WO2008148303A1

WO2008148303A1 - A composition for treating vegetative dystonine syndrome and pharmaceutical preparation and application thereof

Info

Publication number: WO2008148303A1
Application number: PCT/CN2008/001071
Authority: WO
Inventors: Shouzhu Hao
Original assignee: Beijing Century Biocom Pharmaceutical Technology Co., Ltd.
Priority date: 2007-05-31
Filing date: 2008-05-30
Publication date: 2008-12-11
Also published as: CN101313908A; CN101313908B

Abstract

The composition containing cycloartenol ferulic acid ester and 24-methylenecycloaltanol ferulic acid ester as the active components and pharmaceutical preparation and application thereof are provided. The weight percent of the two active components is above over 90% in the composition. The said composition can be injections, freeze-dried powders or oral solid preparation, and can be used to treat vegetative dystonie syndrome, climacteric period syndrome, essential dysmenorrhea, premenstrual tension, periodic psychosis, vascular headache, head injury syndrome, stomach intestine nerve detuning syndrome and hyperlipoidemia etc.

Description

Composition, therapeutic preparation and use thereof for treating autonomic dysfunction

The present invention relates to a treatment for autonomic disorders, menopausal syndrome, primary dysmenorrhea, premenstrual tension, periodic psychosis, vascular headache, head trauma syndrome, gastrointestinal disorders, hyperlipidemia A composition, a formulation containing the pharmaceutical composition, a preparation process, and use thereof. Background technique

With the accelerated pace of life and work in modern society, the sub-health status of modern urbanites is not optimistic. According to statistics, autonomic dysfunction, menopausal syndrome, primary dysmenorrhea, premenstrual tension, etc. due to autonomic dysfunction, leading to the imbalance of sympathetic and parasympathetic nerves, the incidence of organic diseases is increasing year by year. trend.

Autonomic disorders are usually caused by trauma and long-term stress and fatigue, leading to a decrease in the function of the cerebral cortex, causing transitional excitement and rapid fatigue. The disease is characterized by a wide onset of symptoms. Common ones are: headache, dizziness, dizziness, tinnitus, insomnia, multiple dreams, lack of concentration, memory loss, chest tightness, bloating, loss of appetite, indigestion, constipation, diarrhea, etc.; , nervous or lack of energy, back pain, fatigue, weakness, palpitations, sweating, cold and cold limbs. This disease causes many inconveniences to the patient's physical and mental health and the family, and the recurrence rate of the disease is high.

Menopausal syndrome refers to cardiovascular, neurological, and endocrine system dysfunction caused by decreased estrogen and progesterone levels in women after menopause, leading to functional uterine bleeding, paroxysmal hot flashes and sweating, vulva and vaginal atrophy, and bone mass. Symptoms such as looseness and personality changes. Menopause is a period of great change in a person's life. It is also the time when life is the only way to live, which accounts for 1/3-2/5 of the life of the whole life. Especially in women, when the ovarian endocrine secretion in the body has a significant decline, and the organ function is gradually declining, some symptoms such as irritability, impatience, depression, anxiety, anger and temper are easily generated. Early onset of women, dizziness, chest tightness, mood change, moodiness and menstrual disorders; and autonomic symptoms such as flushing, hot flashes, sweating, dizziness, headache, tinnitus, finger numbness, paresthesia, insomnia, functional circulatory symptoms Wait. Men often have irritability, tinnitus, palpitations, loss of libido, and fatigue.

Primary pain has attracted people's attention because of its high incidence. In several surveys of young women, the rate of female workers' dysmenorrhea caused by dysmenorrhea is between 34% and 50%, and about 10% of patients with primary dysmenorrhea will Severe to 1 to 3 days per month can not work, the absence of this situation in the United States and the corresponding economic loss is about every year There are 600 million working hours and 2 billion dollars. In addition, among those patients who are seriously ill but still persistent in their work, it is easy to cause a decline in productivity, an increase in the likelihood of an accident, and a decline in the quality of work. Idiopathic dysmenorrhea refers to the absence of organic lesions in the reproductive organs. Abdominal pain, backache, lower abdominal bulge or other discomfort occur before, during or after menstruation, affecting life and work. Occurs in 15 to 25 years old and 6 months after menarche ~ 2 years, the cause is still unclear, is one of the common symptoms of puberty. The incidence rate is different, about 42 to 90%, of which severe dysmenorrhea accounts for about 18%. The cause is still unclear, and the research on the causes of primary dysmenorrhea has been extended to various fields of physiology, psychology and society.

