ferulate, 24-methylene basic ring jackfruit alcohol ferulic acid ester is more than 90%), can further make water soluble parenteral solution and freeze-dried powder that injection for intravenous is used, well solve the product bad water-solubility.The preparation that adopts the present composition to make is compared with commercially available oryzanol oil for injection, and zest reduces greatly, and drug effect obviously strengthens.And, the preparation technology that the present invention adopts, cost is low, be convenient to operation, controllability is good, is suitable for industrialized great production.
The invention provides a kind of pharmaceutical composition, the percentage composition sum of effective ingredient cycloartenyl ferulate wherein, 24-methylene basic ring jackfruit alcohol ferulic acid ester is brought up to more than 90% (containing 90%) by original 70%, preferred 95%, more preferably 99%.
The chemical structural formula of cycloartenyl ferulate, 24-methylene basic ring jackfruit alcohol ferulic acid ester is as shown below:
Contrast by the percentage composition of modern chromatography the ferulic acid ester component in commercially available oryzanol medicine material and the raw material of the present invention.
The content ratio of cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester is 4 in the compositions of the present invention: 1-1: 4, preferred 2: 1-1: 2, more preferably 1.5: 1-1: 1.5.
The percentage composition contrast of the ferulic acid ester component among the commercially available oryzanol medicine material of table 1 and the present invention
Above-mentioned test data shows, raw material of the present invention has carried out control preferably from purity, make the content of main component cycloartenyl ferulate in the raw material and 24-methylene basic ring jackfruit alcohol ferulic acid ester obtain substantial raising, removed other composition.
A large amount of experimental studies show that the present invention is owing to contain highly purified cycloartenyl ferulate, 24-methylene basic ring jackfruit alcohol ferulic acid ester, and it has more advantage than the miscellaneous oryzanol of multiple composition aspect active.
A kind of injection for intravenous uses but the present invention further provides, and contains the preparation of drug combination method of cycloartenyl ferulate, 24-methylene basic ring jackfruit alcohol ferulic acid ester, may further comprise the steps:
1. (the percentage composition sum of cycloartenyl ferulate, 24-methylene basic ring jackfruit alcohol ferulic acid ester is about 70-75% to get commercially available oryzanol raw material, be called for short " purity is 70-75% ", down together), with first solvent and second solvent solution backflow dissolving, filter, filtrate is left standstill, and separates out crystallization, filter drying.
2. exsiccant crystallization is redissolved with first solvent refluxing, filter, leave standstill, separate out crystallization, filter drying.
3. repeating step 2,1-10 time.
4. the 1-5 that the mother solution that leaches behind the recrystallization in the above step is reclaimed solution to volume and be contained solute doubly leaves standstill, and separates out crystallization, filters drying.
5. the crystallization that step 4 is obtained is dissolved with first solvent refluxing, filters, and leaves standstill, and separates out crystallization, filters drying.
6. repeating step 5,1-10 time.
7. the mother solution that leaches behind the recrystallization in the step 5,6 is merged be recycled to volume be contained solute 1-5 doubly after, leave standstill, separate out crystallization, filter drying.
8. the crystallization of gained in the step 7 is done recrystallization and handled, method is with step 5.
9. with step 3, the crystallized mixed of gained in 6,8, finished product.
Wherein, first solvent is selected from ethyl acetate and acetone, is preferably ethyl acetate, and second solvent is selected from dehydrated alcohol, and methanol is preferably dehydrated alcohol.
In the step 1, the mixed proportion of first solvent and second solvent is 1: 200-200: 1; Preferably, the ratio of the two is 1: 100-100: 1; More preferably, the ratio of the two is 1: 50-50: 1; Most preferably, the ratio of the two is 1: 1-50: 1.
In the method for the present invention, the preferred reflux of the backflow of each step, heating-up temperature 40-90 ℃, preferred 50-80 ℃.
In the method for the present invention, the quantity of solvent that adds during recrystallization is 1-50 a times of solute amount, and preferred 1-10 times, preferred 2-8 doubly.
The present invention also provides a kind of pharmaceutical preparation, contains above pharmaceutical composition and pharmaceutically acceptable carrier.Pharmaceutical preparation can be the preparation that oral formulations and injections, particularly injection for intravenous such as tablet, capsule, powder, granule, pill are used, more especially the injection used of the injection for intravenous of non-oily solvent.
