Background technology
Along with the aged tendency of population process is accelerated, senile osteoporosis and women's osteosporosis after menopause sickness rate increase sharply.Present osteoporosis has become China and even one of bigger disease is consumed in sickness rate, mortality rate and health care in the world.Osteoporosis (OP) is to reduce with the bone amount clinically, and the microstructure degeneration of bone is a feature, causes the fragility of bone to increase and easy a kind of general skeletal diseases that fracture takes place.The main feature of osteoporosis (OP) is: bone ore deposit composition and bone matrix equal proportion reduce, and the bone microstructure is impaired, the attenuation of cortex form, and bone trabecula quantity and gap length all reduce.Osteoporotic sign shows as: osteodynia and lumbago and backache, bow-backed and easily generation fracture three big primary symptoms.Osteoporosis sickness rate in elderly population especially elderly woman is very high.The cause of disease of osteoporosis is that bone resorption and bone formation effect are unbalance, and a large amount of bone resorptions makes the minimizing of bone amount, downgrade, forms osteoporosis.
At present, still lack active drug for the treatment of osteoporosis, clinically the Western medicine diphosphonic acid salt of Ying Yonging: according to for phosphate (according to woods, Bang Delin), chlorine bends phosphate (bone phosphorus) etc.; Listing also has nitrogenous diphosphonic acid salt successively.As Pamidronic Acid salt, Alendronic Acid salt and sharp plug phosphate etc.Diphosphate has become a line medicine of treatment osteoporosis, and its main therapeutic effect is to suppress bone resorption by blocking-up osteoclast function to come bone density improving, less fracture rates.The drawback of this class medicine maximum is when effectively suppressing the osteoclast function, has also suppressed the mineral deposit process of normal bone.
Estrogens and estrogen antagonism and class: estrogen is the clinical common drug that prevents postmenopausal osteoporosis, and this method is called Hormone Replacement Therapy.Its mechanism be mainly estrogen can with the receptors bind on the osteoblast, by promoting osteoblast secretion collagenase, discharge growth and cytokine etc. and promote the synthetic and bone of organic matrixs to rebuild, what participate in this effect also has excretory insulin-like growth factor of osteocyte (IGF-1) and transforming growth factor (TGF-β 1) etc.; Estrogen can directly suppress the osteoclast bone resorption simultaneously, and under effective inhibition concentration, estrogen can directly cause the osteoclast apoptosis, and is time and dose dependent.Clinical data is reported such medicine and is used separately, can make the carcinoma of endometrium incidence rate improve 3~8 times, makes breast cancer incidence improve 25%.Estrogenic untoward reaction mainly vaginal hemorrhage, tenderness of breasts, upper gastrointestinal hemorrhage occur to the postmenopausal women; The risk increase of long-term treatment generation breast carcinoma, carcinoma of endometrium etc.Above untoward reaction causes the compliance of this drug use lower.The result of (WHZ) clinical trial of NIH's WomanHealth startup in 2002 proposes to stop uniting continuously the decision of using hormonal supplementation treatment (HRT).The clinical test results of its multicenter large sample has shown that the risk index of artificial hormone alternative medicine is greater than performance index.Its risk mainly shows aspects such as increasing coronary heart disease, breast carcinoma, apoplexy and pulmonary infarction.
Be used for the treatment of the another kind of calcitonin class of osteoporosis medicine.Calcitonin is the polypeptide that excretory 32 amino acid residues of a kind of mammal parafollicular cells of thyroid gland are formed.The salmon calcitonin see calcimar that uses clinically can be used for the treatment of postmenopausal women's osteoporosis at present.As if but its curative effect to bone density improving and prevention fracture does not have estrogen and diphosphate strong.Calcitonin is a biological preparation, clinical use nasal cavity spray medicine; The dosage form of this medicine is special, carries and deposits inconvenience.That common side effect has is nauseating, local inflammation and face or hand flushing.