Premenstrual stress refers to a group of clinical syndromes in which anxiety is the main clinical manifestation of irritability, irritability, headache, insomnia, breast tenderness, and bloating. The prevalence of premenstrual stress is high and the performance is complex, which directly affects the physical and mental health of women.

Oryzanol is currently the most commonly used drug for the treatment of these conditions, and is also used in functional foods to improve the body's constitution and prevent the above-mentioned conditions. The raw material is derived from the extract of rice bran oil. The carrageenan ferulate is a trace bioactive substance present in rice bran oil. It was discovered by Tsuchiya Tatsuro in 1953, and it was named as oryzanol after extraction. It is composed of a dozen alcohols and triterpene alcohol. The ester is mixed. The composition of the raw materials is complex, the current production process is confusing, and the proportion of its constituents varies. Moreover, in the commercially available oryzanol, the sum of the percentages of the main components of the cycloartenol ferulate and the 24-methylene ring-buckylan ferulate is only about 70%, and contains a large amount of other components. . Due to the large number of ingredients, the quality of oryzanol is difficult to control and the water solubility is extremely poor. At present, oryzanol is an oral preparation with poor bioavailability. At present, the oryzanol injection preparation on the market is an oil-soluble injection, which is only used for intramuscular injection. After the injection, the patient is prone to cause side effects such as pain at the injection site and even muscle necrosis, and the patient compliance is poor.

Patent 02135610.6 discloses a process for purifying 60-70% pure oryzanol by solvent extraction, but the oryzanol mentioned is of low purity. Patent 00122929.X discloses a therapeutic treatment of oryzanol injection, but does not further study the purification of oryzanol.

Oryzanol and its application in functional foods (Food and Oil 2002, 1:37-40) comprehensively described the nutritional effects and disease prevention of oryzanol, but did not discuss the purification of oryzanol and the application of specific ingredients.

Accordingly, there is an urgent need in the prior art for a process for preparing the above compositions in a high purity, injectable oryzanol composition and a convenient, economical, industrially suitable process. Summary of the invention

On the basis of a large number of studies, the applicant removed the ingredients of the non-cyclo-bambolan alcohol ferulic acid ester in most of the oryzanol raw materials by means of modern separation and purification means on the basis of a large number of studies, so that the ring in the present invention The sum of the percentages of wood pineappenol ferulate and 24-methylene cyclobolinol ferulate increased from 70% to over 90% (including 90%). The purified and purified carrageenan alcohol ferulate composition (the sum of the percentages of the cycloartenol ferulate and the 24-methylene cyclopentyl alcohol ferulate) is 90% or more) It can be further prepared into a water-soluble injection solution and a lyophilized powder preparation for intravenous injection, which solves the problem of poor water solubility of the product. Compared with the commercially available oryzanol injection oil, the preparation prepared by using the composition of the present invention has greatly reduced irritation and markedly enhanced drug efficacy. Moreover, the preparation process adopted by the invention has low cost, is easy to operate, has good controllability, and is suitable for industrial large-scale production.

The present invention provides a pharmaceutical composition in which the sum of the percentages of the active ingredients cyclopentylenol ferulate and 24-methylenecyclo-bambolanol ferulate is increased from 70% to 90% (containing 90%) or more, preferably 95%, more preferably 99%.

The chemical structure of cycloartenol ferulate and 24-methylene cyclopentyl alcohol ferulate is shown in the figure below.

Methylene ringwood pineapple ester ester The percentage of the commercially available oryzanol drug raw material and the ferulic acid ester component in the raw material of the present invention was compared by modern chromatography.