Injection of the present invention contains pharmaceutical composition of the present invention and surfactant, described surfactant can be anion, cation or non-ionic surface active agent, include but not limited to the polyoxyethylene sorbitan ester class, for example, polyoxyethylene sorbitan fatty acid ester, Polyethylene Glycol, sodium lauryl sulphate, dodecyl sodium sulfate, lithium dodecyl sulfate, chenodeoxycholic acid, NaTDC, Sodium glycodeoxycholate., N-lauryl sarcosine, cetylpyridinium chloride, phospholipid.Preferred surfactants is tween, Polyethylene Glycol or its mixture.Tween wherein can be a polysorbas20,40,60,80; Polyethylene Glycol can be a Macrogol 200,400,600,800,1000,2000,4000,8000 or its mixture, preferred Macrogol 200,400,800 or its mixture; Most preferably be Tween 80, PEG400 or its mixture.
Injection of the present invention also can randomly further comprise other acceptable accessories such as excipient, antioxidant, PH regulator, antiseptic, isotonic agent.Wherein can be selected from but to be not limited to be in mannitol, lactose, glucose, sorbitol, sodium chloride, gelatin hydrolysate, dextran, sucrose, glycine, the polyvinylpyrrolidone etc. one or more to excipient; Be preferably mannitol or glucose.Antiseptic can be selected from but be not limited to is in phenol, cresol, three tert-butyl alcohols, benzyl alcohol, the nipalgin one or more.Stabilizing agent can be selected from but be not limited in sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, thiourea, vitamin C, butylated hydroxyarisol, dibutyl phenol, propyl gallate, tocopherol, ascorbyl palmitate, ethylenediaminetetraacetic acid, the disodiumedetate one or more.The PH regulator can be the acceptable organic acid of pharmacy, organic base, mineral acid, inorganic base, include but not limited to hydrochloric acid, citric acid, tartaric acid, phosphoric acid, Metaphosphoric acid, poly-Metaphosphoric acid, carbonic acid, sulphuric acid, nitric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium citrate, potassium citrate, sodium bicarbonate, potassium bicarbonate, amine carbonate, sodium hydrogen phosphate, dipotassium hydrogen phosphate, ethanolamine, diethanolamine, triethanolamine, 1, one or more in 2-hexamethylene diamine, sodium carbonate, potassium sodium tartrate, potassium metaphosphate, Kurrol's salt, the Polymeric sodium metaphosphate..
The injection that provides of the present invention can be water soluble parenteral solution, transfusion, lyophilized injectable powder, preferred water soluble parenteral solution and lyophilized injectable powder, most preferably lyophilized injectable powder.
Injection of the present invention can adopt the preparation method of the injection of this area routine to prepare.
The present invention also provides above pharmaceutical composition and the purposes of pharmaceutical preparation in the medicine of diseases such as preparation treatment autonomic nervous function deficiency disorder, primary dysmenorrhea, climacteric syndrome, pre-menstrual period nercousness.
Embodiment 1
1. getting commercially available oryzanol raw material (purity is 70-75% ") 1kg, is ethyl acetate and 5 times of amounts of dehydrated alcohol mixed solution of 20: 1 with ratio, and the dissolving that refluxes is filtered, and leaves standstill, and separates out crystallization and filters drying.Exsiccant crystallization (purity is about 84-88%) is redissolved with the ethyl acetate backflow of 8 times of amounts, filter, leave standstill, separate out crystallization, filter drying.Above re-crystallization step is repeated 3-5 time.
2. the mother solution that leaches behind the recrystallization in the step 1 is merged that to be recycled to volume be behind 2 times of contained solute, to leave standstill, separate out crystallization, filter drying.
3. with the ethyl acetate backflow dissolving of the crystallization in the step 2 (purity is about 85-87%), filter, leave standstill, separate out crystallization, filter drying with 8 times of amounts.Repeat above re-crystallization step 3-5 time.
4. the mother solution that leaches behind the recrystallization in the step 3 is merged that to be recycled to volume be behind 2 times of contained solute, to leave standstill, separate out crystallization, filter drying.
5. the crystallization (purity is about 85-87%) of gained in the step 4 is done recrystallization and handled, method is with step 3.
6. with step 1, the crystallized mixed of gained in 3,5, finished product.
