CN1319417A - Medicine for treating menopausal syndrome and preparation process thereof - Google Patents
Medicine for treating menopausal syndrome and preparation process thereof Download PDFInfo
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Abstract
The present invention relates to a medicine for curing climateric syndrome and its preparation method. It is made of forest forg's oviduct, zedoary, B-cyclodextrin and edible soybean oil according to a certain proportion through a certain preparation process. Said invention is simple in prescription, and can regulate the hormone level of climacteric women, improve imbalance of endocrine system, effectively relieving climatric symptom and improved blood-lipid metabolism, so that it can effecitvely cure climateric syndrome.
Description
The present invention relates to a kind of medicine and manufacture method thereof for the treatment of climacteric syndrome.
Climacteric syndrome is the women before and after menopause since the estrogen level fluctuation or descend due to based on the autonomic nervous system dysfunction, wait the group with a group of neural mental symptoms.According to domestic and international interrelated data statistics, between year, 90% women all has the different clinical manifestation of degree, and causes many relevant diseases in view of the above at 45-55, wherein much more to see, seriously endangering numerous women's physical and mental health with osteoporosis and cardiovascular disease.Along with the trend of human longevity aging development,, medical science problem and social problem that the whole world is paid close attention to have been become to effective control of climacteric syndrome.
The climacteric syndrome pathogeny is mainly hormonal system and neurotransmitter disorder.Wherein estrogen deficiency is morbidity and the initiating link that causes relevant disease.Abroad, adopt HPH (gonadal hormone replacement therapy) treatment comprehensive card of climacteric to obtain the world medical circle approval over nearly 50 years, and improving the corresponding symptom of climacteric women to some extent.But have following shortcoming clinically: 1, mostly be the synthetic hormone, gastrointestinal reaction is big, not only inconvenient patient of intramuscular injection but also difficult acceptance.2, can condense by platelet increasing with estrogen merely, reduce the level of the plain III of antithrombotic, increase the danger of coronary heart attack.3 thus the class medicine need take for a long time, increase the sickness rate and the abnormal vaginal bleeding of adenomyoma.Although emphasize drug combination at present both at home and abroad and select medication, but still can not the above-mentioned drawback of fine solution.
At home, treatment climacteric Chinese patent medicine mainly contains GENGNIANAN capsule, climacteric health, climacteric and relaxes etc.These medicines have certain curative effect clinically, but also have the following disadvantages: 1, medicine composition spininess is established certain disease, and clinical limitation is arranged.2, it is more that prescription is formed flavour of a drug, complicated component, difficult quality control.3, extraction process and dosage form are comparatively traditional.
The object of the present invention is to provide a kind of medicine and manufacture method thereof for the treatment of climacteric syndrome, its utilization Chinese medicine natural sex hormone and plurality of active ingredients are to human body too many levels, multi-level, many target spots comprehensive drug effect, regulate the climacteric women hormonal readiness, improve the imbalance hormonal system, effectively alleviate menopause syndrome, improve blood lipid metabolism, and help complying with and regulating of function of human body.
The component of constituent of the present invention and each composition is: Oviductus Ranae 40～50, Rhizoma Curcumae 50～60, B-cyclodextrin 1.8～2.5, edible soybean oil 1.8～2.5.
This medicine Oviductus Ranae, fills bone and fills out marrow, solid the congenital foundation the kidney invigorating and essence nourishing, improves estrogen level, improves the clinical all diseases of menopausal women, Zhi Qiben; That accessory drugs Rhizoma Curcumae, harmonizing the functional activities of vital QI, mediation blood vessels, removing food stagnancy are dispelled is turbid, control its mark, and two combine, and tonify without causing stagnation is dredged and do not decreased, reinforcement and elimination in combination, and the kidney invigorating and essence nourishing, QI and blood regulating, the removing food stagnancy turbid effect of dispelling is played in treating both the principal and the secondary aspects of a disease at the same time altogether.Cure mainly climacteric syndrome, be used for diseases such as palpitation and insomnia due to the endocrine regulation, hyperhidrosis, bone are soft, spirit depressing, menoxenia, fatigue and asthenia, hyposexuality.
The present invention's manufacture method is: get Oviductus Ranae, the some 40 order coarse powder that are ground into of Rhizoma Curcumae, mixing is put CO
2Separation and Extraction is 2 hours in-SFE (CO 2 supercritical) extraction pot, and extracting solution adds the B-cyclodextrin, stirs, and adds edible soybean oil, grinds to form even oily suspension in the colloid mill, makes circular capsule by encapsulating machine, and low temperature is promptly air-dry.
Below in conjunction with embodiment the present invention is described in detail.
Get Oviductus Ranae 3000g, Rhizoma Curcumae 5000g and be ground into 40 order coarse powder, mixing is put CO
2Separation and Extraction is 2 hours in the-SFE extraction pot, and extracting solution adds B-cyclodextrin 150g, stirs, and adds the 150g edible soybean oil, grinds to form even oily suspension in the colloid mill, makes circular capsule by encapsulating machine, and low temperature is air-dry promptly to get 1000 soft capsules.Usage, consumption: 1～2/time, 1 time/day, oral, one month is a course of treatment.
The invention is not restricted to an above-mentioned described embodiment.