The content ratio of the cycloartipenol ferulate to the 24-methylenecyclo-bambolanol ferulate in the composition of the present invention is 4: 1-1: 4, preferably 2: 1-1: 2, more Preferably 1.5: 1 -1 : 1.5. Comparison of percentages of commercially available oryzanol drug raw materials and ferulic acid ester components in the present invention

Commercial oryzanol

Component The content of the raw material of the invention (%) The content of the raw material of the drug (%)

Sterols ferulic acid ester

Wherein: β-glutanol ferulate 6~8 0~0.5

Vegetable oil Alcohol ferulic acid ester. 10~12 0~0.5 Soybean meal ferulic acid ester Bu 2 0~0.2 Triterpene alcohol ferulic acid 酉 ί

Wherein: Ringwood pineapple alcohol ferulate 8~10 0~2

Cycloartenol ferulate fermentate 25-30 20~79

24-methylene ring wood pineapple alcohol ferulate 35~40 20~79

24-Methylcyclo-coniferin ferulate 0.2-0.5 0~5 The above test data shows that the raw material of the present invention is better controlled in terms of purity, and the main component of the raw material is rhododendron ferulic acid. The content of ester and 24-methylenecyclo-bambolanol ferulate has been substantially improved, removing other components.

A large number of experimental studies have shown that the present invention is superior in activity to oryzanol which is mixed with various components due to the high purity of the cyclopentenol ferulate and the 24-methylene ringwood pyruvate ferulic acid ester. .

The present invention further provides a method for preparing a pharmaceutical composition comprising a cyclic wood pineolinol ferulate, 24-methylenecyclo-bambolanol ferulate, for intravenous injection, comprising the steps of:

1. The sum of the percentages of commercially available oryzanol raw materials (cycloartenol ferulate and 24-methylene cyclopentyl alcohol ferulate) is about 70-75%, referred to as "purity 70-75". %", the same below), the first solvent and the second solvent mixed solution are reflux-dissolved, filtered, and the filtrate is allowed to stand, crystallized, filtered, and dried.

2. The dried crystals are reconstituted with a first solvent, filtered, allowed to stand, crystallized, filtered, and dried.

3. Repeat steps 2, 1-10 times.

4. The mother liquor recovered by recrystallization after the above step is recovered to a volume of 1-5 times the volume of the solute contained therein, allowed to stand, crystallized, filtered, and dried.

5. The crystal obtained in the step 4 is dissolved in a first solvent under reflux, filtered, allowed to stand, crystallized, filtered, and dried.

6. Repeat steps 5 and 1-10 times.

7. The mother liquor filtered out after the recrystallization in steps 5 and 6 is combined and recovered to a volume of 1-5 times the volume of the solute contained, and then allowed to stand, crystallized, filtered, and dried.

8. The crystallization obtained in step 7 is recrystallized in the same manner as in step 5.

9. Mix the crystals obtained in steps 3, 6, 8 to give the final product. Wherein the first solvent is selected from the group consisting of ethyl acetate and acetone, preferably ethyl acetate, and the second solvent is selected from the group consisting of anhydrous ethanol, methanol, preferably anhydrous ethanol.

In the step 1, the mixing ratio of the first solvent and the 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 process of the present invention, the reflux of each step is preferably heated under reflux at a temperature of from 40 to 90 ° C, preferably from 50 to 80 ° C. In the method of the present invention, the amount of the solvent to be added during recrystallization is 1 to 50 times, preferably 1 to 10 times, preferably 2 to 8 times the mass of the solution.

The invention also provides a pharmaceutical formulation comprising the above pharmaceutical composition and a pharmaceutically acceptable carrier. The pharmaceutical preparation may be an oral preparation such as a tablet, a capsule, a powder, a granule or a pill, and an injection, particularly a preparation for intravenous injection, more particularly a non-oil-soluble injection for intravenous injection. .

The injection of the present invention contains the pharmaceutical composition of the present invention and a surfactant, and the surfactant may be an anionic, cationic or nonionic surfactant, including but not limited to polyoxyethylene sorbitan esters, for example, polyoxygen Ethylene sorbitan fatty acid ester, polyethylene glycol, sodium lauryl sulfate, sodium dodecyl sulfate, lithium dodecyl sulfate, chenodeoxycholic acid, sodium deoxycholate, glycodeoxycholic acid Sodium, N-lauryl sarcosine, hexadecanoyl chloride, phospholipids. Preferred surfactants are Tween, polyethylene glycol or mixtures thereof. The Tween may be Tween 20, 40, 60, 80; the polyethylene glycol may be polyethylene glycol 200, 400, 600, 800, 1000, 2000, 4000, 8000 or a mixture thereof, preferably polyethylene glycol 200, 400, 800 or a mixture thereof; most preferred is Tween 80, polyethylene glycol 400 or a mixture thereof.