By the high performance liquid chromatogram detection method, the percentage composition sum that draws cycloartenyl ferulate, 24-methylene basic ring jackfruit alcohol ferulic acid ester brings up to 93% by original 70%.Cycloartenyl ferulate is 1.16: 1 with the content ratio of 24-methylene basic ring jackfruit alcohol ferulic acid ester in the compositions.
Embodiment 2
1. chromatographic condition and system suitability test: with the octadecylsilane chemically bonded silica is filler; Methanol-acetonitrile (40: 60) is a mobile phase; Flow velocity is 1.5ml/min; The detection wavelength is 327nm; Sensitivity is 0.005AUFS.Theoretical cam curve should be not less than 2000 by calculating.
2. need testing solution preparation: precision takes by weighing commercially available oryzanol raw material, each 10mg of raw material of the present invention, to the 10ml measuring bottle, is dissolved in water and standardize solution, shakes up, and is need testing solution.
3. measure: the accurate need testing solution 10 μ l that draw, inject chromatograph of liquid, write down chromatogram, check the percentage composition of each component with area normalization method.
4. measurement result
Table 2 measurement result
The more commercially available oryzanol raw material of material purity of the present invention height is described.
Embodiment 3
Prescription
1000 bottles of injection freeze-dried powders of the present invention (containing 20mg/ bottle of the present invention):
Raw material 20g of the present invention
PEG400 250g
Tween 80 250g
10% mannitol 6000g
Water for injection adds to 5000ml
Be lyophilized into 1000 altogether
Be principal agent with raw material of the present invention in the prescription, Tween 80 is solubilizing agent, and PEG400 is a cosolvent, and mannitol is proppant, and water for injection is freezing solvent.
The preparation process
Take by weighing the water for injection of raw material of the present invention, tween 80, PEG-400, mannitol and 80% recipe quantity of recipe quantity, stirring is clarified material dissolution of the present invention to solution, stirring at room 20 minutes, with 0.45 μ m microporous filter membrane coarse filtration, filtrate adds to the full amount of water for injection, reuse 0.22 μ m microporous filter membrane aseptic filtration.Gained filtrate is carried out visible foreign matters, pH and content check.
Import cillin bottle, plug and fine straining liquid after cleaning, sterilizing into bottling department, determine that according to content the packing volume carries out fill false add plug simultaneously.
The cillin bottle that branch the is installed sample lyophilizing dish of packing into is put into freeze drying box, lyophilizing, and lyophilizing finishes, and plug is pressed in the cillin bottle fully, and logical at last atmosphere takes out freeze dried sample.Promptly get injection freeze-dried powder of the present invention.
Embodiment 4
The sedative-hypnotic effect of raw material of the present invention
Method:
The sleep test down of 1 pentobarbital sodium threshold
70 of ICR mices, initial body weight 18-22g is divided into 7 groups, 10 every group at random: 1. blank group; 2. raw material I group of the present invention (25mg/kg); 3. raw material II group of the present invention (50mg/kg); 4. raw material II I group of the present invention (100mg/kg); 5. stable organize (2mg/kg); 6. oryzanol group (100mg/kg); 7. oryzanol group (200mg/kg).
Each organizes the mouse stomach administration for three days on end, and blank group gives the equal-volume solvent.Last administration in the 5th day (stable group lumbar injection is stable) back 1h, lumbar injection pentobarbital sodium (20mg/kg), the administration volume is 0.1ml/10g, respectively organizes the number of animals of righting reflex loss in observation and the record 15min.
The test of 2 autonomic activitieses
70 of ICR mices, initial body weight 18-22g is divided into 7 groups, 10 every group at random: 1. blank group; 2. raw material I group of the present invention (25mg/kg); 3. raw material II group of the present invention (50mg/kg); 4. raw material II I group of the present invention (100mg/kg); 5. stable organize (2mg/kg); 6. oryzanol group (100mg/kg); 7. oryzanol group (200mg/kg).
Each organizes the mouse stomach administration for three days on end, and blank group gives the equal-volume solvent.1h after the last administration in the 4th day (behind the stable 20min of stable group lumbar injection) places mice in the autonomic activities case, adapts to 5min, the autonomic activities number of times in the record 10min.
The result:
Investigate the sedative-hypnotic effects of freeze-dried powders of the present invention by two tests of sleep under autonomic activities, the pentobarbital threshold.The result is as shown in table 1, and raw material of the present invention all shows tangible sedative-hypnotic effect in 2 different tests, reduces the autonomic activities number of times of mice significantly, increases the number of elements of the animal that falls asleep in the sleep test under the threshold.Its sedative-hypnotic effect also demonstrates clear and definite dose-effect relationship, and is the most obvious with the high dose group effect, all has statistical significance with the difference of matched group, and its effect is suitable with the high dose effect of oryzanol crude drug; Middle dosage is suitable with the effect of oryzanol crude drug low dosage.