The present invention is made up of monarch drug Oviductus Ranae and ministerial drug Rhizoma Curcumae, and Oviductus Ranae is the dry ovary of Rana temporaria chensinensis David, and lung, kidney channel are equalled, gone into to its property sweet-salty, has the effect of the kidney invigorating and essence nourishing, Replenishing QI and nourishing YIN.Contain compositions such as estradiol, progesterone, testosterone, unsaturated fatty acid and phospholipid through chemical research proof Oviductus Ranae.Modern pharmacological research proof Oviductus Ranae has significant defying age, resisting fatigue, enhancing body resistance, anticoagulant and effect for reducing fat.It is reported: androgen has the effect that alleviates climacteric syndrome emotion spirit aspect symptom, can promote the synthetic and sclerotin formation of albumen, and help hypersexuality, progestogen can make atrophy of endometrium, reduce malignant change, Rhizoma Curcumae, bitter flat, go into liver, spleen channel, have the collateral dredging circulation of qi promoting, the effect of removing food stagnancy pain relieving.The woman is this with blood, and promoting flow of QI and blood is for treating gynecopathy's well-established law, so be gynecological's product commonly used.Compositions such as modern pharmacological research proof curcumenol, curdione, Oleum Curcumae can strengthen the immunogenicity of cancerous cell, thereby brings out or promote the immunologic rejection effect of body to tumor, and is especially remarkable to the clinical therapeutic efficacy of uterus carcinoma, remove this and also have significant anticoagulant, the blood flow increasing effect.Oviductus Ranae, the kidney invigorating and essence nourishing fills bone and fills out marrow, Gu the congenital foundation improves estrogen level, improves the clinical all diseases of menopausal women, Zhi Qiben; The accessory drugs Rhizoma Curcumae, harmonizing the functional activities of vital QI, the mediation blood vessels, removing food stagnancy is dispelled turbid, controls its mark, and biphase being harmonious, tonify without causing stagnation is dredged and is not decreased, reinforcement and elimination in combination, the kidney invigorating and essence nourishing is played in treating both the principal and the secondary aspects of a disease at the same time altogether, QI and blood regulating, the removing food stagnancy turbid effect of dispelling.Through clinical treatment observation, medication after 1 month the Tidal fever with perspiration symptom obviously alleviate, subjective symptoms is obviously improved after three months, the Kuppermen score value obviously reduces, patient's blood estradiol (E2) level raises, and short follicle generates plain (FSH), and metakentrin (LH) descends.This project intends adopting supercritical CO according to the little physicochemical property of effective ingredient polarity in the side
2(CO
2-SFE) the technology of extraction separation.Supercritical fluid has the advantage of liquids and gases concurrently, has good dissolving, transmission and response characteristic.Its critical pressure (7.37mpo) and critical temperature (31.04 ℃) are low; the operating condition gentleness; destroy little to active ingredient; extract shorter with tradition " decocting in water " and organic solvent body method; no solvent residue; nontoxic, do not fire, characteristics such as " environmental friendliness " have antioxidation and protective effect to thermal sensitivity and volatile component.Preliminary experiment through us shows, needs 8 hours with the active ingredient of alcohol reflux Oviductus Ranae in the past, and extracting me with the way of distillation is 10 hours the art volatile oil time, and CO
2-SFE only uses 2 hours, mainly contains effective constituent (E2, curcumenol, curdione) content and improves 2-4 respectively doubly.And extraction separation beyond the region of objective existence sight color and luster is good, and every batch variation coefficient is little, and production technology is controlled easily.
The present invention has following advantage:
1, flavour of a drug are little, and prescription is simple and direct, help the quality control of product.2, drug effect is paid attention to integrally-regulatedly, has that the kidney invigorating and essence nourishing, QI invigorating are lived, collateral dredging disappears turbid effect.Can improve the imbalance hormonal system, effectively alleviate menopause syndrome, prevention aedoeatrophia pathological changes.The prevention bone loss improves blood and refers to and thank.3, we are contained natural estrogen, progestogen, testosterone, help complying with and regulating of function of human body, have avoided single many side effect that produce with estrin treatment.4, extraction process advanced person.
Be the present invention's (trade name is female safe oral liquid or female safe capsule) Pharmacodynamic test of active extract data, long-term toxicity test for animals data, animal acute toxicity test data relevant below with function.One, the female safe oral liquid Pharmacodynamic test of active extract data relevant with function
Female safe oral liquid is made up of Chinese medicine Oviductus Ranae, Rhizoma Curcumae, have beneficial essence and consolidate, change turbid collateral dredging function, clinically be used to cure mainly climacteric syndrome, be used for diseases such as cardiopalmus due to the endocrine regulation, insomnia, hyperhidrosis, bone are soft, spirit depressing, menoxenia, fatigue and asthenia, hyposexuality.Evident in efficacy, according to the function that cures mainly of female safe oral liquid, we have carried out neuter blood hormonal readiness, bone density are reached the tests such as hemorheological influence to the blood stasis animal, and its main pharmacodynamics research report is as follows:
Experiment material
The every ml of the female safe oral liquid of medicine contains crude drug 0.8g, lot number: 981216.Be diluted to desired concn with preceding with aquae destillata, contrast gives the isometric(al) aquae destillata.Climactero tablet, White Cloud Mountain, Guangzhou pharmaceutical factory produces, lot number: 970203.The aspirin sheet, Xuzhou pharmaceutical factory produces, lot number: 980102, hydrocortisone injection, Lanzhou pharmaceutical factory produces, lot number: 970202, E
2, FSH, FH radioimmunological kit, Tianjin nine ancient cooking vessel biological product company limiteies provide.
The animal Kunming mouse, body weight 18-22g, male and female half and half.SD rat 180-220g, male and female half and half.Provided by No.1 Military Medical Univ. animal.