The medicine that is used for the treatment of the osteoporosis of fracturing also has the fluoride class.Fluoride class medicine has the silk division that promotes the osteocyte strain, and then promotes the outgrowth effect of osteocyte.Though there is dispute in the clinical bone density (increase 5% every year approximately) that shows when it can significantly increase osteoporosis to improving the fracture incidence rate.The heavy dose of treatment of its 75mg makes non-spinal column fracture increase on the contrary.If the untoward reaction of fluoride class medicine is more serious, swashs and reaction such as lower abdominal pain such as the top gastrointestinal.
Also having of treatment osteoporosis according to flapping fragrant class medicine, it is the isoflavone derivative of synthetic, have direct inhibition bone resorption and stimulation of bone formation dual function, also can work in coordination with estrogen and promote the calcitonin secretion indirectly, regulate the metabolism of calcium, suppress the function of osteoclast, slow down osteoporotic process.But some scholars think, can not effectively reduce the danger that fracture takes place according to flapping sweet smell.
Chinese medicine has at treatment osteoporosis medicine commonly used: JINGUI SHENQI WAN, WUJI BAIFENG WAN, LIUWEI DIHUANG WAN and XIANLING GUBAO JIAONANG etc.But the ubiquitous problem of this type of medicine is effective ingredient, the mechanism of action and preparation technology and quality standard etc. exists uncertainty.Clinical efficacy is also not obvious or uncertain.In a word, existing all kinds of Chinese medicine and western medicine is neither enough desirable to osteoporotic therapeutic effect.The medicine that does not still have at present a kind of efficient, safety and simplify.
Summary of the invention
The objective of the invention is to avoid the deficiency of existing above-mentioned therapy, from endocrine regulation with improve nutriture and start with, provide a kind of therapeutic effect better osteosporosis resistant medicament, and the effect that osteoporosis is had concurrently health care, prevents.
The inventor is engaged in the interior biochemistry of herbal pharmacology, effective ingredient, body of seabuckthorn plant and the research work of Nutrition and Metabolism aspect for a long time.Once in Chinese patent ZL94118300, proposed with Oleum Hippophae as the medicine of regulating endocrine function of woman.Evidence: this medicine has remarkable result to aspects such as treatment menopausal syndrome, premature ovarian failure, premenstrualtension syndrome and thyroid are hyperfunction; Its Mechanisms to treatment Woman climacteric aspect obtained Ministry of Science and Technology's " original new drug and modernization of Chinese medicine " 863 special funds and gratuitously supports in once continuous 2 years.Obtain the biological effect that Oleum Hippophae has signal transduction in vivo, body is had the adjusting and the treatment function of multiple shafting, and be better than the result of study of similar Chinese medicine.
The inventor thinks that climacteric syndrome and osteoporosis are that different disease is sick together, and promptly both cause of disease mechanism is closely related.From existing clinical report data as can be seen osteoporosis and climacteric syndrome all belong to the spectrum of disease of the human senility degeneration that estrogen deficiency causes, many similarities are being arranged aspect some symptom.According to its pathogenesis and result of the test the present invention a kind of effective pharmaceutical preparation is proposed.
The present invention proposes the fruit oil and/or the application of Marc oil in preparation treatment prevention of osteoporosis disease drug of seabuckthorn plant first.Fruit oil that this medicine main component is a seabuckthorn plant and Marc oil be the compositions of compatibility by a certain percentage, comprises wherein natural various effective ingredient that contain such as Fructus Hippophae flavone and becomes to grade.
Above-mentioned Oleum Hippophae and Marc oil can be distinguished use separately, also can mix use by a certain percentage.
Its preferable weight proportion is:
Oleum Hippophae: Fructus Hippophae dreg oil=1: 0.6~1.2.
Best proportioning is:
Oleum Hippophae: Fructus Hippophae dreg oil=1.1: 0.9.
On basis of the present invention, add the osteoporotic medicine of various known treatments and all belong to protection scope of the present invention.