Table 3 sedative-hypnotic effect (X ± SD)
Compare with the blank group:
*P＜0.05,
*P＜0.01,
* *P＜0.001
Embodiment 5
Raw material of the present invention merges the influence that chronic stress causes the mice climacteric syndrome to castration
96 of female ICR mices, be divided into 19 cages at random by body weight, every cage 5-6 only, take out 10 at random as sham operated rats, all the other 86 mices are all as animal pattern, and mouse peritoneal is anaesthetized, and (sham operated rats is only cut to remove bilateral ovaries, do not remove ovary), sew up back benzylpenicillin sodium for injection infection 4d.Postoperative the 4th day beginning give in the following order the chronic imprevision of mice stress, (1) foot-shock: the 36V alternating current, stimulate once every 1min, continue 10s, totally 15 times; (2) frozen water swimming: 4 ℃, 5min; (3) thermostimulation: 45 ℃, 5min; (4) rock: 140 times/min, 1.5hr; (5) folder tail: apart from the 1cm of root of the tail place, 1min; (6) prohibit water: 24hr; (7) fasting: 24hr; (8) put upside down round the clock: 24hr; Every kind stimulates 3 times.Model mice is divided into 7 groups (10 every group) at random behind the chronic stress: 1. model group, 2. nilestriol group (0.25mg/kg/d), raw material I group 3. of the present invention (25mg/kg); 4. raw material II group of the present invention (50mg/kg); 5. raw material II I group of the present invention (100mg/kg); 6.; Oryzanol group (100mg/kg); 7. oryzanol group (200mg/kg).
Press 20ml/kg volume gastric infusion every day twice (sham operated rats and model group only give solvent), continuously 16d.Behind the last administration 45min, mouse orbit is got blood, and separation of serum is measured E2, FSH; Rapidly broken end is got brain afterwards, gets the uterus, the adrenal gland weighs, and calculates organ index.The result carries out statistical procedures (t check).
The result: after the modeling, model group uterus index significantly reduces (P＜0.01); Compare with model group, positive drug nilestriol and oryzanol (200mg/kg/d) group uterus weight and index be obviously rising (P＜0.01) all, after the filling stomach gave raw material of the present invention, high dose group (100mg/kg/d) uterus index significantly raise (P＜0.01), sees table 4 for details.
Table 4 pair climacteric model mice uterus, the exponential influence of adrenal gland (X ± SD)
Compare with model group:
*P＜0.05,
*P＜0.01; Compare with sham operated rats:
ΔP＜0.05,
The Δ ΔP＜0.01.
Embodiment 6
Raw material of the present invention is to the influence of dysmenorrhea mice
80 of female ICR mices, initial body weight 18-22g is divided into 8 groups, 10 every group at random: 1. blank group; 2. model group; 3. raw material I group of the present invention (25mg/kg); 4. raw material II group of the present invention (50mg/kg); 5. raw material II I group of the present invention (100mg/kg); 6. ibuprofen group (100mg/kg); 7. oryzanol group (100mg/kg); 8. oryzanol group (200mg/kg).
For increasing the sensitivity of uterus to oxytocin, except that the blank group, mouse subcutaneous injection diethylstilbestrol 0.1mg/, once a day, totally 10 days, the first day and doomsday dosage doubled.Begin gastric infusion after ten days, for three days on end, 1h after the last administration in the 4th day, lumbar injection oxytocin 0.5u/ only carry out writhing test immediately, observe in the 20min animal and turn round the body time first, turn round the body number of times and calculate and on average turn round the body number of times.
By selecting the dysmenorrhea mouse model of oxytocin modeling for use, investigate the analgesic effect of raw material of the present invention, the result is as shown in table 5.Raw material of the present invention, high dose especially, that can significantly reduce the dysmenorrhea mice turns round the body number of times, prolongs incubation period, improves and turns round the body suppression ratio.Effect obviously is better than the oryzanol raw material.