Method and result
1. female safe oral liquid is to the influence of castrated rats serum sex hormone level and uterine cancer cell.
1.1 modeling and medication: 70 rats are got 10 at random and are the normal control group, all the other 60 under the anesthesia of 0.25% pentobarbital sodium, abdomen position fixing row bilateral ovaries enucleation.The postoperative 5d vaginal smear that begins, 5d proves that castration is thorough continuously.Divide 6 groups at random: model control group, the large, medium and small dosage group of female Thailand, climacteric health group.Castration 5d rises normal and model control group gavages normal saline, the large, medium and small dosage of female Thailand is given the suspension of 32,24,12% variable concentrations that is made into aquae destillata, the climacteric health is mixed with the suspension of 0.15g/ml with aquae destillata, each treated animal is irritated stomach (ig) normal saline or medicine 1ml/100g (body weight), continuous 4 weeks every day.Broken end is got blood, separation of serum ,-20 ℃ of preservations.Ria-determination E
2, LH, FSH (by the operation of each medicine box description method); Dissect rat and take by weighing the uterus weight in wet base and calculate relatively uterus weight coefficient, the uterus, back of weighing is fixed in 4% formalin solution, dehydration, embedding, conventional section, HE dyeing, om observation.
1.2. result
1.2.1. to blood E
2, FSH and LH influence
Shown in table 1 result, rat and normal group compare E behind the removal ovary
2Level obviously reduces (p＜0.01), and FSH, LH level obviously raise (p＜0.01), and the modeling success is described.Large, medium and small dosage of female safe oral liquid and model group compare, E
2Obviously raise, FSH, LH reduce, and the climacteric health is to removal ovary rat E
2Level does not have remarkable change.
The female Thailand of table 1 is to rat blood serum E
2, LH, FSH level influence
| Group | Dosage (g/kg) | ?????????E 2???????(pg/ml) | ??????FSH ????(mlo/ml) | ???????LH ????(mlo/ml) |
| The female safe oral liquid climacteric health of normal model | ????3.2 ????2.4 ????1.2 ????1.5 | ??4.52±0.35 ??2.12±0.73 Δ???3.01±0.45 **??2.94±0.34 **??2.65±0.31 *??2.36±0.51 | ??2.40±0.30 ??3.44±0.21 Δ???2.90±0.25 **??2.93±0.60 *??3.01±0.69 ??2.94±0.61 * | ??3.07±0.89 ??5.04±1.05 Δ???3.95±0.57 **??3.99±0.41 **??4.05±0.21 **??3.81±0.51 ** |
Compare with normal group
ΔP＜0.01
Compare with model group
*,
*P＜0.05, p＜0.01
2. to the influence of castrated rats uterus weight
As shown in table 2, obviously reduce (p＜0.01) with rat uterus weight and coefficient behind the normal group comparison removal ovary, each medication group all obviously increases, and uterus weight that alleviates behind the removal ovary and coefficient (p＜0.05,0.01), female safe oral liquid are more remarkable and dose-effect relationship arranged than climactero tablet effect.
The female safe oral liquid of table 2 is to the influence of castrated rats uterus weight
| Group | Dosage (g/kg) | Uterus heavy (mg) | The uterus weight coefficient |
| The female safe oral liquid climacteric health of normal model | ????3.2 ????2.4 ????1.2 ????1.5 | ????142.3±27.6 ????50.4±18.2 Δ???????123.3±12.7 **????115.91±9.6 **????75.6±24.1 *?????65.1±10.4 * | ???6.30±1.30 ???2.08±1.14 Δ??????5.80±0.62 **???5.13±0.51 **???3.56±1.25 *???2.98±0.67 * |
Group compares with often ending
ΔP＜0.01
Compare with model group
*,
*P＜0.05, p＜0.01
3. histopathology is observed
Normal rats body of uterus outward appearance, thickness is normal, and inner membrance, flesh layer, placenta percreta basic structure are clear.The release of the visible apocrine secretion vesicle of mucous layer.The brached tubular gland body is a bunch shape distribution in the theca interna, and body of gland and lumen of gland are not of uniform size, the visible rare thick secretions that does not wait of intracavity.Each stratum proportion of model group rat uterus obviously changes than normal group, atrophic occurs and changes; Each dosage group of female Thailand and climacteric health group have the similar atrophic pathological features of model group, but female Thailand is big or middle, the group pathological changes is light, show as the inner membrance Interstitial cell and be about 1/3 near normal group with decidua like cell ratio, and secretory activity is tending towards normal.The bigger or middle dosage of small dose group atrophy degree is obvious, and secretions is few, but light than the model group pathological changes.