The said medicine composition can be made soft capsule, hard capsule, also can make oral liquor and other types of formulations.
The mechanism of action of Oleum Hippophae treatment osteoporosis is comparatively complicated, utilize modern means research tentatively to think: the biological effect that the Oleum Hippophae of taking, Marc oil transform generation in vivo raises body estrogen and insulin-like growth factor (IGF-1) level, thereby bone density improving stops osteoporotic development effectively.
Clinical test results is thought: take Oleum Hippophae single medicinal material or the Oleum Hippophae and the Marc oil of compatibility by a certain percentage, can make the more aged blank Mus of old and feeble female (22 monthly age) rat blood serum estrogen level that obvious rising is arranged.Uterus estrogen SABC and in situ hybridization analysis show: through taking blended by a certain percentage Oleum Hippophae and Marc oil 45 days, the estrogen receptor expression all has increase on its uterus, the bone.Research data also confirms: increase and especially enter the menopausal women estrogen level age (old people) and reduce, its insulin-like growth factor (IGF-1) and transforming growth factor (the TGF-β 1) concentration in people's cortical bone also descends, and insulin-like growth factor (IGF-1) is proportionate with bone density, might play a decisive role to peak bone.This experimental study confirms: through taking Oleum Hippophae old female Mus estrogen level is raise, aged Mus serum insulin somatomedin (IGF-1) and transforming growth factor (TGF-β 1) are also raise.Infer that its Oleum Hippophae not only has the function of reconciling estrogen target receptor, also can pass through the level that autocrine, paracrine and cell adhesion mode etc. promote cytokine secretion simultaneously, the function that regulation and control bone metabolism and bone are rebuild.Therefore, the rising of insulin-like growth factor (IGF-1) and transforming growth factor (TGF-β 1) is that one of mechanism of action with development takes place the impedance osteoporosis.
The present invention treats the osteoporotic mechanism of action and may be: takes the Oleum Hippophae of compatibility and the biological effect that Marc oil transforms generation in vivo in proportion, body estrogen and insulin-like growth factor (IGF-1) level raise,
At present, Chinese scholars has given more sure conclusion to the effect of estrin treatment osteoporosis, and has done the comparative study of more insulin-like growth factor (IGF-1) determination of serum and sufferers of osteoporosis face DXA bone density.Measurement result to serum insulin somatomedin (IGF-1) and the nearly section of femur bone density shows, serum insulin somatomedin (IGF-1) level and femur density are proportionate, and propose insulin-like growth factor (IGF-1) and can prevent and treat osteoporotic generation.People such as domestic Shu Qiang propose aspect insulin-like growth factor (IGF-1) research, and the shortage of insulin-like growth factor (IGF-1) is a major reason senile, idiopathic osteoporosis.Result of study of the present invention shows that also insulin-like growth factor (I6F-1) is the strong promoter of bone formation, is identical consistent with domestic and international result of study.
The specific embodiment
The test grouping is divided into five groups with the old female Mus, promptly heavy dose of (A), middle dosage (B), low dose of (C) medicine group, aged blank group (D) and positive drug (diethylstilbestrol) matched group (E), and other establishes young rat blank group (F).
Oleum Hippophae and Marc oil are prepared into test liquid in 1.1: 0.9 ratio compatibilities.