The injection of the present invention may also optionally further comprise other pharmaceutically acceptable excipients such as excipients, antioxidants, pH adjusting agents, preservatives, isotonic agents, and the like. Wherein the excipient may be selected from, but not limited to, one or more of mannitol, lactose, glucose, sorbitol, sodium chloride, hydrolyzed gelatin, dextran, sucrose, glycine, polyvinylpyrrolidone, etc.; preferably mannitol Or glucose. The preservative may be selected from, but not limited to, one or more of phenol, cresol, tri-tert-butanol, benzyl alcohol, and paraben. The stabilizer may be selected from, but not limited to, sodium sulfite, sodium hydrogen sulfite, sodium metabisulfite, sodium thiosulfate, thiourea, vitamin C, tert-butyl p-hydroxyanisole, dibutyl phenol, propyl gallate, tocopherol, One or more of ascorbyl palmitate, ethylenediaminetetraacetic acid, and disodium edetate. The pH adjusting agent may be a pharmaceutically acceptable organic acid, an organic base, an inorganic acid, an inorganic base, including but not limited to hydrochloric acid, citric acid, tartaric acid, phosphoric acid, metaphosphoric acid, polymetaphosphoric acid, acid, sulfuric acid, nitric acid, acetic acid, Sodium hydroxide, potassium hydroxide, sodium citrate, potassium citrate, sodium hydrogencarbonate, potassium hydrogencarbonate, ammonium carbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, ethanolamine, diethanolamine, triethanolamine, 1, 2 - already diamine, carbonic acid One or more of sodium, potassium sodium tartrate, potassium metaphosphate, potassium polymetaphosphate, and sodium metaphosphate.

The injection provided by the present invention may be a water-soluble injection, an infusion, a lyophilized powder injection, preferably a water-soluble injection liquid and a lyophilized powder injection, and most preferably a lyophilized powder injection.

The injection of the present invention can be produced by a method of preparing a conventional injection in the art.

The present invention also provides the use of the above pharmaceutical compositions and pharmaceutical preparations for the preparation of a medicament for the treatment of autonomic dysfunction, primary dysmenorrhea, menopausal syndrome, premenstrual tension and the like. Example 1

1. Take commercially available oryzanol raw material (purity: 70-75%") lkg, use a mixture of ethyl acetate and absolute ethanol in a ratio of 20:1 for 5 times, dissolve at reflux, filter, let stand, precipitate crystal filtration, The dried crystals (purity: about 84-88%) were reconstituted with 8 times of ethyl acetate under reflux, filtered, allowed to stand, crystals were precipitated, filtered, and dried. The above recrystallization step was repeated 3-5 times.

2. The mother liquor which has been recrystallized in the step 1 is recovered and recovered to a volume twice the volume of the solute contained, and then allowed to stand, crystallized, filtered, and dried.

3. The crystals in step 2 (purity of about 85-87%) were refluxed with 8 times the amount of ethyl acetate, filtered, allowed to stand, crystallized, filtered, and dried. Repeat the above recrystallization step 3-5 times.

4. The mother liquor filtered out after recrystallization in step 3 is combined and recovered to a volume twice the volume of the solute contained, and then allowed to stand, crystallized, filtered, and dried.

5. The crystal obtained in step 4 (purity is about 85-87%) is recrystallized in the same manner as in step 3.

6. Mix the crystals obtained in steps 1, 3, and 5 to obtain the final product.

By the high-performance liquid phase detection method, it was found that the sum of the percentages of the cycloartenol ferulate and the 24-methylene cyclobambolan ferulate increased from 70% to 93%. The content ratio of the cycloartenol ferulate to the 24-methylene cyclobukilan ferulate in the composition was 1.16:1. Example 2

1. Chromatographic conditions and system suitability test: octadecyl silane bonded silica as a filler; methanol-acetonitrile

(40: 60) is the mobile phase; the flow rate is L5ml/min; the detection wavelength is 327nm; the sensitivity is 0.005AUFS. The number of theoretical plates should be no less than 2000.