4. to the osteoporotic influence of rat experiment
Get 50 of body weight 160-200g male rats, be divided into normal control group, model group, the large and small dosage group of female Thailand and SHENGU JIAONANG group.Except that the normal control group, gavage retinoic acid 70mg/kg, continuous 2 weeks all the other 4 groups of every days.Afterwards, administration group difference female safe oral liquid of ig every day and SHENGU JIAONANG (dosage sees Table 2), normal control group and model group be ig normal saline 1ml/100g body weight then, continuous 4 weeks, each treated animal is put to death, get its femur and carry out check pathological section, and carry out bone strength respectively, bone density and calcium content of bone measure.The results are shown in Table 3
The female safe oral liquid of table 3 causes the influence of osteoporosis rat to retinoic acid
| Group | Dosage (g/kg) | ?????????E 2???????(pg/ml) | ???????FSH ?????(g/cm 3) | Bone strength (kg/cm) |
| The female safe oral liquid bone kidney capsules of normal model | ?????3.2 ?????1.2 ?????0.5 | ??0.221?±0.035 ??0.121±0.027 Δ????0.199±0.033 **??0.164±0.056 *??0.183±0.088 * | ??2.425±0.057 ??2.063±0.054 Δ??2.267±0.049 **??2.204±0.160 *??2.220±0.182 * | ??4.69±0.82 ??2.43±0.71 Δ?????4.01±0.69 **???3.58±1.20 *???3.61±1.43 * |
Compare with normal group
Δ,
The Δ ΔP＜0.05, p＜0.01
Compare with model group
*P＜0.01
Table 3 is the result show, model group and normal control group be calcium content of bone relatively, and bone density and bone strength more all have obvious reduction, and the modeling success is described.The calcium content of bone of each administration group, bone density and bone strength are all apparently higher than model group.The effect of female safe heavy dose of group smaller dose group is strong, and dose-effect trend is arranged.Pathological section as seen, that the cortical bone of model group all has is loose, attenuation, and the bone trabecula pathological change that loosens, attenuate and even disappear.Each administration treated animal all has different above pathological changes, and slight pathological change only appears in female safe heavy dose of group, and low dose of and SHENGU JIAONANG only has the cortical bone attenuation and the bone trabecula of individual animal to attenuate, but routine number is few, and lesion degree is light.
5. to the influence of " yang deficiency syndrome " mice tolerance to cold and thymus, spleen weight
Get 50 of body weight 20-22g mices, male and female half and half, be divided into normal, model, the large and small dosage of female Thailand and bone kidney group at random, every group 10, remove normal each the administration group of model group animal ig every day normal saline 1ml/20g that reaches and press table 4 dosed administration, in administration simultaneously except that matched group, all the other respectively organize im hydrocortisone 25mg/kg/d, continuous 21 days, per 3 days of experimental period, weighed once, regulates dosage by body weight, after the last administration 1 hour, mice is put-20 ℃ of icehouses and observe its tolerance to cold, get thymus behind the animal dead, spleen is weighed.The results are shown in Table 4
The female Thailand of table 4 is to the influence of mice tolerance to cold and thymus, spleen weight
| Group | Dosage (g/kg) | The body weight gain rate | Death time (20 ℃) | Thymus (mg/10g) | Spleen (mg/10g) |
| The female safe oral liquid bone kidney capsules of normal model | ????3.2 ????2.4 ????0.5 | ??31.9±17.4 ??6.3±6.9 Δ????18.9±5.9 **??15.4±7.1 **??11.3±7.8 * | ??69.2±21.2 ??38.8±15.4 Δ????68.7±24.2 **??61.3±13.2 **??64.3±19.8 ** | ??26.4±10.9 ??12.3±7.8 Δ????19.5±6.8 *??18.2±4.2 *??12.3±4.5 | ??70.1±15.6 ??41.6±7.5 Δ????51.2±12.0 *??48.3±5.7 *??42.3±11.9 |
Compare with normal group
ΔP＜0.01
Compare with model group
*,
*P＜0.05, p＜0.01
From table 4 result as seen, compare with matched group, model group the weight of animals, cold tolerance all obviously descend, and thymus and spleen weight also obviously alleviate, and " yang deficiency " symptoms such as cold extremities, hogback, perpendicular hair occur.Female Thailand (3.2,2.4g/kg) can obviously increase animal pattern body weight and tolerance to cold, and can increase thymus and spleen weight.
6. to the influence of blood stasis model hemorheology of rat
Rat is divided 5 groups at random, and 1,2 group of ig normal saline is done normal control and model contrast; 3, distinguish ig aspirin and the large and small dosage of female safe oral liquid for 4,5 groups, every day 1 time, administration the 5th day, 2,3,4,5 treated animal subcutaneous injections every day, 0.1% epinephrine 0.2ml/ only, twice on the 1st, be 6 hours twice blanking time, back 3 hours of the 1st injection put into 5 minutes capable cold stimulations of 4 ℃ of frozen water 1 time with animal, continuous 2 days, cause the animal blood stasis, last injection epinephrine is after 18 hours, with pentobarbital sodium anesthesia, abdominal aortic blood, carry out whole blood, plasma viscosity and HCT in accordance with the law and measure, the results are shown in Table 5
The female safe oral liquid of table 5 is to the influence of blood stasis model hemorheology of rat (x ± s)
| Group | Dosage (g/kg) | Whole blood viscosity (mpas) | Blood viscosity (mpas) | ???HCT(％) | ||
| ??????????1 | ?????????50 | ????200s -1 | ||||
| The female Thailand of normal model aspirin | ????0.1 ????3.2 ????2.4 | ??9.33±1.05 ??12.78±2.30 ΔΔ????9.57±0.81 **??10.88±0.46 *??9.89±0.70 ** | ??4.28±0.35 ??5.77±1.09 ΔΔ????4.34±0.38 **??4.77±0.25 *??4.67±0.25 ** | ??3.75±0.33 ??4.98±0.90 ΔΔ????3.78±0.35 **??4.25±0.31 *??4.10±0.21 ** | ??1.56±0.18 ??1.79±0.25 Δ????1.46±0.30 *??1.60±0.13 ??1.64±0.11 | ??39.1±2.0 ??3.0±4.4 Δ????39.0±2.6 *??38.9±4.0 *??39.5±3.69 |
Compare with normal group
Δ,
The Δ ΔP＜0.05, p＜0.01
Compare with model group
*,
*P＜0.05, p＜0.016. is to the mouse anti-reflecting fatigue effect
Get 40 of mices and be divided into 4 groups, every group 10, gavage every day female safe oral liquid 3.2,2.4/kg and etc. the capacity normal saline, continuous 7 days, after the last administration, every Mus tail base portion is adopted weight 1g/10g, puts depth of water 30cm respectively into, swims in 26 ± 0.5 ℃ of bathtubs of water temperature, the time that no longer emerges in the 20s after the record mice begins to sink from swimming, the results are shown in Table 6
The female safe oral liquid of table 6 is to the influence of mice swimming time
| Group | Dosage (g/kg) | Swimming time (min) | ??????P |
| Normal female safe oral liquid | ????3 ????3.2 ????2.4 | ????21.6±9.8 ????46.6±11.2 ????49.6±13.3 ????43.2±8.6 | ????＜0.01 ????＜0.01 ????＜0.05 |
From table 6 result as seen, the large and small dosage of female safe oral liquid all can obviously prolong the swimming time of mice, and remarkable antifatigue effect is arranged.Brief summary
With 3.2,2.4, the female safe oral liquid of 1.2g/kg various dose irritated stomach continuous 28 days to castrated rats, can significantly increase removal ovary rat E
2Level reduces FSH, LH level, can increase removal ovary rat uterus weight, and alleviate removal ovary rat uterus atrophy degree, makes the uterine cancer cell pathological change be tending towards normal and shows dose-effect relationship trend.For the imbalance of clinical treatment climacteric syndrome gonadal hormone provides the pharmacodynamics foundation.