Serum hormone and cytokine assay result
Rat blood serum estrogen is measured: young rat blank group and estrogen group compare, and its hormone serum level is respectively 17.64 ± 7.53pg/ml and 8.60 ± 3.79pg/ml apparently higher than old female blank group.Aged blank group hormonal readiness descends about 50%, two group than young blank group relatively statistical significance (P<0.01).Medicine heavy dose, middle dosage, small dose group estrogen level and aged blank group relatively have significant difference (P<0.05), confirm that medicine group hormonal readiness after treating obviously rises.(seeing Table 1)
Rat blood serum TGF-β 1 and IGF-1 measure: administration is after 45 days, and rat blood serum transforming growth factor (TGF-β 1) and insulin-like growth factor (IGF-1) level significantly raise, as table 1.Between each group of transforming growth factor (TGF-β 1) value notable difference is arranged.Learn check by statistics, medicine heavy dose (A), middle dosage (B) small dose group (C) and young blank group (F) group relatively have statistical significance (P<0.05) with aged blank group (D).Respectively take medicine simultaneously and organize the also obviously rising of insulin-like growth factor (IGF-1) concentration level, compare with old-age group's blank group (D), A organizes, B organizes, C organizes and the F group all has statistical significance (P<0.05).Studies confirm that: the test liquid of Oleum Hippophae and Marc oil compatibility can promote rat.The secretion of transforming growth factor (TGF-β 1) and insulin-like growth factor (IGF-1).Table 1 can be seen the variation tendency of each group intuitively.
Respectively organize rat blood serum estrogen and transforming growth factor (TGF-β 1) level after table 1 administration relatively
The detection index (X ± S) |
17β-estrdiol (pg/ml) |
TGF-β1 (ng/ml) |
IGF-1 (ng/ml) |
The young blank group of the aged blank group E positive drug group F of dosage group C medicine small dose group D in the heavy dose of group of the A medicine B medicine |
14.27±1.78* 13.45±2.76* 13.57±4.49* 8.60±3.79 10.07±5.49*# 17.64±7.53*# |
89.79±16.57*# 82.54±16.12*# 80.41±18.22*# 55.76±20.39 66.33±22.77 81.93±10.62**# |
1218.00±378.12* 1095.00±311.33* 1179.21±151.55*# 915.00±271.87 950.00±268.02 1242.30±365.78*# |
Annotate: above α=0.05 is the statistical significance standard.* expression and aged blank the group relatively; * P<0.05, * * P<0.01# represent with positive group relatively.
Table 1 test shows that this miscella can promote the secretion of aged Mus (22 monthly age) serum insulin somatomedin (IGF-1) of nature and transforming growth factor (TGF-β 1) and the function that the tool bone is rebuild.This function has significant effect to improving the osteoporosis clinical symptoms.
Fig. 1 is serum TG F-β 1 and IGF-1 level determination result.
Table 2 can see intuitively that the Oleum Hippophae administration respectively organizes the situation that hormonal readiness and TGF-β 1 and IGF-1 level change.
Rat blood serum estrogen respectively organized by table 2 and transforming growth factor (TGF-β 1) level compares
The detection index (X ± S) |
17β-estrdiol (pg/ml) |
TGF-β1 (ng/ml) |
IGF-1 (ng/ml) |
The young blank group of the aged blank group E positive drug group F of dosage group C medicine small dose group D in the heavy dose of group of the A medicine B medicine |
13.10±1.74* 10.45±3.73 13.54±5.23* 8.60±3.79 10.07±5.49*# 17.64±7.53*# |
90.63±18.71**# 80.32±18.71*# 68.11±16.22 55.76±20.39 66.33±22.77 81.93±10.62**# |
1199.00±482.12** 1095.00±311.33 1169.27±177.55*# 915.00±271.87 950.00±268.02 1242.30±365.78*# |
Annotate: above α=0.05 is the statistical significance standard.* expression and aged blank the group relatively; * P<0.05, * * P<0.01# represent with positive group relatively.
Experiment shows that Oleum Hippophae single medicinal material, Fructus Hippophae dreg oil single medicinal material and Oleum Hippophae and Fructus Hippophae dreg oil can both obtain similar effect by the preparation of 1: 0.6~1.2 mixed, do not give unnecessary details one by one at this.Wherein press 1.1: 0.9 blending constituent best results with Oleum Hippophae and Marc oil.For ease of oral and carry, can be prepared into multiple dosage forms such as soft capsule, oral liquid and solid hard capsule.For ease of oral and carry, can be prepared into soft capsule, hard capsule and oral liquor and other types of formulations.