2. Preparation of test solution: Weigh accurately the commercially available oryzanol raw material, 10mg of the raw material of the invention, into a 10ml volumetric flask, add water to dissolve and make up to volume, and shake well, that is, the test solution. 3. Determination: Precision extraction of the test solution ΙΟμΙ, injection into the liquid chromatograph, recording the chromatogram, the area content normalization method to check the percentage of each component.

4. Measurement results

Table 2 Measurement results

环木菠萝醇醇阿魏 24-Methylene ring wood pineapple alcohol A A; +今昼 Test sample

Acid content (%) Wei ester content (%) ( % ) Sale of oryzanol raw materials 32 38 70

Inventive materials of the invention 50 43 93

It is indicated that the raw material of the present invention has higher purity than the commercially available oryzanol raw material. Example 3

Prescription

1000 bottles of frozen powder needle of the invention (including 20mg/bottle of the invention) for injection:

The raw material of the invention 20g

Polyethylene glycol 400 250g

Tween 80 250g

10% mannitol 6000g

Add water to 5000ml

Co-freeze into 1000 prescriptions with the main raw material of the present invention, Tween 80 as a solubilizer, polyethylene glycol 400 as a cosolvent, mannitol as a proppant, and water for injection as a lyophilized solvent.

Formulation process

Weigh the prescribed amount of the material of the present invention, Tween-80, PEG-400, mannitol and 80% of the prescribed amount of water for injection, stir to dissolve the raw material of the present invention until the solution is clarified, stir at room temperature for 20 minutes, and use a 0.45 μm microporous membrane. After coarse filtration, the filtrate was added with water for injection to the whole amount, and then sterilized by filtration using a 0.22 μm microporous membrane. The obtained filtrate was subjected to visible foreign matter, ρΗ and content test.

The washed and sterilized vials, rubber stoppers and fine filtrates are introduced into the filling room, and the filling volume is determined according to the content to be filled and half-filled.

The sampled vials are placed in a freeze-dried tray, placed in a freeze-drying tray, lyophilized, lyophilized, the gel plug is completely pressed into the vial, and finally the atmosphere is taken out, and the lyophilized sample is taken out. That is, the lyophilized powder for injection of the present invention is obtained. Example 4

The sedative and hypnotic effect of the raw material of the invention

method-

1 pentobarbital sodium subthreshold sleep test

70 ICR mice, initial weight 18-22 _g , were randomly divided into 7 groups, 10 in each group: 1 blank control group; 2 Inventive material group I (25 mg/kg); 3 Inventive material group II (50 mg/ Kg); 4 The present invention group III (100 mg / kg); 5 stability group (2 mg / kg); 6 oryzanol group (100 mg / kg); 7 oryzanol group (200 mg / kg;).

Each group of mice was intragastrically administered for 3 consecutive days, and the blank group was given an equal volume of vehicle. On the 5th day after the last administration (in the stable group, intraperitoneal injection of diazepam), lh barbital sodium (20mg/kg) was intraperitoneally injected, the dosage volume was 0.1ml/10g, and the corrective reflex disappeared in each group within 15 minutes. The number of animals.

2 Independent activity test

70 ICR mice, initial weight 18-22 g, were randomly divided into 7 groups, 10 in each group: 1 blank control group; 2 Inventive material group I (25 mg/kg); 3 Inventive material group II (50 mg/kg) 4; the present invention raw material group III (100mg / kg); 5 stability group (2mg / kg); 6 oryzanol group UOOmg / kg); 7 oryzanol group (200mg / kg).