2. the female safe oral liquid with above same dose caused the osteoporosis model rat oral gavage continuous 14 days to retinoic acid, can obviously increase calcium content of bone, bone density and the bone strength of osteoporosis rat and alleviate bone pathology to learn variation.This pharmacological action has crucial clinical meaning to the osteoporosis symptom that climacteric syndrome occurs.
With 3.2, the female safe oral liquid of 2.4g/kg causes " yang deficiency syndrome " model mice to hydrocortisone and irritates body weight, thymus, spleen weight and the tolerance to cold that stomach can increase " syndrome of deficiency of kidney-YANG " mice in 21 days; The same female safe oral liquid of dosage also can obviously increase the swimming time of normal mouse, illustrate that said preparation has to improve " yang deficiency syndrome " mice body weight, thymus, the weight saving of spleen gland, and cold-hartliness reduction symptom also has the obvious anti-fatigue effect.
4.3.2, the female safe oral liquid of 2.4g/kg gives continuous 7 days of blood stasis rat oral gavage, large and small dosage can reduce obviously that the rat whole blood is low, height is cut viscosity, plasma viscosity and HCT, illustrate that female Thailand can improve the blood stasis hemorheology of rat, this effect conforms to the effect of its promoting blood circulation to remove obstruction in the collateral.Two, the female Thailand thing long term toxicity test data materials and methods that surges
The female safe oral liquid ethanol extraction of medicine is made up of Oviductus Ranae, Rhizoma Curcumae.Lot number: 981216, the suitable crude drug in whole 4.8g of every ml extract is prepared by the Drug Manufacturing Room of Pharmacy Department, Nanfan Hospital.Used female safe oral liquid dosage is all by the crude drug amount in the literary composition.
Animal SD (7 age in week) rat, body weight 180-220g, male and female half and half are provided by No.1 Military Medical Univ.'s Experimental Animal Center, quality certification 99A033.
The method rat is in constant temperature (25 ± 1 ℃) 1 week of indoor feeding, choose 60 of behavior normal rats, the male and female rat is respectively by the body weight numbering, divide 3 groups at random, every group 20 (each 10 of male and female), heavy dose of group and small dose group gastric infusion every day dosage are that the every 100g body weight of 48g/kg and 12g/kg (be equivalent to recommend clinical dosage 150 times and 37 times) is to 1ml, matched group is given with the volume normal saline, 8 weeks of successive administration, observe the general behavior activity of rat therebetween, hair and feces etc., claim body weight weekly 1 time, drug withdrawal after 1 month, every group is selected each 5 Mus of male and female to survey its hemogram (RBC at random, Hb, WBC and classification thereof, Plat and clotting time), 12 (BUN of biochemical indicator, CR, GLU, CHOL, TBIL, TP, ALB, G, ALT, AST, ALP, r-CT), to the heart, liver, spleen, lung, kidney, brain, the adrenal gland, thymus, prostate, ovary, and uterus, testis, and epididymis, thyroid is totally 14 pathologic findings, and weighs the calculating organ coefficient to preceding 12.Second half rat drug withdrawal repeats above-mentioned experiment after continuing to observe two weeks.The result
One. general situation administration group and control rats are all movable normal, and hair color is glossy to cling to the body, and class reaches just that diet is normal, and body weight constantly increases, indifference between group.Dynamic change in average sees Table 1.
Two. hemogram administration group and matched group hematological indices RBC, Hb, WBC and classification, Plat and clotting time all in normal range, there was no significant difference between group.Its leading indicator sees Table 2.