The influence of table 5 pair dysmenorrhea mouse writhing
Embodiment 7
The freeze-dried powder that embodiment 2 is made carries out the zest of animal blood vessels.Method is to get 6 of health, ear edge not damaged rabbit, is divided into two groups at random by body weight, i.e. test group and sodium chloride injection matched group.Absorb with oryzanol oil with clinical adult that to penetrate the liquor amount serve as according to design rabbit dosage, slowly inject administration from rabbit left side auricular vein, matched group gives the isometric(al) sodium chloride injection, gives 5 days continuously.Result of the test shows, compare with the sodium chloride injection group, the intravenous injection freeze-dried powder of feedstock production of the present invention, reach the last administration during the administration after 24 hours, blood vessel and surrounding tissue redness are not seen in perusal, the visible rabbit ear vein clear in structure of tissue slice inspection, indivedual vasodilation are obvious, the tube wall thickness is even, and inwall is level and smooth, the Guan Zhouwu inflammatory exudate.Show that the freeze-dried powder with feedstock production of the present invention does not have the obvious stimulation effect to the rabbit auricular vein under the experiment condition.
Get the commercially available molten injection of oryzanol oil equally and make irritation test, the result shows injection site and surrounding tissue redness thereof, scleroma occurs, tissue slice is checked the visible vessels expansion obviously, pipe has inflammatory exudate in week, shows that the molten injection of oryzanol oil produces tangible stimulation to intramuscular injection site under experiment condition.
Claims (10)
1. a pharmaceutical composition it is characterized in that active component is cycloartenyl ferulate and 24-methylene basic ring jackfruit alcohol ferulic acid ester, and the content sum of these two kinds of materials accounts for more than 90%, by weight percentage of total composition.
2. according to the compositions of claim 1, it is characterized in that the cycloartenyl ferulate percentage composition is higher than 30%.
3. according to the compositions of claim 1, it is characterized in that the cycloartenyl ferulate percentage composition is higher than 50%.
4. each preparation of drug combination method of claim 1-3, it comprises that first solvent wherein is selected from ethyl acetate and acetone with first solvent and second solvent step of recrystallization purifying repeatedly, second solvent is selected from dehydrated alcohol and methanol.
5. according to the preparation method of claim 4, may further comprise the steps
I. get the oryzanol raw material, reflux with first solvent and the second solvent solution and dissolve, filter, filtrate is left standstill, and separates out crystallization, filters drying.
Ii. exsiccant crystallization is redissolved with first solvent refluxing, filter, leave standstill, separate out crystallization, filter drying.
Iii. repeating step ii, 1-10 time.
Iv. the 1-5 that the mother solution that leaches behind the recrystallization in the above step is reclaimed solution to volume and be contained solute doubly leaves standstill, and separates out crystallization, filters drying.
V. the crystallization that step I v is obtained is dissolved with first solvent refluxing, filters, and leaves standstill, and separates out crystallization, filters drying.
Vi. repeating step v, 1-10 time.
Vii. the mother solution that leaches behind the recrystallization among step v, the vi is merged be recycled to volume be contained solute 1-5 doubly after, leave standstill, separate out crystallization, filter drying.
Viii. the crystallization of gained among the step vii is done recrystallization and handled, method is with step v..
Ix. with step I ii, vi, the crystallized mixed of gained among the viii, finished product.
6. pharmaceutical preparation is characterized in that containing each pharmaceutical composition and pharmaceutically acceptable carrier among the claim 1-3.
7. according to the preparation of claim 6, it is injection, lyophilized injectable powder, transfusion.
8. according to the preparation of claim 7, contain surfactant in the preparation.
9. preparation according to Claim 8, surfactant wherein is selected from tween, Polyethylene Glycol or its mixture.
10. the described compositions of claim 1-3 is in treatment autonomic nerve disorder, climacteric syndrome, primary dysmenorrhea, premenstrual tension syndrome, the application of periodic psychosis, vascular headache, injury of head syndrome, gastrointestinal nervous disorder disease, hyperlipemia.
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| JPH0745512B2 (en) * | 1986-10-21 | 1995-05-17 | タマ生化学株式会社 | Method for concentrating and purifying oryzanol constituents |
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- 2008-05-30 WO PCT/CN2008/001071 patent/WO2008148303A1/en active Application Filing
- 2008-05-30 CN CN200810097493XA patent/CN101313908B/en active Active
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| Publication number | Publication date |
|---|---|
| CN101313908B (en) | 2010-09-01 |
| WO2008148303A1 (en) | 2008-12-11 |
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