Each group of mice was intragastrically administered for 3 consecutive days, and the blank group was given an equal volume of vehicle. On the 4th day after the last administration of lh (after the intraperitoneal injection of diazepam for 20 minutes), the mice were placed in an autonomous activity box for 5 minutes, and the number of spontaneous activities within 10 minutes was recorded. Results - The sedative and hypnotic effects of the freeze-dried powder needle of the present invention were examined by two experiments of autonomous activity and sub-threshold sleep of pentobarbital. The results are shown in Table 1. The raw materials of the present invention exhibited significant sedative and hypnotic effects in two different tests, significantly reducing the number of spontaneous activities of the mice, and increasing the number of sleeping animals in the subthreshold sleep test. Its sedative and hypnotic effect also showed a clear dose-effect relationship. The effect was most obvious in the high-dose group, and the difference from the control group was statistically significant. The effect was similar to the high-dose effect of oryzanol drug substance; medium dose and oryzanol bulk drug The low dose is equivalent. Table 3 Sedative and hypnotic effects (±SD)

Compared with the blank group: *P<0.05, **P<0.01, ***P<0.001 Example 5

Effect of the raw materials of the invention on ovarian syndrome caused by castration combined with chronic stress

96 female ICR mice were randomly divided into 19 cages according to body weight, 5-6 per cage, 10 randomly selected as sham operation group, and the remaining 86 mice were used as model animals. The mice were anesthetized by abdominal cavity to remove bilateral ovaries ( The sham operation group only cut open, did not remove the ovaries. After suturing, the injection was treated with penicillin sodium for 4 days. On the fourth day after surgery, the mice were given chronic unpredictable stress in the following order: (1) electric shock foot: 36V alternating current, stimulated every lmin for 10s, 15 times; (2) ice water swimming: 4° C, 5min; (3) Thermal stimulation: 45 ° C, 5 min; (4) Shake: 140 times / min, 1.5 hr _; (5) Tail: lcm from the base of the tail, lmin; (6) Water ban: 24 hr; (7) Fasting: 24hr _; (8) Upside down: 24hr; 3 times for each stimulus. The mice after chronic stress were randomly divided into 7 groups (10 in each group): 1 model group, 2 Nilestriol group (0.25 mg/kg/d), 3 inventive material group I (25 mg/kg); 4 The raw material of the present invention group II (50 mg/kg); 5 The raw material mash group of the invention (100 mg/kg); 6; the oryzanol group (100 mg/kg); 7 the oryzanol group (200 mg/kg).

The rats were intragastrically administered twice a day in a volume of 20 ml/kg (the sham-operated group and the model group were given only the vehicle) for 16 days. After 45 minutes of the last administration, the mice were bled for blood, and the serum was separated to measure E2 and FSH. After that, the brain was quickly decapitated, and the uterus and adrenal gland were weighed to calculate the organ index. The results were statistically processed (t-test).

RESULTS: After modeling, the uterus index of the model group was significantly decreased (PO.01). Compared with the model group, the uterine weight and index of the positive drug nylestriol and oryzanol (200 mg/kg/d) were significantly increased (P<0.01 After the administration of the raw materials of the present invention by intragastric administration, the uterus index of the high dose group (100 mg/kg/d) was significantly increased (PO.01), as shown in Table 4. Effect on uterus and adrenal index of menopausal model mice (±SD)

Compared with the model group: *P<0.05, **P<0.01; compared with the sham group: ^Δ Ρ<0.05, ^ΔΔ Ρ<0·01.

Example 6

Effect of the raw materials of the invention on dysmenorrhea mice

Eighty female ICR mice, with an initial body weight of 18-22 g, were randomly divided into 8 groups, 10 in each group: 1 blank control group; 2 model group; 3 Inventive material group I (25 mg/kg) _; 4 Inventive material II Group (50 mg/kg) _; 5 raw material sputum group (100 mg/kg) _; 6 ibuprofen group (100 mg/kg) _; 7 oryzanol group (100 mg/kg) _; 8 oryzanol group (200 mg/kg) o

In order to increase the sensitivity of the uterus to oxytocin, in addition to the blank control group, the mice were injected subcutaneously with diethylstilbestrol O. lmg/only once daily for 10 days, and the first day and the last day were doubled. Ten days later, intragastric administration was started for 3 consecutive days. On the fourth day after the last administration, lh, intraperitoneal injection of oxytocin 0.5u/only, the writhing test was performed immediately, and the first writhing time and the number of writhing times were calculated and calculated in 20 minutes. The average number of twists. The analgesic effect of the raw material of the present invention was examined by using a dysmenorrhea mouse model modeled by oxytocin. The results are shown in Table 5. The raw material of the invention, especially high dose, can significantly reduce the number of writhing in dysmenorrhea mice, prolong the incubation period, and High writhing inhibition rate. The effect is significantly better than oryzanol raw materials.