Find through clinical research for many years, take the blended preparation of Oleum Hippophae or Fructus Hippophae dreg oil, the bones of limbs density of old female rat (22 monthly age) is strengthened, the development of osteoporosis symptom obtains impedance effectively.The evidence of animal pharmacodynamics: Oleum Hippophae or Oleum Hippophae and Marc oil mix preparation truly have prevention and treat osteoporotic effect.This medicine has the feature that promotes body to produce collagen protein, and its collagen protein is rebuild for bone has important effect.Similar medicine with other relatively, this medicine generates insulin-like growth factor (IGF-1) and transforming growth factor (TGF-β 1) by the biotransformation of body, thereby promotes the function that bone is rebuild, be a kind of treat osteoporotic efficiently, safety and the medicine of simplifying.To the result that human trial is observed, find in the effect of bone density improving and prevention fracture as if strong than estrogen and diphosphate.
The clinical experiment data are verified, Oleum Hippophae and/or Marc oil according to the above ratio, particularly the two mixes by proportioning 1.1: 0.9 and uses, and osteoporosis is truly had the obvious treatment effect.
Clinical trial
Indication: deficiency of the liver and kindey disease
Method: select 61 routine cases.Male's 11 examples (accounting for experimenter's total number of persons 18.03%) wherein, women's 50 examples account for experimenter's total number of persons 81.79%.
The course of treatment: 6 months
Clinical criterion
Clinical recovery: transference cure-;
Produce effects: symptom take a turn for the better by +++→+;
Effectively: symptom take a turn for the better by +++→ ++ or ++ →+
Invalid: symptom does not have change or alleviates not obvious +++→ +++or ...
Observation of curative effect and result
Oleum Hippophae: Marc oil (1.1: 0.9) mix preparation
Tcm symptom changes relatively (n=61) before and after the table 3 treatment group patient treatment
Symptom |
Before the treatment |
After the treatment |
Ridit analyzes |
|
+ |
++ |
+++ |
|
+ |
++ |
+++ |
μ |
p |
The lumbar vertebrae pain weakness of the lower extremities can not knot dizzy by prudent lower limb |
23 25 7 19 10 |
16 11 33 23 35 |
20 19 18 18 12 |
2 6 3 2 4 |
51 45 58 45 24 |
9 12 3 14 32 |
1 4 0 2 3 |
0 0 0 0 2 |
4.8638 3.8561 8.1594 4.6530 3.0309 |
<0.01 <0.01 <0.01 <0.01 <0.01 |
Observe to show through 6 months medication of 61 routine cases, can significantly improve patient's lumbar vertebrae pain, weakness of the lower extremities, can not be prudent, lower limb knot and symptom such as dizzy.
Table 4 clinical efficacy result
Symptom |
The clinical trial curative effect |
n |
Recovery from illness |
Produce effects |
Effectively |
Invalid |
Total effective rate (%) |
The lumbar vertebrae pain weakness of the lower extremities can not knot dizzy by prudent lower limb |
37 39 49 54 48 |
28 25 33 51 36 |
1 2 2 1 4 |
8 7 9 2 6 |
0 5 5 0 7 |
100 87.18 89.80 100 95.83 |
The clinical treatment result shows: Oleum Hippophae: Marc oil (1.1: 0.9) miscella is demonstrate,proved clinical symptoms at treatment primary osteoporosis deficiency of the liver and kindey: lumbar vertebrae pain effective percentage 100%; Weakness of the lower extremities effective percentage 87.18%; Can not prudent effective percentage 89.80%; Lower limb knot 100%; Dizzy 95.83%.