Three. BUN, CR, TB, AIB, G, AST, AIP, GLU, TBIL, the r-CT there was no significant difference of each group of biochemical indicator administration and control rats, heavy dose of group ALT and matched group have significant difference, but in normal range.See Table 3
Four. pathologic finding administration group is compared there was no significant difference (table 4) with the relative weight (organ weight g/100 body weight) of the main organs of control rats, pathological examination results, remove the slight fat of 3 rat livers of heavy dose of group and become, it is all no abnormal that other each treated animal detects internal organs.Each internal organs no abnormality seen of rat behind the drug withdrawal two weeks.Discuss
One. the clinical consumption 0.32g/kg/d of the recommendation of female safe oral liquid, because The acute toxicity tests proof toxicity is very low, can not survey the oral LD of mice
50, only record the oral MDT＞200g/kg of mice, so two dosage groups and matched group are only established in this experiment.Heavy dose of group 40g/kg/d, small dose group 12g/kg/d, 150,37 times of suitable clinical dosage respectively.Be 4 weeks the course of treatment according to female safe liquid, and this experiment successive administration time was 8 weeks.
Two. rat is with continuous 8 weeks of the female safe liquid of 150 times of suitable recommendation clinical dosages, hemogram between administration group and control rats, blood parameters measurement result there was no significant difference, and all in normal range, pathological examination results is not also seen the infringement of tangible medicine sexually transmitted disease (STD) reason, illustrates that the oral female safe liquid of rat is safe.
Three. after around the administration, heavy dose of group has 2 animal liverss to have slight fat to become, and after two weeks of drug withdrawal, remains each treated animal liver and does not find that fat becomes, and the female safe liquid of ig gives continuous 4 weeks of rat 48g/kg/d influential to liver, but can recover after the drug withdrawal.The variation of the female safe liquid long term toxicity test body weight of table 1 rat (g) (x ± SD)
| Time (my god) | Matched group | Small dose group | Heavy dose of group |
| ????0 ????7 ????14 ????21 ????28 ????35 ????42 ????49 ????56 ????63 ????70 | ????190.0±11.6 ????209.0±22.0 ????224.0±23.0 ????236.5±28.5 ????254.3±42.9 ????259.5±43.3 ????266.0±46.2 ????271.5±49.4 ????278.0±52.9 ????287.5±57.3 ????295.3±61.7 | ????192.3±14.8 ????206.8±26.2 ????218.3±29.3 ????229.0±31.8 ????246.0±36.6 ????255.0±38.9 ????262.0±39.2 ????268.0±42.5 ????274.0±44.1 ????279.0±45.0 ????284.0±48.7 | ????189.0±12.2 ????206.0±21.5 ????216.3±23.3 ????227.3±26.0 ????241.3±31.5 ????250.5±37.4 ????256.5±39.3 ????267.6±40.2 ????274.3±43.1 ????284.0±47.3 ????296.8±52.6 |
N=20 played n=10 in 56 days
The variation of the red system of the female safe liquid long term toxicity test blood of table 2 rat (x ± SD)
| Time | Matched group | Small dose group | Heavy dose of group | |
| RBC (T/L) Hb (g/L) HCT ?MCV (fL) MCH (Pg) MCHC (g/L) | ?D56 ?D70 ?D56 ?D70 ?D56 ?D70 ?D56 ?D70 ?D56 ?D70 ?D56 ?D70 | ?????7.36±0.73 ?????8.00±0.77 ????134.3±10.6 ????144.4±8.8 ?????0.69±0.059 ?????0.74±0.035 ?????94.7±8.8 ?????93.4±7.1 ?????18.3±1.9 ?????18.2±1.6 ????192.5±2.1 ????194.3±4.0 | ????7.40±0.70 ????7.00±1.32 ???130.0±11.2 ???129.3±21.9 ????0.70±0.061 ????0.67±0.090 ????92.8±4.8 ????96.1±8.7 ????18.1±1.0 ????18.6±1.5 ???194.6±2.1 ???192.8±10.1 | ?????7.60±0.76 ?????7.28±0.95 ????137.1±11.8 ????134.3±10.9 ?????0.67±0.059 ?????0.69±0.058 ?????90.9±5.6 ?????96.8±10.0 ?????17.6±1.2 ?????18.6±1.5 ????193.5±3.2 ????193.4±3.8 |
The variation of female safe liquid long term toxicity test leukocyte of table 3 rat and classification thereof (x ± SD)
| Time | Matched group | Small dose group | Heavy dose of group | |
| WBC (G/L) GRAN (G/L) LYM ?(G/L) | ?D56 ?D70 ?D56 ?D70 ?D56 ?D70 | ????6.89±2.66 ????7.04±1.92 ????2.25±1.58 ????1.93±0.85 ????3.94±2.20 ????4.42±1.04 | ????7.99±3.08 ????6.77±2.45 ????2.89±1.12 ????2.14±0.81 ????4.33±2.07 ????4.09±1.92 | ????6.79±1.77 ????7.42±2.28 ????1.96±0.53 ????2.43±0.77 ????4.42±1.65 ????4.26±1.62 |
The variation of female safe liquid long term toxicity test platelet of table 4 rat and clotting time (x ± SD)
| Time | Matched group | Small dose group | Heavy dose of group | |