Table 5 Effect on writhing of dysmenorrhea mice

Example 7

The lyophilized powder needle prepared in Example 2 was subjected to irritation of animal blood vessels. The method was to take 6 healthy rabbits with no ear damage and randomly divided into two groups according to body weight, namely the experimental group and the sodium chloride injection control group. The dosage of rabbits was designed based on the dose of oryzanol oil-soluble injection in clinical adults. The rabbits were given a slow bolus injection from the left ear vein of the rabbit, and the control group was given an equal volume of sodium chloride injection for 5 consecutive days. The results of the test showed that, compared with the sodium chloride injection group, the lyophilized powder needle prepared by using the raw material of the present invention was administered intravenously, and no red blood vessels and surrounding tissues were observed by the naked eye after the administration and 24 hours after the last administration. The tissue section examination showed that the structure of the rabbit ear vein was clear, the individual blood vessels were dilated, the wall thickness was uniform, the inner wall was smooth, and there was no inflammatory exudate around the tube. It is indicated that the lyophilized powder prepared by using the raw material of the present invention under the experimental conditions has no obvious stimulating effect on the rabbit ear vein.

The commercially available oryzanol oil-soluble injection was also used as a irritant test. The results showed that the injection site and its surrounding tissues were red and swollen, and induration was observed. The tissue section showed obvious vasodilation, and there was inflammatory exudate around the tube, indicating that the valley under experimental conditions Vitamin E oil-soluble injection has a significant stimulating effect on the muscle injection site.

Claims

Rights request

A pharmaceutical composition characterized in that the active ingredient is cyclopentanol ferulate and 24-methylenecyclopentanol ferulate, and the sum of the contents of the two substances is a total component More than 90%, in weight percent.

2. Composition according to claim 1, characterized in that the percentage of cycloartenol ferulate is higher than 30%.

3. Composition according to claim 1, characterized in that the percentage of cycloartenol ferulate is higher than 50%.

The process for producing a pharmaceutical composition according to any one of claims 1 to 3, which comprises the step of repeating recrystallization from a first solvent and a second solvent, wherein the first solvent is selected from the group consisting of ethyl acetate and acetone, and the second solvent Selected from anhydrous ethanol and methanol.

5. The preparation method according to claim 4, comprising the following steps

i. Take the oryzanol raw material, dissolve it by refluxing with the first solvent and the second solvent mixed solution, filter, and leave the filtrate to stand, crystallize, filter, and dry.

Ii. The dried crystals are reconstituted with a first solvent, filtered, allowed to stand, crystallized, filtered, and dried. Iii. Repeat steps ii, 1-10 times.

Iv. The mother liquor recovered after recrystallization in the above step is recovered to a volume of 1-5 times the volume of the solute contained therein, allowed to stand, crystallized, filtered, and dried.

v. The crystal obtained in the step iv is dissolved in a first solvent under reflux, filtered, allowed to stand, crystallized, filtered, and dried.

Vi. Repeat step v, 1 - 10 times.

Vii. The mother liquor filtered after recrystallization in steps v and vi is combined and recovered to a volume of 1-5 times the volume of the solute contained, and then allowed to stand, crystallized, filtered, and dried.

Viii. The crystal obtained in the step vii is subjected to recrystallization treatment in the same manner as the step v.

Ix. Mix the crystals obtained in step iii, vi, viii to obtain the final product.

A pharmaceutical preparation comprising a pharmaceutical composition according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier.

7. A formulation according to claim 6 which is an injectable solution, a lyophilized powder injection, an infusion solution.

8. A formulation according to claim 7 which contains a surfactant.

9. A formulation according to claim 8 wherein the surfactant is selected from the group consisting of Tween, polyethylene glycol or mixtures thereof.

10. The composition of claims 1-3 for treating autonomic dysfunction, menopausal syndrome, primary dysmenorrhea, Premenstrual tension, periodic psychosis, vascular headache, head trauma syndrome, gastrointestinal neurological disorders, hyperlipidemia.