Primary osteoporosis belongs to the traditional Chinese medical science " lumbago categories such as " bone fistula " according to its clinical symptoms." element ask fistula opinion " said: " bone is withered and marrow subtracts for heat in the kidney, failure of the spinal column to keep in upright position then, sends out to be bone fistula ".Illustrate that the kidney being the origin of congenital constitution.Kidney storing essence, main bone is given birth to marrow, marrow is hidden in the bone, nourishes skeleton, the kidney essense abundance, then marrow is biochemical active, skeleton obtain marrow nourishing and firm effectively.Primary osteoporosis comes from the kidney qi degradation, and kidney-jing deficiency is few, and the change source deficiency of bone marrow can not the nutrition skeleton and the skeleton fragility to occur unable.A series of deficiency of the liver and kindey symptoms appear clinically: lumbocrural pain, weakness of the lower extremities, can not be prudent, lower limb knot and dizzy etc.Oleum Hippophae and Marc oil (1.1~0.9) mixed preparation for treating 61 routine osteoporosis observation of curative effect show, the loose deficiency of the liver and kindey patient's of this mix preparation scalable sclerotin endocrine, its mechanism may generate insulin-like growth factor (IGF-1) and transforming growth factor (TGF-β 1) by biotransformation in vivo, thereby promotes the function that bone is rebuild.Therefore in the osteoporotic clinical symptoms of improvement significant effect is arranged.
About research datas such as further detailed testing data and pharmacological mechanism can be enclosed at any time.
This preparation is seen Chinese patent ZL94118300 to the effect of regulating endocrine function of woman, does not give unnecessary details.
This preparation is taken functions such as also having the immunity of raising, blood fat reducing and endocrine regulation for a long time, compares curative effect higher, safer, without any side effects (toxicity is seen relevant report) with other drug or method.Taking for a long time all has remarkable effect to clinical prevention and treatment osteoporosis, is the effective ways that effect a permanent cure, and has the market prospect of extensive use.Found a new medical approach for the application of Oleum Hippophae and Marc oil simultaneously.
Pharmaceutical preparation of the present invention is fruit oil and the Marc oil that extracts from seabuckthorn plant.Seabuckthorn plant belongs to Elaeangnaceae, machaka or dungarunga.The used Fructus Hippophae kind of the present invention is that Chinese sea buckthorn (Hippo-phae rhamnoides L.Sinesp.Sinensis Rousi) generally is distributed in provinces and regions such as northwest, northeast, Gansu and Inner Mongol.
The extraction process of Oleum Hippophae adopts the physical extraction method.Its method: place dull and stereotyped squeezer to squeeze sea-buchthorn fresh fruit, juice is by filling formula filter, the fine straining 4 times of pressurizeing continuously, and pressurization at last enters newborn ester butterfly centrifugal machine and separates, and can obtain Oleum Hippophae.
The extraction process of Fructus Hippophae dreg oil: get sea-buckthorn pomace under 75 ℃~80 ℃ environment, dry two hours, pulverize 16 orders~40 mesh sieves and obtained mixed powder, add normal hexane, merceration 30 minutes extracted with hot reflux in the electronic thermostatic water-bath in eight hours, extracting solution cools to room temperature, use the vacuum pump sucking filtration, reclaim solvent to the no solvent abnormal smells from the patient of oil, get final product Fructus Hippophae dreg oil.
Effective dose and using method
Soft capsule preparation: Oleum Hippophae and Marc oil are mixed by said ratio, be closed in the capsule, be the sealing shape by the soft capsule machine.Like this fatty acid be difficult for oxidized, become sour and pollute.
The present invention's prescription can also be made oral solutions.Oral liquid matched proportion density oil is advisable with 1: 2~3 with the ratio of water, makes through emulsifying.Oleum Hippophae mixes to cooperate with Marc oil and is used as medicine, and every day, taking dose should be no less than 5ml, and suitably many clothes better effects if are free from side effects.Dosage is lower than 5ml DeGrain or invalid, preferably takes on an empty stomach.The Oleum Hippophae single medicinal material also can be taken with reference to this dosage.
Up to now, the reported in literature that does not still have " with Oleum Hippophae and Marc oil as the osteoporotic medicine of treatment " both at home and abroad.Utilizing this preparation osteoporosis is the valuable new discovery of field of medicaments, belongs to the first both at home and abroad.