| PLT (G/L) clotting time (min) | ?D56 ?D70 ?D56 ?D70 | ????904.9±270.1 ????968.7±124.2 ?????2.10±0.44 ?????1.77±0.72 | ????1043.7±233.3 ?????976.8±278.9 ??????2.63±0.44 ??????1.95±0.68 | ????1048.7±160.6 ?????966.5±95.9 ??????2.04±0.68 ??????2.04±0.69 |
The variation of the female safe liquid long term toxicity test blood parameters of table 5 rat (x ± SD)
| Time | Matched group | Small dose group | Heavy dose of group | |
| ????ALT ????(u) ????AST ????(u) ????ALP ??(1u/L) ???BUN ??(mmol/L) ????Cr ?(μmol/L) ????TP ??(g/L) ???Alb ??(g/L) ???Glu ?(mmol/L) ???Tch ?(mmol/L) ??VLDL ?(mmol/L) ????TG ?(mmol/L) | ?D56 ?D70 ?D56 ?D70 ?D56 ?D70 ?D56 ?D70 ?D56 ?D70 ?D56 ?D70 ?D56 ?D70 ?D56 ?D70 ?D56 ?D70 ?D56 ?D70 ?D56 ?D70 | ?????50.5±13.7 ?????59.1±13.9 ????220.6±43.0 ????198.3±45.9 ????144.8±33.4 ????110.4±49.0 ??????8.1±0.9 ?????10.2±1.5 ?????72.1±5.7 ?????73.7±7.7 ?????70.8±4.7 ?????77.2±6.2 ?????34.8±4.0 ?????33.4±2.0 ?????4.18±1.26 ?????5.46±0.59 ?????1.12±0.17 ?????1.39±0.26 ?????0.27±0.13 ?????0.33±0.09 ?????0.60±0.30 ?????0.74±02.0 | ?????53.4±21.2 ?????49.6±20.4 ????175.3±52.5 ????164.9±35.0 *????148.0±70.8 ?????94.7±46.6 ??????7.4±1.5 ??????8.6±1.1 ?????69.5±7.7 ?????65.3±8.3 *?????69.0±7.4 ?????70.9±5.6 ?????31.6±3.4 ?????32.8±3.3 ?????4.57±1.04 ?????6.76±1.13 *?????1.03±0.21 ?????1.41±0.33 ?????0.28±0.11 ?????0.33±0.11 ?????0.62±0.21 ?????0.74±0.24 | ?????59.2±14.6 *?????50.9±19.0 ????190.5±60.0 ????181.4±38.9 ????131.0±70.6 ????121.6±51.2 ??????7.5±1.3 ??????8.6±1.3 ?????69.1±10.2 ?????67.4±7.0 ?????68.7±4.3 ?????72.6±2.9 ?????33.5±3.0 ?????29.9±2.7 ?????4.44±0.66 ?????5.34±1.99 ?????1.06±0.22 ?????0.90±0.22 *?????0.29±0.09 ?????0.32±0.20 ?????0.63±0.17 ?????0.67±0.49 |
Compare with the normal control group
*P＜0.05
The variation of the female safe liquid long term toxicity test main organs relative weight of table 6 rat (x ± SD)
| Detect index | Time | Matched group | Small dose group | Heavy dose of group |
| The heart | ????D56 ????D70 | ????0.28±0.028 ????0.30±0.041 | ????0.27±0.026 ????0.30±0.070 | ????0.31±0.042 ????0.28±0.016 |
| Liver | ????D56 ????D70 | ????2.58±0.34 ????2.39±0.20 | ????2.77±0.28 ????2.59±0.58 | ????2.78±0.50 ????2.27±0.19 |
| Spleen | ????D56 ????D70 | ????0.40±0.12 ????0.42±0.20 | ????0.46±0.13 ????0.35±0.066 | ????0.39±0.15 ????0.36±0.043 |
| Lung | ????D56 ????D70 | ????0.63±0.13 ????0.62±0.15 | ????0.71±0.15 ????0.65±0.15 | ????0.66±0.18 ????0.51±0.11 |
| Kidney | ????D56 ????D70 | ????0.58±0.048 ????0.58±0.053 | ????0.62±0.067 ????0.58±0.11 | ????0.64±0.085 ????0.58±0.037 |
| Adrenal gland (mg) thyroid (mg) | ????D56 ????D70 ????D56 ????D70 | ????17.13±6.59 ????16.48±6.14 ????4.89±1.19 ????4.87±1.02 | ????18.84±5.93 ????17.41±4.64 ????4.50±1.43 ????3.87±0.71 | ????17.78±4.18 ????13.75±3.46 ????4.21±1.76 ????5.30±1.56 |
| Brain | ????D56 ????D70 | ????0.56±0.076 ????0.55±0.13 | ????0.60±0.091 ????0.54±0.093 | ????0.60±0.093 ????0.48±0.097 |
| Prostate | ????D56 ????D70 | ????0.18±0.093 ????0.24±0.14 | ????0.22±0.062 ????0.34±0.078 | ????0.13±0.059 ????0.24±0.083 |
| Testis | ????D56 ????D70 | ????0.77±0.14 ????0.78±0.073 | ????0.81±0.14 ????0.89±0.19 | ????0.93±0.10 ????0.74±0.15 |
| Uterus and ovary | ????D56 ????D70 | ????0.22±0.058 ????0.27±0.017 | ????0.26±0.10 ????0.27±0.12 | ????0.29±0.082 *????0.29±0.12 |
N=10, testis, uterus and ovary n=5
*Compare p＜0.05 with the normal control group
List of references
1. Ministry of Health of the People's Republic of China's " provisions for new drugs approval " JIUYUE in 1992 was carried out on the 1st
2. Ministry of Health of the People's Republic of China's political situation " study of tcm new drug guide " is 1994
3. " pharmacological experimental methodology " second publishing house such as Xu's uncle cloud is 1994
4. Shanghai City medical science assay office chief editor " clinical biochemical check " Shanghai science tech publishing house front page nineteen eighty-two three, female safe oral liquid animal acute toxicity test data materials and methods
The female safe oral liquid ethanol extraction of medicine is made up of Oviductus Ranae, Rhizoma Curcumae.Lot number: 981216, the suitable crude drug in whole 13g of every ml extract is prepared by the Drug Manufacturing Room of Pharmacy Department, Nanfan Hospital.Used female safe oral liquid dosage is all by the crude drug amount in the literary composition.
The animal Kunming mouse, body weight 18-22g, male and female half and half are provided by No.1 Military Medical Univ. animal.
Method
20 mices adapt to 3d in constant temperature (24-28) chamber after, fasting 12h, gastric infusion gavages female safe fluid extract (maximum can be irritated concentration, makes solvent with 10% alcoholic solution) with 0.5ml/10g (maximum permission capacity) at every turn.Observe the toxic reaction and survival number of mice in the 7d.The result
Experiment mice can gavage concentration and the female safe oral liquid of maximum permission capacity ig with maximum, and its dosage is up to 65g/kg (be equivalent to recommend a clinical daily dose 200 times), and mice all survives in the 7d, and administration 10 minutes is movable to increase ear, tail is rubescent.Behavioral activity is normal behind the 2h, does not arch in the north, the not loose not perpendicular hair of fur.Body weight increases (table 1) before than administration in the 7d.Maximum tolerated dose (MTD)＞65g/kg (in the crude drug amount) of female safe oral liquid ig mice.The result shows that female safe oral liquid gastric infusion is nontoxic substantially to mice.
The variation of table 1 Ig chmice acute toxicity body weight (x ± s, g)
| ??????????????♀ | ??????????????♂ |
| ????d0?????????????????d7 ????18?????????????????24 ????20?????????????????25 ????18?????????????????25 ????18?????????????????27 ????19?????????????????25 ????20?????????????????27 ????20?????????????????26 ????19?????????????????27 ????20?????????????????28 ????18?????????????????23 | ????d0?????????????????d7 ????19?????????????????26 ????21?????????????????27 ????18?????????????????24 ????20?????????????????28 ????18?????????????????27 ????19?????????????????25 ????19?????????????????26 ????20?????????????????28 ????20?????????????????23 ????21?????????????????29 |
| ??19.1±1.1?????????25.9±1.3 | 19.5±1.1??????????26.2±1.7 |
Claims (2)
1, a kind of medicine for the treatment of climacteric syndrome is characterized in that it is the medicament of being made by the following weight proportion raw material: Oviductus Ranae 40～50, Rhizoma Curcumae 50～60, B-cyclodextrin 1.8～2.5, edible soybean oil 1.8～2.5.
2, a kind of manufacture method for the treatment of the medicine of climacteric syndrome, it is characterized in that: get Oviductus Ranae, the some 40 order coarse powder that are ground into of Rhizoma Curcumae, mixing, put in the carbon dioxide supercritical fluid extraction jar separation and Extraction 2 hours, extracting solution adds the B-cyclodextrin, stirs, add edible soybean oil, grind to form even oily suspension in the colloid mill, make circular capsule by encapsulating machine, low temperature is promptly air-dry.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1806840B (en) * | 2005-01-21 | 2010-06-16 | 中国科学院上海药物研究所 | Chinese medicinal compound preparation and its preparing process |
| CN103690672A (en) * | 2013-12-31 | 2014-04-02 | 贵阳新天药业股份有限公司 | Controlled release preparation for treating dysfunctional uterine bleeding caused by female ovarian dysfunction and preparation method thereof |
| CN105688088A (en) * | 2016-04-03 | 2016-06-22 | 马兆峰 | Pharmaceutical preparation for treating climacteric depression syndrome |
| CN106344553A (en) * | 2016-08-03 | 2017-01-25 | 江西省妇幼保健院 | Application of curcumol in intervening endometrial stromal cells |
| CN111991405A (en) * | 2020-08-28 | 2020-11-27 | 广州中医药大学第一附属医院 | Application of curdione and ginkgoneoic acid in preparation of bone formation promoting medicine |
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2001
- 2001-01-18 CN CN01107471XA patent/CN1217675C/en not_active Expired - Fee Related
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1806840B (en) * | 2005-01-21 | 2010-06-16 | 中国科学院上海药物研究所 | Chinese medicinal compound preparation and its preparing process |
| CN103690672A (en) * | 2013-12-31 | 2014-04-02 | 贵阳新天药业股份有限公司 | Controlled release preparation for treating dysfunctional uterine bleeding caused by female ovarian dysfunction and preparation method thereof |
| CN103690672B (en) * | 2013-12-31 | 2016-08-31 | 贵阳新天药业股份有限公司 | For treating controlled release preparation of anovulatory dysfunctional uterine hemorrhage that women's ovary dysfunction causes and preparation method thereof |
| CN105688088A (en) * | 2016-04-03 | 2016-06-22 | 马兆峰 | Pharmaceutical preparation for treating climacteric depression syndrome |
| CN106344553A (en) * | 2016-08-03 | 2017-01-25 | 江西省妇幼保健院 | Application of curcumol in intervening endometrial stromal cells |
| CN106344553B (en) * | 2016-08-03 | 2019-12-13 | 江西省妇幼保健院 | Application of curcumenol in preparation of medicine for treating adenomyosis by intervening endometrial interstitial cells |
| CN111991405A (en) * | 2020-08-28 | 2020-11-27 | 广州中医药大学第一附属医院 | Application of curdione and ginkgoneoic acid in preparation of bone formation promoting medicine |
| CN111991405B (en) * | 2020-08-28 | 2021-10-29 | 广州中医药大学第一附属医院 | Application of curdione and ginkgoneoic acid in preparation of bone formation promoting medicine |
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